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1
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Izzo D, Ascione L, Guidi L, Marsicano RM, Koukoutzeli C, Trapani D, Curigliano G. Innovative payloads for ADCs in cancer treatment: moving beyond the selective delivery of chemotherapy. Ther Adv Med Oncol 2025; 17:17588359241309461. [PMID: 39759830 PMCID: PMC11694294 DOI: 10.1177/17588359241309461] [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] [Received: 07/16/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Antibody-drug conjugates (ADCs) have emerged as a transformative approach in cancer therapy by enhancing tumor targeting and minimizing systemic toxicity compared to traditional chemotherapy. Initially developed with chemotherapy agents as payloads, ADCs have now incorporated alternative payloads, such as immune-stimulating agents, natural toxins, and radionuclides, to improve therapeutic efficacy and specificity. A significant advancement in ADC technology is the integration of Proteolysis Targeting Chimeras (PROTACs), which enable the precise degradation of cellular targets involved in tumorigenesis. This strategy enhances the specificity and precision of cancer therapies, addressing key mechanisms in cancer cell survival. Moreover, incorporating radioactive isotopes into ADCs is an emerging strategy aimed at further improving therapeutic outcomes. By delivering localized radiation, this approach offers the potential to enhance the efficacy of treatment and expand the therapeutic arsenal. Despite these innovations, challenges remain, including dysregulated immune activation, severe adverse effects, and intrinsic immunogenicity of some agents. These emerging issues highlight the ongoing need for optimization in ADC therapy. This review summarizes the latest developments in ADC technology, focusing on novel payloads, PROTAC integration, and the potential for combining ADCs with other therapeutic modalities to refine cancer treatment and improve patient outcomes.
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Affiliation(s)
- Davide Izzo
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Liliana Ascione
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Lorenzo Guidi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Renato Maria Marsicano
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Chrysanthi Koukoutzeli
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Dario Trapani
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development, European Institute of Oncology, IRCCS, Via Giuseppe Ripamonti 435, Milan 20141, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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2
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Mekala JR, Nalluri HP, Reddy PN, S B S, N S SK, G V S D SK, Dhiman R, Chamarthy S, Komaragiri RR, Manyam RR, Dirisala VR. Emerging trends and therapeutic applications of monoclonal antibodies. Gene 2024; 925:148607. [PMID: 38797505 DOI: 10.1016/j.gene.2024.148607] [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: 08/15/2023] [Revised: 04/02/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Monoclonal antibodies (mAbs) are being used to prevent, detect, and treat a broad spectrum of malignancies and infectious and autoimmune diseases. Over the past few years, the market for mAbs has grown exponentially. They have become a significant part of many pharmaceutical product lines, and more than 250 therapeutic mAbs are undergoing clinical trials. Ever since the advent of hybridoma technology, antibody-based therapeutics were realized using murine antibodies which further progressed into humanized and fully human antibodies, reducing the risk of immunogenicity. Some of the benefits of using mAbs over conventional drugs include a drastic reduction in the chances of adverse reactions, interactions between drugs, and targeting specific proteins. While antibodies are very efficient, their higher production costs impede the process of commercialization. However, their cost factor has been improved by developing biosimilar antibodies, which are affordable versions of therapeutic antibodies. Along with biosimilars, innovations in antibody engineering have helped to design bio-better antibodies with improved efficacy than the conventional ones. These novel mAb-based therapeutics are set to revolutionize existing drug therapies targeting a wide spectrum of diseases, thereby meeting several unmet medical needs. In the future, mAbs generated by applying next-generation sequencing (NGS) are expected to become a powerful tool in clinical therapeutics. This article describes the methods of mAb production, pre-clinical and clinical development of mAbs, approved indications targeted by mAbs, and novel developments in the field of mAb research.
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Affiliation(s)
- Janaki Ramaiah Mekala
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram 522502, Guntur, Andhra Pradesh, INDIA.
| | - Hari P Nalluri
- Department of Biotechnology, Vignan's (Deemed to be) University, Guntur 522213, AP, India
| | - Prakash Narayana Reddy
- Department of Microbiology, Dr. V.S. Krishna Government College, Visakhapatnam 530013, India
| | - Sainath S B
- Department of Biotechnology, Vikrama Simhapuri University, Nellore 524320, AP, India
| | - Sampath Kumar N S
- Department of Biotechnology, Vignan's (Deemed to be) University, Guntur 522213, AP, India
| | - Sai Kiran G V S D
- Santhiram Medical College and General Hospital, Nandyal, Kurnool 518501, AP, India
| | - Rohan Dhiman
- Laboratory of Mycobacterial Immunology, Department of Life Sciences, National Institute of Technology Rourkela-769008, India
| | - Sahiti Chamarthy
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram 522502, Guntur, Andhra Pradesh, INDIA
| | - Raghava Rao Komaragiri
- Department of CSE, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram 522302, Andhra Pradesh, INDIA
| | - Rajasekhar Reddy Manyam
- Amrita School of Computing, Amrita Vishwa Vidyapeetham, Amaravati Campus, Amaravati, Andhra Pradesh, India
| | - Vijaya R Dirisala
- Department of Biotechnology, Vignan's (Deemed to be) University, Guntur 522213, AP, India.
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Xi M, Zhu J, Zhang F, Shen H, Chen J, Xiao Z, Huangfu Y, Wu C, Sun H, Xia G. Antibody-drug conjugates for targeted cancer therapy: Recent advances in potential payloads. Eur J Med Chem 2024; 276:116709. [PMID: 39068862 DOI: 10.1016/j.ejmech.2024.116709] [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: 07/12/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Antibody-drug conjugates (ADCs) represent a promising cancer therapy modality which specifically delivers highly toxic payloads to cancer cells through antigen-specific monoclonal antibodies (mAbs). To date, 15 ADCs have been approved and more than 100 ADC candidates have advanced to clinical trials for the treatment of various cancers. Among these ADCs, microtubule-targeting and DNA-damaging agents are at the forefront of payload development. However, several challenges including toxicity and drug resistance limit the potential of this modality. To tackle these issues, multiple innovative payloads such as immunomodulators and proteolysis targeting chimeras (PROTACs) are incorporated into ADCs to enable multimodal cancer therapy. In this review, we describe the mechanism of ADCs, highlight the importance of ADC payloads and summarize recent progresses of conventional and unconventional ADC payloads, trying to provide an insight into payload diversification as a key step in future ADC development.
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Affiliation(s)
- Meiyang Xi
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Jingjing Zhu
- NovoCodex Biopharmaceuticals Co. Ltd., Shaoxing, 312090, China
| | - Fengxia Zhang
- NovoCodex Biopharmaceuticals Co. Ltd., Shaoxing, 312090, China
| | - Hualiang Shen
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Jianhui Chen
- College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Ziyan Xiao
- College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Yanping Huangfu
- College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Chunlei Wu
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China
| | - Haopeng Sun
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
| | - Gang Xia
- NovoCodex Biopharmaceuticals Co. Ltd., Shaoxing, 312090, China
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Xu L, Xie Y, Gou Q, Cai R, Bao R, Huang Y, Tang R. HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future. Front Pharmacol 2024; 15:1446414. [PMID: 39351085 PMCID: PMC11439691 DOI: 10.3389/fphar.2024.1446414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 08/30/2024] [Indexed: 10/04/2024] Open
Abstract
Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.
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Affiliation(s)
- Luying Xu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuxin Xie
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiheng Gou
- Department of Radiation Oncology and Department of Head & Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cai
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Rong Bao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yucheng Huang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ruisi Tang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
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5
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Chandra SD, Gunasekera S, Noichl BP, Patrick BO, Perrin DM. Synthesis of (2 S,3 R,4 R)-Dihydroxyisoleucine for Use in Amatoxin Synthesis. J Org Chem 2024; 89:12739-12747. [PMID: 39167711 DOI: 10.1021/acs.joc.4c01051] [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: 08/23/2024]
Abstract
We report a streamlined synthesis of (2S,3R,4R)-4,5-dihydroxy isoleucine (DHIle), an amino acid found in α-amanitin, which appears to be critical for toxicity. This synthetic route is transition metal-free and enables the production of significant quantities of DHIle with suitable protection for use in peptide synthesis. Its incorporation into a cytotoxic amatoxin analog is reported.
