B77-22 Mesenchymal Targeted Therapeutics for Selectively Modulating Kinase Signaling in Pulmonary Fibrosis

Abstract Rationale Pulmonary fibrosis (PF) is a devastating disease process where the lung replaces functional tissue with scar, causing disability and death. Current therapeutics have modest benefit and are difficult for patients to tolerate. Kinase inhibitors have been tested in clinical trials for PF and several candidates have shown early phase efficacy but were not developed further due to systemic toxicity. We describe an antibody-drug conjugate (ADC) approach with the goal of specifically targeting small molecule kinase inhibitors and kinase directed molecular glue degraders to pathogenic fibroblasts. We hypothesize that targeted inhibition of kinase signaling in mesenchymal cells will allow the development of better tolerated and more effective treatments in pulmonary fibrosis. Methods We used single cell transcriptomics to characterize collagen producing cell subpopulations in a murine model of pulmonary fibrosis and identify cell surface markers. We synthesized antibodies against proteins broadly expressed by fibroblasts or specifically induced in emergent fibroblasts. We synthesized and chemically characterized kinase inhibitors conjugated to a cleavable self-immolative ADC linker and synthesized ADCs. We tested antibodies, kinase inhibitors, and molecular glue degraders in assays evaluating proliferation, collagen production, and differentiation in human and mouse primary pulmonary fibroblasts. Results Monoclonal antibodies targeting surface markers enriched in fibroblasts bind cultured human and/or mouse fibroblasts. Tested antibodies, kinase inhibitors, molecular glue degraders, and ADCs modulate Col1A1 and CTHRC mRNA levels to variable degrees. Conclusions We have synthesized antibody-drug conjugates targeting kinase signaling in mesenchymal cells and characterized their effects in vitro in MRC-5 cells and in murine primary fibroblasts. Best candidates will be tested in a murine model of pulmonary fibrosis and in precision-cut lung slices from human patients with idiopathic pulmonary fibrosis. This abstract is funded by: NIH, HHMI