SHR-2005, an FcγR-Dependent CD40 Agonistic Antibody with Potent Antitumor Activities and Favorable Safety Profile

Abstract

Activation of CD40, a pivotal component of immune oncology, could facilitate the infiltration of immune cells into the tumor microenvironment. In this investigation, we characterized SHR-2005, a second-generation CD40 agonistic mAb, as a potential candidate for cancer immune therapy. Our results showed that SHR-2005 possessed high affinity in binding to both human and rhesus CD40 and could effectively compete with CD40L for CD40 binding. Notably, SHR-2005 was engineered to exert a strong affinity for human FcγRIIb, consistent with its observed Fc receptor–dependent agonistic activity. Treatment with SHR-2005 led to robust activation of the CD40 signaling pathway and subsequent immune response. The murine surrogate SHR-2005–mIgG1 exhibited potent inhibition of tumor growth in the MC38 allograft model and showed enhanced antitumor efficacy in combination with the anti–PD-L1 antibody. Furthermore, intravesical instillation of SHR-2005–mIgG1 also increased the populations of dendritic cells (DC), CD3+ T cells, and CD4+ T cells in bladder tissue. No obvious abnormality except for a reversible local irritation was observed via intravesical instillation. Notably, SHR-2005 induced significantly lower IL-6 secretion than the APX005M analogue in human peripheral blood mononuclear cells, indicating a favorable safety profile. In conclusion, the CD40 agonistic antibody SHR-2005 was highly reliant on FcγR for agonistic activation and exhibited promising potential for clinical development as monotherapy or in combination with the anti–PD-L1 antibody for the treatment of solid tumors. Based on promising efficacy and tolerance in preclinical studies, SHR-2005 is currently being evaluated in an ongoing phase I clinical trial for the intravesical treatment of high-risk non–muscle-invasive bladder cancer.