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Affiliation(s)
- Shambhu Deo Chandra
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 Canada
| | - Shanal Gunasekera
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 Canada
| | - Benjamin Philipp Noichl
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 Canada
| | - Brian O Patrick
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 Canada
| | - David M Perrin
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 Canada
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6
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Li C, Shi K, Zhao S, Liu J, Zhai Q, Hou X, Xu J, Wang X, Liu J, Wu X, Fan W. Natural-source payloads used in the conjugated drugs architecture for cancer therapy: Recent advances and future directions. Pharmacol Res 2024; 207:107341. [PMID: 39134188 DOI: 10.1016/j.phrs.2024.107341] [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: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Drug conjugates are obtained from tumor-located vectors connected to cytotoxic agents via linkers, which are designed to deliver hyper-toxic payloads directly to targeted cancer cells. These drug conjugates include antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), nucleic acid aptamer-drug conjugates (ApDCs), and virus-like drug conjugate (VDCs), which show great therapeutic value in the clinic. Drug conjugates consist of a targeting carrier, a linker, and a payload. Payloads are key therapy components. Cytotoxic molecules and their derivatives derived from natural products are commonly used in the payload portion of conjugates. The ideal payload should have sufficient toxicity, stability, coupling sites, and the ability to be released under specific conditions to kill tumor cells. Microtubule protein inhibitors, DNA damage agents, and RNA inhibitors are common cytotoxic molecules. Among these conjugates, cytotoxic molecules of natural origin are summarized based on their mechanism of action, conformational relationships, and the discovery of new derivatives. This paper also mentions some cytotoxic molecules that have the potential to be payloads. It also summarizes the latest technologies and novel conjugates developed in recent years to overcome the shortcomings of ADCs, PDCs, SMDCs, ApDCs, and VDCs. In addition, this paper summarizes the clinical trials conducted on conjugates of these cytotoxic molecules over the last five years. It provides a reference for designing and developing safer and more efficient conjugates.
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Affiliation(s)
- Cuiping Li
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Kourong Shi
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Siyuan Zhao
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Juan Liu
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Qiaoli Zhai
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Xiaoli Hou
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Jie Xu
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
| | - Xinyu Wang
- Shanghai Wei Er Lab, Shanghai 201707, China.
| | - Jiahui Liu
- Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China.
| | - Xin Wu
- Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China; Shanghai Wei Er Lab, Shanghai 201707, China.
| | - Wei Fan
- Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
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Ning D, Xue J, Lou X, Shao R, Liu Y, Chen G. Transforming toxins into treatments: the revolutionary role of α-amanitin in cancer therapy. Arch Toxicol 2024; 98:1705-1716. [PMID: 38555326 DOI: 10.1007/s00204-024-03727-0] [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: 01/17/2024] [Accepted: 03/07/2024] [Indexed: 04/02/2024]
Abstract
Amanita phalloides is the primary species responsible for fatal mushroom poisoning, as its main toxin, α-amanitin, irreversibly and potently inhibits eukaryotic RNA polymerase II (RNAP II), leading to cell death. There is no specific antidote for α-amanitin, which hinders its clinical application. However, with the advancement of precision medicine in oncology, including the development of antibody-drug conjugates (ADCs), the potential value of various toxic small molecules has been explored. These ADCs ingeniously combine the targeting precision of antibodies with the cytotoxicity of small-molecule payloads to precisely kill tumor cells. We searched PubMed for studies in this area using these MeSH terms "Amanitins, Alpha-Amanitin, Therapeutic use, Immunotherapy, Immunoconjugates, Antibodies" and did not limit the time interval. Recent studies have conducted preclinical experiments on ADCs based on α-amanitin, showing promising therapeutic effects and good tolerance in primates. The current challenges include the not fully understood toxicological mechanism of α-amanitin and the lack of clinical studies to evaluate the therapeutic efficacy of ADCs developed based on α-amanitin. In this article, we will discuss the role and therapeutic efficacy of α-amanitin as an effective payload in ADCs for the treatment of various cancers, providing background information for the research and application strategies of current and future drugs.
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Affiliation(s)
- Deyuan Ning
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Jinfang Xue
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Xiran Lou
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Ruifei Shao
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Yu Liu
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Guobing Chen
- Department of Emergency Medicine, The First People's Hospital of Yunnan Province, No 157 Jinbi Road, Xishan District, Kunming, 650032, China.
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8
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Chao TH, Renata H. Chemoenzymatic Synthesis of 4,5-Dihydroxyisoleucine Fragment of α-Amanitin. Org Lett 2024; 26:3263-3266. [PMID: 38598422 DOI: 10.1021/acs.orglett.4c00901] [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: 04/12/2024]
Abstract
The ability of α-amanitin to potently inhibit RNA polymerase II (RNAP II) has elicited further research into its use as a novel payload for antibody-drug conjugates. Despite this promise, the de novo synthesis of α-amanitin is still a major challenge as it possesses an unusual bicyclic octapeptide structure that contains several oxidized amino acids, most notably 4,5-dihydroxy-l-isoleucine. Here, we report a concise chemoenzymatic synthesis of this key amino acid residue, which features two regioselective and diastereoselective enzymatic C-H oxidations on l-isoleucine.
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Affiliation(s)
- Tsung-Han Chao
- Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, Texas 77005, United States
| | - Hans Renata
- Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, Texas 77005, United States
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9
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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10
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Gunasekera S, Pryyma A, Jung J, Greenwood R, Patrick BO, Perrin DM. Diphenylphosphinylhydroxylamine (DPPH) Affords Late-Stage S-imination to access free-NH Sulfilimines and Sulfoximines. Angew Chem Int Ed Engl 2024; 63:e202314906. [PMID: 38289976 DOI: 10.1002/anie.202314906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/01/2024]
Abstract
Sulfilimines, as potential aza-isosteres of sulfoxides, are valued as building blocks, auxiliaries, ligands, bioconjugation handles, and as precursors to versatile S(VI) scaffolds including sulfoximines and sulfondiimines. Here, we report a thioether imination methodology that exploits O-(diphenylphosphinyl)hydroxyl amine (DPPH). Under mild, metal-free, and biomolecule-compatible conditions, DPPH enables late-stage S-imination on peptides, natural products, and a clinically trialled drug, and shows both excellent chemoselectivity and broad functional group tolerance. This methodological report is extended to an efficient and high-yielding one-pot reaction for accessing free-NH sulfoximines with diverse substrates including ones of potential clinical importance. In the presence of a rhodium catalyst, sulfoxides are S-iminated in higher yields to afford free-NH sulfoximines. S-imination was validated on an oxidatively delicate amatoxin to give sulfilimine and sulfoximine congeners. Interestingly, these new sulfilimine and sulfoximine-amatoxins show cytotoxicity. This method is further extended to create sulfilimine and sulfoximine-Fulvestrant and buthionine analogues.
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Affiliation(s)
- Shanal Gunasekera
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
| | - Alla Pryyma
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
| | - Jimin Jung
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
| | - Rebekah Greenwood
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
| | - Brian O Patrick
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
| | - David M Perrin
- Chemistry Department, University of British Columbia, 2036 Main Mall, V6T 1Z1, Vancouver, B.C., Canada
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11
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Reshetnyak YK, Andreev OA, Engelman DM. Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides. Front Pharmacol 2024; 15:1355893. [PMID: 38545547 PMCID: PMC10965573 DOI: 10.3389/fphar.2024.1355893] [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: 12/14/2023] [Accepted: 01/05/2024] [Indexed: 11/11/2024] Open
Abstract
The family of pH (Low) Insertion Peptides (pHLIP) comprises a tumor-agnostic technology that uses the low pH (or high acidity) at the surfaces of cells within the tumor microenvironment (TME) as a targeted biomarker. pHLIPs can be used for extracellular and intracellular delivery of a variety of imaging and therapeutic payloads. Unlike therapeutic delivery targeted to specific receptors on the surfaces of particular cells, pHLIP targets cancer, stromal and some immune cells all at once. Since the TME exhibits complex cellular crosstalk interactions, simultaneous targeting and delivery to different cell types leads to a significant synergistic effect for many agents. pHLIPs can also be positioned on the surfaces of various nanoparticles (NPs) for the targeted intracellular delivery of encapsulated payloads. The pHLIP technology is currently advancing in pre-clinical and clinical applications for tumor imaging and treatment.
