Abstract 5615: YH008, a PD-1-CD40 bispecific antibody, inhibits tumor growth in vivo through PD-1-dependent activation of CD40 signaling

Abstract

Abstract PD-1/PD-L1 inhibition immunotherapy is very popular in cancer treatment and has become one of the most pursued therapeutic strategies in the field. Combination treatment using anti-PD-1/PD-L1 agents with other immunomodulators brings additional benefits, such as preventing refractory effects towards PD-1/PD-L1 antibodies, and better inhibitory effects on tumor growth. Biocytogen developed YH008, a tetravalent anti PD-1/CD40 Fc-silenced IgG1 bispecific antibody (BsAb) that agonizes CD40 in a PD-1-dependent manner. Previously, YH008 demonstrated dose-dependent inhibitory efficacy against B16F10 engrafted tumors in PD-1/CD40 double humanized mice (established by Biocytogen: B-hPD1/CD40). Interestingly, in humanized CD40 mice that do not express human PD-1 expression, YH008 did not show tumor inhibition activity against the MC38 engrafted tumor. This observation indicates that YH008 activates the CD40 pathway in a PD-1 dependent manner. When compared with an anti-PD-L1/CD40 BsAb, YH008 showed superior tumor growth inhibition (TGI) against MC38 engrafted tumors in a triple humanized PD-1/PD-L1/CD40 mouse model (B-hPD-1/hPD-L1/hCD40). YH008 was observed to promote the proliferation and activation of dendritic cells, as well as increase CD8+/Treg ratio in B16F10 tumor-infiltrating lymphocytes (TILs). Furthermore, YH008 showed a superior liver toxicity profile compared to a selicrelumab analog. At a high dose of 100mg/kg, YH008 did not elevate liver enzymes in the blood of B-hPD1/hCD40 mice. Similarly, no significant adverse events were observed in a cynomolgus dose-escalation study. YH008 is currently in pre-clinical development with anticipated IND application in 2022. Citation Format: Baihong Liu, Hao Yang, Li Hui, Benny Yang. YH008, a PD-1-CD40 bispecific antibody, inhibits tumor growth in vivo through PD-1-dependent activation of CD40 signaling [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 5615.