title: Effects of a second-generation human anti-ErbB2 ImmunoRNase on trastuzumab-resistant tumors and cardiac cells.
abstract: The inhibition of ErbB2 by the use of human antibodies can be a valuable strategy for the treatment of breast and gastric cancer. Trastuzumab, a humanized anti-ErbB2 antibody in clinical use, is effective but can engender resistance as well as cardiotoxicity. ImmunoRNases, made up of a human anti-ErbB2 scFv and human pancreatic ribonucleases (HP-RNases), have been engineered to overcome the limits of other immunotoxins, such as immunogenicity and nonspecific toxicity. Here, we report that a novel anti-ErbB2 immunoRNase, called Erb-HPDDADD-RNase, obtained by fusing Erbicin, a human ErbB2-directed scFv, with an HP-RNase variant that resists the cytosolic inhibitor protein, binds with high affinity to a panel of ErbB2-positive gastric tumor cells and inhibits their growth more than does the parental immunoRNase, which is not resistant to the inhibitor. Moreover, Erb-HP-DDADD-RNase is endowed with antiproliferative activity for trastuzumab-resistant cancer cells both in vitro and in vivo that is more potent than that of the parental immunoRNase. Importantly, Erb-HP-DDADD-RNase does not show cardiotoxic effects in vitro on human cardiomyocytes and does not impair cardiac function in a mouse model. Thus, Erb-HP-DDADD-RNase could fulfil the therapeutic need of cancer patients ineligible for trastuzumab treatment due to primary or acquired trastuzumab resistance or to cardiac dysfunction.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University 'Federico II', Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Avino
authors.forename: Rolando
authors.initials: R
authors.lastname: Paciello
authors.forename: Gennaro
authors.initials: G
authors.lastname: Riccio
authors.forename: Carmela
authors.initials: C
authors.lastname: Coppola
authors.forename: Melina
authors.initials: M
authors.lastname: Coppola
authors.forename: Paolo
authors.initials: P
authors.lastname: Laccetti
authors.forename: Nicola
authors.initials: N
authors.lastname: Maurea
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
authors.forename: Claudia
authors.initials: C
authors.lastname: De Lorenzo
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D054715:Cardiotoxins / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000473:pathology; D015202:Protein Engineering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity*; D012259:Ribonuclease, Pancreatic / Q000737:chemistry* / Q000235:genetics; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054715:Cardiotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D012259:Ribonuclease, Pancreatic; D000068878:Trastuzumab
keywords: ErbB2; breast cancer; cardiotoxicity; gastric cancer; trastuzumab-resistance