Obinutuzumab in kidney transplantation: Past, present, and future

Table 1 Main anti-B-cell agents with potential use in kidney transplantation

Drug	Approval	Target	Structure	CDC	ADCC	ADCP	DCD	Notes/unique properties
Rituximab	1997 (FDA/EMA)	Type 1 anti-CD20	Chimeric IgG1κ (mouse-human)	+++	++	++	±	First approved anti-CD20 monoclonal antibody; complement-dependent; widely used
Obinutuzumab	2013 (FDA); 2014 (EMA)	Type 2 anti-CD20	Glycoengineered humanized IgG1	+	+++	++	+++	Enhanced ADCC, ADCP and DCD; low CDC; resistant to complement inhibition, high-dose IgG, and trogocytosis
Ofatumumab	2009 (FDA)	Type 1 anti-CD20	Fully human IgG1κ	++++	+	+	-	Strong CDC; high affinity for CD20 membrane-proximal epitope
Ocrelizumab	2017 (FDA/EMA)	Type 1 anti-CD20	Humanized IgG1	++	++	+	±	Reduced immunogenicity vs RTX
Ublituximab	2022 (FDA)	Type 1 anti-CD20	Glycoengineered chimeric IgG1	++	+++	++	±	Enhanced FcγRIIIA binding; increased ADCC
Inebilizumab	2020 (FDA)	Anti-CD19	Humanized IgG1	++	++	++	±	CD19-depleting agent; long-lived plasma cells modulation
Belimumab	2011 (FDA/EMA)	BLyS-inhibitor	Human IgG1λ	-	-	-	-	Inhibits B-cell survival factor B-cell activating factor
Daratumumab	2015 (FDA); 2016 (EMA)	Anti-CD38	Human IgG1κ	+++	+++	+++	++	Targets CD38 on plasma cells and activated B cells/T cells; depletes donor-specific anti-HLA antibodies-producing clones; synergizes with anti-CD20

+ to ++++: Reflects relative strength of activity; ±: Variable or minimal activity; –: Absent activity; ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell phagocytosis; CDC: Complement-dependent cytotoxicity; DCD: Direct cell death; EMA: European Medicines Agency; FcγR: Fragment crystallizable receptor; FDA: Food and Drug Administration; IgG: Immunoglobulin G; RTX: Rituximab.

Table 2 Current literature on obinutuzumab use in kidney transplantation

Ref.	Year	Focus	Study design	Population	Treatment scheme	Main outcomes	IRR	SAE	FU
Redfield et al[37]	2019	Desensitization in highly sensitized KT candidates	Phase 1b, open label	25 ESRD patients (cPRA ≥ 98%); 5 received 1 OBI dose, 20 received 2 OBI doses	OBI 1 gon days 1 and 15 (± week 24) + IVIg 2 g/kg on days 22 and 43	> 90% peripheral CD19+ B-cell depletion; modest anti-HLA MFI reduction; 8/25 candidates proceeded to transplant	Mild–moderate IRRs in 52% (mainly chills, nausea, hypotension after first infusion)	44% had infections (11 SAEs in 9 patients), including pneumonia and nocardiosis	12 months
Zhang et al[72]	2021	B-cell depletion and CDC crossmatch	Observational cohort	12 sensitized KT candidates (6 OBI vs 6 RTX)	OBI 1 g vs RTX	Obinutuzumab achieved a median of 98% CD19+ B-cell reduction; CDC crossmatch results not influenced by OBI (unlike RTX)	Not reported	Not reported	2 weeks
Zhang et al[72]	2021	Lymphoid-tissue B-cell depletion	Sub study of Phase 1b trial	7 KT recipients	Same OBI + IVIg regimen as Redfield et al[37]	Significant reduction in CD20+ B-cell frequency in retroperitoneal lymph nodes vs non- OBI controls; depletion of naïve B cells, memory B cells, and plasmablasts	Not specified	Not specified	Up to 24 weeks
Favi et al[35]	2022	Induction in DEAP-HUS	Case report	1 high-risk KT recipient with CFHR1/CFHR3 deletion and anti-CFH antibody	Eculizumab 900 mgon days 0, and 30 + OBI 1 g on day 6	Complete complement blockade; rapid, full, and sustained CD20+ B-cell depletion; undetectable anti-CFH antibody; stable graft function	None	None	1 year
NasrAllah et al[38]	2022	OBI vs RTX: B-cell depletion and CDC-crossmatch	Comparative cohort	12 highly sensitized KT candidates/recipients (6 OBI, 6 RTX)	OBI 1 g or RTX 375 mg/m² with B-cell count and CDC-crossmatch assessed pre- and 2 weeks post-infusion	OBI induced a 98% median reduction in CD19+ B cells; unlike RTX, OBI did not cause false positive CDC-crossmatch	Not reported	Not reported	Not applicable
Favi et al[36]	2024	Treatment of ABMR	Case series	2 high-risk KT recipients with early active ABMR refractory to conventional therapy	Eculizumab 900 mg followed by OBI 1 g	Complement inhibition with clearance of intra-graft C4d and C5b-9 depositions; durable peripheral B-cell depletion; preformed and de novo DSA decline; preserved graft function with no signs of ABMR after 3 years	Nausea, vomiting, tachycardia,	CMV viremia, SARS-CoV2 infection, leukopenia	3 years
Ravani et al[71]	2024	Recurrent FSGS	Case series	2 KT recipients with early, RTX-resistant recurrent FSGS	OBI 1 g and DAR 16 mg/kg (two doses)	Rapid and complete remission of proteinuria; plasmapheresis discontinued; sustained albumin normalization; no further relapses	Not reported	None reported	≥ 12 months

