title: A FcγRIII-engaging bispecific antibody expands the range of HER2-expressing breast tumors eligible to antibody therapy.
abstract: Trastuzumab is established as treatment of HER2high metastatic breast cancers but many limitations impair its efficacy. Here, we report the design of a Fab-like bispecific antibody (HER2bsFab) that displays a moderate affinity for HER2 and a unique, specific and high affinity for FcγRIII. In vitro characterization showed that ADCC was the major mechanism of action of HER2bsFab as no significant HER2-driven effect was observed. HER2bsFab mediated ADCC at picomolar concentration against HER2high, HER2low as well as trastuzumab-refractive cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth by recruitment of mouse FcγRIII and IV-positive resident effector cells and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2low tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of V/F158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Thus, taking advantage of its epitope specificity and affinity for HER2 and FcγRIIIA, HER2bsFab exhibits potent anti-tumor activity against HER2low tumors while evading most of trastuzumab Fc-linked limitations thereby potentially enlarging the number of patients eligible for breast cancer immunotherapy.
authors: INSERM, U1068, CRCM, Marseille, France. Institut Paoli-Calmettes, Marseille, France. Aix-Marseille Université, UM105, Marseille, France. CNRS, UMR7258, CRCM, Marseille, France.
authors: Marc
authors: M
authors: Turini
authors: INSERM, U1068, CRCM, Marseille, France. Institut Paoli-Calmettes, Marseille, France. Aix-Marseille Université, UM105, Marseille, France. CNRS, UMR7258, CRCM, Marseille, France.
authors: Patrick
authors: P
authors: Chames
authors: Département d'Immunologie, Laboratoire Anticorps en Thérapie et Pathologie, Institut Pasteur, Paris, France. INSERM, U760, Paris, France.
authors: Pierre
authors: P
authors: Bruhns
authors: INSERM, U1068, CRCM, Marseille, France. Institut Paoli-Calmettes, Marseille, France. Aix-Marseille Université, UM105, Marseille, France. CNRS, UMR7258, CRCM, Marseille, France.
authors: Daniel
authors: D
authors: Baty
authors: INSERM, U1068, CRCM, Marseille, France. Institut Paoli-Calmettes, Marseille, France. Aix-Marseille Université, UM105, Marseille, France. CNRS, UMR7258, CRCM, Marseille, France.
authors: Brigitte
authors: B
authors: Kerfelec
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C508053:ERBB2 protein, human