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Affiliation(s)
- Yana K. Reshetnyak
- Physics Department, University of Rhode Island, Kingston, RI, United States
| | - Oleg A. Andreev
- Physics Department, University of Rhode Island, Kingston, RI, United States
| | - Donald M. Engelman
- Molecular Biophysics and Biochemistry Department, Yale, New Haven, CT, United States
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12
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Kasper SH, Otten S, Squadroni B, Orr‐Terry C, Kuang Y, Mussallem L, Ge L, Yan L, Kannan S, Verma CS, Brown CJ, Johannes CW, Lane DP, Chandramohan A, Partridge AW, Roberts LR, Josien H, Therien AG, Hett EC, Howell BJ, Peier A, Ai X, Cassaday J. A high-throughput microfluidic mechanoporation platform to enable intracellular delivery of cyclic peptides in cell-based assays. Bioeng Transl Med 2023; 8:e10542. [PMID: 37693049 PMCID: PMC10487316 DOI: 10.1002/btm2.10542] [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: 03/25/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 09/12/2023] Open
Abstract
Cyclic peptides are poised to target historically difficult to drug intracellular protein-protein interactions, however, their general cell impermeability poses a challenge for characterizing function. Recent advances in microfluidics have enabled permeabilization of the cytoplasmic membrane by physical cell deformation (i.e., mechanoporation), resulting in intracellular delivery of impermeable macromolecules in vector- and electrophoretic-free approaches. However, the number of payloads (e.g., peptides) and/or concentrations delivered via microfluidic mechanoporation is limited by having to pre-mix cells and payloads, a manually intensive process. In this work, we show that cells are momentarily permeable (t 1/2 = 1.1-2.8 min) after microfluidic vortex shedding (μVS) and that lower molecular weight macromolecules can be cytosolically delivered upon immediate exposure after cells are processed/permeabilized. To increase the ability to screen peptides, we built a system, dispensing-microfluidic vortex shedding (DμVS), that integrates a μVS chip with inline microplate-based dispensing. To do so, we synced an electronic pressure regulator, flow sensor, on/off dispense valve, and an x-y motion platform in a software-driven feedback loop. Using this system, we were able to deliver low microliter-scale volumes of transiently mechanoporated cells to hundreds of wells on microtiter plates in just several minutes (e.g., 96-well plate filled in <2.5 min). We validated the delivery of an impermeable peptide directed at MDM2, a negative regulator of the tumor suppressor p53, using a click chemistry- and NanoBRET-based cell permeability assay in 96-well format, with robust delivery across the full plate. Furthermore, we demonstrated that DμVS could be used to identify functional, low micromolar, cellular activity of otherwise cell-inactive MDM2-binding peptides using a p53 reporter cell assay in 96- and 384-well format. Overall, DμVS can be combined with downstream cell assays to investigate intracellular target engagement in a high-throughput manner, both for improving structure-activity relationship efforts and for early proof-of-biology of non-optimized peptide (or potentially other macromolecular) tools.
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Affiliation(s)
| | | | | | | | - Yi Kuang
- Merck & Co., Inc.CambridgeMassachusettsUSA
| | | | - Lan Ge
- Merck & Co., Inc.KenilworthNew JerseyUSA
| | - Lin Yan
- Merck & Co., Inc.KenilworthNew JerseyUSA
| | | | - Chandra S. Verma
- Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | | | | | - David P. Lane
- Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
| | | | | | | | | | | | | | | | | | - Xi Ai
- Merck & Co., Inc.KenilworthNew JerseyUSA
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13
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Lyons MJ, Ehrhardt C, Walsh JJ. Orellanine: From Fungal Origin to a Potential Future Cancer Treatment. JOURNAL OF NATURAL PRODUCTS 2023; 86:1620-1631. [PMID: 37308446 PMCID: PMC10294258 DOI: 10.1021/acs.jnatprod.2c01068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Indexed: 06/14/2023]
Abstract
Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.
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Affiliation(s)
- Mark J. Lyons
- School of Pharmacy and Pharmaceutical
Sciences, Trinity College Dublin, Dublin 2, Ireland
| | - Carsten Ehrhardt
- School of Pharmacy and Pharmaceutical
Sciences, Trinity College Dublin, Dublin 2, Ireland
| | - John J. Walsh
- School of Pharmacy and Pharmaceutical
Sciences, Trinity College Dublin, Dublin 2, Ireland
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14
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Nawrocka D, Krzyscik MA, Sluzalska KD, Otlewski J. Dual-Warhead Conjugate Based on Fibroblast Growth Factor 2 Dimer Loaded with α-Amanitin and Monomethyl Auristatin E Exhibits Superior Cytotoxicity towards Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1. Int J Mol Sci 2023; 24:10143. [PMID: 37373291 DOI: 10.3390/ijms241210143] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Targeting fibroblast growth factor receptor 1 (FGFR1) is a promising therapeutic strategy for various cancers associated with alterations in the FGFR1 gene. In this study, we developed a highly cytotoxic bioconjugate based on fibroblast growth factor 2 (FGF2), which is a natural ligand of this receptor, and two potent cytotoxic drugs-α-amanitin and monomethyl auristatin E-with completely independent mechanistic modes of action. Utilizing recombinant DNA technology, we produced an FGF2 N- to C-end dimer that exhibited superior internalization capacity in FGFR1-positive cells. The drugs were site-specifically attached to the targeting protein using SnoopLigase- and evolved sortase A-mediated ligations. The resulting dimeric dual-warhead conjugate selectively binds to the FGFR1 and utilizes receptor-mediated endocytosis to enter the cells. Moreover, our results demonstrate that the developed conjugate exhibits about 10-fold higher cytotoxic potency against FGFR1-positive cell lines than an equimolar mixture of single-warhead conjugates. The diversified mode of action of the dual-warhead conjugate may help to overcome the potential acquired resistance of FGFR1-overproducing cancer cells to single cytotoxic drugs.
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Affiliation(s)
- Daria Nawrocka
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland
| | - Mateusz Adam Krzyscik
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland
| | - Katarzyna Dominika Sluzalska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland
| | - Jacek Otlewski
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland
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15
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Corbu VM, Gheorghe-Barbu I, Dumbravă AȘ, Vrâncianu CO, Șesan TE. Current Insights in Fungal Importance-A Comprehensive Review. Microorganisms 2023; 11:1384. [PMID: 37374886 DOI: 10.3390/microorganisms11061384] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/20/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Besides plants and animals, the Fungi kingdom describes several species characterized by various forms and applications. They can be found in all habitats and play an essential role in the excellent functioning of the ecosystem, for example, as decomposers of plant material for the cycling of carbon and nutrients or as symbionts of plants. Furthermore, fungi have been used in many sectors for centuries, from producing food, beverages, and medications. Recently, they have gained significant recognition for protecting the environment, agriculture, and several industrial applications. The current article intends to review the beneficial roles of fungi used for a vast range of applications, such as the production of several enzymes and pigments, applications regarding food and pharmaceutical industries, the environment, and research domains, as well as the negative impacts of fungi (secondary metabolites production, etiological agents of diseases in plants, animals, and humans, as well as deteriogenic agents).
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Affiliation(s)
- Viorica Maria Corbu
- Genetics Department, Faculty of Biology, University of Bucharest, 060101 Bucharest, Romania
- Research Institute of the University of Bucharest-ICUB, 91-95 Spl. Independentei, 050095 Bucharest, Romania
| | - Irina Gheorghe-Barbu
- Research Institute of the University of Bucharest-ICUB, 91-95 Spl. Independentei, 050095 Bucharest, Romania
- Department of Microbiology and Immunology, Faculty of Biology, University of Bucharest, 060101 Bucharest, Romania
| | - Andreea Ștefania Dumbravă
- Department of Microbiology and Immunology, Faculty of Biology, University of Bucharest, 060101 Bucharest, Romania
| | - Corneliu Ovidiu Vrâncianu
- Research Institute of the University of Bucharest-ICUB, 91-95 Spl. Independentei, 050095 Bucharest, Romania
- Department of Microbiology and Immunology, Faculty of Biology, University of Bucharest, 060101 Bucharest, Romania
| | - Tatiana Eugenia Șesan
- Department of Microbiology and Immunology, Faculty of Biology, University of Bucharest, 060101 Bucharest, Romania
- Academy of Agricultural Sciences and Forestry, 61 Bd. Mărăşti, District 1, 011464 Bucharest, Romania
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16
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Wu H, Ding X, Chen Y, Cai Y, Yang Z, Jin J. Constructed Tumor-Targeted and MMP-2 Biocleavable Antibody Conjugated Silica Nanoparticles for Efficient Cancer Therapy. ACS OMEGA 2023; 8:12752-12760. [PMID: 37065049 PMCID: PMC10099448 DOI: 10.1021/acsomega.2c07949] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/17/2023] [Indexed: 06/19/2023]
Abstract
Antibody-drug conjugates (ADC) are an inevitable trend in the development of modern "precision medicine". The goal of this work is to produce enzyme-responsive antibody nanoparticle-loaded medication (FMSN-Dox-H2-AE01) based on the EGFR antibody (AE01) and human serum albumin (HSA) shelled mesoporous silica nanoparticles. HSA and antibodies on the surface of the particlescan not only enhance the biocompatibility of the particle and avoid early drug leakage but also allow selective biodegradation triggered by matrix metalloproteinase-2 (MMP-2), which are overexpressed enzymes in some tumor tissues. The cytotoxicity test confirmed favorable safety and efficacy of the ADC. The mortality rate of cancer cells is about 85-90%. Moreover, the antibody nanoparticle-loaded drug showed distinguishing controlled release efficiency toward cancer cells induced by different levels of MMP-2 and pH. This enzyme-responsive FMSN-Dox-H2-AE01 offers a promising option for cancer therapy.
