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1
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Zhang W, Hong X, Xiao Y, Wang H, Zeng X. Sorafenib resistance and therapeutic strategies in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2025; 1880:189310. [PMID: 40187502 DOI: 10.1016/j.bbcan.2025.189310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.
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Affiliation(s)
- Weijing Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
| | - Xuechuan Hong
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Yuling Xiao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
| | - Xiaodong Zeng
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
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2
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Boixareu C, Taha T, Venkadakrishnan VB, de Bono J, Beltran H. Targeting the tumour cell surface in advanced prostate cancer. Nat Rev Urol 2025:10.1038/s41585-025-01014-w. [PMID: 40169837 DOI: 10.1038/s41585-025-01014-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2025] [Indexed: 04/03/2025]
Abstract
Prostate cancer remains a substantial health challenge, with >375,000 annual deaths amongst men worldwide. Most prostate cancer-related deaths are attributable to the development of resistance to standard-of-care treatments. Characterization of the diverse and complex surfaceome of treatment-resistant prostate cancer, combined with advances in drug development that leverage cell-surface proteins to enhance drug delivery or activate the immune system, have provided novel therapeutic opportunities to target advanced prostate cancer. The prostate cancer surfaceome, including proteins such as prostate-specific membrane antigen (PSMA), B7-H3, six transmembrane epithelial antigen of the prostate 1 (STEAP1), delta-like ligand 3 (DLL3), trophoblastic cell-surface antigen 2 (TROP2), prostate stem cell antigen (PSCA), HER3, CD46 and CD36, can be exploited as therapeutic targets, as regulatory mechanisms might contribute to the heterogeneity of expression of these proteins and subsequently affect treatment response and resistance. Specific treatment strategies targeting the surfaceome are in clinical development, including radionuclides, antibody-drug conjugates, T cell engagers and chimeric antigen receptor (CAR) T cells. Ultimately, biomarker development and clinical implementation of these agents will be informed and refined by further understanding of the biology of various targets; the target specificity and sensitivity of different agents; and off-target and toxic effects associated with these agents. Understanding the dynamic nature of cell-surface targets and non-overlapping expression patterns might also lead to future combinational strategies.
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Affiliation(s)
- Cristina Boixareu
- The Institute of Cancer Research, The Royal Marsden Hospital, London, UK
| | - Tarek Taha
- The Institute of Cancer Research, The Royal Marsden Hospital, London, UK
| | | | - Johann de Bono
- The Institute of Cancer Research, The Royal Marsden Hospital, London, UK.
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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3
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Khoshbakht M, Forghanifard MM, Aghamollaei H, Amani J. In silico and in vitro evaluation of a PE38 and Nb-based recombinant immunotoxin targeting the GRP78 receptor in cancer cells. Biotechnol Appl Biochem 2025; 72:484-497. [PMID: 39397264 DOI: 10.1002/bab.2678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/10/2024] [Indexed: 10/15/2024]
Abstract
Cancer is a global health problem despite the most developed therapeutic modalities. The delivery of specific therapeutic agents to a target increases the effectiveness of cancer treatment by reducing side effects and post-treatment issues. Our aim in this study was to design a recombinant protein consisting of nanobody molecules and exotoxin that targets the surface GRP78 receptor on tumor cells. Bioinformatics methods make drug design and recombinant protein evaluation much easier before the laboratory steps. Two constructs were designed from a single-variable domain on heavy chain nanobody domains and PE toxin domains II, Ib, and III. The physicochemical properties, secondary structure, and solubility of the chimeric protein were analyzed using different software. Prostate cancer DU-145 and breast cancer MDA-MB-468 cell lines were used as GRP78-positive and negative controls, respectively. Accordingly, the cytotoxicity, binding affinity, cell internalization, and apoptosis were evaluated using MTT, enzyme-linked immunosorbent assay, and western blot. The results showed that in the DU-145 cell line, the cytotoxicity of two recombinant immunotoxins is dose and time-dependent. In MDA-MB-468 and HEK-293 cells, such an event does not occur. It is possible that two constructs designed for immunotoxins can attach to GRP78-positive cancer cells and then eradicate cancer cells by internalization and apoptosis. As our in vitro results were in line with in silico data confirming the Bioinformatics predictions, it can be concluded that the designed recombinant immunotoxins may exhibit therapeutic potential against GRP78-positive tumor cells.
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Affiliation(s)
- Mona Khoshbakht
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | | | - Hossein Aghamollaei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jafar Amani
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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4
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Varanko AK, Deshpande S, Li X, Chilkoti A. Binding Strength, Not Valency, Dictates Accumulation and Penetration of Affinity Targeted Macromolecules into Solid Tumors. Biomacromolecules 2025; 26:503-513. [PMID: 39729341 DOI: 10.1021/acs.biomac.4c01303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
The efficacy of tumor-targeted therapeutics, engineered to engage specific cellular receptors to promote accumulation and penetration, is strongly influenced by the carrier's affinity for its target and the valency of binding molecules incorporated into the carrier. Previous research has primarily focused on improving targeting by augmenting the number of binding proteins on the carrier, inadvertently raising avidity without isolating the individual effects of binding strength and valency. Herein, we precisely evaluate the impact of multivalency on tumor targeting with a recombinant approach to independently control valency, avidity, and size. Our findings reveal that constructs with equivalent binding strength exhibit comparable receptor engagement and tumor extravasation, regardless of valency. Moreover, excessive avidity adversely affected tumor accumulation and penetration, with the highest-avidity construct showing diminished exposure. These results indicate that overall binding strength, not valency, is the primary determinant of tumor targeting, providing valuable insights for designing effective macromolecular drug carriers.
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Affiliation(s)
- Anastasia K Varanko
- Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
| | - Sonal Deshpande
- Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
| | - Xinghai Li
- Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
| | - Ashutosh Chilkoti
- Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, United States
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5
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Jiao J, Qian Y, Lv Y, Wei W, Long Y, Guo X, Buerliesi A, Ye J, Han H, Li J, Zhu Y, Zhang W. Overcoming limitations and advancing the therapeutic potential of antibody-oligonucleotide conjugates (AOCs): Current status and future perspectives. Pharmacol Res 2024; 209:107469. [PMID: 39433169 DOI: 10.1016/j.phrs.2024.107469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 10/23/2024]
Abstract
As cancer incidence rises due to an aging population, the importance of precision medicine continues to grow. Antibody-drug conjugates (ADCs) exemplify targeted therapies by delivering cytotoxic agents to specific antigens. Building on this concept, researchers have developed antibody-oligonucleotide conjugates (AOCs), which combine antibodies with oligonucleotides to regulate gene expression. This review highlights the mechanism of AOCs, emphasizing their unique ability to selectively target and modulate disease-causing proteins. It also explores the components of AOCs and their application in tumor therapy while addressing key challenges such as manufacturing complexities, endosomal escape, and immune response. The article underscores the significance of AOCs in precision oncology and discusses future directions, highlighting their potential in treating cancers driven by genetic mutations and abnormal protein expression.
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Affiliation(s)
- Jinlan Jiao
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China
| | - Yun Qian
- Dermatologic Surgery Department, Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing 210042, China
| | - Yinhua Lv
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Wenqian Wei
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Yongxuan Long
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China
| | - Xiaoling Guo
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China
| | - Anya Buerliesi
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China
| | - Jiahui Ye
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China
| | - Hao Han
- Department of Ultrasound, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Jinbo Li
- State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China.
| | - Yun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing 210008, China.
| | - Weijie Zhang
- Division of Breast Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China.
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Kim J, Maharjan R, Park J. Current Trends and Innovative Approaches in Cancer Immunotherapy. AAPS PharmSciTech 2024; 25:168. [PMID: 39044047 PMCID: PMC11573471 DOI: 10.1208/s12249-024-02883-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
Immunotherapy is one of the most promising therapeutic approaches in the field of cancer treatment. As a tumor progresses, tumor cells employ an array of immune-regulatory mechanisms to suppress immune responses within the tumor microenvironment. Using our understanding of these mechanisms, cancer immunotherapy has been developed to enhance the immune system's effectiveness in treating cancer. Numerous cancer immunotherapies are currently in clinical use, yet many others are either in different stages of development or undergoing clinical studies. In this paper, we briefly discuss the features and current status of cancer immunotherapies. This includes the application of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy, cytokine therapy, cancer vaccines, and gene therapy, all of which have gained significant recognition in clinical practice. Additionally, we discuss limitations that may hinder successful clinical utilization and promising strategies, such as combining immunotherapy with nanotechnology.
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Affiliation(s)
- Jaechang Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY, 40506, USA
| | - Ruby Maharjan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY, 40506, USA
| | - Jonghyuck Park
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY, 40506, USA.
- Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA.
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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7
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Paul S, Konig MF, Pardoll DM, Bettegowda C, Papadopoulos N, Wright KM, Gabelli SB, Ho M, van Elsas A, Zhou S. Cancer therapy with antibodies. Nat Rev Cancer 2024; 24:399-426. [PMID: 38740967 PMCID: PMC11180426 DOI: 10.1038/s41568-024-00690-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2024] [Indexed: 05/16/2024]
Abstract
The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.
