Abstract 590: Efficacy evaluation of bispecific antibodies in humanized mice after B cell depletion

Abstract

Abstract The development of bifunctional/multifunctional therapeutics have gained tremendous traction in recent years. Preclinical efficacy evaluation of bi-functional antibody drugs faces two main problems: first is the often limited cross-reaction between the anti-human antibody and murine target in animals; second is the reduced efficacy as a result of neutralization of antibodies by anti-drug antibodies (ADA) in animals due to the high immunogenicity of some bi-specific antibodies. To eliminate the ADA production against bi-specific therapeutic agents, Biocytogen developed a B cell depletion method based on humanized mouse syngeneic xenograft tumor model for preclinical efficacy evaluation of bispecific antibodies. To a syngeneic xenograft tumor model (PD-L1 humanized mice inoculated subcutaneously with MC38-hPD-L1 cells), CD20 antibody was injected to deplete B cells in the mice for the inhibition anti-antibody production. A model bi-specific agent against PD-L1 and TGF-β was sequentially injected to the mice. The tumor inhibitory effect of the bi-specific was assessed by tumor growth inhibition rate (TGI) calculated from measured tumor volume. Blood samples were drawn from mice for B cell analysis. The clearance of B cells in the blood flow and the serum concentration (including ADA) in mice were analyzed by flow cytometry and ELISA, respectively. The results showed that B cells were effectively eliminated from the murine blood after injection of CD20 antibody. Despite of the absence of B cells, the tumor growth was inhibited upon the treatment with M7824 analog, compared with the control group. Corresponding to the efficacy results, the mice in B cells-depleted group maintained a normal drug concentration in the blood while reducing the production of anti-drug antibodies. In summary, the B cell depletion mice have been validated as a promising model for the efficacy evaluation of complex structure antibody (bi or multi-functional antibody). Citation Format: Tian Gan, Dirui Li, Hao Yang, Gary Ng, Yanan Li, Qingcong Lin. Efficacy evaluation of bispecific antibodies in humanized mice after B cell depletion [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 590.