153P - 23ME-01473, an Fc-enhanced anti-ULBP6/2/5 antibody, restores anti-tumor NK cell function through NKG2D and FcgRIIIa activation

Background

ULBP6 is a stress-induced, high affinity NKG2D ligand that can be shed by tumors into a soluble form to attenuate NK and T cell activity, and was identified as a novel immuno-oncology drug target from the 23andMe genetic database. Here, we characterize the ability of 23ME-01473, an Fc-enhanced anti-ULBP6/2/5 antibody, to block the immunosuppressive effects of soluble ULBP6 (sULBP6) and restore anti-tumor immunity. Further, we describe the prevalence of tumor and sULBP6/2/5 in cancers to support the evaluation of 23ME-01473 in a phase1/2a clinical trial in patients with advanced solid tumors.

Methods

Co-cultures of healthy donor PBMCs and COV644 cells were used to assess the effects of targeting soluble and membrane ULBP6 with 23ME-01473. Human ULBP6 was overexpressed in an MC38 mouse model to evaluate its effects in vivo. To profile the levels of (s)ULBP6/2/5 in cancer, mRNA was analyzed from publicly available data, and ISH, IHC, and MSD assays were developed and validated in human and mouse tumors and plasma.

Results

As the dominant inhibitory soluble NKG2D ligand, sULBP6 suppressed immune cell IFNγ secretion and promoted tumor cell growth. Moreover, ULBP6 overexpression in an MC38 model decreased tumor infiltration of NK and CD8+ T cells in vivo. 23ME-01473-mediated restoration of NKG2D activation by blocking sULBP6 from binding NKG2D resulted in immune cell cytokine release and tumor cell killing. Given its ability to also bind cell surface ULBP6/2/5, 23ME-01473 was purposefully designed with an Fc-enhanced domain to activate FcγRIIIa and induce ADCC, which is synergistic with NKG2D activation to enhance anti-tumor immunity. Elevated plasma sULBP6/2/5 and tumor membrane ULBP6/2/5 levels were confirmed in squamous cell carcinomas and a subset of adenocarcinomas, which may be promising tumors to assess 23ME-01473 clinical activity. Moreover, sULBP6/2/5 in circulation may be used to monitor ligand shedding and total ULBP6/2/5 burden.

Conclusions

23ME-01473 is a novel anti-ULBP6/2/5 that reverses sULBP6-mediated immunosuppression and activates NKG2D and FcγRIIIa to synergistically enhance NK-mediated anti-tumor immunity, and may have potential anti-tumor activity in diverse tumors.

Clinical trial identification

NCT06290388; March 4, 2024.

Editorial acknowledgement

Legal entity responsible for the study

23andMe, Inc.

Funding

23andMe, Inc., GSK.

Disclosure

K. Gerrick, A. Jarret, C. Hom, A.N. Diep, S. Shi, G. Fuh: Financial Interests, Institutional, Full or part-time Employment: 23andMe, Inc; Financial Interests, Institutional, Stocks/Shares: 23andMe, Inc. P. Sood, M. Schmidt: Financial Interests, Institutional, Full or part-time Employment: 23andMe, Inc; Financial Interests, Stocks/Shares: 23andMe, Inc. J. Benjamin, S. Yadav, D. Ayupova, I. Chen, D. Kellar, C. Bonnans, P. Koenig, M. Poggio: Financial Interests, Institutional, Stocks/Shares: 23andMe, Inc.