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Background: B cells play an important role in the pathogenesis of autoimmune diseases, through the production of autoantibodies, secretion of inflammatory cytokines, antigen presentation and T cell co-stimulation. Anti-CD20 monoclonal antibodies have been used in the treatment of autoimmune disease, however incomplete B cell depletion in tissues is common and associated with non-response. T-cell engagers (TCEs) that deplete B cells are showing early clinical evidence of safety and efficacy for the treatment of autoimmune diseases [1–4]. GB261 (also known as CND261) is a recombinant bispecific antibody against CD20 and CD3, designed with a high affinity CD20 binding domain (KD = 804 pM) and very low CD3 binding affinity (2.00 μM) to maximize B cell depletion while minimizing risk of possible complications of treatment with TCEs, such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Additionally, GB261 (CND261) has active Fc effector function to kill CD20+ B cells, specifically, but not T cells, via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In line with its molecular design, GB261 (CND261) induced comparable in vitro T cell activation and CD20+ cell killing compared to a benchmark anti-CD20/CD3 bispecific TCE but lower levels of cytokine release [5]. In vivo, GB261 (CND261) caused sustained reductions in peripheral B cells and limited cytokine production in cynomolgus monkeys, suggesting it has a suitable therapeutic window for clinical use.
Objectives: The primary objective is to confirm translation of GB261 (CND261) preclinical findings with clinical activity of GB261 (CND261) from a Phase 1 study, including characterization of CRS and ICANS.
Methods: A Phase 1, open-label, multicenter, dose escalation study was conducted to evaluate the safety, tolerability, pharmacokinetics and efficacy of GB261 (CND261) in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma (R/R B-NHL). Dose escalation was conducted using an accelerated titration method followed by a 3 + 3 design with flat and step-up dosing regimens. The doses studied ranged from 1mg to 300mg.
Results: In the Phase 1 oncology study with 93 patients with R/R B-NHL, 18 (19.4%) patients experienced 27 cases of CRS with most CRS events (>95%) being Grade 1 (70.4%) or Grade 2 (26.0%). The median onset of CRS occurred on the second day after the target dose (≥3mg) was reached, with a median duration of 13 hours. No ICANS was observed. Post-hoc exposure-response (ER) analyses revealed no significant ER relationship for CRS, confirming its favorable tolerability profile. Of note, GB261 (CND261) achieved efficacy comparable to other CD20/CD3 T cell engagers with demonstration of its biologic and pharmacodynamic effects.
Conclusion: GB261 (CND261), a CD20/CD3 TCE, is capable of potent and specific killing of CD20+ B cells through multiple mechanisms (T cell dependent cellular cytotoxicity, ADCC and CDC) and is optimized to induce lower levels of cytokine production relative to other TCEs. Clinical data with GB261 (CND261) in R/R B-NHL patients showed a favorable safety profile with predominantly low-grade, transient CRS and no incidents of ICANs. GB261 (CND261) demonstrated clinical activity comparable to other CD20/CD3 TCEs. Preclinical and clinical data support the potential for development of GB261 (CND261) in autoimmune diseases.
REFERENCES: [1] Tajiri K, Hu S, Chang S, et al. A-319, a CD3 × CD19 T-cell engager (TCE) for the treatment of severe refractory SLE: Early evidence of rapid reset of disease-specific autoimmunity.
Abstract presented at:
ACR Convergence 2023; November 10-15, 2023; San Diego, CA. Abstract No. 1621. Available from:
[2] Hagen M, Bucci L, Boltz S, et al. BCMA-Targeted T-cell engager therapy for autoimmune diseases. N Engl J Med 2024; 391(9): 867-869.
[3] Bucci L, Hagen M, Rothe T, et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med 2024; 30(6): 1593-1601.
[4] Alexander T, Kronke J, Cheng Q, et al. Teclistamab-induced remission in refractory systemic lupus erythematosus. N Engl J Med 2024; 391(9): 864-866.
[5] Cai W, Dong J, Kankanamalage SG, et al. Biological activity validation of a computationally designed Rituximab/CD3 T cell engager targeting CD20+ cancers with multiple mechanisms of action. Antib Ther 2021; 4(4): 228-241.
Acknowledgements: NIL.
Disclosure of Interests: Yuqin Song Roche, Beigene, AZ, Abbvie, Beigene, AZ, Abbvie, MSD, Beigene, Zengjun Li: None declared, Ling Li: None declared, Zhengzi Qian: None declared, Keshu Zhou: None declared, Lei Fan: None declared, Peter Tan: None declared, Pratyush Giri: None declared, Zhiming Li: None declared, Jie Jin: None declared, Wei Liu: None declared, Jamie Haddon Equity in BigHat Biosciences and Candid Therapeutics, Previous employee of BigHat, current employee of Candid Therapeutics, Peter Morcos Consultant for Candid Therapeutics, Jeremy Lim F. Hoffman La Roche, Candid Therapeutics, I am an employee of Candid Therapeutics and a former employee of F. Hoffman La Roche, Peter Wung I’m an employee of Candid Therapeutics and have equity of the company, I’m an employee of Candid Therapeutics, Shafqat Inam: None declared, Yan Xie: None declared, Tong Li I am an employee and own shares of the Genor Biopharma, I am an employee of the Genor Biopharma, Jun Zhu: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (