Abstract
Abstract Bispecific antibodies (BsAbs) have emerged as a potent therapeutic tool in cancer treatment, gaining increasing centrality in therapeutic applications. However, the development of bispecific antibodies is hindered by the mispairing of light and heavy chains. In response to this challenge, our company developed the KY-CLC-mouse, featuring an identical κ light chain without the expression of the λ light chain. This mouse shows great promise in bispecific antibody development, as the identical κ light chain, modified from a frequently occurring light chain in mice, pairs with multiple heavy chains. The advantages of such a light chain include good solubility and stability, as well as ease of humanization without post-translational modifications in the complementary-determining regions (CDRs). Furthermore, the CDRs were modified to reduce immunogenicity. This KY-CLC-mouse platform has facilitated the identification of antibodies that specifically target over a dozen antigens, such as PD-1, LAG33, MET, PSMA, and CD28, with KD ranging from 0.1 nM to 10 nM. We apply the knob-in-hole technology to assemble bispecific antibodies, targeting two antigens or different epitopes of the same antigen, following their humanization. Prime examples include fully humanized BsAbs PD1xLAG-3, PDL1xEGFR, PSMAxCD28, and EGFRxB7H3. These bispecific antibodies have an identical light chain and were developed with knob-into-hole technology. With different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, the BsAbs show neither aggregation nor degradation, suggesting good developability of these antibodies. Additionally, these BsAbs have a half-life of more than five days in the blood of both mice and monkeys. In conclusion, our common light chain KY-CLC-mouse is a powerful bispecific antibody discovery platform. Citation Format: Hao Peng, Guojin Wu, Feng Hao, Feng He, Yi Gu, Jinying Ning. KY-CLC-mouse: a common light chain bispecific antibody discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2382.
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