Background: Early clinical evidence suggests that depleting BCMA-expressing plasmablasts and plasma cells via CAR-T or T cell engagers (TCEs) is a promising therapeutic approach for autoantibody-driven autoimmune diseases. CND106 (formerly known as EMB-06) is a novel 2 + 2 BCMA×CD3 T-cell engaging bispecific antibody featuring tetravalent binding domains in cis-configuration with high affinity for BCMA and optimized affinity for CD3 to reduce cytokine production while maintaining cytolytic activity.

Objectives: The primary objectives of this study are to 1) demonstrate proof-of-concept preclinical efficacy supporting use of CND106 for the treatment of autoimmune disease and 2) confirm translation of CND106 preclinical safety and efficacy findings in a Phase 1 clinical study in patients with multiple myeloma, including characterization of cytokine release syndrome (CRS), Immune effector cell-associated neurotoxicity syndrome (ICANS) and clinical activity.

Methods: Binding of CND106 to BCMA-expressing myeloma cell lines as well as CD3-positive Jurkat T cells was assessed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy donors were co-cultured with myeloma cell lines in the presence of CND106 for 48 hours and T cell activation, B cell killing, and cytokine release (IFN-γ, IL-2, IL-6, IL-10, TNF-α) were assessed compared to benchmark BCMAxCD3 TCEs. Cynomolgus monkeys were administered a single IV dose (0.5 mg/kg) of CND106 and pharmacodynamic effects on circulating immune cells and serum cytokines were assessed. Immunodeficient mice (NCG) were reconstituted with systemic lupus erythematosus patients’ PBMCs (hSLE-PBMC mice; Day 0), treated with 4 doses of CND106 (1 mg/kg IP on Days 7, 14, 21, 27), and levels of human serum IgG, anti-dsDNA levels, splenic B cells and immune complexes in the kidneys were compared to untreated hSLE-PBMC mice (Day 28).A Phase 1 dose escalation study was completed in patients with relapsed or refractory multiple myeloma (RRMM) (NCT04735575). The dose escalation was conducted using a Bayesian optimal interval (BOIN) design with an accelerated titration design (ATD) stage. Efficacy was analyzed in response-evaluable patients, defined as those who received at least one dose of CND106 and had at least one post-baseline response evaluation. Safety was analyzed in all patients who received at least one dose of CND106.

Results: In vitro, CND106 showed comparable binding to BCMA-expressing cell lines and lower binding to T cells compared to the benchmark TCEs. Co-culture of healthy donor PBMCs with BCMA-expressing cell lines resulted in comparable T cell activation and T cell mediated cell killing, but lower cytokine release compared to the benchmark TCEs. In cynomolgus monkeys treated with a single IV dose of CND106, there was a transient decrease in peripheral blood T cells indicative of margination, sustained reductions in circulating B cells, and limited, transient induction of cytokines. CND106 treatment caused significant reductions in human serum IgG, anti-dsDNA, splenic B cells, and immune complexes in the kidneys of SLE-PBMC mice relative to untreated hSLE-PBMC controls. In the Phase 1 study, forty patients were treated with CND106 at doses ranging from 0.2 mg to 300 mg. All CRS cases were Grade 1 (18%) or Grade 2 (8%) per ASTCT criteria. The median time to onset from most recent dose was 1 day (range 1-2 days). No ICANS was observed. Rates of CRS/ICANS are favorable compared to approved BCMAxCD3 TCEs and CAR-T in oncology. CND106 achieved efficacy comparable to other approved BCMAxCD3 TCEs with demonstration of its biologic and pharmacodynamic effects.

Conclusion: CND106 demonstrates a differentiated safety profile based on preclinical and clinical data. Furthermore, preclinical data support the potential for development of CND106 in autoantibody-driven autoimmune diseases.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Peter Tan: None declared, Li Bao: None declared, Qingsong Yin: None declared, Chunrui Li: None declared, Sorab Jehangir Shavaksha: None declared, Henry Miles Prince: None declared, Jamie Haddon Employee of Candid Therapeutics, Peter Morcos Consultant with Candid Therapeutics, Jessica Rearden Employee of Candid Therapeutics, Peter Wung Employee of Candid Therapeutics, Mingfei Zhang Employee of EpimAb Biotherapeutics, Qiumei Deng Employee of EpimAb Biotherapeutics, Qiaoyang Lu Employee of EpimAb Biotherapeutics, Chengjun Jiang Employee of EpimAb Biotherapeutics, Fang Ren Employee of EpimAb Biotherapeutics, Danqing Wu Employee of EpimAb Biotherapeutics, Xuan Wu Employee of EpimAb Biotherapeutics, Gaowa Naren Employee of EpimAb Biotherapeutics, Yonghong Zhu Employee of EpimAb Biotherapeutics, Jian-Qing Mi: 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 ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.