Abstract 4260: PT886, an anti-claudin18.2/anti-CD47 bispecific antibody constructed with the PACbody࣪ and SPECpair࣪ technology platforms, exhibits robust anti-tumor activity in a pancreatic cancer xenograft model

Abstract

Abstract Claudin 18.2 (CLDN18.2) is a surface protein overexpressed in gastric and pancreatic tumors and has been demonstrated to be a clinically validated target for developing mAb and CAR-T therapies for these tumors. CD47 is a well-established “don’t eat me” signal and commonly overexpressed by many types of tumor cells as a mechanism for evading the innate immune system. It has been demonstrated in clinic that blocking CD47 from interacting with its ligand SIRPα leads to reduced growth of certain hematological tumors, presumably by activating the innate immune system against tumor cells. Here we present a therapeutic strategy for targeting both CLDN18.2 and CD47 with a bispecific antibody to achieve cancer killing by two mechanisms: (1) Blocking the CD47-SIRPα interaction and stimulating phagocytosis of tumor cells by macrophages. (2) Delivering robust effector effect (ADCC by NK cells and ADPC by macrophages) mediated by the functional Fc of the bispecific antibody. We report a native IgG-like anti-CLDN18.2/anti-CD47 bispecific antibody, PT886, that was generated using our newly developed PACbody™ and SPECpair™ technology platforms. The PACbody™ and SPECpair™ technologies are designed to allow assembled bispecific antibodies to have excellent biophysical properties and to be manufactured by a conventional three-step platform process commonly used for mAbs. PT886 has high affinity monovalent binding to cell surface CLDN18.2 and low affinity monovalent binding to cell surface CD47. This combination allows for the preferential binding of PT886 to tumor cells which overexpress both CLDN18.2 and CD47, but reduced binding to normal cells that only express CD47. Consequently, PT886 exhibits higher activity toward CLDN18.2-expressing tumor cells and lower to no activity to normal cells that do not express CLDN18.2. This was demonstrated in a phagocytosis assay where PT886 stimulates stronger phagocytosis in the presence of CLDN18.2 binding in vitro. In addition to targeting both CLDN18.2 and CD47, PT886 has a fully functional Fc to directly recruit the tumor cell killing activities of NK cells and macrophages. The potent anti-tumor activity of PT886 was demonstrated in vivo in a pancreatic cancer xenograft model, where PT886 treatment resulted in a complete tumor clearance at doses as low as 1 mg/kg. PT886 also demonstrated a good safety profile in NHP studies and exhibited regular mAb-like manufacturability in process development and CMC. These data support the proof of concept of the PACbody™ and SPECpair™ technology platforms and demonstrate the unique profile of our anti-CD47 arm that’s suitable for the bispecific antibody approach. PT886 is a first-in-class anti-CLDN18.2/anti-CD47 bispecific antibody with native IgG-like structure and phase 1 clinical trial is planned for the first quarter of 2022. Citation Format: Jack Li, Haiqun Jia, Erin Ramsey, Huiwen Wu, Yang Long, Kelan Chen, Albert Lam, Ming Wang, Hui Zou. PT886, an anti-claudin18.2/anti-CD47 bispecific antibody constructed with the PACbody࣪ and SPECpair࣪ technology platforms, exhibits robust anti-tumor activity in a pancreatic cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4260.