Data from RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

• DOI: 10.1158/1535-7163.c.6538687.v1
• Publication Date: 2023-04-03T20:48:33Z
• Authors: Peter Brünker; Katharina Wartha; Thomas Friess; Sandra Grau-Richards; Inja Waldhauer; Claudia Ferrara K...; Barbara Weiser; Meher Majety; Valeria Runza; Huifeng Niu; Kathryn Packman; Ningping Feng; Sherif Daouti; Ralf J. Hosse; Ekkehard Mössner; Thomas G. Weber; Frank Herting; Werner Scheuer; Hadassah Sade; Cuiying Shao; Bin Liu; Peng Wang; Gary Xu; Suzana Vega-Harring; Christian Klein; Klaus Bosslet; Pablo Umaña
• Keywords: Avidity

<div>Abstract<p>Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation disease progression. Therefore, the development agents that overcome dysregulation in tumor cells is an attractive therapeutic approach. Activation extrinsic apoptotic pathway strongly dependent on receptor (DR) hyperclustering surface. However, strategies activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue alternative approach for tumor-targeted induction apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) cancer-associated fibroblasts stroma cells. We hypothesized bivalent binding both FAP leads avidity-driven subsequently strong but not normal Here, show RG7386, optimized FAP-DR5 BsAb, triggers potent <i>in vitro</i> vivo</i> preclinical models with FAP-positive stroma. RG7386 antitumor efficacy was strictly dependent, independent FcR cross-linking, superior conventional antibodies. In combination irinotecan doxorubicin, treatment resulted substantial regression patient-derived xenograft models. also demonstrated single-agent activity against FAP-expressing malignant cells, due cross-binding across Taken together, these data demonstrate novel agent mono- therapies, overcomes limitations previous represents promising conquer tumor-associated apoptosis. <i>Mol Cancer Ther; 15(5); 946–57. ©2016 AACR</i>.</p></div>