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Affiliation(s)
- Suman Paul
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Maximilian F Konig
- Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Drew M Pardoll
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Katharine M Wright
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA
| | - Sandra B Gabelli
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA.
| | - Mitchell Ho
- Antibody Engineering Program, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | | | - Shibin Zhou
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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8
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Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol 2024; 17:31. [PMID: 38720342 PMCID: PMC11077829 DOI: 10.1186/s13045-024-01544-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
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Affiliation(s)
- Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Chaxian Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Duanwu Zhang
- Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
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Nassiri M, Ghovvati S, Gharouni M, Tahmoorespur M, Bahrami AR, Dehghani H. Engineering Human Pancreatic RNase 1 as an Immunotherapeutic Agent for Cancer Therapy Through Computational and Experimental Studies. Protein J 2024; 43:316-332. [PMID: 38145445 DOI: 10.1007/s10930-023-10171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2023] [Indexed: 12/26/2023]
Abstract
Most plant and bacterial toxins are highly immunogenic with non-specific toxic effects. Human ribonucleases are thought to provide a promising basis for reducing the toxic agent's immunogenic properties, which are candidates for cancer therapy. In the cell, the ribonuclease inhibitor (RI) protein binds to the ribonuclease enzyme and forms a tight complex. This study aimed to engineer and provide a gene construct encoding an improved version of Human Pancreatic RNase 1 (HP-RNase 1) to reduce connection to RI and modulate the immunogenic effects of immunotoxins. To further characterize the interaction complex of HP-RNase 1 and RI, we established various in silico and in vitro approaches. These methods allowed us to specifically monitor interactions within native and engineered HP-RNase 1/RI complexes. In silico research involved molecular dynamics (MD) simulations of native and mutant HP-RNase 1 in their free form and when bound to RI. For HP-RNase 1 engineering, we designed five mutations (K8A/N72A/N89A/R92D/E112/A) based on literature studies, as this combination proved effective for the intended investigation. Then, the cDNA encoding HP-RNase 1 was generated by RT-PCR from blood and cloned into the pSYN2 expression vector. Consequently, wild-type and the engineered HP-RNase 1 were over-expressed in E. coli TG1 and purified using an IMAC column directed against a poly-his tag. The protein products were detected by SDS-PAGE and Western blot analysis. HP-RNase 1 catalytic activity, in the presence of various concentrations of RI, demonstrated that the mutated version of the protein is able to escape the ribonuclease inhibitor and target the RNA substrate 2.5 folds more than that of the wild type. From these data, we tend to suggest the engineered recombinant HP-RNase 1 potentially as a new immunotherapeutic agent for application in human cancer therapy.
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Affiliation(s)
- Mohammadreza Nassiri
- Department of Animal Science, College of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
- Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Shahrokh Ghovvati
- Department of Animal Sciences, Faculty of Agriculture, University of Guilan, 41635-1314, Rasht, Guilan, Iran.
| | - Marzieh Gharouni
- Department of Biochemistry, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Mojtaba Tahmoorespur
- Department of Animal Science, College of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
- Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Molecular Cell Biology, College of Applied Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hesam Dehghani
- Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Physiology, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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10
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Wysor SK, Synoground BF, Harcum SW, Marcus RK. In-line buffer exchange in the coupling of Protein A chromatography with weak cation exchange chromatography for the determination of charge variants of immunoglobulin G derived from chinese hamster ovary cell cultures. J Chromatogr A 2024; 1718:464722. [PMID: 38359690 DOI: 10.1016/j.chroma.2024.464722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/05/2024] [Accepted: 02/07/2024] [Indexed: 02/17/2024]
Abstract
Immunoglobulin G (IgG) is the most common monoclonal antibody (mAb) grown for therapeutic applications. While IgG is often selectively isolated from cell lines using protein A (ProA) chromatography, this is only a stepping stone for complete characterization. Further classification can be obtained from weak cation exchange chromatography (WCX) to determine IgG charge variant distributions. The charge variants of monoclonal antibodies can influence the stability and efficacy in vivo, and deviations in charge heterogeneity are often cell-specific and sensitive to upstream process variability. Current methods to characterize IgG charge variants are often performed off-line, meaning that the IgG eluate from the ProA separation is collected, diluted to adjust the pH, and then transferred to the WCX separation, adding time, complexity, and potential contamination to the sample analysis process. More recently, reports have appeared to streamline this separation using in-line two-dimensional liquid chromatography (2D-LC). Presented here is a novel, 2D-LC coupling of ProA in the first dimension (1D) and WCX in the second dimension (2D) chromatography. As anticipated, the initial direct column coupling proved to be challenging due to the pH incompatibility between the mobile phases for the two stages. To solve the solvent compatibility issue, a size exclusion column was placed in the switching valve loop of the 2D-LC instrument to act as a means for the on-line solvent exchange. The efficacy of the methodology presented was confirmed through a charge variant determination using the NIST monoclonal antibody standard (NIST mAb), yielding correct acidic, main, and basic variant compositions. The methodology was employed to determine the charge variant profile of IgG from an in-house cultured Chinese hamster ovary (CHO) cell supernatant. It is believed that this methodology can be easily implemented to provide higher-throughput assessment of IgG charge variants for process monitoring and cell line development.
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Affiliation(s)
- Sarah K Wysor
- Department of Chemistry, Biosystems Research Complex, Clemson University, Clemson, SC 29634-0973, USA
| | - Benjamin F Synoground
- Department of Bioengineering, Biosystems Research Complex, Clemson University, Clemson, SC 29634-0973, USA
| | - Sarah W Harcum
- Department of Bioengineering, Biosystems Research Complex, Clemson University, Clemson, SC 29634-0973, USA
| | - R Kenneth Marcus
- Department of Chemistry, Biosystems Research Complex, Clemson University, Clemson, SC 29634-0973, USA.
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11
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Chandnani N, Gupta I, Mandal A, Sarkar K. Participation of B cell in immunotherapy of cancer. Pathol Res Pract 2024; 255:155169. [PMID: 38330617 DOI: 10.1016/j.prp.2024.155169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/10/2024]
Abstract
Even though their effector roles extend beyond conventional humoral immunity, B and plasma cells may exhibit antitumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade. Depending on whether they are positioned in immature or mature compartments termed tertiary lymphoid structures (TLS), which include T cells, B cells are believed to play numerous functions in modulating the immune system's capacity to destroy cancer cells. These formations represent a process of lymphoid neogenesis that takes place in peripheral tissues in response to prolonged exposure to inflammatory signals. Activated in the germinal centres of tertiary lymphoid structures, B cells may directly present tumor-associated antigens to T cells, make antibodies that enhance antigen presentation to T cells, or kill tumour cells, resulting in a favourable therapeutic effect. Immune complexes may also enhance inflammation, angiogenesis, and immunosuppression via the activation of macrophages and complement, resulting in detrimental effects. The functional variety of B-cell subsets includes professional antigen-presenting cells, regulatory cells, memory populations, and plasma cells that produce antibodies. Importantly, antibodies may independently generate innate immune responses and the cancer immunity cycle. B cells and B-cell-mediated antibody responses constitute the largely underestimated second arm of the adaptive immune system and unquestionably need more consideration in cancer. This article reviews the known roles of B lymphocytes in the tumour microenvironment, their contribution to anticancer activity of immunotherapies, and their significance in overall survival of cancer patients. In addition to producing antibodies, B cells regulate the immune system and serve as effective antigen-presenting cells.
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Affiliation(s)
- Nikhil Chandnani
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Ishika Gupta
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Ayush Mandal
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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Fateh ST, Fateh ST, Salehi-Najafabadi A, Aref AR. Commercial and regulatory challenges in cancer nanomedicine. FUNCTIONALIZED NANOMATERIALS FOR CANCER RESEARCH 2024:579-601. [DOI: 10.1016/b978-0-443-15518-5.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Georg Magalhães C, Ploeger Mansueli C, Manieri TM, Quintilio W, Garbuio A, de Jesus Marinho J, de Moraes JZ, Tsuruta LR, Moro AM. Impaired proliferation and migration of HUVEC and melanoma cells by human anti-FGF2 mAbs derived from a murine hybridoma by guided selection. Bioengineered 2023; 14:2252667. [PMID: 37661761 PMCID: PMC10478743 DOI: 10.1080/21655979.2023.2252667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 09/05/2023] Open
Abstract
Disadvantages of using murine monoclonal antibodies (mAb) in human therapy, such as immunogenicity response, led to the development of technologies to transform murine antibodies into human antibodies. The murine anti-FGF2 3F12E7 mAb was proposed as a promising agent to treat metastatic melanoma tumors; once it blocks the FGF2, responsible for playing a role in tumor growth, angiogenesis, and metastasis. Considering the therapeutic potential of anti-FGF2 3F12E7 mAb and its limited use in humans due to its origin, we used this antibody as the template for a guided selection humanization technique to obtain human anti-FGF2 mAbs. Three Fab libraries (murine, hybrid, and human) were constructed for humanization. The libraries were phage-displayed, and the panning was performed against recombinant human FGF2 (rFGF2). The selected human variable light and heavy chains were cloned into AbVec vectors for full-length IgG expression into HEK293-F cells. Surface plasmon resonance analyses showed binding to rFGF2 of seven mAbs out of 20 expressed. Assays performed with these mAbs resulted in two that showed proliferation reduction and cell migration attenuation of HUVEC and SK-Mel-28 melanoma cells. In-silico analyses predicted that these two human anti-FGF2 mAbs interact with FGF2 at a similar patch of residues than the chimeric anti-FGF2 antibody, comprehending a region within the heparin-binding domains of FGF2, essential for its function. These results are comparable to those achieved by the murine anti-FGF2 3F12E7 mAb and showed success in the humanization process and selection of two human mAbs with the potential to inhibit undesirable FGF2 roles.
