23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function
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 gen...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2217737 |
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| author | Jill Fenaux Xin Fang Yao-ming Huang Cristina Melero Caroline Bonnans Earth Light Lowe Tiziana Palumbo Cecilia Lay Zuoan Yi Aileen Zhou Mauro Poggio Wei-Jen Chung Sophia R. Majeed Dylan Glatt Alice Chen Maike Schmidt Clarissa C. Lee |
| author_facet | Jill Fenaux Xin Fang Yao-ming Huang Cristina Melero Caroline Bonnans Earth Light Lowe Tiziana Palumbo Cecilia Lay Zuoan Yi Aileen Zhou Mauro Poggio Wei-Jen Chung Sophia R. Majeed Dylan Glatt Alice Chen Maike Schmidt Clarissa C. Lee |
| author_sort | Jill Fenaux |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5b1a4e2f8e6a433f9b2901ba88665afe |
| institution | OA Journals |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-5b1a4e2f8e6a433f9b2901ba88665afe2025-08-20T02:01:30ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.221773723ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell functionJill Fenaux0Xin Fang1Yao-ming Huang2Cristina Melero3Caroline Bonnans4Earth Light Lowe5Tiziana Palumbo6Cecilia Lay7Zuoan Yi8Aileen Zhou9Mauro Poggio10Wei-Jen Chung11Sophia R. Majeed12Dylan Glatt13Alice Chen14Maike Schmidt15Clarissa C. Lee16Immuno-Oncology, 23andMe, South San Francisco, CA, USAComputational Biology, 23andMe, South San Francisco, CA, USAAntibody and Protein Engineering, 23andMe, South San Francisco, CA, USAAntibody and Protein Engineering, 23andMe, South San Francisco, CA, USAIn Vivo Pharmacology, 23andMe, South San Francisco, CA, USAIn Vivo Pharmacology, 23andMe, South San Francisco, CA, USAIn Vivo Pharmacology, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USAComputational Biology, 23andMe, South San Francisco, CA, USAClinical Science, 23andMe, South San Francisco, CA, USAClinical Pharmacology, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USABiomarker Translation, 23andMe, South San Francisco, CA, USAImmuno-Oncology, 23andMe, South San Francisco, CA, USAImmune 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.https://www.tandfonline.com/doi/10.1080/2162402X.2023.221773723ME-00610cancer immunotherapyCD200CD200R1immune checkpoint |
| spellingShingle | Jill Fenaux Xin Fang Yao-ming Huang Cristina Melero Caroline Bonnans Earth Light Lowe Tiziana Palumbo Cecilia Lay Zuoan Yi Aileen Zhou Mauro Poggio Wei-Jen Chung Sophia R. Majeed Dylan Glatt Alice Chen Maike Schmidt Clarissa C. Lee 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function OncoImmunology 23ME-00610 cancer immunotherapy CD200 CD200R1 immune checkpoint |
| title | 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function |
| title_full | 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function |
| title_fullStr | 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function |
| title_full_unstemmed | 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function |
| title_short | 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function |
| title_sort | 23me 00610 a genetically informed first in class antibody targeting cd200r1 to enhance antitumor t cell function |
| topic | 23ME-00610 cancer immunotherapy CD200 CD200R1 immune checkpoint |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2217737 |
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