IN THIS ISSUE

Extract

Geldanamycin/MAb Conjugate and HER2 Overexpression

Breast carcinomas that overexpress HER2, a membrane receptor with tyrosine kinase activity, are associated with poor prognosis. Inhibition of HER2 activity with anti-HER2 antibodies can reduce growth of tumors overexpressing HER2; however, the objective response rate is low. The antibiotic geldanamycin can also reduce HER2 activity, but it is highly toxic in vivo. To enhance the inhibitory activity of the antibody and to decrease the toxicity of free geldanamycin, Mandler et al. (p. 1573) coupled an anti-HER2 monoclonal antibody (MAb), e21, to geldanamycin to form an immunoconjugate. The e21 monoclonal antibody can be internalized by HER2-positive cells. They found that the immunoconjugate inhibited proliferation of HER2-overexpressing cells and reduced the levels of HER2 much better than the free antibody or than a noninternalizing monoclonal antibody conjugated to geldanamycin. The authors conclude that conjugating geldanamycin to an internalizing anti-HER2 antibody enhances the inhibitory effect of the antibody.