Abstract 534: Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format

Abstract

Abstract This research aimed to produce anti-claudin18.2 (CLDN 18.2)/anti-PD-L1 bispecific antibodies to enhance the therapeutic index and expand the responsive population of the parent anti-CLDN 18.2 and anti-PD-L1 antibodies through the mechanisms of tumor-specific distribution and synergistic tumor killing. CLDN 18.2 is highly expressed in several tumors but is minimally expressed in normal tissues and a chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. However, the response rate was moderate (~10%), leaving room for further improvement. Anti-PD-L1 antibodies showed remarkable efficacy in lung cancer and melanoma but in various settings of gastric cancer they showed weaker benefits, which warrant optimization. We designed anti-claudin18.2/anti-PD-L1 bispecific antibodies in the SMARTOPTM format, where a single-chain diabody containing optimized CLDN 18.2 and PD-L1 binding variable domains is connected to the Fc domain by linkers that can be optimized by phage display libraries. The bispecific antibodies were selected by affinity at low pH values and slow off-rate to improve the therapeutic window by enhancing tumor retention and preserving or improving binding affinity in the low pH tumor microenvironment. Immunogenicity was optimized by mutating the surface residues and disulfide bonds were inserted to improve stability. A representative bispecific antibody SPX-301 showed comparable binding affinity to the CLDN 18.2 and PD-L1 antigens to the parent antibodies (SPX-101 and durvalumab, respectively). SPX-301 represents a novel anti-claudin18.2/anti-PD-L1 bispecific antibody in the SMARTOPTM format. The format demonstrated excellence retention of antigen binding affinity, high expression levels, minimal aggregation, and straightforward purification. The preclinical characterizations of SPX-301 will also be presented. Citation Format: Guidong Zhu, Jingdong Ye, Jichun Ma, Jingdong Qin, Yi Cai. Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format [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 534.