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A2235 - Human Anti- Wnt1-Inducible Signaling Protein (WISP) 1 Antibodies Attenuate Experimental Lung Fibrosis Ex Vivo
Author Block: M. Lehmann1, S. Klee2, G. Kaufmann3, M. Koenigshoff4; 1CPC, Helmholtz-Zentrum Munich, München, Germany, 2CPC, Helmholtz Zentrum München, Munich, Germany, 3Sorrento Therapeutics, Inc., San Diego, CA, United States, 4Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Denver, Aurora, CO, United States.
Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by dysfunctional lung epithelium leading to fibrotic remodeling and impaired lung function. The Wnt1-inducible signaling protein (WISP) 1, a common downstream mediator of different pro-fibrotic signaling pathways, is highly upregulated in IPF and experimental lung fibrosis. Previous studies have demonstrated that neutralizing WISP1 led to attenuation of experimental lung fibrosis in vivo. Here, we aimed to develop and further validate human antibodies targeting WISP1. Methods: We generated and tested fully human anti-WISP1 antibodies to assess anti-fibrotic activity and identify promising antibody candidates for further studies. Anti-WISP1 antibodies were tested towards their anti-fibrotic activity on primary human lung fibroblasts (phLFs) using a WST-1 proliferation assay and imaging. Selected antibodies were further analyzed for potential anti-fibrotic capacity on 3D lung tissue cultures (3D-LTCs) ex vivo derived from mice with experimental lung fibrosis. Results: Out of several antibodies tested, we found three antibodies to induce a significant reduction of the cell numbers as evident in microscopic images and in the metabolic activity of the phLF. Of note, the effect size of the newly developed human anti-WISP1 antibodies was greater than the commercially available antibody (more than 30% reduction as opposed to 10%). We treated healthy and fibrotic murine 3D-LTCs with these antibodies and found reductions in profibrotic marker gene expression including collagens (Col1a1, Col5a3), fibronectin, and WISP1. Notably, these effects were dominantly found in fibrotic 3D-LTCs, while none of the fibrotic markers were significantly altered in non-fibrotic 3D-LTCs upon treatment with anti-WISP1 antibodies. Conclusions: We identified novel human anti-WISP1 antibody clones possessing anti-fibrotic properties ex vivo and thus might represent promising therapeutic candidates for the treatment of IPF patients.