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Affiliation(s)
| | | | | | - Wagner Quintilio
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
| | - Angélica Garbuio
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
| | | | - Jane Zveiter de Moraes
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Ana Maria Moro
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
- CeRDI, Center for Research and Development in Immunobiologicals, Butantan Institute, São Paulo, Brazil
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14
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Sharma P, Joshi RV, Pritchard R, Xu K, Eicher MA. Therapeutic Antibodies in Medicine. Molecules 2023; 28:6438. [PMID: 37764213 PMCID: PMC10535987 DOI: 10.3390/molecules28186438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
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Affiliation(s)
- Prerna Sharma
- Geisinger Commonwealth School of Medicine, Scranton, PA 18509, USA
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15
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Rahman T, Das A, Abir MH, Nafiz IH, Mahmud AR, Sarker MR, Emran TB, Hassan MM. Cytokines and their role as immunotherapeutics and vaccine Adjuvants: The emerging concepts. Cytokine 2023; 169:156268. [PMID: 37320965 DOI: 10.1016/j.cyto.2023.156268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
Cytokines are a protein family comprising interleukins, lymphokines, chemokines, monokines and interferons. They are significant constituents of the immune system, and they act in accordance with specific cytokine inhibiting compounds and receptors for the regulation of immune responses. Cytokine studies have resulted in the establishment of newer therapies which are being utilized for the treatment of several malignant diseases. The advancement of these therapies has occurred from two distinct strategies. The first strategy involves administrating the recombinant and purified cytokines, and the second strategy involves administrating the therapeutics which inhibits harmful effects of endogenous and overexpressed cytokines. Colony stimulating factors and interferons are two exemplary therapeutics of cytokines. An important effect of cytokine receptor antagonist is that they can serve as anti-inflammatory agents by altering the treatments of inflammation disorder, therefore inhibiting the effects of tumour necrosis factor. In this article, we have highlighted the research behind the establishment of cytokines as therapeutics and vaccine adjuvants, their role of immunotolerance, and their limitations.
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Affiliation(s)
- Tanjilur Rahman
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Ayan Das
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Mehedy Hasan Abir
- Faculty of Food Science and Technology, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh
| | - Iqbal Hossain Nafiz
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Aar Rafi Mahmud
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
| | - Md Rifat Sarker
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chattogram 4381, Bangladesh; Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Mohammad Mahmudul Hassan
- Department of Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh; Queensland Alliance for One Health Sciences, School of Veterinary Science, The University of Queensland, Queensland 4343, Australia.
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16
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Lara-Vega I, Correa-Lara MVM, Vega-López A. Effectiveness of radiotherapy and targeted radionuclide therapy for melanoma in preclinical mouse models: A combination treatments overview. Bull Cancer 2023; 110:912-936. [PMID: 37277266 DOI: 10.1016/j.bulcan.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/29/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023]
Abstract
Cutaneous melanoma is an aggressive and highly metastatic skin cancer. In recent years, immunotherapy and targeted small-molecule inhibitors have improved the overall survival of patients. Unfortunately, most patients in advanced stages of disease exhibit either intrinsically resistant or rapidly acquire resistance to these approved treatments. However, combination treatments have emerged to overcome resistance, and novel treatments based on radiotherapy (RT) and targeted radionuclide therapy (TRT) have been developed to treat melanoma in the preclinical mouse model, raising the question of whether synergy in combination therapies may motivate and increase their use as primary treatments for melanoma. To help clarify this question, we reviewed the studies in preclinical mouse models where they evaluated RT and TRT in combination with other approved and unapproved therapies from 2016 onwards, focusing on the type of melanoma model used (primary tumor and or metastatic model). PubMed® was the database in which the search was performed using mesh search algorithms resulting in 41 studies that comply with the inclusion rules of screening. Studies reviewed showed that synergy with RT or TRT had strong antitumor effects, such as tumor growth inhibition and fewer metastases, also exhibiting systemic protection. In addition, most studies were carried out on antitumor response for the implanted primary tumor, demonstrating that more studies are needed to evaluate these combined treatments in metastatic models on long-term protocols.
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Affiliation(s)
- Israel Lara-Vega
- National School of Biological Sciences, National Polytechnic Institute, Environmental Toxicology Laboratory, Avenida Wilfrido Massieu s/n, Unidad Profesional Adolfo López Mateos, Mexico City CP 07738, Mexico
| | - Maximiliano V M Correa-Lara
- National School of Biological Sciences, National Polytechnic Institute, Environmental Toxicology Laboratory, Avenida Wilfrido Massieu s/n, Unidad Profesional Adolfo López Mateos, Mexico City CP 07738, Mexico
| | - Armando Vega-López
- National School of Biological Sciences, National Polytechnic Institute, Environmental Toxicology Laboratory, Avenida Wilfrido Massieu s/n, Unidad Profesional Adolfo López Mateos, Mexico City CP 07738, Mexico.
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17
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Zhang NZ, Zhao LF, Zhang Q, Fang H, Song WL, Li WZ, Ge YS, Gao P. Core fucosylation and its roles in gastrointestinal glycoimmunology. World J Gastrointest Oncol 2023; 15:1119-1134. [PMID: 37546555 PMCID: PMC10401475 DOI: 10.4251/wjgo.v15.i7.1119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 07/12/2023] Open
Abstract
Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.
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Affiliation(s)
- Nian-Zhu Zhang
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Li-Fen Zhao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Qian Zhang
- Department of Cell Therapy, Shanghai Tianze Yuntai Biomedical Co., Ltd., Shanghai 200100, China
| | - Hui Fang
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-0005, Ibaraki, Japan
| | - Wan-Li Song
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Zhe Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Song Ge
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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18
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Farasati Far B, Safaei M, Mokhtari F, Fallahi MS, Naimi-Jamal MR. Fundamental concepts of protein therapeutics and spacing in oncology: an updated comprehensive review. Med Oncol 2023; 40:166. [PMID: 37147486 DOI: 10.1007/s12032-023-02026-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/06/2023] [Indexed: 05/07/2023]
Abstract
Current treatment regimens in cancer cases cause significant side effects and cannot effectively eradicate the advanced disease. Hence, much effort has been expended over the past years to understand how cancer grows and responds to therapies. Meanwhile, proteins as a type of biopolymers have been under commercial development for over three decades and have been proven to improve the healthcare system as effective medicines for treating many types of progressive disease, such as cancer. Following approving the first recombinant protein therapeutics by FDA (Humulin), there have been a revolution for drawing attention toward protein-based therapeutics (PTs). Since then, the ability to tailor proteins with ideal pharmacokinetics has provided the pharmaceutical industry with an important noble path to discuss the clinical potential of proteins in oncology research. Unlike traditional chemotherapy molecules, PTs actively target cancerous cells by binding to their surface receptors and the other biomarkers particularly associated with tumorous or healthy tissue. This review analyzes the potential and limitations of protein therapeutics (PTs) in the treatment of cancer as well as highlighting the evolving strategies by addressing all possible factors, including pharmacology profile and targeted therapy approaches. This review provides a comprehensive overview of the current state of PTs in oncology, including their pharmacology profile, targeted therapy approaches, and prospects. The reviewed data show that several current and future challenges remain to make PTs a promising and effective anticancer drug, such as safety, immunogenicity, protein stability/degradation, and protein-adjuvant interactions.
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Affiliation(s)
- Bahareh Farasati Far
- Research Laboratory of Green Organic Synthesis and Polymers, Department of Chemistry, Iran University of Science and Technology, Narmak, Tehran, Iran
| | - Maryam Safaei
- Department of Pharmacology, Faculty of Pharmacy, Eastern Mediterranean University, Via Mersin 10, TR. North Cyprus, Famagusta, Turkey
| | - Fatemeh Mokhtari
- Department of Chemistry, Faculty of Basic Science, Azarbaijan Shahid Madani (ASMU), Tabriz, 53751-71379, Iran
| | | | - Mohammad Reza Naimi-Jamal
- Research Laboratory of Green Organic Synthesis and Polymers, Department of Chemistry, Iran University of Science and Technology, Narmak, Tehran, Iran.
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Pogostin BH, Saenz G, Cole CC, Euliano EM, Hartgerink JD, McHugh KJ. Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel. Bioconjug Chem 2023; 34:193-203. [PMID: 36580277 PMCID: PMC10061233 DOI: 10.1021/acs.bioconjchem.2c00461] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recently, there has been increased interest in using mannan as an immunomodulatory bioconjugate. Despite notable immunological and functional differences between the reduced (R-Man) and oxidized (O-Man) forms of mannan, little is known about the impact of mannan oxidation state on its in vivo persistence or its potential controlled release from biomaterials that may improve immunotherapeutic or prophylactic efficacy. Here, we investigate the impact of oxidation state on the in vitro and in vivo release of mannan from a biocompatible and immunostimulatory multidomain peptide hydrogel, K2(SL)6K2 (abbreviated as K2), that has been previously used for the controlled release of protein and small molecule payloads. We observed that O-Man released more slowly from K2 hydrogels in vitro than R-Man. In vivo, the clearance of O-Man from K2 hydrogels was slower than O-Man alone. We attributed the slower release rate to the formation of dynamic imine bonds between reactive aldehyde groups on O-Man and the lysine residues on K2. This imine interaction was also observed to improve K2 + O-Man hydrogel strength and shear recovery without significantly influencing secondary structure or peptide nanofiber formation. There were no observed differences in the in vivo release rates of O-Man loaded in K2, R-Man loaded in K2, and R-Man alone. These data suggest that, after subcutaneous injection, R-Man naturally persists longer in vivo than O-Man and minimally interacts with the peptide hydrogel. These results highlight a potentially critical, but previously unreported, difference in the in vivo behavior of O-Man and R-Man and demonstrate that K2 can be used to normalize the release of O-Man to that of R-Man. Further, since K2 itself is an adjuvant, a combination of O-Man and K2 could be used to enhance the immunostimulatory effects of O-Man for applications such as infectious disease vaccines and cancer immunotherapy.
