Abstract 5297: CLN-619, a clinical stage MICA/B-specific hIgG1 monoclonal antibody, engages multiple immune effector cells to promote anti-tumor activity

Abstract

Abstract CLN-619 is a humanized IgG1 monoclonal antibody that targets MICA and MICB (MICA/B) and is currently in phase 1 clinical development in cancer patients (NCT05117476). MICA/B serve as activating signals on target cells for recognition by the NKG2D receptor, which is expressed on NK cells and a subset of T cell populations. MICA/B expression is induced in response to stressed conditions, thereby enabling NKG2D-mediated elimination of target cells. On NK cells, NKG2D is one of many receptors in the complex network of activating and inhibitory receptors, whereby NKG2D pathway activation results in cytokine production, enhancement of ADCC and target cell death. On CD8 T cells, the NKG2D axis plays a costimulatory role in lowering the threshold for lysis upon TCR engagement, and may also drive direct CD8-mediated killing following prior TCR activation. MICA/B is expressed broadly on a range of solid and hematological malignancies. However, tumor cells evade NKG2D-mediated elimination by shedding MICA/B ligand from the cell surface via proteases present in the tumor microenvironment (TME). CLN-619 functions by binding to MICA/B and preventing shedding, thereby increasing MICA/B cell surface expression to restore the NKG2D-MICA/B axis to promote tumor cell killing by NK cells and T cells. Additionally, CLN-619 can mediate ADCC and ADCP by NK cells and macrophages. In preclinical xenograft models, doses as low as 0.03 mg/kg inhibited tumor outgrowth. We investigated the effects of CLN-619 on a variety of primary immune cells including NK cells, T cells and macrophages. In the evaluation of NK cells, we measured CLN-619 modulation of cytokine production and cytotoxicity in the presence of MICA/B expressing target cells. In addition, we demonstrated the contribution of Fc-mediated functions of CLN-619. In the context of T cells, we explored the requirement of TCR co-stimulation or prior antigen exposure in the activation of the NKG2D pathway by CLN-619. In the context of macrophages, we measured the ability of CLN-619 to mediate ADCP against MICA/B-expressing target cells. These data highlight the potential of CLN-619 to engage multiple immune cell types within the TME, which may lead to greater and broader efficacy compared to IO therapies targeting a single immune cell type. Citation Format: Kerry A. Whalen, Catherine C. Henry, Kavya Rakhra, Kristan Meetze, Jennifer S. Michaelson, Patrick A. Baeuerle. CLN-619, a clinical stage MICA/B-specific hIgG1 monoclonal antibody, engages multiple immune effector cells to promote anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5297.