Differential binding of human immunoagents and Herceptin to the ErbB2 receptor.
Overexpression of the ErbB2 receptor is associated with the progression of breast cancer, and is a sign of a poor prognosis. Herceptin, a humanized antibody directed to the ErbB2 receptor, has been proven to be effective in the immunotherapy of breast cancer. However, it can result in cardiotoxicity, and a large fraction of breast cancer patients are resistant to Herceptin treatment. We have engineered three novel, fully human, anti-ErbB2 immunoagents: Erbicin, a human single-chain antibody fragment; ERB-hRNase, a human immunoRNase composed of Erbicin fused to a human RNase; ERB-hcAb, a human 'compact' antibody in which two Erbicin molecules are fused to the Fc fragment of a human IgG1. Both ERB-hRNase and ERB-hcAb strongly inhibit the growth of ErbB2-positive cells in vivo. The interactions of the Erbicin-derived immunoagents and Herceptin with the extracellular domain of ErbB2 (ErbB2-ECD) were investigated for the first time by three different methods. Erbicin-derived immunoagents bind soluble extracellular domain with a lower affinity than that measured for the native antigen on tumour cells. Herceptin, by contrast, shows a higher affinity for soluble ErbB2-ECD. Accordingly, ErbB2-ECD abolished the in vitro antitumour activity of Herceptin, with no effect on that of Erbicin-derived immunoagents. These results suggest that the fraction of immunoagent neutralized by free extracellular domain shed into the bloodstream is much higher for Herceptin than for Erbicin-derived immunoagents, which therefore may be used at lower therapeutic doses than those employed for Herceptin.
Troise
Fulvia
F
Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Italy.
Cafaro
Valeria
V
Giancola
Concetta
C
D'Alessio
Giuseppe
G
De Lorenzo
Claudia
C
D000906:Antibodies / Q000235:genetics / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007128:Immunoglobulin Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab