Selective Targeting of Multiple Myeloma with BCMA x CD3 Antibodies: Minimizing Cytokine Release for Enhanced Therapy

Multiple myeloma (MM), a malignant plasma cell disorder, has a yearly occurrence of approximately 25,000 cases. Despite advancements in treatment that have increased median survival to over five years, MM that is resistant to bortezomib and lenalidomide has a median life expectancy of less than nine months. There is a pressing need for new therapeutic strategies. Early clinical trials have shown that chimeric antigen receptor T cells (CAR-Ts) that target the B-cell maturation antigen (BCMA), a protein unique to plasma cells, are effective against relapsed/refractory MM. However, challenges such as T-cell over-activation and the large-scale production of CAR-Ts remain.

To address these issues, a new approach was taken using TeneoSeek, a next-generation sequencing (NGS) platform that employs computational analysis of antibody sequences to identify antigen-specific antibodies. This led to the development of a high-affinity heavy chain antibody (HCA) against BCMA and a series of fixed light chain antibodies (Flic) with varying EC50s for T-cell activation. Notably, a low-activating αCD3 antibody was identified that caused T-cell dependent destruction of MM cells while minimizing cytokine release.

The efficacy and therapeutic potential of this molecule were further explored by combining both high- and low-activating αCD3 components with a bivalent αBCMA arm to form bispecific antibodies. These were evaluated for T-cell activation, MM cell killing, and toxicity both in vitro and in vivo, as well as ex vivo.

The methods included measuring T-cell activation through flow cytometry and cytokine ELISA, assessing the lysis of MM cell lines in vitro, and evaluating the survival of patient MM cells ex vivo after exposure to the antibodies. In vivo studies involved NSG mice implanted with MM cells and human peripheral blood mononuclear cells (huPBMC), treated with either of the bispecific antibodies or a negative control.

Results indicated that both bispecific antibodies bound to BCMA with high affinity and were effective against MM cell lines in vitro. The low-activating antibody demonstrated significantly reduced cytokine release compared to the high-activating one. Both antibodies efficiently lysed primary MM cells ex vivo and mediated the clearance of MM tumors in vivo.

Pharmacokinetic studies in mice and monkeys showed profiles consistent with an IgG, and no T-cell activation was observed in the absence of BCMA-expressing target cells. The conclusion drawn is that both the low-activating and high-activating bispecific antibodies have potential as therapeutic agents for MM, offering a differentiated approach from current T-cell targeted therapies in clinical trials.

The disclosures section lists affiliations and potential conflicts of interest for several individuals involved in the study, indicating employment at TeneoBio, Inc., and other affiliations with various pharmaceutical and biotech companies.