Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody–Drug Conjugate Targeting Fibroblast Activation Protein

• DOI: 10.1158/2767-9764.crc-24-0248
• Publication Date: 2024-05-15T12:52:56Z
• Authors: Joseph P. Gallant; Hallie M. Hintz; Gihan S. Gunaratne; Matthew T. Breneman; Emma E. Recchia; Jayden L. West; Kendahl L. Ott; Erika Heninger; Abigail E. Jackson; Natalie Y. Luo; Zachary T. Rosenk...; Reinier Hernandez; Shuang G. Zhao; Joshua M. Lang; Labros Meimetis; David Kosoff; Aaron M. LeBeau
• Keywords: 0301 basic medicine; Immunoconjugates; Serine Endopeptidases; Membrane Proteins; Xenograft Model Antitumor Assays; Mice; 03 medical and health sciences; Cancer-Associated Fibroblasts; Gelatinases; Cell Line, Tumor; Endopeptidases; Tumor Microenvironment; Humans; Animals; Female; Oligopeptides; Research Article

Cancer-associated fibroblasts (CAF) are a prominent cell type within the tumor microenvironment (TME) where they known to promote cancer growth and survival, angiogenesis, drug resistance, immunosuppression. The transmembrane prolyl protease fibroblast activation protein (FAP) is expressed on surface of highly protumorigenic CAFs found in stroma nearly every epithelial origin. widespread expression FAP has made it an attractive therapeutic target based underlying hypothesis that eliminating will disrupt cross-talk between components TME resulting death immune infiltration. This hypothesis, however, never been directly proven. To eliminate FAP-expressing CAFs, we developed antibody-drug conjugate using our anti-FAP antibody, huB12, coupled monomethyl auristatin E (huB12-MMAE) payload. After determining huB12 was effective targeting vector, huB12-MMAE potently eliminated cells as monocultures vitro significantly prolonged survival vivo xenograft engineered overexpress FAP. We investigated effects selectively layered, open microfluidic coculture platform, Stacks. Analysis mRNA treatment with resulted increased secretion proinflammatory cytokines IL6 IL8 by associated increase genes cells. also detected CSF1, cytokine involved myeloid recruitment differentiation. Our findings suggest mechanism FAP-targeted therapies through antitumor response.