Abstract
Abstract The B-cell maturation antigen (BCMA) is an attractive target in multiple myeloma since it is more selectively expressed on myeloma cells. Meanwhile, T-cell-engaging bispecific antibodies (BsAbs) are an important class of antibody therapeutics in cancer therapy. BCMA-CD3 BsAbs simultaneously bind to CD3 on T cells and BCMA on tumor cells, activate T cells, and redirect T cells' cytotoxicity against tumor cells. BCMA is shed from the surface of plasma cells by gamma-secretase-mediated cleavage, leading to detectable, soluble BCMA (sBCMA) in circulation. Higher concentrations of sBCMA in patients with myeloma are associated with poorer clinical outcomes. Furthermore, sBCMA in circulation may act as a drug sink, especially when it is present in a relatively higher amount compared to the drug concentration, potentially attenuating the intended pharmacological mechanism and impacting pharmacokinetics and efficacious dose predictions. To address the complexities, we leveraged a quantitative systems model to characterize the kinetics of a model BsAb, T-cell, cytokines and serum M-protein upon BsAb treatment based on the literature data. This model incorporated T-cell activation, cytokine profiles as well as serum M-protein following various dosing regimens and baseline sBCMA levels. This model could assist in the design of clinical dosing strategies for BCMA-CD3 BsAb programs. Citation Format: Chandrasekhar Udata, Dai Wei, Sibo Jiang, Alison Forgie, Andrea Hooper, Wenlian Qiao, Cynthia Musante, Donghua Yin. BCMA-CD3 bispecific antibodies: A modeling framework to characterize kinetics of bispecific antibody, T cell, cytokines, and serum M-protein [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5508.
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