Abstract LB139: Preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody for the treatment of advanced solid tumors resistant to immune checkpoint inhibitors

Abstract Despite the revolution of therapeutic landscape for solid tumors advanced by immune checkpoint inhibitors (ICIs), primary or acquired resistance to ICI remain major unmet medical challenges in substantial proportion of patients. Activation of antigen presentation and priming may provide feasible solution to the insufficiency of endogenous anti-tumor immune activity in ICI-resistant tumors and cover multiple types of cold tumors. Here we report the first disclosure of preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody that simultaneously activates CD40 and blocks PD-1/L1 interactions. IAR037 incorporates a 2+1 molecule structure, with two anti-CD40 Fab regions and one anti-PD-L1 VHH linked to the C-terminus of Fc region. Fc effector functions are abrogated by LALA mutations to reduce peripheral FcƳR-mediated CD40 clustering and consequent toxicities. IAR037 has shown strong in vitro potency of PD-1/L1 blockade and PD-L1-dependent activation of CD40. IAR037 has also shown significant in vivo anti-tumor efficacy in multiple mice syngeneic models, including PD-1 resistant models. It strongly synergized with IBI363, a clinical-stage PD-1/IL-2v bispecific fusion protein, and demonstrated superior tumor regression in highly PD-1-resistant tumor model. IAR037 showed good safety profile in pilot-toxicology study in cynomolgus monkey and displayed large therapeutic window for further development. Dual functionality of IAR037 enables potential coverage of broad ranges of tumor types and larger patient populations due to widespread expression of PD-L1 in advanced solid tumors. IAR037 could specifically activate immune responses in the tumor microenvironment and tumor-draining lymph node while minimizing systemic side effects, showing unique advantages over other CD40-targeting anti-tumor therapies. In summary, IAR037 presents a novel therapeutic approach for ICI-resistant advanced solid tumors and the IND enabling study of IAR037 is ongoing. Citation Format: Shi Chen, Shuaixiang Zhou, Yao Xiong, Li Li, Qian Guo, Yucong Lei, Zhimin Zhang, Meng Ni, Zhihai Wu, Bingliang Chen, Kaijie He. Preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody for the treatment of advanced solid tumors resistant to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB139.