Background Immune checkpoint inhibitors have revolutionized cancer immunotherapy, however, only a small subset of patients respond to the treatment. There is still a high unmet medical need, especially for those who are resistant to immune checkpoint inhibitors. Developing new therapeutic targets are urgently needed. CD200-CD200R1 signaling pathway has been shown to inhibit the functions of T cells and myeloid cells, and represents a promising therapeutic target for cancer treatment. In a PD1-resistant mouse tumor model, CD200R1 expression is highly upregulated in tumor infiltrating T cells from PD1-resistant group.¹ Thus, blocking CD200-mediated CD200R1 inhibitory signaling pathway offers promising therapeutic potential for PD1-resistant patients. Moreover, CD200 is highly expressed in many human cancers such as non-small cell lung cancer, pancreatic cancer and brain cancer, which are potential indications for anti-CD200R1 antagonist antibody.^2-4

Methods Utilizing the unique Harbour Mice® antibody discovery platform, we generated fully human anti-CD200R1 antibodies that efficienctly blocked CD200-CD200R1 interaction. After further characterization and functional screening, we identified a novel fully human anti-CD200R1 antagonistic antibody – HBM1047.

Results HBM1047 demonstrated high binding affinity to both human and cyno CD200R1. It effeciently blocked CD200-CD200R1 interaction and inhibited CD200-induced CD200R1 reporter activity. In human primary cell assays, HBM1047 enhanced T cell activation when combined with anti-PD1 antibody. Furthermore, HBM1047 selectively bound to CD8+ T cells and myeloid cells in human tumor infiltrating lymphocytes from a variety of cancer types. More importantly, when used as monotherapy in preclinical models, HBM1047 showed potent anti-tumor efficacy in both CD200+ and CD200- humanized CDX models. In addition, HBM1047 had a favorable PK profile in mice and exhibited good developability properties.

Conclusions In conclusion, HBM1047 represents a novel fully human anti-CD200R1 antagonistic antibody with promising therapeutic potential for the treatment of cancer.

References

1. Markowitz GJ, Havel LS, Crowley MJ, et al. Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. JCI Insight. 2018;3(13):1–21.

2. Vathiotis IA, Macneil T, Zugazagoitia J, et al. Quantitative assessment of cd200 and cd200r expression in lung cancer. Cancers (Basel). 2021;13(5):1–15.

3. Choueiry F, Torok M, Shakya R, et al. CD200 promotes immunosuppression in the pancreatic tumor microenvironment. J Immunother Cancer. 2020;8(1):1–12.

4. Xin C, Zhu J, Gu S, et al. CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment. Cancer Immunol Immunother. 2020;69(11):2333–2343.

Ethics Approval This study obtained ethics approval and all participants gave informed consent before taking part. IRB NO: 3764. IRB protocol: MTG-015