195 Pharmacodynamic activities of the anti-MICA/B monoclonal antibody CLN-619, evaluated as a monotherapy, support the proposed mechanisms of action and correlate with response

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Background CLN-619 is a humanized IgG1 antibody that binds to and prevents proteolytic release of the NKG2D ligands MICA and MICB (MICA/B) from the surface of tumor cells, increasing cell killing by innate and adaptive immune cells in the tumor microenvironment (TME). CLN-619 as a monotherapy and in combination with pembrolizumab demonstrated a favorable safety profile and objective RECIST responses in patients with multiple solid tumor types in a Phase I clinical trial (NCT05117476).1 Here we report pharmacodynamic activities associated with CLN-619 monotherapy. Methods Patients with advanced solid tumors received escalating doses of CLN-619 administered IV by a Q3W schedule. Serum, whole blood, and paired tumor biopsies were collected from patients at baseline and on-treatment including 12 paired biopsies from patients dosed at 3 mg/kg (N=2), 6 mg/kg (N=2), or 10 mg/kg (N=8). MICA/B membrane expression was assessed by immunohistochemistry. Tumor samples were examined using multiplexed immunofluorescence panels comprised of T cell and NK cell markers. Peripheral blood mononuclear cells (PBMC) were analyzed via flow cytometry to detect changes in T cell and NK cell numbers and activation status. Patients who achieved confirmed complete response, partial response or stable disease (>18 weeks) by RECIST criteria were defined as ‘responders’ for the purpose of this analysis. Results Pharmacodynamic changes consistent with the proposed mechanism of action of CLN-619 were observed in on-treatment tumor biopsies. This included increased MICA/B membrane expression (7/12 pairs: 5/5 Responders (R); 2/7 Non-Responders (NR)), increased CD56+/NKG2D+ cell infiltration in tumor (5/12 pairs: 4/5 R; 1/7 NR) and stroma (5/12 pairs: 3/5 R; 2/7 NR), and reduction of CD4+/FOXP3+ cell infiltration in tumor (7/12 pairs: 3/5 R; 4/7 NR) and stroma (8/12 pairs: 4/5 R; 3/7 NR). These results were consistent with on-treatment pharmacodynamic changes in PBMCs including a decrease in CD4+/FOXP3+ T cells, and dose-dependent increase in NKG2D+ cells, with the greatest changes observed in responders patients. CLN-619 also induced a dose- and time- dependent increase in activated T cells in the periphery. Conclusions The pharmacodynamic data presented here supports the proposed mechanisms of action of CLN-619, i.e., the stabilization of MICA/B expression on the tumor cell surface thereby enabling engagement of NKG2D+ cells in the tumor and periphery, coupled with alterations in immune cell subsets. Furthermore, these changes appear associated with response. The results emphasize the potential of CLN-619 as a novel immunotherapy for the treatment of a range of solid tumors. Trial Registration NCT05117476. References Bermejo I, Wang J, Gutierrez M, et al. ‘CLN-619 (anti-MICA/MICB antibody) alone and in combination with pembrolizumab for advanced solid tumors: Updated results of a phase 1 study’, Poster Presented at 2024 ASCO May 31st-June 4th.

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