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ABSTRACT
Immune checkpoint inhibition (ICI) has revolutionized cancer treatment; however, only a subset of patients benefit long term. Therefore, methods for identification of novel checkpoint targets and development of therapeutic interventions against them remain a critical challenge. Analysis of human genetics has the potential to inform more successful drug target discovery. We used genome-wide association studies of the 23andMe genetic and health survey database to identify an immuno-oncology signature in which genetic variants are associated with opposing effects on risk for cancer and immune diseases. This signature identified multiple pathway genes mapping to the immune checkpoint comprising CD200, its receptor CD200R1, and the downstream adapter protein DOK2. We confirmed that CD200R1 is elevated on tumor-infiltrating immune cells isolated from cancer patients compared to the matching peripheral blood mononuclear cells. We developed a humanized, effectorless IgG1 antibody (23ME-00610) that bound human CD200R1 with high affinity (KD <0.1 nM), blocked CD200 binding, and inhibited recruitment of DOK2. 23ME-00610 induced T-cell cytokine production and enhanced T cell-mediated tumor cell killing in vitro. Blockade of the CD200:CD200R1 immune checkpoint inhibited tumor growth and engaged immune activation pathways in an S91 tumor cell model of melanoma in mice.
Acknowledgments
Scientific writing and editorial assistance was provided by Rand Miller, Ph.D. We would like to thank Steve Pitts, Adam Auton, Alex Owyang, Germaine Fuh, and Louise Scharf for their scientific guidance. We thank past and present 23andMe Therapeutics scientists who contributed to 23ME-00610, including Ben Chung, Pete Yeung, Patrick Koenig, Lance Larrabee, Jean Crilly, Mike Eby, Tina Thai, Shiteng Duan, Suk Lee, Dina Ayupova, Sushil Kumar, and Pierre Fontanillas. 23andMe is grateful to the millions of participants who consented to using their genetic and health survey data for research.
The results associated with TCGA are based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Disclosure statement
XF, YH, CM, ELL, TP, AZ, MP, SRM, DG, MS, CCL: Employees of 23andMe JF, CB, CL, ZY, WC, AC: Employees of 23andMe at the time this work was performed
Data availability statement
The data that support the findings of this study are available upon reasonable request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2217737.
List of Abbreviations
| ADCC | = | antibody-dependent cellular cytotoxicity |
| CDC | = | complement-dependent cytotoxicity |
| CTLA-4 | = | cytotoxic T-lymphocyte-associated protein 4 |
| DEG | = | differentially expressed gene |
| DOK | = | downstream of tyrosine kinase |
| EC50 | = | half-maximal effective concentration |
| ELISA | = | enzyme-linked immunosorbent assay |
| EMAD | = | endometrial adenocarcinoma |
| Fc | = | fragment crystallizable |
| FIH | = | first-in-human |
| GFP | = | green fluorescent protein |
| GWAS | = | genome-wide association study |
| I/O | = | immuno-oncology |
| ICI | = | immune checkpoint inhibitor |
| Ig | = | immunoglobulin |
| KCC | = | kidney clear cell carcinoma |
| KD | = | equilibrium dissociation constant |
| mAb | = | monoclonal antibody |
| MoDC | = | monocyte-derived dendritic cell |
| NSCLC | = | non-small cell lung cancer |
| OC | = | ovarian cancer |
| PBMC | = | peripheral blood mononuclear cell |
| PCA | = | principle component analysis |
| PD-1 | = | programmed cell death protein 1 |
| RasGAP | = | Ras GTPase activating protein |
| SD | = | standard deviation |
| TCGA | = | The Cancer Genome Atlas |
| TIL | = | tumor-infiltrating lymphocyte |
| TME | = | tumor microenvironment |