We have engineered novel fully human anti-ErbB2 immunoagents: Erbicin, a human scFv (1); ERB-hRNase, a human immunoRNase made up of Erbicin fused to a human RNase (2); ERB-hcAb, a human, “compact” antibody, in which two Erbicin molecules are fused to the Fc of a human IgG1(3,4). Both ERB-hRNase and ERB-hcAb severely inhibit the growth of ErbB2-positive tumours sensitive and resistant to Trastuzumab treatment (5). Furthermore, they are not immunogenic and do not display cardiotoxic effects in vitro and in vivo whereas Trastuzumab was strongly toxic (6). An analysis by three independent methodologies of the interactions of Erbicin-Derived-ImmunoAgents (EDIAs) and Trastuzumab with the ErbB2 extracellular domain (ECD) led to the finding that EDIAs bind soluble ECD with a lower affinity than that for the native receptor on tumor cells. Trastuzumab instead shows a higher affinity for soluble ErbB2-ECD. Accordingly, ErbB2-ECD abolished the biological properties of Trastuzumab with no effects on those of EDIAs (7). These results suggest that the fraction of immunoagent neutralized by free ECD shed into the bloodstream is much higher for Trastuzumab than for EDIAs, thus the latter could be used at lower therapeutic doses compared to those employed with Trastuzumab. More interestingly, we found through the use of three different methods, that the epitope recognized by EDIAs is different from those recognized by Trastuzumab and Pertuzumab, and it is located in the domain I of the extracellular region of ErbB2. This finding could lead to the identification of novel epitopes on ErbB2 to be used as potential therapeutic targets to mitigate anti-ErbB2 associated cardiotoxicity and eventually overcome resistance. 1De Lorenzo, C.; Palmer, DB.; Piccoli, R; Ritter, MA.; and D'Alessio, G.; Clin. Cancer Res. 2002, 8, 1710-1719. 2De Lorenzo, C.; Arciello, A.; Cozzolino, R.; Palmer, DB.; Laccetti, P.; Piccoli, R; and D'Alessio, G.; Cancer Res. 2004, 64, 4870-4874. 3De Lorenzo, C.; Tedesco, A.; Terrazzano, G.; Cozzolino, R.; Laccetti, P.; Piccoli, R.; and D'Alessio, G.; Br. J. Cancer 2004, 91, 1200-1204. 4De Lorenzo, C.; Cozzolino, R.; Carpentieri, A.; Pucci, P.; Laccetti, P.; and D'Alessio, G.; Carcinogenesis 2005, 26 ,1890-1895. 5 Gelardi, T.; Damiano, V.; Rosa, R..; Bianco, R..; Cozzolino, R.; Tortora, G.; Laccetti, P.; D'Alessio, G.; and De Lorenzo, C; Br. J. Cancer 2010, 102, 513-519. 6 Riccio, G.; Esposito, G.; Leoncini, E.; Contu, R..; Condorelli, G.; Chiariello, M.; Laccetti, P.; Hrelia, S.; D'Alessio, G.; and De Lorenzo, C.; Faseb J. 2009, 23, 3171-3178 7Troise, F.; Cafaro,V.; Giancola, C.; D’Alessio G.; and De Lorenzo, C.; FEBS J. 2008, 275, 4967–4979.

A novel ErbB2 epitope targeted by Human antitumor Immunoagents

TROISE, FULVIA;MONTI, MARIA;MERLINO, ANTONELLO;Cozzolino F.;FEDELE, CARMINE;CAFARO, VALERIA;SICA, FILOMENA;PUCCI, PIETRO;DE LORENZO, CLAUDIA
2010

Abstract

We have engineered novel fully human anti-ErbB2 immunoagents: Erbicin, a human scFv (1); ERB-hRNase, a human immunoRNase made up of Erbicin fused to a human RNase (2); ERB-hcAb, a human, “compact” antibody, in which two Erbicin molecules are fused to the Fc of a human IgG1(3,4). Both ERB-hRNase and ERB-hcAb severely inhibit the growth of ErbB2-positive tumours sensitive and resistant to Trastuzumab treatment (5). Furthermore, they are not immunogenic and do not display cardiotoxic effects in vitro and in vivo whereas Trastuzumab was strongly toxic (6). An analysis by three independent methodologies of the interactions of Erbicin-Derived-ImmunoAgents (EDIAs) and Trastuzumab with the ErbB2 extracellular domain (ECD) led to the finding that EDIAs bind soluble ECD with a lower affinity than that for the native receptor on tumor cells. Trastuzumab instead shows a higher affinity for soluble ErbB2-ECD. Accordingly, ErbB2-ECD abolished the biological properties of Trastuzumab with no effects on those of EDIAs (7). These results suggest that the fraction of immunoagent neutralized by free ECD shed into the bloodstream is much higher for Trastuzumab than for EDIAs, thus the latter could be used at lower therapeutic doses compared to those employed with Trastuzumab. More interestingly, we found through the use of three different methods, that the epitope recognized by EDIAs is different from those recognized by Trastuzumab and Pertuzumab, and it is located in the domain I of the extracellular region of ErbB2. This finding could lead to the identification of novel epitopes on ErbB2 to be used as potential therapeutic targets to mitigate anti-ErbB2 associated cardiotoxicity and eventually overcome resistance. 1De Lorenzo, C.; Palmer, DB.; Piccoli, R; Ritter, MA.; and D'Alessio, G.; Clin. Cancer Res. 2002, 8, 1710-1719. 2De Lorenzo, C.; Arciello, A.; Cozzolino, R.; Palmer, DB.; Laccetti, P.; Piccoli, R; and D'Alessio, G.; Cancer Res. 2004, 64, 4870-4874. 3De Lorenzo, C.; Tedesco, A.; Terrazzano, G.; Cozzolino, R.; Laccetti, P.; Piccoli, R.; and D'Alessio, G.; Br. J. Cancer 2004, 91, 1200-1204. 4De Lorenzo, C.; Cozzolino, R.; Carpentieri, A.; Pucci, P.; Laccetti, P.; and D'Alessio, G.; Carcinogenesis 2005, 26 ,1890-1895. 5 Gelardi, T.; Damiano, V.; Rosa, R..; Bianco, R..; Cozzolino, R.; Tortora, G.; Laccetti, P.; D'Alessio, G.; and De Lorenzo, C; Br. J. Cancer 2010, 102, 513-519. 6 Riccio, G.; Esposito, G.; Leoncini, E.; Contu, R..; Condorelli, G.; Chiariello, M.; Laccetti, P.; Hrelia, S.; D'Alessio, G.; and De Lorenzo, C.; Faseb J. 2009, 23, 3171-3178 7Troise, F.; Cafaro,V.; Giancola, C.; D’Alessio G.; and De Lorenzo, C.; FEBS J. 2008, 275, 4967–4979.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/372455
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