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Affiliation(s)
- Brett H Pogostin
- Department of Bioengineering, Rice University, Houston, Texas77005, United States
| | - Gabriel Saenz
- Department of Chemistry, Rice University, Houston, Texas77005, United States
| | - Carson C Cole
- Department of Chemistry, Rice University, Houston, Texas77005, United States
| | - Erin M Euliano
- Department of Bioengineering, Rice University, Houston, Texas77005, United States
| | - Jeffrey D Hartgerink
- Department of Bioengineering, Rice University, Houston, Texas77005, United States
- Department of Chemistry, Rice University, Houston, Texas77005, United States
| | - Kevin J McHugh
- Department of Bioengineering, Rice University, Houston, Texas77005, United States
- Department of Chemistry, Rice University, Houston, Texas77005, United States
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20
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Huang CY, Lok YY, Lin CH, Lai SL, Wu YY, Hu CY, Liao CB, Ho CH, Chou YP, Hsu YH, Lo YH, Chern E. Highly reliable GIGA-sized synthetic human therapeutic antibody library construction. Front Immunol 2023; 14:1089395. [PMID: 37180155 PMCID: PMC10174300 DOI: 10.3389/fimmu.2023.1089395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
Background Monoclonal antibodies (mAbs) and their derivatives are the fastest expanding category of pharmaceuticals. Efficient screening and generation of appropriate therapeutic human antibodies are important and urgent issues in the field of medicine. The successful in vitro biopanning method for antibody screening largely depends on the highly diverse, reliable and humanized CDR library. To rapidly obtain potent human antibodies, we designed and constructed a highly diverse synthetic human single-chain variable fragment (scFv) antibody library greater than a giga in size by phage display. Herein, the novel TIM-3-neutralizing antibodies with immunomodulatory functions derived from this library serve as an example to demonstrate the library's potential for biomedical applications. Methods The library was designed with high stability scaffolds and six complementarity determining regions (CDRs) tailored to mimic human composition. The engineered antibody sequences were optimized for codon usage and subjected to synthesis. The six CDRs with variable length CDR-H3s were individually subjected to β-lactamase selection and then recombined for library construction. Five therapeutic target antigens were used for human antibody generation via phage library biopanning. TIM-3 antibody activity was verified by immunoactivity assays. Results We have designed and constructed a highly diverse synthetic human scFv library named DSyn-1 (DCB Synthetic-1) containing 2.5 × 1010 phage clones. Three selected TIM-3-recognizing antibodies DCBT3-4, DCBT3-19, and DCBT3-22 showed significant inhibition activity by TIM-3 reporter assays at nanomolar ranges and binding affinities in sub-nanomolar ranges. Furthermore, clone DCBT3-22 was exceptionally superior with good physicochemical property and a purity of more than 98% without aggregation. Conclusion The promising results illustrate not only the potential of the DSyn-1 library for biomedical research applications, but also the therapeutic potential of the three novel fully human TIM-3-neutralizing antibodies.
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Affiliation(s)
- Chao-Yang Huang
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Ying-Yung Lok
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Chia-Hui Lin
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Szu-Liang Lai
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Yen-Yu Wu
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Chih-Yung Hu
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Chu-Bin Liao
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Chen-Hsuan Ho
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Yu-Ping Chou
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Yi-Hsuan Hsu
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Yu-Hsun Lo
- Development Center for Biotechnology, New Taipei City, Taiwan
| | - Edward Chern
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
- *Correspondence: Edward Chern,
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21
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Karati D, Kumar D. A Comprehensive Review on Targeted Cancer Therapy: New Face of Treatment Approach. Curr Pharm Des 2023; 29:3282-3294. [PMID: 38038008 DOI: 10.2174/0113816128272203231121034814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/11/2023] [Accepted: 10/16/2023] [Indexed: 12/02/2023]
Abstract
Cancer is one of life's most difficult difficulties and a severe health risk everywhere. Except for haematological malignancies, it is characterized by unchecked cell growth and a lack of cell death, which results in an aberrant tissue mass or tumour. Vascularization promotes tumor growth, which eventually aids metastasis and migration to other parts of the body, ultimately resulting in death. The genetic material of the cells is harmed or mutated by environmental or inherited influences, which results in cancer. Presently, anti-neoplastic medications (chemotherapy, hormone, and biological therapies) are the treatment of choice for metastatic cancers, whilst surgery and radiotherapy are the mainstays for local and non-metastatic tumors. Regrettably, chemotherapy disturbs healthy cells with rapid proliferation, such as those in the gastrointestinal tract and hair follicles, leading to the typical side effects of chemotherapy. Finding new, efficient, targeted therapies based on modifications in the molecular biology of tumor cells is essential because current chemotherapeutic medications are harmful and can cause the development of multidrug resistance. These new targeted therapies, which are gaining popularity as demonstrated by the FDA-approved targeted cancer drugs in recent years, enter molecules directly into tumor cells, diminishing the adverse reactions. A form of cancer treatment known as targeted therapy goes after the proteins that regulate how cancer cells proliferate, divide, and disseminate. Most patients with specific cancers, such as chronic myelogenous leukemia (commonly known as CML), will have a target for a particular medicine, allowing them to be treated with that drug. Nonetheless, the tumor must typically be examined to determine whether it includes drug targets.
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Affiliation(s)
- Dipanjan Karati
- Department of Pharmaceutical Chemistry, School of Pharmacy, Techno India University, Kolkata 700091, West Bengal 900017, India
| | - Dileep Kumar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharti Vidyapeeth, Pune, Maharashtra 411038, India
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22
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Wu SY, Wu FG, Chen X. Antibody-Incorporated Nanomedicines for Cancer Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2109210. [PMID: 35142395 DOI: 10.1002/adma.202109210] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 02/06/2022] [Indexed: 06/14/2023]
Abstract
Antibody-based cancer therapy, one of the most significant therapeutic strategies, has achieved considerable success and progress over the past decades. Nevertheless, obstacles including limited tumor penetration, short circulation half-lives, undesired immunogenicity, and off-target side effects remain to be overcome for the antibody-based cancer treatment. Owing to the rapid development of nanotechnology, antibody-containing nanomedicines that have been extensively explored to overcome these obstacles have already demonstrated enhanced anticancer efficacy and clinical translation potential. This review intends to offer an overview of the advancements of antibody-incorporated nanoparticulate systems in cancer treatment, together with the nontrivial challenges faced by these next-generation nanomedicines. Diverse strategies of antibody immobilization, formats of antibodies, types of cancer-associated antigens, and anticancer mechanisms of antibody-containing nanomedicines are provided and discussed in this review, with an emphasis on the latest applications. The current limitations and future research directions on antibody-containing nanomedicines are also discussed from different perspectives to provide new insights into the construction of anticancer nanomedicines.
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Affiliation(s)
- Shun-Yu Wu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| | - Fu-Gen Wu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| | - Xiaoyuan Chen
- Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119077, Singapore
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23
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Stadlmayr G, Stracke F, Stadlbauer K, Rybka J, Dickgiesser S, Rasche N, Becker S, Toleikis L, Rüker F, Knopp GW. Efficient spontaneous site-selective cysteine-mediated toxin attachment within a structural loop of antibodies. Biochim Biophys Acta Gen Subj 2022; 1866:130155. [DOI: 10.1016/j.bbagen.2022.130155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/19/2022] [Accepted: 04/18/2022] [Indexed: 10/18/2022]
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Adhikari E, Liu Q, Burton C, Mockabee-Macias A, Lester DK, Lau E. l-fucose, a sugary regulator of antitumor immunity and immunotherapies. Mol Carcinog 2022; 61:439-453. [PMID: 35107186 DOI: 10.1002/mc.23394] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/20/2022]
Abstract
l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell-intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.
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Affiliation(s)
- Emma Adhikari
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Qian Liu
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Chase Burton
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Andrea Mockabee-Macias
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Daniel K Lester
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Eric Lau
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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25
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Abstract
Polyclonal immunoglobulin (Ig) preparations have been used for several decades for treatment of primary and secondary immunodeficiencies and for treatment of some infections and intoxications. This has demonstrated the importance of Igs, also called antibodies (Abs) for prevention and elimination of infections. Moreover, elucidation of the structure and functions of Abs has suggested that they might be useful for targeted treatment of several diseases, including cancers and autoimmune diseases. The development of technologies for production of specific monoclonal Abs (MAbs) in large amounts has led to the production of highly effective therapeutic antibodies (TAbs), a collective term for MAbs (MAbs) with demonstrated clinical efficacy in one or more diseases. The number of approved TAbs is currently around hundred, and an even larger number is under development, including several engineered and modified Ab formats. The use of TAbs has provided new treatment options for many severe diseases, but prediction of clinical effect is difficult, and many patients eventually lose effect, possibly due to development of Abs to the TAbs or to other reasons. The therapeutic efficacy of TAbs can be ascribed to one or more effects, including binding and neutralization of targets, direct cytotoxicity, Ab-dependent complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity or others. The therapeutic options for TAbs have been expanded by development of several new formats of TAbs, including bispecific Abs, single domain Abs, TAb-drug conjugates, and the use of TAbs for targeted activation of immune cells. Most promisingly, current research and development can be expected to increase the number of clinical conditions, which may benefit from TAbs.
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Affiliation(s)
- Gunnar Houen
- Department of Neurology, Rigshospitalet, Glostrup, Denmark.
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26
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Seitz CM, Mittelstaet J, Atar D, Hau J, Reiter S, Illi C, Kieble V, Engert F, Drees B, Bender G, Krahl AC, Knopf P, Schroeder S, Paulsen N, Rokhvarguer A, Scheuermann S, Rapp E, Mast AS, Rabsteyn A, Schleicher S, Grote S, Schilbach K, Kneilling M, Pichler B, Lock D, Kotter B, Dapa S, Miltenyi S, Kaiser A, Lang P, Handgretinger R, Schlegel P. Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting. Oncoimmunology 2021; 10:2003532. [PMID: 35686214 PMCID: PMC9172918 DOI: 10.1080/2162402x.2021.2003532] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system. AdCAR-T are redirected to surface antigens via biotin-labeled adapter molecules in the context of a specific linker structure, referred to as Linker-Label-Epitope. AdCAR-T execute highly specific and controllable effector function against a multiplicity of target antigens. In mice, AdCAR-T durably eliminate aggressive lymphoma. Importantly, AdCAR-T might prevent antigen evasion by combinatorial simultaneous or sequential targeting of multiple antigens and are capable to identify and differentially lyse cancer cells by integration of adapter molecule-mediated signals based on multiplex antigen expression profiles. In consequence the AdCAR technology enables controllable, flexible, combinatorial, and selective targeting. Adapter CAR-T cells for multiple synchronic targeting.
