title: A novel ErbB2 epitope targeted by human antitumor immunoagents.
abstract: Two novel human antitumor immunoconjugates, engineered by fusion of a single-chain antibody fragment against human ErbB2 receptor, termed Erbicin, with either a human RNase or the Fc region of a human IgG(1) , are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. These Erbicin-derived immunoagents (EDIAs) do not show the most negative properties of Herceptin, the only humanized mAb against ErbB2 used in the therapy of breast carcinoma: cardiotoxicity and the inability to act on resistant tumors. These differences are probably attributable to the different ErbB2 epitopes recognized by EDIAs and Herceptin, respectively, as we have previously reported that they induce different signaling mechanisms that control tumor and cardiac cell viability. Thus, to accurately identify the novel epitope recognized by EDIAs, three independent and complementary methodologies were used. They gave coherent results, which are reported here: EDIAs bind to a different ErbB2 epitope than Herceptin and the other human/humanized antibodies against ErbB2 reported so far. The epitope has been successfully located in region 122-195 of extracellular domain I. These findings could lead to the identification of novel epitopes on ErbB2 that could be used as potential therapeutic targets to mitigate anti-ErbB2-associated cardiotoxicity and eventually overcome resistance.
authors.affiliation: Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Troise
authors.forename: Maria
authors.initials: M
authors.lastname: Monti
authors.forename: Antonello
authors.initials: A
authors.lastname: Merlino
authors.forename: Flora
authors.initials: F
authors.lastname: Cozzolino
authors.forename: Carmine
authors.initials: C
authors.lastname: Fedele
authors.forename: Irene
authors.initials: I
authors.lastname: Russo Krauss
authors.forename: Filomena
authors.initials: F
authors.lastname: Sica
authors.forename: Piero
authors.initials: P
authors.lastname: Pucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Alessio
authors.forename: Claudia
authors.initials: C
authors.lastname: De Lorenzo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology; D003198:Computer Simulation; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000939:Epitopes; D018796:Immunoconjugates; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab