Differential binding of human immunoagents and Herceptin to the ErbB2 receptor

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Abstract
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.