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Affiliation(s)
- Christian M. Seitz
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | | | - Daniel Atar
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Jana Hau
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Selina Reiter
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Clara Illi
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Verena Kieble
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Fabian Engert
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Britta Drees
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Giulia Bender
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Ann-Christin Krahl
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Philipp Knopf
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, Germany
| | - Sarah Schroeder
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Nikolas Paulsen
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Alexander Rokhvarguer
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Sophia Scheuermann
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Elena Rapp
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Anna-Sophia Mast
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Armin Rabsteyn
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
| | - Sabine Schleicher
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Stefan Grote
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Karin Schilbach
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
| | - Manfred Kneilling
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
| | - Bernd Pichler
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
| | - Dominik Lock
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Bettina Kotter
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Sandra Dapa
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Stefan Miltenyi
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Andrew Kaiser
- R&D Department, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Peter Lang
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
| | - Rupert Handgretinger
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
| | - Patrick Schlegel
- Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tuebingen, Germany
- Cluster of Excellence iFIT (Exc 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Germany
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Cellular Cancer Therapeutics Unit, Children’s Medical Research Institute, Westmead, Australia
- Department of Pediatric Hematology and Oncology, Westmead Children’s Hospital, Westmead, Australia
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27
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Ebihara T, Masuda A, Takahashi D, Hino M, Mon H, Kakino K, Fujii T, Fujita R, Ueda T, Lee JM, Kusakabe T. Production of scFv, Fab, and IgG of CR3022 Antibodies Against SARS-CoV-2 Using Silkworm-Baculovirus Expression System. Mol Biotechnol 2021; 63:1223-1234. [PMID: 34304364 PMCID: PMC8310559 DOI: 10.1007/s12033-021-00373-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 07/16/2021] [Indexed: 01/15/2023]
Abstract
COVID-19, caused by SARS-CoV-2, is currently spreading around the world and causing many casualties. Antibodies against such emerging infectious diseases are one of the important tools for basic viral research and the development of diagnostic and therapeutic agents. CR3022 is a monoclonal antibody against the receptor binding domain (RBD) of the spike protein (S protein) of SARS-CoV found in SARS patients, but it was also shown to have strong affinity for that of SARS-CoV-2. In this study, we produced large amounts of three formats of CR3022 antibodies (scFv, Fab and IgG) with high purity using a silkworm-baculovirus expression vector system. Furthermore, SPR measurements showed that the affinity of those silkworm-produced IgG antibodies to S protein was almost the same as that produced in mammalian expression system. These results indicate that the silkworm-baculovirus expression system is an excellent expression system for emerging infectious diseases that require urgent demand for diagnostic agents and therapeutic agents.
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Affiliation(s)
- Takeru Ebihara
- Laboratory of Insect Genome Science, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Akitsu Masuda
- Laboratory of Insect Genome Science, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Daisuke Takahashi
- Laboratory of Protein Structure, Function and Design, Faculty of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masato Hino
- Laboratory of Sanitary Entomology, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Hiroaki Mon
- Laboratory of Insect Genome Science, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Kohei Kakino
- Laboratory of Insect Genome Science, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Tsuguru Fujii
- Laboratory of Creative Science for Insect Industries, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Ryosuke Fujita
- Laboratory of Sanitary Entomology, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Tadashi Ueda
- Laboratory of Protein Structure, Function and Design, Faculty of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Jae Man Lee
- Laboratory of Creative Science for Insect Industries, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Takahiro Kusakabe
- Laboratory of Insect Genome Science, Faculty of Agriculture, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan.
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28
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Ahn WS, Kim TS, Park YJ, Park YK, Kim HD, Kim J. Production, characterization, and epitope mapping of monoclonal antibodies of ribosomal protein S3 (rpS3). Anim Cells Syst (Seoul) 2021; 25:323-336. [PMID: 34745438 PMCID: PMC8567880 DOI: 10.1080/19768354.2021.1980100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Ribosomal protein S3 (rpS3), a member of 40S small ribosomal subunit, is a multifunctional protein with various extra-ribosomal functions including DNA repair endonuclease activity and is secreted from cancer cells. Therefore, antibodies with high specificity against rpS3 protein could be useful cancer biomarkers. In this study, polyclonal antibody (pAb) and monoclonal antibodies (mAbs) were raised against rpS3 protein and epitope mapping was performed for each antibody; the amino acid residues of rpS3 were scanned from amino acid 185 to 243 through peptide scanning to reveal the epitopes of each mAb. Results showed that pAb R2 has an epitope from amino acid 203 to 230, mAb M7 has an epitope from amino acid 213 to 221, and mAb M8 has an epitope from amino acid 197 to 219. Taken together, novel mAbs and pAb against rpS3 were raised and mapped against rpS3 with different specific epitopes.
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Affiliation(s)
- Woo-Sung Ahn
- Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Tae-Sung Kim
- Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Yong Jun Park
- Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Young Kwang Park
- Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Hag Dong Kim
- HAEL Lab, Korea University, Seoul, Republic of Korea
| | - Joon Kim
- Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea.,HAEL Lab, Korea University, Seoul, Republic of Korea
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29
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Sharifi-Rad J, Quispe C, Patra JK, Singh YD, Panda MK, Das G, Adetunji CO, Michael OS, Sytar O, Polito L, Živković J, Cruz-Martins N, Klimek-Szczykutowicz M, Ekiert H, Choudhary MI, Ayatollahi SA, Tynybekov B, Kobarfard F, Muntean AC, Grozea I, Daştan SD, Butnariu M, Szopa A, Calina D. Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3687700. [PMID: 34707776 PMCID: PMC8545549 DOI: 10.1155/2021/3687700] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022]
Abstract
Paclitaxel is a broad-spectrum anticancer compound, which was derived mainly from a medicinal plant, in particular, from the bark of the yew tree Taxus brevifolia Nutt. It is a representative of a class of diterpene taxanes, which are nowadays used as the most common chemotherapeutic agent against many forms of cancer. It possesses scientifically proven anticancer activity against, e.g., ovarian, lung, and breast cancers. The application of this compound is difficult because of limited solubility, recrystalization upon dilution, and cosolvent-induced toxicity. In these cases, nanotechnology and nanoparticles provide certain advantages such as increased drug half-life, lowered toxicity, and specific and selective delivery over free drugs. Nanodrugs possess the capability to buildup in the tissue which might be linked to enhanced permeability and retention as well as enhanced antitumour influence possessing minimal toxicity in normal tissues. This article presents information about paclitaxel, its chemical structure, formulations, mechanism of action, and toxicity. Attention is drawn on nanotechnology, the usefulness of nanoparticles containing paclitaxel, its opportunities, and also future perspective. This review article is aimed at summarizing the current state of continuous pharmaceutical development and employment of nanotechnology in the enhancement of the pharmacokinetic and pharmacodynamic features of paclitaxel as a chemotherapeutic agent.
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Affiliation(s)
- Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | - Jayanta Kumar Patra
- Research Institute of Biotechnology & Medical Converged Science, Dongguk University, Goyangsi, Republic of Korea
| | - Yengkhom Disco Singh
- Department of Post-Harvest Technology, College of Horticulture and Forestry, Central Agricultural University, Pasighat, 791102 Arunachal Pradesh, India
| | - Manasa Kumar Panda
- Environment and Sustainability Department, CSIR-Institute of Minerals and Materials Technology, Bhubaneswar, 751013 Odisha, India
| | - Gitishree Das
- Research Institute of Biotechnology & Medical Converged Science, Dongguk University, Goyangsi, Republic of Korea
| | - Charles Oluwaseun Adetunji
- Applied Microbiology, Biotechnology and Nanotechnology Laboratory, Department of Microbiology, Edo University Iyamho, PMB 04, Auchi, Edo State, Nigeria
| | - Olugbenga Samuel Michael
- Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Osun State, Nigeria
| | - Oksana Sytar
- Department of Plant Biology Department, Institute of Biology, Taras Shevchenko National University of Kyiv, Kyiv 01033, Ukraine
- Department of Plant Physiology, Slovak University of Agriculture, Nitra 94976, Slovakia
| | - Letizia Polito
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Jelena Živković
- Institute for Medicinal Plants Research “Dr. Josif Pančić”, Tadeuša Košćuška 1, 11000 Belgrade, Serbia
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal
| | - Marta Klimek-Szczykutowicz
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Halina Ekiert
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Muhammad Iqbal Choudhary
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Seyed Abdulmajid Ayatollahi
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
- Department of Pharmacognosy and Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bekzat Tynybekov
- Department of Biodiversity of Bioresources, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Farzad Kobarfard
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ana Covilca Muntean
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Ioana Grozea
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
- Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
| | - Monica Butnariu
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Agnieszka Szopa
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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30
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Ruiz-Garcia H, Ramirez-Loera C, Malouff TD, Seneviratne DS, Palmer JD, Trifiletti DM. Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma. Int J Mol Sci 2021; 22:9673. [PMID: 34575840 PMCID: PMC8465220 DOI: 10.3390/ijms22189673] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 01/09/2023] Open
Abstract
Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.
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Affiliation(s)
- Henry Ruiz-Garcia
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA; (H.R.-G.); (T.D.M.); (D.S.S.)
- Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL 32224, USA;
| | | | - Timothy D. Malouff
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA; (H.R.-G.); (T.D.M.); (D.S.S.)
| | - Danushka S. Seneviratne
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA; (H.R.-G.); (T.D.M.); (D.S.S.)
| | - Joshua D. Palmer
- Department of Radiation Oncology, Ohio State University, Columbus, OH 43210, USA;
| | - Daniel M. Trifiletti
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA; (H.R.-G.); (T.D.M.); (D.S.S.)
- Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL 32224, USA;
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31
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Structure-Indicated LC-MS/MS Bioanalysis of Therapeutic Antibodies. Methods Mol Biol 2021; 2313:187-205. [PMID: 34478139 DOI: 10.1007/978-1-0716-1450-1_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Monoclonal antibodies bind to Protein A/G resin with 100 nm-diameter pores, which orients the Fab toward the reaction solution. Then, they can be proteolyzed using trypsin immobilized on the surface of 200 nm-diameter nanoparticles. The difference between the two particle diameters allows Fab-selective proteolysis by limiting trypsin access to the antibody substrate. The specific signature peptide of monoclonal antibody is collected, which comprises the complementarity-determining regions (CDRs). Excess trypsin protease and peptide fragments from common sequences in Fc that inhibit the analysis can then be separated and removed. The resulting peptide samples are separated through high performance liquid chromatography on a 20 nm-diameter pore-size reversed-phase C18 column. These are then sequentially ionized with an electrospray interface and subjected to mass spectrometry (MS). In MS, peptide ions are trapped and fragment ions are generated by the collision-induced dissociation with argon gas. These are detected with multiple reaction monitoring measurements to perform a highly sensitive and accurate quantitative analysis.By focusing on various physicochemical features at each analytical scene, such as characteristic structure and orientation of antibody, control of trypsin reaction field, carry-over on HPLC column, ionization suppression effect from endogenous proteins, and detection of amino acid sequence specificity of antibody, we optimized the overall conditions from the sample processing up to MS detection and developed analytical validation and clinical application of many therapeutic antibodies using our Fab-selective proteolysis technology that is based on the structure-indicated approach.
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32
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Debela DT, Muzazu SGY, Heraro KD, Ndalama MT, Mesele BW, Haile DC, Kitui SK, Manyazewal T. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med 2021; 9:20503121211034366. [PMID: 34408877 PMCID: PMC8366192 DOI: 10.1177/20503121211034366] [Citation(s) in RCA: 621] [Impact Index Per Article: 155.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/05/2021] [Indexed: 01/11/2023] Open
Abstract
Cancer is a global health problem responsible for one in six deaths worldwide. Treating cancer has been a highly complex process. Conventional treatment approaches, such as surgery, chemotherapy, and radiotherapy, have been in use, while significant advances are being made in recent times, including stem cell therapy, targeted therapy, ablation therapy, nanoparticles, natural antioxidants, radionics, chemodynamic therapy, sonodynamic therapy, and ferroptosis-based therapy. Current methods in oncology focus on the development of safe and efficient cancer nanomedicines. Stem cell therapy has brought promising efficacy in regenerating and repairing diseased or damaged tissues by targeting both primary and metastatic cancer foci, and nanoparticles brought new diagnostic and therapeutic options. Targeted therapy possessed breakthrough potential inhibiting the growth and spread of specific cancer cells, causing less damage to healthy cells. Ablation therapy has emerged as a minimally invasive procedure that burns or freezes cancers without the need for open surgery. Natural antioxidants demonstrated potential tracking down free radicals and neutralizing their harmful effects thereby treating or preventing cancer. Several new technologies are currently under research in clinical trials, and some of them have already been approved. This review presented an update on recent advances and breakthroughs in cancer therapies.
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Affiliation(s)
- Dejene Tolossa Debela
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Seke GY Muzazu
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Enteric Diseases and Vaccines Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Kidist Digamo Heraro
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Wachemo University, Hossana, Ethiopia
| | - Maureen Tayamika Ndalama
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Betelhiem Woldemedhin Mesele
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Kotebe Metropolitan University, Addis Ababa, Ethiopia
| | - Dagimawi Chilot Haile
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- University of Gondar, Gondar, Ethiopia
| | - Sophia Khalayi Kitui
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tsegahun Manyazewal
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Purification of antibody fragments via interaction with detergent micellar aggregates. Sci Rep 2021; 11:11697. [PMID: 34083598 PMCID: PMC8175343 DOI: 10.1038/s41598-021-90966-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 05/20/2021] [Indexed: 11/08/2022] Open
Abstract
The research described in this report seeks to present proof-of-concept for a novel and robust platform for purification of antibody fragments and to define and optimize the controlling parameters. Purification of antigen-binding F(ab')2 fragments is achieved in the absence of chromatographic media or specific ligands, rather by using clusters of non-ionic detergent (e.g. Tween-60, Brij-O20) micelles chelated via Fe2+ ions and the hydrophobic chelator, bathophenanthroline (batho). These aggregates, quantitatively capture the F(ab')2 fragment in the absence or presence of E. coli lysate and allow extraction of only the F(ab')2 domain at pH 3.8 without concomitant aggregate dissolution or coextraction of bacterial impurities. Process yields range from 70 to 87% by densitometry. Recovered F(ab')2 fragments are monomeric (by dynamic light scattering), preserve their secondary structure (by circular dichroism) and are as pure as those obtained via Protein A chromatography (from a mixture of F(ab')2 and Fc fragments). The effect of process parameters on Ab binding and Ab extraction (e.g. temperature, pH, ionic strength, incubation time, composition of extraction buffer) are reported, using a monoclonal antibody (mAb) and polyclonal human IgG's as test samples.
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34
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Martinelli C. Smart Nanocarriers for Targeted Cancer Therapy. Anticancer Agents Med Chem 2021; 21:546-557. [PMID: 32560615 DOI: 10.2174/1871520620666200619181425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/27/2020] [Accepted: 04/24/2020] [Indexed: 11/22/2022]
Abstract
Cancer is considered one of the most threatening diseases worldwide. Although many therapeutic approaches have been developed and optimized for ameliorating patient's conditions and life expectancy, however, it frequently remains an incurable pathology. Notably, conventional treatments may reveal inefficient in the presence of metastasis development, multidrug resistance and inability to achieve targeted drug delivery. In the last decades, nanomedicine has gained a prominent role, due to many properties ascribable to nanomaterials. It is worth mentioning their small size, their ability to be loaded with small drugs and bioactive molecules and the possibility to be functionalized for tumor targeting. Natural vehicles have been exploited, such as exosomes, and designed, such as liposomes. Biomimetic nanomaterials have been engineered, by modification with biological membrane coating. Several nanoparticles have already entered clinical trials and some liposomal formulations have been approved for therapeutic applications. In this review, natural and synthetic nanocarriers functionalized for actively targeting cancer cells will be described, focusing on their advantages with respect to conventional treatments. Recent innovations related to biomimetic nanoparticles camouflaged with membranes isolated from different types of cells will be reported, together with their promising applications. Finally, a short overview on the latest advances in carrier-free nanomaterials will be provided.
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Affiliation(s)
- Chiara Martinelli
- Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa, Italy
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35
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Moholkar DN, Sadalage PS, Havaldar DV, Pawar KD. Engineering the liposomal formulations from natural peanut phospholipids for pH and temperature sensitive release of folic acid, levodopa and camptothecin. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 123:111979. [PMID: 33812607 DOI: 10.1016/j.msec.2021.111979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 01/12/2021] [Accepted: 02/13/2021] [Indexed: 11/29/2022]
Abstract
The present study demonstrates the extraction and identification of phospholipids (PLs) from peanut seed for formulation of liposomes for pH and thermo-sensitive delivery and release of folic acid (FA), levodopa (DOPA) and, camptothecin (CPT). The TLC, FTIR and GC-MS based characterization of extracted peanut PLs showed phosphatidylethanolamine, cardiolipin and phosphatidic acid as major PLs and palmitic acid and oleic acid as major fatty acids. Liposomes (LSMs) of size 1-2 μm formulated by optimized thin-film hydration method were found to entrap FA, DOPA and CPT with 58, 61.4 and 52.12% efficiency, respectively with good stability. The effect of external stimuli like pH and temperature on the release pattern of FA, DOPA and CPT indicated that FA was optimally released at pH 10 and 57 °C, DOPA at pH 2 and 37 °C, while CPT was best released at pH 6 and 47 °C. When tested for the in vitro activity, DOPA released by DOPA@LSMs showed lower toxicity to 3T3 than to SH-SY5Y cells. Similarly, CPT released by CPT@LSMs showed remarkable anticancer activity against MCF-7 cells with an IC50 value of 17.99 μg/mL. Thus peanut PLs can be efficiently used for liposomal formulations for pH and thermo-sensitive release of drugs.
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Affiliation(s)
- Disha N Moholkar
- School of Nanoscience and Biotechnology, Shivaji University, Kolhapur, Maharashtra, India
| | | | - Darshana V Havaldar
- School of Nanoscience and Biotechnology, Shivaji University, Kolhapur, Maharashtra, India
| | - Kiran D Pawar
- School of Nanoscience and Biotechnology, Shivaji University, Kolhapur, Maharashtra, India.
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36
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Dissecting the impact of target-binding kinetics of protein binders on tumor localization. iScience 2021; 24:102104. [PMID: 33615202 PMCID: PMC7881221 DOI: 10.1016/j.isci.2021.102104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/10/2021] [Accepted: 01/21/2021] [Indexed: 12/17/2022] Open
Abstract
Systematic control of in vivo behavior of protein-based therapeutics is considered highly desirable for improving their clinical outcomes. Modulation of biochemical properties including molecular weight, surface charge, and binding affinity has thus been suggested to enhance their therapeutic effects. However, establishing a relationship between the binding affinity and tumor localization remains a debated issue. Here we investigate the influence of the binding affinity of proteins on tumor localization by using four repebodies having different affinities to EGFR. Biochemical analysis and molecular imaging provided direct evidence that optimal affinity with balanced target binding and dissociation can facilitate deep penetration and accumulation of protein binders in tumors by overcoming the binding-site-barrier effect. Our findings suggest that binding kinetics-based protein design can be implicated in the development of fine-tuned protein therapeutics for cancers.
