Abstract 3260: The preclinical characterization of CS1001, an anti-PD-L1 IgG4 monoclonal antibody and its activity beyond T cell regulation

Abstract

Abstract CS1001 is a high-affinity, fully human programmed death ligand-1 (PD-L1) blocking IgG4 monoclonal antibody. So far three therapeutic anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab) have been approved by US FDA in different cancer indications. CS1001 selectively bound to PD-L1 and blocked PD-L1/PD-1 ligation. The crystal structure of CS1001 complexed with human PD-L1 solved at 2.3Å revealed that CS1001 bound perpendicularly to PD-L1 and the binding epitope region well overlapped with the hPD1-binding region. In the Mixed Lymphocyte Reaction (MLR) assay, CS1001 effectively induced the proliferation of CD4+ T lymphocytes and the production of interferon-γ (IFN-γ) and interleukin-2 (IL-2). CS1001 employs IgG4 isotype and lacks antibody-dependent cellular mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Furthermore, the in vivo efficacy of CS1001 in inhibiting tumor growth was demonstrated in the subcutaneous MC38-hPD-L1 murine colon carcinoma (murine MC38 cells expressing human PD-L1) in human PD-1 knock-in mouse (Biocytogen) model. In another dual-humanized animal model, i.e. PD-1/PD-L1 dual knock-in mice implanted with MC38-hPD-L1 tumor (Biocytogen) where human PD-L1 expressed in both tumor and host system, it is interestingly noticed that CS1001 not only enhanced the cytotoxic T cell/regulatory T cell ratio, but also significantly upregulated M1 macrophage & down-regulated MDSC population, suggesting that anti-PD-L1 antibody may play the pro-anti-tumor immune response through modulating myeloid cells that also express PD-L1, thus a non-ADCC/CDC antibody design could be beneficial. CS1001 is currently explored clinically in 5 registration trials as monotherapy or in combination with standard of care therapies. CS1001 monotherapy or combo with chemotherapy or targeted therapy were safe and well tolerated. CS1001 demonstrated promising efficacy in multiple tumor types and support full development of CS1001 as mono/combo therapy for multiple indications in ongoing and planned clinical trials including cHL, ENKTL, GC, EC, and NSCLC. Citation Format: Juan Zhang, Zhenhu Li, Liang Tang, Linlin Liu, Zhaoxiang Ren, Jingshu Ma, Qingmei Shi, Yuanwu Bao, Liang Lu, Yong Zheng, Baotian Yang, Jing Li, Xinzhong Jon Wang. The preclinical characterization of CS1001, an anti-PD-L1 IgG4 monoclonal antibody and its activity beyond T cell regulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3260.