ABMR: Antibody-mediated rejection; CDC: Complement-dependent cytotoxicity; CFHR: Complement factor H-related plasma proteins; cPRA: Calculated Panel Reactive Antibody; DAR: Daratumumab; DEAP-HUS: Deficiency of complement factor H-related plasma proteins and autoantibody positive form of hemolytic uremic syndrome; DSA: Donor-specific antibodies; ESRD: End-stage renal disease; FSGS: Focal segmental glomerulosclerosis; FU: Follow-up; KT: Kidney transplant; IRR: Infusion-related reaction; IVIg: Intravenous human polyclonal immunoglobulin; MFI: Mean fluorescence intensity; OBI: Obinutuzumab; RTX: Rituximab; SAE: Serious adverse event.

Table 3 Ongoing studies with Obinutuzumab in nephrology settings

NCT number	Study title	Type	Phase	Condition(s) studied	Summary	Status	Sponsor
NCT02550652	A Study to Evaluate the Safety and Efficacy of Obinutuzumab in Patients with Lupus Nephritis	I	II	LN	Compare efficacy and safety of OBI plus MMF/MPA with placebo plus MMF/MPA in patients with proliferative LN	Completed	Hoffmann-La Roche
NCT04629248	A Study Evaluating the Efficacy and Safety of Obinutuzumab in Participants with Primary Membranous Nephropathy (MAJESTY)	I	II	pMN	Evaluate efficacy, safety, PD/PK of OBI compared with tacrolimus in pMN	Active, not recruiting	Hoffmann-La Roche
NCT05050214	Obinutuzumab in primary MN (ORION)	I	II	pMN		Active, not recruiting	Mario Negri Institute for Pharmacological Research
NCT05845762	Obinutuzumab in the management of Idiopathic Membranous Nephropathy	O		Idiopathic MN		Not yet recruiting	Qianfoshan Hospital
NCT06120673	REmission in Membranous Nephropathy International Trial (REMIT)	I	III	pMN	Multi-centre, prospective, randomized, open-label, parallel-group trial: 224 adult participants will be recruited to receive either CCS and CP or OBI	Not yet recruiting	The University of Queensland
NCT02586051	A Study of Obinutuzumab to Evaluate Safety and Tolerability in Hypersensitized Adult Participants with End Stage Renal Disease Awaiting Transplantation	I	Ib	End-stage renal disease awaiting KT	Assessment of safety and tolerability of OBI regimen (1 infusion vs 2 infusions) at week 24 of desensitization phase and week 28 post-KT	Completed	Hoffmann-La Roche
NCT06781944	OBINUTUZUMAB Versus Cyclophosphamide + Glucocorticoids in Primary Membranous Nephropathy (Blossom Study)	I	III	pMN	Compare OBI against CP combined with CCS in pMN patients. Primary endpoint: Non-inferiority	Recruiting	Huashan Hospital
NCT06295770	Obinutuzumab in Treatment of Fibrillary Glomerulonephritis	I	II	FGN	Efficacy and safety in FGN	Recruiting	Mayo Clinic
NCT04983888	Obinutuzumab in Primary FSGS	I	II	FSGS	Safety and efficacy in inducing complete or partial remission of proteinuria	Active, not recruiting	Mayo Clinic
NCT05786768	Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome (OBIRINS)	I	II–III	FRNS, SDNS	Assess efficacy and safety of a single infusion of low-dose OBI compared to a single infusion of RTX in children with FRNS/SDNS	Recruiting	Assistance Publique-Hôpitaux de Paris
NCT04221477	A Study to Evaluate The Efficacy And Safety Of Obinutuzumab In Patients With ISN/RPS 2003 Class III Or IV Lupus Nephritis (REGENCY)	I	III	LN	Evaluate efficacy, safety, and PK of OBI compared with placebo in patients with ISN/RPS class III or IV LN when added on to standard-of-care therapy (MMF + CCS)	Active, not recruiting	Hoffmann-La Roche
NCT06265220	AB-101 in Combination With B-Cell Depleting mAb in Patients Who Failed Treatment for Class III or IV Lupus Nephritis or Other Forms of Refractory Systemic Lupus Erythematosus	I	I	LN	Assess safety, tolerability, and preliminary activity of AB-101 plus a B-cell depleting mAb after CP and fludarabine in adult with relapsed/refractory LN class III/IV	Recruiting	Artiva Biotherapeutics, Inc.
NCT05039619	A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Obinutuzumab in Adolescents with Active Class III or IV Lupus Nephritis and the Safety and PK of Obinutuzumab in Pediatric Participants (POSTERITY)	I	II	LN	Evaluate safety, efficacy and PK of OBI in adolescent aged 12-17 years with biopsy-confirmed proliferative LN and pediatrics aged 5-11 years with LN	Recruiting	Hoffmann-La Roche
NCT05627557	A Study to Evaluate the Efficacy and Safety of Obinutuzumab Versus MMF in Participants with Childhood Onset Idiopathic Nephrotic Syndrome (INShore)	I	III	INS, FRNS, SDNS	Assess efficacy, safety, and PK/PD of OBI compared with MMF in patients with FRNS SDNS	Active, not recruiting	Hoffmann-La Roche
NCT04702256	Induction Therapy for Lupus Nephritis With no Added Oral Steroids: A Trial Comparing Oral Corticosteroids Plus Mycophenolate Mofetil (MMF) Versus Obinutuzumab and MMF (OBILUP)	I	III	LN	Demonstrate that a regimen free of additional oral CCS but with OBI (and MMF) is not inferior to a regimen based on oral CCS and MMF in achieving complete renal response at week 52 without receiving CCS above a prespecified dose	Recruiting	Assistance Publique-Hôpitaux de Paris