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Affiliation(s)
- Hao Wu
- School
of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic
of China
| | - Xuefeng Ding
- School
of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic of China
| | - Yun Chen
- School
of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic
of China
| | - Yanfei Cai
- School
of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic
of China
| | - Zhaoqi Yang
- School
of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic
of China
| | - Jian Jin
- School
of Life Sciences and Health Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi 214000, People’s Republic
of China
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17
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Characterization of human anti-EpCAM antibodies for developing an antibody-drug conjugate. Sci Rep 2023; 13:4225. [PMID: 36918661 PMCID: PMC10015092 DOI: 10.1038/s41598-023-31263-x] [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: 07/28/2022] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
We previously generated fully human antibody-producing TC-mAb mice for obtaining potential therapeutic monoclonal antibodies (mAbs). In this study, we investigated 377 clones of fully human mAbs against a tumor antigen, epithelial cell adhesion molecule (EpCAM), to determine their antigen binding properties. We revealed that a wide variety of mAbs against EpCAM can be obtained from TC-mAb mice by the combination of epitope mapping analysis of mAbs to EpCAM and native conformational recognition analysis. Analysis of 72 mAbs reacting with the native form of EpCAM indicated that the EpCL region (amino acids 24-80) is more antigenic than the EpRE region (81-265), consistent with numerous previous studies. To evaluate the potential of mAbs against antibody-drug conjugates, mAbs were directly labeled with DM1, a maytansine derivative, using an affinity peptide-based chemical conjugation (CCAP) method. The cytotoxicity of the conjugates against a human colon cancer cell line could be clearly detected with high-affinity as well as low-affinity mAbs by the CCAP method, suggesting the advantage of this method. Thus, this study demonstrated that TC-mAb mice can provide a wide variety of antibodies and revealed an effective way of identifying candidates for fully human ADC therapeutics.
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18
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Payload diversification: a key step in the development of antibody-drug conjugates. J Hematol Oncol 2023; 16:3. [PMID: 36650546 PMCID: PMC9847035 DOI: 10.1186/s13045-022-01397-y] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
Antibody-drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity of monoclonal antibodies with the potency of a payload consisting of cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at the forefront of ADC development. The recent approval and clinical success of trastuzumab deruxtecan (Enhertu®) and sacituzumab govitecan (Trodelvy®), two topoisomerase 1 inhibitor-based ADCs, has shown the potential of conjugating unconventional payloads with differentiated mechanisms of action. Among future developments in the ADC field, payload diversification is expected to play a key role as illustrated by a growing number of preclinical and clinical stage unconventional payload-conjugated ADCs. This review presents a comprehensive overview of validated, forgotten and newly developed payloads with different mechanisms of action.
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19
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Liu Y, Wang Y, Sun S, Chen Z, Xiang S, Ding Z, Huang Z, Zhang B. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Exp Hematol Oncol 2022; 11:97. [PMID: 36369033 PMCID: PMC9650829 DOI: 10.1186/s40164-022-00352-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) functions not only in physiological processes but also participates in the development and progression of cancer. In recent decades, extensive efforts have been made to decipher the role of EpCAM in cancers. Great advances have been achieved in elucidating its structure, molecular functions, pathophysiological mechanisms, and clinical applications. Beyond its well-recognized role as a biomarker of cancer stem cells (CSCs) or circulating tumor cells (CTCs), EpCAM exhibits novel and promising value in targeted therapy. At the same time, the roles of EpCAM in cancer progression are found to be highly context-dependent and even contradictory in some cases. The versatile functional modules of EpCAM and its communication with other signaling pathways complicate the study of this molecule. In this review, we start from the structure of EpCAM and focus on communication with other signaling pathways. The impacts on the biology of cancers and the up-to-date clinical applications of EpCAM are also introduced and summarized, aiming to shed light on the translational prospects of EpCAM.
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Affiliation(s)
- Yiyang Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Sun
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeyu Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Xiang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission, Chinese Academy of Medical Sciences, Wuhan, China.
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20
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Fu X, Zhang W, Li S, Ling N, Yang Y, Dazhi Z. Identification of alanine aminotransferase 1 interaction network via iTRAQ-based proteomics in alternating migration, invasion, proliferation and apoptosis of HepG2 cells. Aging (Albany NY) 2022; 14:7137-7155. [PMID: 36107005 PMCID: PMC9512495 DOI: 10.18632/aging.204286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 08/31/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To investigate the mechanism of alanine aminotransferase 1 (ALT1) in the progression of HCC, the differentially expressed proteins (DEPs) in the ALT1 interaction network were identified by targeted proteomic analysis. METHODS Wound healing and transwell assays were conducted to assess the effect of ALT1 on cellular migration and invasion. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were performed to identify alterations in proliferation and apoptosis. After coimmunoprecipitation processing, mass spectrometry with iso-baric tags for relative and absolute quantitation was utilized to explore the protein interactions in ALT1 knockdown HepG2 cells. RESULTS The results showed that ALT1 knockdown inhibits the migration, invasion, proliferation of HepG2 cells, and promotes apoptosis. A total of 116 DEPs were identified and the bioinformatics analysis suggested that the ALT1-interacting proteins were primarily associated with cellular and metabolic processes. Knockdown of ALT1 in HepG2 cells reduced the expression of Ki67 and epithelial cell adhesion molecule (EP-CAM), while the expression of apoptosis-stimulating protein 2 of p53 (ASPP2) was increased significantly. Suppression of the ALT1 and EP-CAM expression contributed to alterations in epithelial-mesenchymal transition (EMT) -associated markers and matrix metalloproteinases (MMPs). Additionally, inhibition of ALT1 and Ki67 also decreased the expression of apoptosis and proliferation factors. Furthermore, inhibition of ALT1 and ASPP2 also changed the expression of P53, which may be the signaling pathway by which ALT regulates these biological behaviors. CONCLUSIONS This study indicated that the ALT1 protein interaction network is associated with the biological behaviors of HepG2 cells via the p53 signaling pathway.
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Affiliation(s)
- Xiao Fu
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Wenyue Zhang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, P.R. China
| | - Shiying Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Ning Ling
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yixuan Yang
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Zhang Dazhi
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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21
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Moshnikova A, Golijanin B, Amin A, Doyle J, Kott O, Gershman B, DuPont M, Li Y, Lu X, Engelman DM, Andreev OA, Reshetnyak YK, Golijanin D. Targeting Bladder Urothelial Carcinoma with pHLIP-ICG and Inhibition of Urothelial Cancer Cell Proliferation by pHLIP-amanitin. FRONTIERS IN UROLOGY 2022; 2:868919. [PMID: 36439552 PMCID: PMC9691284 DOI: 10.3389/fruro.2022.868919] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Acidity is a useful biomarker for the targeting of metabolically active-cells in tumors. pH Low Insertion Peptides (pHLIPs) sense the pH at the surfaces of tumor cells and can facilitate intracellular delivery of cell-permeable and cell-impermeable cargo molecules. In this study we have shown the targeting of malignant lesions in human bladders by fluorescent pHLIP agents, intracellular delivery of amanitin toxin by pHLIP for the inhibition of urothelial cancer cell proliferation, and enhanced potency of pHLIP-amanitin for cancer cells with 17p loss, a mutation frequently present in urothelial cancers. Twenty-eight ex-vivo bladder specimens, from patients undergoing robotic assisted laparoscopic radical cystectomy for bladder cancer, were treated via intravesical incubation for 15-60 minutes with pHLIP conjugated to indocyanine green (ICG) or IR-800 near infrared fluorescent (NIRF) dyes at concentrations of 4-8 μM. White light cystoscopy identified 47/58 (81%) and NIRF pHLIP cystoscopy identified 57/58 (98.3%) of malignant lesions of different subtypes and stages selected for histopathological processing. pHLIP NIRF imaging improved diagnosis by 17.3% (p < 0.05). All carcinoma-in-situ cases missed by white light cystoscopy were targeted by pHLIP agents and were diagnosed by NIRF imaging. We also investigated the interactions of pHLIP-amanitin with urothelial cancer cells of different grades. pHLIP-amanitin produced concentration- and pH-dependent inhibition of the proliferation of urothelial cancer cells treated for 2 hrs at concentrations up to 4 μM. A 3-4x enhanced cytotoxicity of pHLIP-amanitin was observed for cells with a 17p loss after 2 hrs of treatment at pH6. Potentially, pHLIP technology may improve the management of urothelial cancers, including imaging of malignant lesions using pHLIP-ICG for diagnosis and surgery, and the use of pHLIP-amanitin for treatment of superficial bladder cancers via intravesical instillation.
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Affiliation(s)
- Anna Moshnikova
- Physics Department, University of Rhode Island, Kingston, RI, USA
| | - Borivoj Golijanin
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, The Miriam Hospital, Providence, RI, USA
- Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, RI, USA
| | - Ali Amin
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, The Miriam Hospital, Providence, RI, USA
| | - Joshua Doyle
- Physics Department, University of Rhode Island, Kingston, RI, USA
- Current address: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Ohad Kott
- Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, RI, USA
| | - Boris Gershman
- Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, RI, USA
- Current address: Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Michael DuPont
- Physics Department, University of Rhode Island, Kingston, RI, USA
| | - Yujing Li
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiongbin Lu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Melvin & Bren Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Donald M. Engelman
- Department of Molecular Biophysics and Biochemistry, Yale, New Haven, CT, USA
| | - Oleg A. Andreev
- Physics Department, University of Rhode Island, Kingston, RI, USA
| | | | - Dragan Golijanin
- Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, RI, USA
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22
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Barzaman K, Vafaei R, Samadi M, Kazemi MH, Hosseinzadeh A, Merikhian P, Moradi-Kalbolandi S, Eisavand MR, Dinvari H, Farahmand L. Anti-cancer therapeutic strategies based on HGF/MET, EpCAM, and tumor-stromal cross talk. Cancer Cell Int 2022; 22:259. [PMID: 35986321 PMCID: PMC9389806 DOI: 10.1186/s12935-022-02658-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 07/19/2022] [Indexed: 02/08/2023] Open
Abstract
As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.
