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British Journal of Cancer (2010) 102, 513 519& 2010 Cancer Research UK All rights reserved 0007 0920/10 $32.00
http://www.bjcancer.com
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Two novel human anti-ErbB2 immunoagents are active on trastuzumab-resistant tumours
T Gelardi1, V Damiano1, R Rosa1, R Bianco1, R Cozzolino2, G Tortora1, P Laccetti2, G DAlessio2and C De Lorenzo*,21Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universit di Napoli Federico II, via Pansini 5, Napoli 80131, Italy; 2Dipartimento di
Biologia Strutturale e Funzionale, Universit di Napoli Federico II, via Cinthia, Napoli 80126, Italy
BACKGROUND: Overexpression of ErbB2 receptor in breast cancer is associated with disease progression and poor prognosis. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer, has proven to be effective; however, a relevant problem for clinical practice is that a high fraction of breast cancer patients shows primary or acquired resistance to trastuzumab treatment.
METHODS: We tested on trastuzumab-resistant cells two novel human anti-tumour immunoconjugates engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either a human RNase or the Fc region of a human IgG1. Both Erbicin-derived immunoagents (EDIAs) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo, target an ErbB2 epitope different from that recognised by trastuzumab and do not show cardiotoxic effects.
RESULTS: We report that EDIAs are active also on trastuzumab-resistant tumour cells both in vitro and in vivo, most likely because of the different epitope recognised, as EDIAs, unlike trastuzumab, were found to be able to inhibit the signalling pathway downstream of ErbB2.
CONCLUSION: These results suggest that EDIAs are immunoagents that could not only fulfil the therapeutic need of patients ineligible to trastuzumab treatment due to cardiac dysfunction but also prove to be useful for breast cancer patients unresponsive to trastuzumab treatment.
British Journal of Cancer (2010) 102, 513519. doi:http://dx.doi.org/10.1038/sj.bjc.6605499
Web End =10.1038/sj.bjc.6605499 http://www.bjcancer.com
Web End =www.bjcancer.com Published online 5 January 2010& 2010 Cancer Research UK
Keywords: ErbB2/Her2; immunotherapy; ImmunoRNase; trastuzumab; resistance
TranslationalTherapeutics
Breast cancer is a disease with more than one million new diagnoses worldwide each year and with a high risk of metastases. Several studies have shown that up to 25% of breast cancers overexpress a member of the HER/ErbB transmembrane receptor tyrosine kinase family, ErbB2, associated with poor prognosis and with a...