CCS: Corticosteroids; CP: Cyclophosphamide; FGN: Focal glomerulonephritis; FRNS: Frequently relapsing nephrotic syndrome; FSGS: Focal segmental glomerulosclerosis; ISN/RPS: International Society of Nephrology/Renal Pathology Society; KT: Kidney transplant; LN: Lupus nephritis; mAb: Monoclonal antibodies; MMF/MPA: Mycophenolate mofetil/mycophenolic acid; MN: Membranous nephropathy; OBI: Obinutuzumab; PD: Pharmacodynamics; PK: Pharmacokinetics; SDNS: Steroid-dependent nephrotic syndrome.

Table 4 Cost of main B-cell, T-cell, and complement-targeted therapies in Italy

Active substance	Dosage form	Trade name	Manufacturer brand	Price per unit (€)
Rituximab	500 mg, 50 mL	Mabthera	Roche	2067
Ofatumumab	20 mg, 0.4 mL	Kesimpta	Novartis	2035
Ocrelizumab	300 mg, 10 mL	Ocrevus	Roche	9309
Ublituximab	150 mg, 6 mL	Briumvi	Neuraxpharm	5067
Obinutuzumab	1000 mg, 40 mL	Gazyvaro	Roche	4668
Daratumumab	1800 mg, 15 mL	Darzalex	Janssen-Cilag	8418
Bortezomib	3.5 mg	Bortezomib BV	Sandoz	1277
Alemtuzumab	12 mg, 1 mL	Lemtrada	Sanofi	13126
Thymoglobulin	50 mg, 10 mL	Thymoglobuline	Sanofi	239
Basiliximab	20 mg, 5 mL	Simulect	Novartis	1515
Belimumab	400 mg	Benlysta	GlaxoSmithKline	726
Eculizumab	300 mg, 30 mL	Soliris	Alexion	6852
Ravulizumab	100 mg, 11 mL	Ultomiris	Alexion	27407
Imlifidase	11 mg	Idefirix	Hansa Biopharma	245084
Intravenous human polyclonal immunoglobulin	10 g, 200 mL	Ig vena	Kedrion	1073
Fresh-frozen plasma	200 mL	Octaplas	Octapharma	75