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He MQ, Wang MQ, Chen ZH, Deng WQ, Li TH, Vizzini A, Jeewon R, Hyde KD, Zhao RL. Potential benefits and harms: a review of poisonous mushrooms in the world. FUNGAL BIOL REV 2022. [DOI: 10.1016/j.fbr.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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24
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Todorovic M, Rivollier P, Wong AAWL, Wang Z, Pryyma A, Nguyen TT, Newell KC, Froelich J, Perrin DM. Rationally Designed Amanitins Achieve Enhanced Cytotoxicity. J Med Chem 2022; 65:10357-10376. [PMID: 35696491 DOI: 10.1021/acs.jmedchem.1c02226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
For 70 years, α-amanitin, the most cytotoxic peptide in its class, has been without a synthetic rival; through synthesis, we address the structure-activity relationships to inform the design of new amatoxins and disclose analogues that are more cytotoxic than the natural product when evaluated on CHO, HEK293, and HeLa cells, whereas on liver-derived HepG2 cells, the same toxins show diminished cytotoxicity.
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Affiliation(s)
- Mihajlo Todorovic
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Paul Rivollier
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Antonio A W L Wong
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Zhou Wang
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Alla Pryyma
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Tuan Trung Nguyen
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Kayla C Newell
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - Juliette Froelich
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
| | - David M Perrin
- Chemistry Department, 2036 Main Mall, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T-1Z1, Canada
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25
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Teicher BA, Morris J. Antibody-Drug Conjugate Targets, Drugs and Linkers. Curr Cancer Drug Targets 2022; 22:463-529. [PMID: 35209819 DOI: 10.2174/1568009622666220224110538] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/22/2021] [Accepted: 11/09/2021] [Indexed: 11/22/2022]
Abstract
Antibody-drug conjugates offer the possibility of directing powerful cytotoxic agents to a malignant tumor while sparing normal tissue. The challenge is to select an antibody target expressed exclusively or at highly elevated levels on the surface of tumor cells and either not all or at low levels on normal cells. The current review explores 78 targets that have been explored as antibody-drug conjugate targets. Some of these targets have been abandoned, 9 or more are the targets of FDA-approved drugs, and most remain active clinical interest. Antibody-drug conjugates require potent cytotoxic drug payloads, several of these small molecules are discussed, as are the linkers between the protein component and small molecule components of the conjugates. Finally, conclusions regarding the elements for the successful antibody-drug conjugate are discussed.
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Affiliation(s)
- Beverly A Teicher
- Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda, MD 20892,United States
| | - Joel Morris
- Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda, MD 20892,United States
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26
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Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, Chen S, Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther 2022; 7:39. [PMID: 35132063 PMCID: PMC8821599 DOI: 10.1038/s41392-021-00868-x] [Citation(s) in RCA: 233] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex tumor environment. In this review, we summarize antibodies of various molecular types, antibody applications in cancer therapy, and details of clinical study advances. We also discuss the rationale and mechanism of action of various antibody formats, including antibody-drug conjugates, antibody-oligonucleotide conjugates, bispecific/multispecific antibodies, immunocytokines, antibody fragments, and scaffold proteins. With advances in modern biotechnology, well-designed novel antibodies are finally paving the way for successful treatments of various cancers, including precise tumor immunotherapy, in the clinic.
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Affiliation(s)
- Shijie Jin
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yanping Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xiao Liang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xinyu Gu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Jiangtao Ning
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yingchun Xu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Shuqing Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- Department of Precision Medicine on Tumor Therapeutics, ZJU-Hangzhou Global Scientific and Technological Innovation Center, 311200, Hangzhou, China.
| | - Liqiang Pan
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
- Key Laboratory of Pancreatic Disease of Zhejiang Province, 310003, Hangzhou, China.
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27
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Pryyma A, Matinkhoo K, Bu YJ, Merkens H, Zhang Z, Bénard F, Perrin DM. Synthesis and preliminary evaluation of octreotate conjugates of bioactive synthetic amatoxins for targeting somatostatin receptor (sstr2) expressing cells. RSC Chem Biol 2022; 3:69-78. [PMID: 35128410 PMCID: PMC8729174 DOI: 10.1039/d1cb00036e] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/27/2021] [Indexed: 11/28/2022] Open
Abstract
Targeted cancer therapy represents a paradigm-shifting approach that aims to deliver a toxic payload selectively to target-expressing cells thereby sparing normal tissues the off-target effects associated with traditional chemotherapeutics. Since most targeted constructs rely on standard microtubule inhibitors or DNA-reactive molecules as payloads, new toxins that inhibit other intracellular targets are needed to realize the full potential of targeted therapy. Among these new payloads, α-amanitin has gained attraction as a payload in targeted therapy. Here, we conjugate two synthetic amanitins at different sites to demonstrate their utility as payloads in peptide drug conjugates (PDCs). As an exemplary targeting agent, we chose octreotate, a well-studied somatostatin receptor (sstr2) peptide agonist for the conjugation to synthetic amatoxins via three tailor-built linkers. The linker chemistry permitted the evaluation of one non-cleavable and two cleavable self-immolative conjugates. The immolating linkers were chosen to take advantage of either the reducing potential of the intracellular environment or the high levels of lysosomal proteases in tumor cells to trigger toxin release. Cell-based assays on target-positive Ar42J cells revealed target-specific reduction in viability with up to 1000-fold enhancement in bioactivity compared to the untargeted amatoxins. Altogether, this preliminary study enabled the development of a highly modular synthetic platform for the construction of amanitin-based conjugates that can be readily extended to various targeting moieties.
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Affiliation(s)
- Alla Pryyma
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Kaveh Matinkhoo
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Yong Jia Bu
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Helen Merkens
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - Zhengxing Zhang
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - Francois Bénard
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - David M Perrin
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
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28
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Advances with antibody-drug conjugates in breast cancer treatment. Eur J Pharm Biopharm 2021; 169:241-255. [PMID: 34748933 DOI: 10.1016/j.ejpb.2021.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/21/2021] [Accepted: 10/13/2021] [Indexed: 12/21/2022]
Abstract
Antibody-drug conjugate-based therapy for treatment of cancer has attracted much attention because of its enhanced efficacy against numerous cancer types. Commonly, an ADC includes a mAb linked to a therapeutic payload. Antibody, linker and payload are the three main components of ADCs. The high specificity of antibodies is integrated with the strong potency of payloads in ADCs. ADCs with potential cytotoxic small molecules as payloads, generate antibody-mediated cancer therapy. Recently, ADCs with DNA-damaging agents have shown favor over microtubule-targeting agents as payloads. Although ADC resistance can be a barrier to effectiveness, several ADC therapies have been either approved or are in clinical trials for cancer treatment. The ADC-based treatments of breast cancers, particularly TNBC, MDR and metastatic breast cancers, have shown promise in recent years. This review discusses ADC drug designs, and developed for different types of breast cancer including TNBC, MDR and metastatic breast cancer.
