Modulating kinase signaling in pulmonary fibroblasts

The National Heart, Lung, and Blood Institute awarded $174,296 to The Regents of the University of California, San Francisco on December 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837). This Project Grant (F32HL184606) supports development of antibody-drug conjugates (ADCs) to specifically target small molecule kinase inhibitors and kinase-directed molecular glue degraders to pathogenic fibroblasts in pulmonary fibrosis. The recipient will use single-cell transcriptomics data to characterize collagen-producing fibroblast subpopulations in murine lung injury models, identify fibroblast-specific or fibroblast-subset-specific cell surface markers, and synthesize antibodies against those targets. The work aims to improve the therapeutic window of kinase inhibitors that have shown early clinical efficacy but were not developed further due to systemic toxicity. Performance occurs in San Francisco, California, with an ultimate completion date of June 30, 2028.

Abstract

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. In this proposal, we aim to develop antibody-drug conjugates (adcs) with the goal of specifically targeting small molecule kinase inhibitors and kinase directed molecular glue degraders to pathogenic fibroblasts. We hypothesize that adcs will specifically target kinase inhibition to fibroblasts or fibroblast subsets in pulmonary fibrosis and will thus allow the development of safer and more effective treatments. To identify methods to target fibroblasts specifically, we used data from single cell transcriptomics to precisely characterize collagen producing cell subpopulations in murine lung injury models. We identified multiple fibroblast subsets with distinct anatomical localization and variable activation of profibrotic pathways enabling migration, proliferation, and collagen production. We hypothesize that these subpopulations are directly responsible for pathogenic tissue fibrosis, and that specifically targeting all fibroblasts or subpopulations that emerge in PF could improve the therapeutic window of candidate drugs. We have identified cell surface expression proteins broadly expressed by fibroblasts or specifically induced in emergent subpopulations, cross- referenced them to proteomics data, and synthesized published antibodies against these targets. We have selected five kinase signaling pathways that are shown to be aberrantly regulated and functionally important in PF with effective inhibitors limited by systemic toxicity. We will use a well validated synthetic route for cleavable self-immolative linkage to antibody. Of these inhibitors, two are scaffolds for commercially available molecular glue degraders which we will test individually and conjugated to adcs. We will first test adcs in vitro in proliferation, migration, and collagen production assays. We will subsequently test the most potent adcs in a murine model of pulmonary fibrosis and in precision-cut lung slices from patients with idiopathic pulmonary fibrosis. We anticipate that these adcs will have improved efficacy and toxicity profiles. At completion, this project will generate novel antibody-drug conjugates for the study of fibroblasts and fibroblast subpopulations in pulmonary fibrosis. The data generated from these tools will provide mechanistic insights into the roles these cells play in pulmonary fibrosis, complementing existing genetic tools. In the longer term, we will apply this paradigm to the development of cell type specific therapies for pulmonary fibrosis, which will represent a new avenue for cell- and organ- specific targeted therapeutics for this currently incurable disease.