Targeting Multiple Myeloma with BCMA x CD3 Bispecific Antibodies: Balancing T Cell Activation and Cytokine Release

3 June 2024
Multiple myeloma is a serious blood cancer with a yearly occurrence of approximately 25,000 cases. Advances in treatment have increased life expectancy to over five years, but patients with resistance to certain drugs face a median survival of less than nine months. New treatment options are urgently needed. Early trials have shown that a specific type of engineered immune cells, known as CAR-T cells targeting BCMA, can be effective against this disease. However, issues such as T-cell over-activation and the complexity of producing these cells limit their use.

A new approach using bispecific antibodies that direct T cells to attack BCMA-expressing cells has been explored, but similar issues with T-cell over-activation persist. A novel method using a next-generation sequencing platform called TeneoSeek has been developed to identify high-affinity antibodies. This method led to the discovery of a high-affinity antibody against BCMA and a series of antibodies against CD3 with varying levels of T-cell activation potency.

A low-activating CD3 antibody was identified that could induce the destruction of myeloma cells with minimal cytokine release when paired with a BCMA-targeting antibody. To evaluate this, two bispecific antibodies were created: one with high T-cell activating properties (TNB-384B) and one with low activating properties (TNB-383B), both combined with a BCMA-targeting component. These were tested for their ability to activate T cells and kill myeloma cells, both in the lab and in animal models, as well as their toxicity.

The tests included measuring T-cell activation and cytokine production in the lab, assessing the destruction of myeloma cell lines, and observing the survival of patient-derived myeloma cells when exposed to the antibodies. Animal studies involved implanting myeloma cells into mice and treating them with the antibodies, with tumor growth monitored using imaging techniques. Additionally, the antibodies' behavior in the body was studied in mice and monkeys.

The results showed that both antibodies bound strongly to BCMA on the surface of myeloma cells and were effective at killing these cells in the lab. The low-activating antibody, TNB-383B, caused less cytokine release than the high-activating one, TNB-384B, even at high concentrations. Both antibodies efficiently destroyed primary myeloma cells in the presence or absence of additional T cells. In animal studies, both antibodies were able to clear established myeloma tumors at low doses. Their behavior in the body was consistent with other antibodies of their type, and they did not cause T-cell activation in the absence of target cells.

In conclusion, both the low-activating and high-activating bispecific antibodies have shown promise in killing myeloma cells in various settings. The low-activating antibody, in particular, induced less cytokine release without reducing the effectiveness of the treatment, suggesting a potential new therapeutic option for multiple myeloma that is distinct from current T-cell targeted treatments in trials.

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