Abstract 1534: MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model

Targeting CD40 with its natural ligand (CD40L) enhances the immune-stimulatory functions of dendritic cells, B cells, monocytes and macrophages, resulting in T cell priming, expansion and differentiation. Thus, activation of the CD40 pathway is an attractive strategy to boost anti-tumor immune responses. MEDI5083 is a novel fusion protein consisting of a hexameric recombinant human CD40L structure covalently linked to human IgG4p Fc. In this study, we present the functional characterization of MEDI5083. MEDI5083 specifically bound to human CD40 and triggered surface CD40 internalization. As a result, MEDI5083 exerted robust CD40 agonist activities as measured by NF-κb activation in Ramos and THP1 cell lines. In assays using primary human B cells and myeloid cells, MEDI5083 potently upregulated co-stimulation molecules including MHCII, CD80 and CD86, and induced secretion of pro-inflammatory cytokines, such as TNFα and IL6. To examine the anti-tumor activity in mice, we constructed a murine surrogate of MEDI5083 (mCD40L-Fc) which has similar physical and target binding properties to those of MEDI5083. In the B16F10 syngeneic mouse model, repeated dosing of mCD40L-Fc significantly decreased tumor volume and/or delayed tumor growth, compared with isotype control dosed animals. Combination treatment of mCD40L-Fc with anti-PD-L1 and/or anti-CTLA-4 further enhanced the anti-tumor immune response. Moreover, treatment with mCD40L-Fc alone or in combination with anti-PD-L1 or anti-CTLA-4 induced elevated levels of TH1 cytokines IFNγ and IL12 in serum, and increased numbers of intratumoral CD8+ T cells, compared with isotype control treated animals. Thus, mCD40L-Fc elicits robust immune activation and significant anti-tumor activity against B16F10 tumors, which have low responsiveness to checkpoint inhibitors. The insights obtained from the preclinical studies support the development of MEDI5083, which is currently in clinical development for a broad spectrum of malignancies. Citation Format: Sean Turman, Kelly McGlinchey, YaYa Wang, Deepali Malhotra, Ronald Herbst, Yue Wang. MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1534.