194 Characterization of the pharmacodynamic activity of CLN-619, an anti-MICA/B monoclonal antibody, in patients from an ongoing Phase 1 trial

BackgroundCLN-619 is a human IgG1 antibody that binds to and prevents proteolytic cleavage of NKG2D ligands MICA/B from the surface of tumor cells, thereby increasing tumor cell killing by innate and adaptive immune cells. CLN-619 is currently being investigated in a Phase I clinical trial in patients with advanced solid tumors as a monotherapy and in combination with pembrolizumab (NCT05117476). CLN-619 monotherapy demonstrated a favorable safety profile and objective RECIST responses in patients with multiple solid tumor types. Here we report pharmacodynamic activities associated with CLN-619 monotherapy.MethodsThe monotherapy arm enrolled patients with advanced solid tumors to receive escalating doses of CLN-619 administered IV on a Q3W schedule. Serum samples, archival tumor samples, and pre-/on-treatment biopsies were collected. Soluble MICA (sMICA) concentration in serum was measured by ELISA. Membrane expression of MICA/B was analyzed by IHC. Multiplex immunofluorescence was used to assess tumor expression of MICA/B, CD8 T cell and NK cell infiltration and activation in response to CLN-619 in 8 paired biopsies collected at doses of 3 mg/kg (N=4), 6 mg/kg (N=3), and 10mg/kg (N=1) from patients with stable and/or progressive disease. Tumor mutational burden and gene expression were assessed by WES and RNASeq, respectively. MICA/B, FcγRIIIA and NKG2D genotyping were performed by targeted NGS or real-time PCR.ResultsAs a measure of target engagement, levels of sMICA were assessed in serum samples at baseline and following CLN-619 treatment. sMICA concentrations increased up to 10-fold in a CLN-619 dose-dependent manner and were accurately captured by the PK/PD model, suggesting that sMICA is stabilized in patients’ sera by binding to CLN-619. Consistent with the proposed mechanisms of action, intratumoral pharmacodynamic effects have been observed in patients dosed with CLN-619. Intratumoral MICA/B expression increased 2 to >100 fold on-treatment in 4/5 paired tumor biopsies. Notably, MICA/B localization to the tumor cell membrane increased in agreement with preclinical data showing stabilization of MICA/B on the cell surface in the presence of CLN-619. NK cell and TIL infiltration and activation were increased 2–4 fold in 3/8 and 3/7 paired tumor biopsies, respectively. Characterization of gene expression profiles and mutational analysis of tumor biopsies is ongoing.ConclusionsPharmacodynamic data presented here are consistent with the proposed mechani