title: RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis.
abstract: Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR cross-linking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis. Mol Cancer Ther; 15(5); 946-57. ©2016 AACR.
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Brünker
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wartha
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grau-Richards
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Claudia Ferrara
authors.initials: CF
authors.lastname: Koller
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Weiser
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Meher
authors.initials: M
authors.lastname: Majety
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Valeria
authors.initials: V
authors.lastname: Runza
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, New York.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Niu
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, New York.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, New York.
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, New York.
authors.forename: Sherif
authors.initials: S
authors.lastname: Daouti
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Hosse
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Mössner
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Weber
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Scheuer
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Hadassah
authors.initials: H
authors.lastname: Sade
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Shao
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
authors.forename: Gary
authors.initials: G
authors.lastname: Xu
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Vega-Harring
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bosslet
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. pablo.umana@roche.com.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umaña
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018093:Gelatinases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C505639:TNFRSF10B protein, human; C548876:drozitumab