Abstract 3506: CLN-619, a clinical-stage MICA/MICB-specific IgG1 antibody, restores the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis
Authors: Whalen Kerry A. , Mehta Naveen K. , Yalcin Safak , Meetze Kristan , Gibson Neil W. , Michaelson Jennifer S. , Baeuerle Patrick A. 
Published: June 2022

Abstract
Natural killer (NK) cells play a central role in the immune surveillance of cancer. NK cells express multiple inhibitory and activating surface receptors, including the activating receptor, NKG2D. Engagement of NKG2D by the stress-induced ligands MICA/MICB stimulates NK cell activation and subsequent target cell lysis. While MICA/MICB expression is restricted in normal tissues, expression is strongly induced upon viral infection, genotoxic stress or malignant transformation. In cancer patients, the tumor microenvironment (TME) facilitates evasion of immune surveillance by NK cells. One mechanism by which tumor cells can escape NKG2D-mediated lysis is via proteolytic release of MICA/MICB from the cell surface due to proteases present in the TME. High concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. In mouse models, expression of MICA on tumor cells delayed tumor growth, while the absence of NKG2D accelerated tumor growth. Given the established role of the MICA/MICB-NKG2D axis in the immune surveillance of tumor cells, a therapeutic agent that effectively restores this axis is a compelling approach to harness the immune system for treating cancer. CLN-619 is a humanized anti-MICA/MICB monoclonal IgG1 antibody being developed for the treatment of multiple cancer indications. The antibody was selected based on its high-affinity binding to MICA/MICB, potent in vitro activity and robust anti-tumor activity in xenograft models. MICA/MICB is highly polymorphic, with &gt;150 MICA and 47 MICB alleles in humans, and expression level, binding affinity to NKG2D, and degree of MICA/MICB shedding is thought to be allele-dependent. CLN-619 demonstrated high affinity binding to all common allelic variants of MICA, including the most prevalent MICA allele, MICA*008, and the canonical allelic variant of MICB. CLN-619 was able to prevent proteolytic cleavage of MICA/MICB as evidenced by the reduction of shed MICA/MICB in cell culture supernatants and the corresponding increase in surface MICA/MICB on cancer cells. In addition to the ability to restore the MICA/MICB-NKG2D axis, CLN-619 enhanced the binding of MICA to NKG2D on NK cells. This was enabled by both FcγR engagement on NK cells as well as an intrinsic enhancement of MICA binding to NKG2D. Finally, CLN-619 was shown to elicit potent ADCC of MICA/MICB expressing tumor cells. Consistent with the multimodal mechanisms of action described above, CLN-619 treatment resulted in robust anti-tumor activity at low doses in mice bearing MICA/MICB-expressing human tumor xenografts. Given the pan-cancer expression of MICA/MICB in both solid and hematological malignancies, CLN-619 is expected to have broad anti-tumor activity. CLN-619 is currently being investigated in a Phase 1 clinical trial for the treatment of patients with advanced solid tumors.
Citation Format: Kerry A. Whalen, Naveen K. Mehta, Safak Yalcin, Kristan Meetze, Neil W. Gibson, Jennifer S. Michaelson, Patrick A. Baeuerle. CLN-619, a clinical-stage MICA/MICB-specific IgG1 antibody, restores the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3506.