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29
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Zhang Z, Li H, Deng Y, Schuck K, Raulefs S, Maeritz N, Yu Y, Hechler T, Pahl A, Fernández-Sáiz V, Wan Y, Wang G, Engleitner T, Öllinger R, Rad R, Reichert M, Diakopoulos KN, Weber V, Li J, Shen S, Zou X, Kleeff J, Mihaljevic A, Michalski CW, Algül H, Friess H, Kong B. AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53. Gastroenterology 2021; 161:1601-1614.e23. [PMID: 34303658 DOI: 10.1053/j.gastro.2021.07.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/25/2021] [Accepted: 07/17/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
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MESH Headings
- Active Transport, Cell Nucleus
- Animals
- Antineoplastic Agents/pharmacology
- Carcinoma in Situ/drug therapy
- Carcinoma in Situ/enzymology
- Carcinoma in Situ/genetics
- Carcinoma in Situ/pathology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Metaplasia
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mucoproteins/genetics
- Mucoproteins/metabolism
- Mutation
- Oligopeptides/pharmacology
- Oncogene Proteins/genetics
- Oncogene Proteins/metabolism
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- RNA Polymerase II/genetics
- RNA Polymerase II/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Mice
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Affiliation(s)
- Zhiheng Zhang
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hongzhen Li
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Yibin Deng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Kathleen Schuck
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Susanne Raulefs
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Nadja Maeritz
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Yuanyuan Yu
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | | | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Ladenburg, Germany
| | - Vanesa Fernández-Sáiz
- Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Center for Translational Cancer Research, Technische Universität München, Munich, Germany
| | - Yuan Wan
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York
| | - Guosheng Wang
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York
| | - Thomas Engleitner
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany
| | - Rupert Öllinger
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany
| | - Roland Rad
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany
| | - Maximilian Reichert
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Verena Weber
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Jingjing Li
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Shanshan Shen
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Xiaoping Zou
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Andre Mihaljevic
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | | | - Hana Algül
- Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Bo Kong
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
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30
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Singh D, Dheer D, Samykutty A, Shankar R. Antibody drug conjugates in gastrointestinal cancer: From lab to clinical development. J Control Release 2021; 340:1-34. [PMID: 34673122 DOI: 10.1016/j.jconrel.2021.10.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022]
Abstract
The antibody-drug conjugates (ADCs) are one the fastest growing biotherapeutics in oncology and are still in their infancy in gastrointestinal (GI) cancer for clinical applications to improve patient survival. The ADC based approach is developed with tumor specific antigen, antibody carrying cytotoxic agents to precisely target and deliver chemotherapeutics at the tumor site. To date, 11 ADCs have been approved by US-FDA, and more than 80 are in the clinical development phase for different oncological indications. However, The ADCs based therapies in GI cancers are still far from having high-efficient clinical outcomes. The limited success of these ADCs and lessons learned from the past are now being used to develop a newer generation of ADC against GI cancers. In this review, we did a comprehensive assessment of the key components of ADCs, including tumor marker, antibody, cytotoxic payload, and linkage strategy, with a focus on technical improvement and some future trends in the pipeline for clinical translation. The various preclinical and clinical ADCs used in gastrointestinal malignancies, their target, composition and bioconjugation, along with preclinical and clinical outcomes, are discussed. The emphasis is also given to new generation ADCs employing novel mAb, payload, linker, and bioconjugation methods are also included.
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Affiliation(s)
- Davinder Singh
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Divya Dheer
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Abhilash Samykutty
- Stephenson Comprehensive Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA.
| | - Ravi Shankar
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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31
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Abstract
Stimuli-responsive, on-demand release of drugs from drug-eluting depots could transform the treatment of many local diseases, providing intricate control over local dosing. However, conventional on-demand drug release approaches rely on locally implanted drug depots, which become spent over time and cannot be refilled or reused without invasive procedures. New strategies to noninvasively refill drug-eluting depots followed by on-demand release could transform clinical therapy. Here we report an on-demand drug delivery paradigm that combines bioorthogonal click chemistry to locally enrich protodrugs at a prelabeled site and light-triggered drug release at the target tissue. This approach begins with introduction of the targetable depot through local injection of chemically reactive azide groups that anchor to the extracellular matrix. The anchored azide groups then capture blood-circulating protodrugs through bioorthogonal click chemistry. After local capture and retention, active drugs can be released through external light irradiation. In this report, a photoresponsive protodrug was constructed consisting of the chemotherapeutic doxorubicin (Dox), conjugated to dibenzocyclooctyne (DBCO) through a photocleavable ortho-nitrobenzyl linker. The protodrug exhibited excellent on-demand light-triggered Dox release properties and light-mediated in vitro cytotoxicity in U87 glioblastoma cell lines. Furthermore, in a live animal setting, azide depots formed in mice through intradermal injection of activated azide-NHS esters. After i.v. administration, the protodrug was captured by the azide depots with intricate local specificity, which could be increased with multiple refills. Finally, doxorubicin could be released from the depot upon light irradiation. Multiple rounds of depot refilling and light-mediated release of active drug were accomplished, indicating that this system has the potential for multiple rounds of treatment. Taken together, these in vitro and in vivo proof of concept studies establish a novel method for in vivo targeting and on-demand delivery of cytotoxic drugs at target tissues.
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Affiliation(s)
- Sandeep Palvai
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Christopher T Moody
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, North Carolina 27607, United States.,Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Sharda Pandit
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, North Carolina 27607, United States.,Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Yevgeny Brudno
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, North Carolina 27607, United States.,Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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32
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Swain JA, Walker SR, Calvert MB, Brimble MA. The tryptophan connection: cyclic peptide natural products linked via the tryptophan side chain. Nat Prod Rep 2021; 39:410-443. [PMID: 34581375 DOI: 10.1039/d1np00043h] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Covering: from 1938 up to March 2021The electron-rich indole side chain of tryptophan is a versatile substrate for peptide modification. Upon the action of various cyclases, the tryptophan side chain may be linked to a nearby amino acid residue, opening the door to a diverse range of cyclic peptide natural products. These compounds exhibit a wide array of biological activity and possess fascinating molecular architectures, which have made them popular targets for total synthesis studies. This review examines the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with a discussion of their first total synthesis, and biosynthesis where this has been studied.
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Affiliation(s)
- Jonathan A Swain
- School of Chemical Sciences, The University of Auckland, Symonds Street, Auckland 1010, New Zealand.
| | - Stephen R Walker
- School of Chemical Sciences, The University of Auckland, Symonds Street, Auckland 1010, New Zealand.
| | - Matthew B Calvert
- School of Chemical Sciences, The University of Auckland, Symonds Street, Auckland 1010, New Zealand.
| | - Margaret A Brimble
- School of Chemical Sciences, The University of Auckland, Symonds Street, Auckland 1010, New Zealand. .,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Symonds Street, Auckland 1010, New Zealand
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33
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Matinkhoo K, Pryyma A, Wong AAWL, Perrin DM. Synthesis and evaluation of " Ama-Flash", a photocaged amatoxin prodrug for light-activated RNA Pol II inhibition and cell death. Chem Commun (Camb) 2021; 57:9558-9561. [PMID: 34477193 DOI: 10.1039/d1cc03279h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Amanitin is used extensively as a research tool to inhibit RNA Pol II thereby implicating its role in mRNA transcription. Recently, amanitin has gained traction as a toxic payload for targeted therapy. Here we report the first-ever photocaged amanitin analog, that is non-toxic and can be pre-loaded into cells. Light provides a means to inhibit RNA Pol II and provoke cell death on-demand.
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Affiliation(s)
- Kaveh Matinkhoo
- Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
| | - Alla Pryyma
- Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
| | - Antonio A W L Wong
- Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
| | - David M Perrin
- Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
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Moin AT, Sarkar B, Ullah MA, Araf Y, Ahmed N, Rudra B. In silico assessment of EpCAM transcriptional expression and determination of the prognostic biomarker for human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Biochem Biophys Rep 2021; 27:101074. [PMID: 34345719 PMCID: PMC8319582 DOI: 10.1016/j.bbrep.2021.101074] [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] [Received: 05/12/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/24/2022] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein which is involved in cell signaling, proliferation, maturation, and movement, all of which are crucial for the proper development of cells and tissues. Cleavage of the EpCAM protein leads to the up-regulation of c-myc, e-fabp, and cyclins A and E which promote tumorigenesis. EpCAM can act as potential diagnostic and prognostic biomarker for different types of cancers as it is also found to be expressed in epithelia and epithelial-derived neoplasms. Hence, we aimed to analyze the EpCAM gene expression and any associated feedback in the patients of two major types of lung cancer (LC) i.e., lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), based on the publicly available online databases. In this study, server-based gene expression analysis represents the up-regulation of EpCAM in both LUAD and LUSC subtypes as compared to the corresponding normal tissues. Besides, the histological sections revealed the over-expression of EpCAM protein in cancerous tissues by depicting strong staining signals. Furthermore, mutation analysis suggested missense as the predominant type of mutation both in LUAD and LUSC in the EpCAM gene. A significant correlation (P-value < 0.05) between the higher EpCAM expression and lower patient survival was also found in this study. Finally, the co-expressed genes were identified with their ontological features and signaling pathways associated in LC development. The overall study suggests EpCAM to be a significant biomarker for human LC prognosis.
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Affiliation(s)
- Abu Tayab Moin
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh
| | - Bishajit Sarkar
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Asad Ullah
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Yusha Araf
- Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Nafisa Ahmed
- Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Dhaka, Bangladesh
| | - Bashudev Rudra
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh
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Matinkhoo K, Wong AAWL, Hambira CM, Kato B, Wei C, Müller C, Hechler T, Braun A, Gallo F, Pahl A, Perrin DM. Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates. Chemistry 2021; 27:10282-10292. [PMID: 34058032 DOI: 10.1002/chem.202101373] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Indexed: 01/08/2023]
Abstract
Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin.
