Abstract 3354: Preclinical evaluation of potential cytokine release syndrome and efficacy of a BCMA-CD3 bispecific antibody for the treatment of multiple myeloma in humanized mice
Authors: Jiao Jing , Cai Danying , Yao Li-Chin , Draheim Kyle , Yang Hongyuan , Cheng Mingshan , Keck James 
Published: September 2020

Abstract
Bispecific antibodies (BsAbs) are now emerging as the next promising class of immunotherapies. BsAbs can bind simultaneously two different antigens or epitopes, which leads to a wide range of applications including redirecting T cells or NK cells to tumor cells and eradicate them more precisely and effectively. BCMA is a cell surface protein that is expressed on the malignant plasma cells, a substantial number of lymphoma and at low levels on normal B cells. This cell surface protein has emerged as a very selective antigen of targeted therapy for the treatment of multiple myeloma. As BsAbs can have significant adverse effects such as cytokine release syndrome (CRS), we decided to evaluate the CRS related safety profile, in addition to efficacy, of this BCMA-CD3 BsAb in pre-clinical studies.
We first evaluated the potential CRS after this BCMA-CD3 bispecific antibody treatment. As in vitro human PBMC assays presently in use do not reliably predict the occurrence of CRS in patients, we have developed a rapid, sensitive and reproducible PBMC humanized mouse model that can measure cytokine release induced by bispecifics in vivo. NSG™ and NSG-MHC Class I/II KO mice, which is a new NSG™ strain useful for studying human immunity in the absence of acute GVHD, are used in this mouse model. The mice were engrafted with human PBMCs for 6 days before being treated with BCMA-CD3 BsAb, OKT3 and anti-CD28 antibodies. Human cytokines IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNFα in serum were measured 6 hours after antibody treatments. Clinical observations of mice were recorded with OKT3, BCMA-CD3 BsAb and other treatments. Dose-dependent cytokine release was observed following BCMA-CD3 BsAb treatment with the highest concentration of 10 mg/kg showing a significant increased cytokine levels over that of 1 or 0.1 mg/kg. BCMA-CD3 BsAb was tested in a total of 8 PBMC donors, demonstrating donor dependent cytokine release. Donor variability for the cytokine release was observed with some donors more sensitive than others. 0.5-1 mg/kg BCMA-CD3 treatment was chosen for evaluating both efficacy and CRS using BCMA expressing NCI-H929 multiple myeloma cells in humanized NSG™ and the results will be discussed.
Together, the data suggests that the BCMA-CD3 BsAb may have cytokine release activity at high doses and supports our humanized mouse platform to evaluate potential CRS and efficacy studies of novel bispecific antibodies.
Citation Format: Jing Jiao, Danying Cai, Li-Chin Yao, Kyle Draheim, Hongyuan Yang, Mingshan Cheng, James Keck. Preclinical evaluation of potential cytokine release syndrome and efficacy of a BCMA-CD3 bispecific antibody for the treatment of multiple myeloma in humanized mice [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 3354.