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Updated: May 21, 2025
Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
23ME-01473, an Fc Effector-Enhanced Anti-ULBP6/2/5 Antibody, Restores NK Cell-Mediated Antitumor Immunity through
Joel S Benjamin1, Abigail Jarret1, Shashank Bharill1
123andMe, Inc. Therapeutics, South San Francisco, California.
Abstract:
The landscape of cancer treatment has been transformed by immune checkpoint inhibitors; however, the failure to benefit a large number of patients with cancer has underlined the need to identify promising targets for more effective interventions. In this study, we leverage 23andMe, Inc.’s large-scale human germline genetic and health database to uncover the previously unknown role of UL16-binding protein 6 (ULBP6), a high-affinity NK group 2D (NKG2D) ligand, in cancer and its promise as an immuno-oncology therapeutic target. We confirm ULBP6 expression in human tumors and demonstrate that soluble ULBP6 shed from tumors circumvents NKG2D activation provided by membrane-anchored NKG2D ligands to inhibit immune cell activation and tumor cell killing. Based on these findings, we developed 23ME-01473, a humanized Fc effector–enhanced antibody that binds to ULBP6 and its closely related family members, ULBP2 and ULBP5. 23ME-01473 effectively blocks soluble ULBP6-mediated immunosuppression to restore the NKG2D axis on NK and T cells to elicit tumor growth control. Moreover, the Fc effector–enhanced design of 23ME-01473 increases its binding affinity to fragment crystallizable gamma receptor IIIa, which, together with 23ME-01473’s binding to membrane-anchored ULBP6/2/5 on cancer cells, allows for augmented antibody-dependent cellular cytotoxicity induction, providing a second activation node for NK cells. Our studies demonstrate the therapeutic potential of an Fc effector–enhanced anti-ULBP6/2/5 antibody to reinvigorate NK cell and T-cell activation and cytotoxicity for the treatment of cancer.
Significance:
This study emphasizes the utility of population-based genome-wide assessments for discovering naturally occurring genetic variants associated with lifetime risks for cancer or immune diseases as novel drug targets. We identify ULBP6 as a potential keystone member of the NKG2D pathway, which is important for antitumor immunity. Targeting ULBP6 may hold therapeutic promise for patients with cancer.
Insights
Researchers identified ULBP6 as a novel target in cancer immunotherapy. An antibody targeting ULBP6 restores immune cell activation, showing promise for treating various cancers.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Immune checkpoint inhibitors have advanced cancer treatment, but many patients do not benefit.
- Novel therapeutic targets are needed to improve cancer immunotherapy efficacy.
- The NKG2D pathway is crucial for anti-tumor immunity.
Purpose of the Study:
- To investigate the role of UL16-binding protein 6 (ULBP6) in cancer.
- To explore ULBP6 as a potential immuno-oncology therapeutic target.
- To develop and evaluate an antibody targeting ULBP6.
Main Methods:
- Leveraged a large-scale human germline genetic and health database.
- Confirmed ULBP6 expression in human tumors.
- Developed a humanized Fc effector–enhanced antibody (23ME-01473) targeting ULBP6, ULBP2, and ULBP5.
- Assessed antibody's ability to block soluble ULBP6-mediated immunosuppression and induce antibody-dependent cellular cytotoxicity (ADCC).
Main Results:
- Soluble ULBP6 inhibits immune cell activation and tumor cell killing by circumventing NKG2D activation.
- The antibody 23ME-01473 effectively blocks soluble ULBP6 immunosuppression.
- 23ME-01473 restores NKG2D pathway activation on NK and T cells, controlling tumor growth.
- The antibody's Fc effector enhancement boosts ADCC induction via FcγRIIIa engagement.
Conclusions:
- ULBP6 plays a significant role in cancer immune evasion.
- Targeting ULBP6 with an Fc effector–enhanced antibody can reinvigorate anti-tumor immunity.
- This approach shows therapeutic potential for cancer treatment by enhancing NK and T cell activity.
