Harnessing the Power of BCMA-Targeted Bispecific Antibodies: A Promising Therapeutic Approach for Multiple Myeloma

Multiple myeloma (MM) is a severe condition marked by malignant plasma cells amassing in bone marrow, persisting as an incurable disease despite therapeutic advancements. A novel approach involves T cell redirecting therapies that leverage T cells' cytotoxic capabilities to target cancer cells. The success of these therapies hinges on the selection of a tumor-associated antigen (TAA) that is absent in vital tissues but abundant on cancer cells. B-cell Maturation Antigen (BCMA), a member of the tumor necrosis factor family, is prevalent on myeloma cells with minimal expression in normal tissues, making it an ideal target.

Preclinical studies have been conducted on a human IgG CD3 bispecific antibody aimed at BCMA. This antibody, with a half-life of approximately 3 days in mice, is designed with anti-BCMA and anti-CD3 targeting domains linked through hinge mutation technology and structured on an IgG2A framework. It exhibits high affinity for BCMA-expressing myeloma cell lines and T cells, with respective affinities of 20pM and approximately 40nM.

In vitro studies demonstrate that T cells, when co-cultured with myeloma cell lines in the presence of the BCMA bispecific, become activated and release granules. The molecule exhibits remarkable potency, inducing the lysis of myeloma cells with an EC50 of 6±8 pM. Additionally, it shows robust efficacy in primary patient samples, with an EC50 of 0.093±0.1 nM, outperforming a BCMA antibody-drug conjugate (ADC) by a significant margin. In mouse models with established tumors from three different MM cell lines, a single dose of the bispecific antibody effectively combated the tumors in a dose-dependent manner, with re-dosing extending the duration of its efficacy.

While T cell redirecting therapies are highly potent, they also carry the risk of damaging normal cells that express trace amounts of the target. Preliminary toxicity studies using cynomologus monkeys revealed that the BCMA bispecific could deplete normal plasma B cells expressing low levels of BCMA, accompanied by an initial cytokine response that subsided after subsequent dosing. Importantly, no additional adverse events were observed, indicating a favorable safety profile for BCMA as a target in MM treatment.

In conclusion, the fully human IgG CD3 bispecific antibody targeting BCMA shows promise as a potent and safe therapy for MM, with an expected antibody-like half-life in humans. The findings underscore the molecule's potential to offer a new avenue for treating this challenging disease. The disclosures section notes affiliations with various pharmaceutical companies, indicating potential conflicts of interest.