High binding affinity limits the tumor localization of protein binders in vivo Moderate-affinity binders can exhibit better tumor localization than higher binders Binding kinetics of binders play a central role in controlling tumor localization Exploring the optimal affinity of binders can enhance their therapeutic potential
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37
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Megha KB, Mohanan PV. Role of immunoglobulin and antibodies in disease management. Int J Biol Macromol 2020; 169:28-38. [PMID: 33340621 DOI: 10.1016/j.ijbiomac.2020.12.073] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/21/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
The immune system is a highly advanced and coordinated mechanism that allows a living organism to distinguish between "self" and "non-self". The host uses both innate and adaptive immune response mechanisms to identify and eliminate pathogenic microorganisms. Human immunoglobulin is the prominently used blood product in the clinical practice. Immunoglobulin applications have improved rapidly due to the exploration of its immunomodulatory and anti-inflammatory properties. This made this blood product into a precious and advanced tool in the treatment of numerous disease conditions which are linked with humoral immune deficiency or that cause immune system dysfunction. Human immunoglobulin (Ig) is used for Ig replacement therapy in both primary and secondary immunodeficiency conditions, for prevention and treatment of certain infections. It also acts as an immunomodulatory agent for autoimmune and inflammatory disorders. Therapeutic antibodies have been successfully used for the treatment of diverse pathological conditions. Drug development programs exclusively select highly specific antibodies that recognize a single disease-associated target. Hopefully this review will give an insight towards the immune system, the involvement of the specialized immune cells, their products and involvement in various immune disorders and pathological conditions.
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Affiliation(s)
- K B Megha
- Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (Govt. of India), Poojapura, Trivandrum 695 012, Kerala, India
| | - P V Mohanan
- Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (Govt. of India), Poojapura, Trivandrum 695 012, Kerala, India.
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38
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Molecular targeted therapy: novel therapeutic approach for head and neck cancer. Ther Deliv 2020; 11:637-651. [DOI: 10.4155/tde-2020-0028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer is a major public health burden worldwide, affecting millions of people each year. One of the major hallmarks of cancer is rapid growth and progression by evasion of host immune responses. Tumor resistance to conventional anticancer drugs by several mechanisms, such as drug inactivation, efflux pumps and enhanced toxicity to normal cells decreases their clinical efficacy. These limitations resulted in the development of new targeted agents, such as monoclonal antibodies and small molecule inhibitors that have high tumor specificity. This paper discusses the therapeutic applications of novel molecular targeted agents and immunotherapy as an alternative treatment option for head and neck cancers, as well as provides insight into future therapeutic approaches for advanced head and neck cancers.
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39
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Kim K, Khang D. Past, Present, and Future of Anticancer Nanomedicine. Int J Nanomedicine 2020; 15:5719-5743. [PMID: 32821098 PMCID: PMC7418170 DOI: 10.2147/ijn.s254774] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022] Open
Abstract
This review aims to summarize the methods that have been used till today, highlight methods that are currently being developed, and predict the future roadmap for anticancer therapy. In the beginning of this review, established approaches for anticancer therapy, such as conventional chemotherapy, hormonal therapy, monoclonal antibodies, and tyrosine kinase inhibitors are summarized. To counteract the side effects of conventional chemotherapy and to increase limited anticancer efficacy, nanodrug- and stem cell-based therapies have been introduced. However, current level of understanding and strategies of nanodrug and stem cell-based therapies have limitations that make them inadequate for clinical application. Subsequently, this manuscript reviews methods with fewer side effects compared to those of the methods mentioned above which are currently being investigated and are already being applied in the clinic. The newer strategies that are already being clinically applied include cancer immunotherapy, especially T cell-mediated therapy and immune checkpoint inhibitors, and strategies that are gaining attention include the manipulation of the tumor microenvironment or the activation of dendritic cells. Tumor-associated macrophage repolarization is another potential strategy for cancer immunotherapy, a method which activates macrophages to immunologically attack malignant cells. At the end of this review, we discuss combination therapies, which are the future of cancer treatment. Nanoparticle-based anticancer immunotherapies seem to be effective, in that they effectively use nanodrugs to elicit a greater immune response. The combination of these therapies with others, such as photothermal or tumor vaccine therapy, can result in a greater anticancer effect. Thus, the future of anticancer therapy aims to increase the effectiveness of therapy using various therapies in a synergistic combination rather than individually.
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Affiliation(s)
- Kyungeun Kim
- College of Medicine, Gachon University, Incheon 21999, South Korea
| | - Dongwoo Khang
- College of Medicine, Gachon University, Incheon 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea.,Gachon Advanced Institute for Health Science & Technology (GAIHST), Gachon University, Incheon 21999, South Korea.,Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea
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40
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Lin WW, Lu YC, Chuang CH, Cheng TL. Ab locks for improving the selectivity and safety of antibody drugs. J Biomed Sci 2020; 27:76. [PMID: 32586313 PMCID: PMC7318374 DOI: 10.1186/s12929-020-00652-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
Monoclonal antibodies (mAbs) are a major targeted therapy for malignancies, infectious diseases, autoimmune diseases, transplant rejection and chronic inflammatory diseases due to their antigen specificity and longer half-life than conventional drugs. However, long-term systemic antigen neutralization by mAbs may cause severe adverse events. Improving the selectivity of mAbs to distinguish target antigens at the disease site from normal healthy tissue and reducing severe adverse events caused by the mechanisms-of-action of mAbs is still a pressing need. Development of pro-antibodies (pro-Abs) by installing a protease-cleavable Ab lock is a novel and advanced recombinant Ab-based strategy that efficiently masks the antigen binding ability of mAbs in the normal state and selectively "turns on" the mAb activity when the pro-Ab reaches the proteolytic protease-overexpressed diseased tissue. In this review, we discuss the design and advantages/disadvantages of different Ab lock strategies, focusing particularly on spatial-hindrance-based and affinity peptide-based approaches. We expect that the development of different masking strategies for mAbs will benefit the local reactivity of mAbs at the disease site, increase the therapeutic efficacy and safety of long-term treatment with mAbs in chronic diseases and even permit scientists to develop Ab drugs for formerly undruggable targets and satisfy the unmet medical needs of mAb therapy.
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Affiliation(s)
- Wen-Wei Lin
- Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yun-Chi Lu
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan
| | - Chih-Hung Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.
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41
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Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update. Biomolecules 2020; 10:biom10060934. [PMID: 32575752 PMCID: PMC7356171 DOI: 10.3390/biom10060934] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/17/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting immunotoxin, as a treatment for patients with hairy cell leukemia. This approval helps to demonstrate the potential role that immunotoxins can play in the cancer therapeutics pipeline. However, concerns have been raised about the use of immunotoxins, including their high immunogenicity and short half-life, in particular for treating solid tumors such as liver cancer. This review provides an overview of recent efforts to develop a glypican-3 (GPC3) targeting immunotoxin for treating HCC, including strategies to deimmunize immunotoxins by removing B- or T-cell epitopes on the bacterial toxin and to improve the serum half-life of immunotoxins by incorporating an albumin binding domain.
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Kafil V, Saei AA, Tohidkia MR, Barar J, Omidi Y. Immunotargeting and therapy of cancer by advanced multivalence antibody scaffolds. J Drug Target 2020; 28:1018-1033. [DOI: 10.1080/1061186x.2020.1772796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Vala Kafil
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ata Saei
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Mohammad Reza Tohidkia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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Inhibition of human lung adenocarcinoma growth and metastasis by JC polyomavirus-like particles packaged with an SP-B promoter-driven CD59-specific shRNA. Clin Sci (Lond) 2020; 133:2159-2169. [PMID: 31693732 DOI: 10.1042/cs20190395] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022]
Abstract
Lung cancer ranks first in both incidence and mortality and is a major health concern worldwide. Upon recognition of specific antigens on tumor cells, complement-dependent cytotoxicity (CDC) is activated, arresting cell growth or inducing apoptosis. However, by overexpressing CD59, a membrane complement regulatory protein (mCRP), lung cancer cells develop resistance to CDC. We previously showed that virus-like particles (VLPs) of human JC polyomavirus (JCPyV) could be used as a gene therapy vector to carry a suicide gene expression plasmid with a lung-specific promoter (SP-B (surfactant protein B)) for lung adenocarcinomas. Herein, we designed a CD59-specific short hairpin RNA (shRNA) expression plasmid driven by SP-B (pSPB-shCD59) to effectively and specifically inhibit CD59 overexpression in lung cancer cells. Treatment of lung cancer cells in vitro with JCPyV VLPs containing pSPB-shCD59 (pSPB-shCD59/VLPs) induces CDC and death of cancer cells. Mice that were subcutaneously injected with human lung cancer cells showed an 87% inhibition in tumor growth after tail vein injection of pSPB-shCD59/VLPs. Moreover, in a mouse model of lung cancer metastasis, a reduction in the lung weight by 39%, compared with the control group, was observed in mice treated with pSPB-shCD59/VLPs after tail vein injection of human lung cancer cells. Furthermore, tissue sectioning showed that the number and size of tumors produced was significantly reduced in the lungs of mice in the treatment group than those of the untreated group, indicating inhibition of metastasis by pSPB-shCD59/VLPs. Together, these results demonstrate the potential of pSPB-shCD59/VLPs as a therapeutic agent for CD59 overexpressed lung cancer.
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Gauzy-Lazo L, Sassoon I, Brun MP. Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations. SLAS DISCOVERY 2020; 25:843-868. [DOI: 10.1177/2472555220912955] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The targeted delivery of potent cytotoxic molecules into cancer cells is considered a promising anticancer strategy. The design of clinically effective antibody–drug conjugates (ADCs), in which biologically active drugs are coupled through chemical linkers to monoclonal antibodies, has presented challenges for pharmaceutical researchers. After 30 years of intensive research and development activities, only seven ADCs have been approved for clinical use; two have received fast-track designation and two breakthrough therapy designation from the Food and Drug Administration. There is continued interest in the field, as documented by the growing number of candidates in clinical development. This review aims to summarize the most recent innovations that have been applied to the design of ADCs undergoing early- and late-stage clinical trials. Discovery and rational optimization of new payloads, chemical linkers, and antibody formats have improved the therapeutic index of next-generation ADCs, ultimately resulting in improved clinical benefit for the patients.