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Affiliation(s)
- Kaveh Matinkhoo
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
| | - Antonio A W L Wong
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
| | - Chido M Hambira
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
| | - Brandon Kato
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
| | - Charlie Wei
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
| | - Christoph Müller
- Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany
| | - Torsten Hechler
- Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany
| | - Alexandra Braun
- Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany
| | - Francesca Gallo
- Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany
| | - Andreas Pahl
- Heidelberg Pharma, Gregor-Mendel-Straße 22, 68526, Ladenburg, Germany
| | - David M Perrin
- Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T-1Z1, Canada
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Antibody-Drug Conjugates Used in Breast Cancers. JOURNAL OF ONCOLOGY 2021; 2021:9927433. [PMID: 34257655 PMCID: PMC8257388 DOI: 10.1155/2021/9927433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/30/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022]
Abstract
The prognosis of breast cancer has radically changed in recent years and continues to improve due to the broad application of effective therapies. New targeting strategies including targeted delivery of cytotoxic drugs via receptor-targeting agents have been developed. We summarize recent publications and developments of novel antibody-drug conjugates (ADCs) used to control breast cancer.
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Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics. Toxins (Basel) 2021; 13:toxins13060417. [PMID: 34208167 PMCID: PMC8230822 DOI: 10.3390/toxins13060417] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
The consumption of mushrooms has become increasingly popular, partly due to their nutritional and medicinal properties. This has increased the risk of confusion during picking, and thus of intoxication. In France, about 1300 cases of intoxication are observed each year, with deaths being mostly attributed to Amanita phalloides poisoning. Among amatoxins, α- and β-amanitins are the most widely studied toxins. Hepatotoxicity is the hallmark of these compounds, leading to hepatocellular failure within three days of ingestion. The toxic mechanisms of action mainly include RNA polymerase II inhibition and oxidative stress generation, leading to hepatic cell apoptosis or necrosis depending on the doses ingested. Currently, there is no international consensus concerning Amanita phalloides poisoning management. However, antidotes with antioxidant properties remain the most effective therapeutics to date suggesting the predominant role of oxidative stress in the pathophysiology. The partially elucidated mechanisms of action may reveal a suitable target for the development of an antidote. The aim of this review is to present an overview of the knowledge on amanitins, including the latest advances that could allow the proposal of new innovative and effective therapeutics.
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38
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The Chemistry Behind ADCs. Pharmaceuticals (Basel) 2021; 14:ph14050442. [PMID: 34067144 PMCID: PMC8152005 DOI: 10.3390/ph14050442] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/29/2021] [Accepted: 05/02/2021] [Indexed: 02/07/2023] Open
Abstract
Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.
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Hambira CM, Matinkhoo K, Pryyma A, Patrick BO, Perrin DM. Scaling Amatoxin Synthesis with an Improved Route to (2 S,3 R,4 R)-Dihydroxyisoleucine Exemplified by a Toxic, Clickable α-Amanitin Analogue. J Org Chem 2021; 86:5362-5370. [PMID: 33710901 DOI: 10.1021/acs.joc.0c03022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Here we report a scalable synthesis of the key amino acid residue, (2S,3R,4R)-4,5-dihydroxyisoleucine (DHIle) in α-amanitin, that in turn enables the scalable synthesis of an equipotent analogue, Asn(N-ethylazide)-S,6'-dideoxy-α-amanitin, suitable for CuAAC conjugation to empower studies on therapeutic antibody-drug conjugates.
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Affiliation(s)
- Chido M Hambira
- Chemistry Department, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada
| | - Kaveh Matinkhoo
- Chemistry Department, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada
| | - Alla Pryyma
- Chemistry Department, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada
| | - Brian O Patrick
- Chemistry Department, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada
| | - David M Perrin
- Chemistry Department, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada
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40
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Kim D, Kim S, Na AY, Sohn CH, Lee S, Lee HS. Identification of Decrease in TRiC Proteins as Novel Targets of Alpha-Amanitin-Derived Hepatotoxicity by Comparative Proteomic Analysis In Vitro. Toxins (Basel) 2021; 13:toxins13030197. [PMID: 33803263 PMCID: PMC7999322 DOI: 10.3390/toxins13030197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/04/2021] [Accepted: 03/06/2021] [Indexed: 11/30/2022] Open
Abstract
Alpha-amanitin (α-AMA) is a cyclic peptide and one of the most lethal mushroom amatoxins found in Amanita phalloides. α-AMA is known to cause hepatotoxicity through RNA polymerase II inhibition, which acts in RNA and DNA translocation. To investigate the toxic signature of α-AMA beyond known mechanisms, we used quantitative nanoflow liquid chromatography–tandem mass spectrometry analysis coupled with tandem mass tag labeling to examine proteome dynamics in Huh-7 human hepatoma cells treated with toxic concentrations of α-AMA. Among the 1828 proteins identified, we quantified 1563 proteins, which revealed that four subunits in the T-complex protein 1-ring complex protein decreased depending on the α-AMA concentration. We conducted bioinformatics analyses of the quantified proteins to characterize the toxic signature of α-AMA in hepatoma cells. This is the first report of global changes in proteome abundance with variations in α-AMA concentration, and our findings suggest a novel molecular regulation mechanism for hepatotoxicity.
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Affiliation(s)
- Doeun Kim
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; (D.K.); (A.-Y.N.)
| | - Sunjoo Kim
- BK21 Four-Sponsored Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea;
| | - Ann-Yae Na
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; (D.K.); (A.-Y.N.)
| | - Chang Hwan Sohn
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 05505, Korea;
| | - Sangkyu Lee
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; (D.K.); (A.-Y.N.)
- Correspondence: (S.L.); (H.S.L.); Tel.: +82-53-950-8571 (S.L.); +82-2-2164-4061 (H.S.L.)
| | - Hye Suk Lee
- BK21 Four-Sponsored Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea;
- Correspondence: (S.L.); (H.S.L.); Tel.: +82-53-950-8571 (S.L.); +82-2-2164-4061 (H.S.L.)
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41
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Landry B, Whitton J, Bazzicalupo AL, Ceska O, Berbee ML. Phylogenetic analysis of the distribution of deadly amatoxins among the little brown mushrooms of the genus Galerina. PLoS One 2021; 16:e0246575. [PMID: 33566818 PMCID: PMC7875387 DOI: 10.1371/journal.pone.0246575] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 01/22/2021] [Indexed: 12/04/2022] Open
Abstract
Some but not all of the species of ’little brown mushrooms’ in the genus Galerina contain deadly amatoxins at concentrations equaling those in the death cap, Amanita phalloides. However, Galerina’s ~300 species are notoriously difficult to identify by morphology, and the identity of toxin-containing specimens has not been verified with DNA barcode sequencing. This left open the question of which Galerina species contain toxins and which do not. We selected specimens for toxin analysis using a preliminary phylogeny of the fungal DNA barcode region, the ribosomal internal transcribed spacer (ITS) region. Using liquid chromatography/mass spectrometry, we analyzed amatoxins from 70 samples of Galerina and close relatives, collected in western British Columbia, Canada. To put the presence of toxins into a phylogenetic context, we included the 70 samples in maximum likelihood analyses of 438 taxa, using ITS, RNA polymerase II second largest subunit gene (RPB2), and nuclear large subunit ribosomal RNA (LSU) gene sequences. We sequenced barcode DNA from types where possible to aid with applications of names. We detected amatoxins only in the 24 samples of the G. marginata s.l. complex in the Naucoriopsis clade. We delimited 56 putative Galerina species using Automatic Barcode Gap Detection software. Phylogenetic analysis showed moderate to strong support for Galerina infrageneric clades Naucoriopsis, Galerina, Tubariopsis, and Sideroides. Mycenopsis appeared paraphyletic and included Gymnopilus. Amatoxins were not detected in 46 samples from Galerina clades outside of Naucoriopsis or from outgroups. Our data show significant quantities of toxin in all mushrooms tested from the G. marginata s.l. complex. DNA barcoding revealed consistent accuracy in morphology-based identification of specimens to G. marginata s.l. complex. Prompt and careful morphological identification of ingested G. marginata s.l. has the potential to improve patient outcomes by leading to fast and appropriate treatment.
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Affiliation(s)
- Brandon Landry
- Department of Botany, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jeannette Whitton
- Department of Botany, University of British Columbia, Vancouver, British Columbia, Canada
| | - Anna L. Bazzicalupo
- Department of Botany, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Mary L. Berbee
- Department of Botany, University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
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Li Y, Sun Y, Kulke M, Hechler T, Van der Jeught K, Dong T, He B, Miller KD, Radovich M, Schneider BP, Pahl A, Zhang X, Lu X. Targeted immunotherapy for HER2-low breast cancer with 17p loss. Sci Transl Med 2021; 13:eabc6894. [PMID: 33568521 PMCID: PMC8351376 DOI: 10.1126/scitranslmed.abc6894] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 01/13/2021] [Indexed: 12/21/2022]
Abstract
The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53 Our analyses revealed that 17p loss leads to global gene expression changes and reduced tumor infiltration and cytotoxicity of T cells, resulting in immune evasion during breast tumor progression. The 17p deletion region also includes POLR2A, a gene encoding the catalytic subunit of RNA polymerase II that is essential for cell survival. Therefore, breast cancer cells with heterozygous loss of 17p are extremely sensitive to the inhibition of POLR2A via a specific small-molecule inhibitor, α-amanitin. Here, we demonstrate that α-amanitin-conjugated trastuzumab (T-Ama) potentiated the HER2-targeted therapy and exhibited superior efficacy in treating HER2-low breast cancer with 17p loss. Moreover, treatment with T-Ama induced immunogenic cell death in breast cancer cells and, thereby, delivered greater efficacy in combination with immune checkpoint blockade therapy in preclinical HER2-low breast cancer models. Collectively, 17p loss not only drives breast tumorigenesis but also confers therapeutic vulnerabilities that may be used to develop targeted precision immunotherapy.