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Affiliation(s)
| | - Ingrid Sassoon
- Immuno-Oncology Therapeutic Area, Sanofi, Vitry-sur-Seine, France
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45
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Nanocarriers as Magic Bullets in the Treatment of Leukemia. NANOMATERIALS 2020; 10:nano10020276. [PMID: 32041219 PMCID: PMC7075174 DOI: 10.3390/nano10020276] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/30/2020] [Accepted: 02/01/2020] [Indexed: 12/21/2022]
Abstract
Leukemia is a type of hematopoietic stem/progenitor cell malignancy characterized by the accumulation of immature cells in the blood and bone marrow. Treatment strategies mainly rely on the administration of chemotherapeutic agents, which, unfortunately, are known for their high toxicity and side effects. The concept of targeted therapy as magic bullet was introduced by Paul Erlich about 100 years ago, to inspire new therapies able to tackle the disadvantages of chemotherapeutic agents. Currently, nanoparticles are considered viable options in the treatment of different types of cancer, including leukemia. The main advantages associated with the use of these nanocarriers summarized as follows: i) they may be designed to target leukemic cells selectively; ii) they invariably enhance bioavailability and blood circulation half-life; iii) their mode of action is expected to reduce side effects. FDA approval of many nanocarriers for treatment of relapsed or refractory leukemia and the desired results extend their application in clinics. In the present review, different types of nanocarriers, their capability in targeting leukemic cells, and the latest preclinical and clinical data are discussed.
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46
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Yamamoto S, Ueda M, Kasai M, Ueda Y, Kinoshita M, Suzuki S. A fast and convenient solid phase preparation method for releasing N-glycans from glycoproteins using trypsin- and peptide-N-glycosidase F (PNGase F)-impregnated polyacrylamide gels fabricated in a pipette tip. J Pharm Biomed Anal 2020; 179:112995. [PMID: 31767225 DOI: 10.1016/j.jpba.2019.112995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/15/2019] [Accepted: 11/16/2019] [Indexed: 12/26/2022]
Abstract
An efficient deglycosylation process is a key requirement for the identification and characterization of glycosylation during the production and purification of therapeutic antibodies. PNGase F is widely used for the deglycosylation of N-linked glycans. The commonly-used in-solution deglycosylation method is relatively time-consuming and requires several hours up to overnight for complete removal of all N-linked glycans. In order to develop a simple and efficient method for the rapid release of N-linked glycans from glycoproteins, we fabricated trypsin- and PNGase F-impregnated polyacrylamide gels in a commercial 200 μL volume pipette tip. Our enzyme reactor is based on simple photochemical copolymerization of monomers using the following procedure: (1) a pipette tip was filled with a gel solution comprising acrylamide, N,N'-methylene-bis-acrylamide containing PNGase F or trypsin with 2,2-azobis(2-methyl-N-(2-hydroxyethyl) propionamide) as a photocatalytic initiator; and (2) in situ polymerization of gel solution approximately 30 mm from the tip was performed by irradiation with a 365 nm blue LED beam from a distance 10 mm. The fixed enzymes maintained their activities in the polyacrylamide gel and the reaction was completed by 40 iterations of suction and discharge with a pipette (hereafter referred to as manual pipetting times) for 8 min with each enzyme digestion. Capillary electrophoresis (CE) of released glycans labeled with 8-aminopyrene-1,3,6-trisulfonate (APTS) demonstrated quantitative recovery of glycans from selected glycoproteins.
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Affiliation(s)
- Sachio Yamamoto
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan.
| | - Maki Ueda
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan
| | - Masataka Kasai
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan
| | - Yusuke Ueda
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan
| | - Mitsuhiro Kinoshita
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan; Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan
| | - Shigeo Suzuki
- Faculty of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan; Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Japan
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47
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Zhao F, Cao M, Jiang XH, Xie K, Ye SR, Yie SM. A specific autoantibody against a novel tumour-association antigen derived from human DNA-topoiomerase I is a potential biomarker for early diagnosis and favourable prognosis in patients with colorectal carcinoma. Biomarkers 2020; 25:149-156. [PMID: 31922440 DOI: 10.1080/1354750x.2020.1714734] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Context: We previously reported a novel tumour associated antigen (TTA) with molecular weight around 48 kDa and identified the novel TTA as a fragment derived from human DNA-topoiomerase I (TOP1). We termed the novel TAA as TOPO48 and termed autoantibody against the TAA as anti-TOPO48 autoantibody.Objective: To explore the clinical significance of anti-TOPO48 autoantibody in patients with colorectal carcinoma (CRC).Materials and methods: Serum levels of the autoantibody in patients with CRC or benign tumours and healthy volunteers were measured with a specific ELISA.Results: CRC patients at early stage had higher frequency of positive levels of the autoantibody and CRC patients with positive autoantibody levels had higher overall survival rate than those with negative autoantibody levels.Conclusion: The autoantibody is a potential biomarker for early diagnosis and favourable prognosis of CRC.
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Affiliation(s)
- Feng Zhao
- State Key Laboratory of Biotherapy and Cancer, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China
| | - Mei Cao
- Core Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospitals, Chengdu, PR China
| | - Xiao-Hui Jiang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, PR China
| | - Ke Xie
- Department of Oncology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospitals, Chengdu, PR China
| | - Shang-Rong Ye
- Chengdu Cancer Bioengineering Research Institute, Chengdu, PR China
| | - Shang-Mian Yie
- Chengdu Cancer Bioengineering Research Institute, Chengdu, PR China
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48
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Lu G, Fakurnejad S, Martin BA, van den Berg NS, van Keulen S, Nishio N, Zhu AJ, Chirita SU, Zhou Q, Gao RW, Kong CS, Fischbein N, Penta M, Colevas AD, Rosenthal EL. Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers. Clin Cancer Res 2020; 26:2582-2594. [PMID: 31980465 DOI: 10.1158/1078-0432.ccr-19-3717] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/20/2019] [Accepted: 01/21/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE The efficacy of antibody-based therapeutics depends on successful drug delivery into solid tumors; therefore, there is a clinical need to measure intratumoral antibody distribution. This study aims to develop and validate an imaging and computation platform to directly quantify and predict antibody delivery into human head and neck cancers in a clinical study. EXPERIMENTAL DESIGN Twenty-four patients received systemic infusion of a near-infrared fluorescence-labeled therapeutic antibody followed by surgical tumor resection. A computational platform was developed to quantify the extent of heterogeneity of intratumoral antibody distribution. Both univariate and multivariate regression analyses were used to select the most predictive tumor biological factors for antibody delivery. Quantitative image features from the pretreatment MRI were extracted and correlated with fluorescence imaging of antibody delivery. RESULTS This study not only confirmed heterogeneous intratumoral antibody distribution in-line with many preclinical reports, but also quantified the extent of interpatient, intertumor, and intratumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both primary tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery. CONCLUSIONS This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies.
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Affiliation(s)
- Guolan Lu
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | | | - Brock A Martin
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Nynke S van den Berg
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Stan van Keulen
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Naoki Nishio
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Ashley J Zhu
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Stefania U Chirita
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Quan Zhou
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California
| | - Rebecca W Gao
- Stanford University School of Medicine, Stanford, California
| | - Christina S Kong
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Nancy Fischbein
- Department of Radiology, Stanford University School of Medicine, Stanford, California
| | - Mrudula Penta
- Department of Radiology, Stanford University School of Medicine, Stanford, California
| | - Alexander D Colevas
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California
| | - Eben L Rosenthal
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California. .,Department of Radiology, Stanford University School of Medicine, Stanford, California
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49
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Li T, Pan S, Gao S, Xiang W, Sun C, Cao W, Xu H. Diselenide-Pemetrexed Assemblies for Combined Cancer Immuno-, Radio-, and Chemotherapies. Angew Chem Int Ed Engl 2020; 59:2700-2704. [PMID: 31805209 DOI: 10.1002/anie.201914453] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Indexed: 12/16/2022]
Abstract
Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor efficacy of most cancer immunotherapies still needs to be improved. Herein, we develop diselenide-pemetrexed assemblies that combine natural killer (NK) cell-based cancer immunotherapy with radiotherapy and chemotherapy in a single system. The assemblies are prepared by co-assembly between pemetrexed and cytosine-containing diselenide through hydrogen bonds. Under γ-radiation, the hydrogen bonds are cleaved, resulting in the release of pemetrexed. At the same time, diselenide can be oxidized to seleninic acid, which suppresses the expression of human leukocyte antigen E (HLA-E) in cancer cells, thus activating the immune response of NK cells. In this way, cancer immunotherapy is combined with radiotherapy and chemotherapy, providing a new strategy for cancer treatment.
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Affiliation(s)
- Tianyu Li
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Shuojiong Pan
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Shiqian Gao
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Wentian Xiang
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Chenxing Sun
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Wei Cao
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208, USA
| | - Huaping Xu
- Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
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50
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Li T, Pan S, Gao S, Xiang W, Sun C, Cao W, Xu H. Diselenide–Pemetrexed Assemblies for Combined Cancer Immuno‐, Radio‐, and Chemotherapies. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.201914453] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Tianyu Li
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
| | - Shuojiong Pan
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
| | - Shiqian Gao
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
| | - Wentian Xiang
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
| | - Chenxing Sun
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
| | - Wei Cao
- Department of ChemistryNorthwestern University 2145 Sheridan Road Evanston IL 60208 USA
| | - Huaping Xu
- Key Lab of Organic Optoelectronics & Molecular EngineeringDepartment of ChemistryTsinghua University Beijing 100084 P. R. China
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