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Affiliation(s)
- Yujing Li
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yifan Sun
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Michael Kulke
- Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany
| | | | - Kevin Van der Jeught
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tianhan Dong
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bin He
- Departments of Surgery and Urology, Immunobiology and Transplant Science Center, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA
| | - Kathy D Miller
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Milan Radovich
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bryan P Schneider
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiongbin Lu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Feni L, Jütten L, Parente S, Piarulli U, Neundorf I, Diaz D. Cell-penetrating peptides containing 2,5-diketopiperazine (DKP) scaffolds as shuttles for anti-cancer drugs: conformational studies and biological activity. Chem Commun (Camb) 2020; 56:5685-5688. [PMID: 32319458 DOI: 10.1039/d0cc01490g] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A series of linear and cyclic peptidomimetics composed of a cell-penetrating peptide and a non-natural, bifunctional 2,5-diketopiperazine scaffold is reported. Conformational studies revealed well-defined helical structures in micellar medium for linear structures, while cyclic peptidomimetics were more flexible. Biological investigations showed higher membrane-activity of cyclic derivatives allowing their use as shuttles for anti-cancer drugs.
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Affiliation(s)
- Lucia Feni
- University of Cologne, Department of Chemistry, Biochemistry, Zülpicher Str. 47a, D-50674 Cologne, Germany.
| | - Linda Jütten
- University of Cologne, Department of Chemistry, Organic Chemistry, Greinstraße 4, D-50939, Cologne, Germany.
| | - Sara Parente
- Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, Via Valleggio 11, 22100, Como, Italy.
| | - Umberto Piarulli
- Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, Via Valleggio 11, 22100, Como, Italy.
| | - Ines Neundorf
- University of Cologne, Department of Chemistry, Biochemistry, Zülpicher Str. 47a, D-50674 Cologne, Germany.
| | - Dolores Diaz
- University of Cologne, Department of Chemistry, Organic Chemistry, Greinstraße 4, D-50939, Cologne, Germany.
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Figueroa-Vazquez V, Ko J, Breunig C, Baumann A, Giesen N, Pálfi A, Müller C, Lutz C, Hechler T, Kulke M, Müller-Tidow C, Krämer A, Goldschmidt H, Pahl A, Raab MS. HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells. Mol Cancer Ther 2020; 20:367-378. [PMID: 33298585 DOI: 10.1158/1535-7163.mct-20-0287] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/09/2020] [Accepted: 11/24/2020] [Indexed: 11/16/2022]
Abstract
Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.
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Affiliation(s)
- Vianihuini Figueroa-Vazquez
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Jonathan Ko
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Anja Baumann
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Nicola Giesen
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Anikó Pálfi
- Heidelberg Pharma Research GmbH, Ladenburg, Germany
| | | | | | | | | | - Carsten Müller-Tidow
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Alwin Krämer
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Hartmut Goldschmidt
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.,National Center of Tumor Diseases (NCT), Heidelberg, Germany
| | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Ladenburg, Germany.
| | - Marc S Raab
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. .,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
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45
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Pryyma A, Matinkhoo K, Wong AAWL, Perrin DM. Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5'-hydroxy-6'-deoxy-amanitin. Chem Sci 2020; 11:11927-11935. [PMID: 34094418 PMCID: PMC8162882 DOI: 10.1039/d0sc04150e] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/02/2020] [Indexed: 12/18/2022] Open
Abstract
Appreciating the need to access synthetic analogs of amanitin, here we report the synthesis of 5'-hydroxy-6'-deoxy-amanitin, a novel, rationally-designed bioactive analog and constitutional isomer of α-amanitin, that is anticipated to be used as a payload for antibody drug conjugates. In completing this synthesis, we meet the challenge of diastereoselective sulfoxidation by presenting two high-yielding and diastereoselective sulfoxidation approaches to afford the more toxic (R)-sulfoxide.
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Affiliation(s)
- Alla Pryyma
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver B.C. V6T 1Z1 Canada
| | - Kaveh Matinkhoo
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver B.C. V6T 1Z1 Canada
| | - Antonio A W L Wong
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver B.C. V6T 1Z1 Canada
| | - David M Perrin
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver B.C. V6T 1Z1 Canada
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Zhao P, Zhang Y, Li W, Jeanty C, Xiang G, Dong Y. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm Sin B 2020; 10:1589-1600. [PMID: 33088681 PMCID: PMC7564033 DOI: 10.1016/j.apsb.2020.04.012] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/25/2020] [Accepted: 03/08/2020] [Indexed: 02/06/2023] Open
Abstract
Antibody drug conjugates (ADCs) normally compose of a humanized antibody and small molecular drug via a chemical linker. After decades of preclinical and clinical studies, a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin (Adcetris®) for relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, gemtuzumab ozogamicin (Mylotarg®) for acute myeloid leukemia, ado-trastuzumab emtansine (Kadcyla®) for HER2-positive metastatic breast cancer, inotuzumab ozogamicin (Besponsa®) and most recently polatuzumab vedotin-piiq (Polivy®) for B cell malignancies. More than eighty ADCs have been investigated in different clinical stages from approximately six hundred clinical trials to date. This review summarizes the key elements of ADCs and highlights recent advances of ADCs, as well as important lessons learned from clinical data, and future directions.
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Gires O, Pan M, Schinke H, Canis M, Baeuerle PA. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer Metastasis Rev 2020; 39:969-987. [PMID: 32507912 PMCID: PMC7497325 DOI: 10.1007/s10555-020-09898-3] [Citation(s) in RCA: 194] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
EpCAM (epithelial cell adhesion molecule) was discovered four decades ago as a tumor antigen on colorectal carcinomas. Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an anchor molecule on circulating and disseminated tumor cells (CTCs/DTCs), which are considered the major source for metastatic cancer cells. Today, EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) of carcinoma cells. To fulfill these functions, EpCAM is instrumental in intra- and intercellular signaling as a full-length molecule and following regulated intramembrane proteolysis, generating functionally active extra- and intracellular fragments. Intact EpCAM and its proteolytic fragments interact with claudins, CD44, E-cadherin, epidermal growth factor receptor (EGFR), and intracellular signaling components of the WNT and Ras/Raf pathways, respectively. This plethora of functions contributes to shaping intratumor heterogeneity and partial EMT, which are major determinants of the clinical outcome of carcinoma patients. EpCAM represents a marker for the epithelial status of primary and systemic tumor cells and emerges as a measure for the metastatic capacity of CTCs. Consequentially, EpCAM has reclaimed potential as a prognostic marker and target on primary and systemic tumor cells.
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Affiliation(s)
- Olivier Gires
- Department of Otorhinolaryngology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
- Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer", Helmholtz Zentrum, Neuherberg, Germany.
| | - Min Pan
- Department of Otorhinolaryngology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Henrik Schinke
- Department of Otorhinolaryngology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Martin Canis
- Department of Otorhinolaryngology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Patrick A Baeuerle
- Institute for Immunology, LMU Munich, Grosshadernerstr. 9, 82152 Planegg, Martinsried, Germany
- MPM Capital, Cambridge MA, 450 Kendall Street, Cambridge, MA, 02142, USA
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Wu Q, Dai T, Song J, Liu X, Song S, Li L, Liu J, Pugazhendhi A, Jacob JA. Effects of herbal and mushroom formulations used in Traditional Chinese Medicine on in vitro human cancer cell lines at the preclinical level: An empirical review of the cell killing mechanisms. Process Biochem 2020. [DOI: 10.1016/j.procbio.2020.04.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Lutz C, Simon W, Werner‐Simon S, Pahl A, Müller C. Totalsynthese von α‐ und β‐Amanitin. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.201914935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Christian Lutz
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Deutschland
| | - Werner Simon
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Deutschland
| | - Susanne Werner‐Simon
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Deutschland
| | - Andreas Pahl
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Deutschland
| | - Christoph Müller
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Deutschland
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Lutz C, Simon W, Werner‐Simon S, Pahl A, Müller C. Total Synthesis of α‐ and β‐Amanitin. Angew Chem Int Ed Engl 2020; 59:11390-11393. [DOI: 10.1002/anie.201914935] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/12/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Christian Lutz
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Germany
| | - Werner Simon
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Germany
| | | | - Andreas Pahl
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Germany
| | - Christoph Müller
- Heidelberg Pharma Research GmbH Department of Chemistry 68529 Ladenburg Germany
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