MM-111: a novel bispecific antibody targeting ErbB3 with potent anti-tumor activity in ErbB2 over-expressing malignancies.

Abstract #4166 ErbB3 has been identified as a preferred dimerization partner of ErbB2, critical for driving the proliferation of ErbB2 over-expressing breast tumors. We have designed a bispecific antibody, MM-111, which inhibits ligand-induced phosphorylation of ErbB3 with sub-nanomolar potency by exploiting the abundant expression of its dimerization partner, ErbB2, for specific targeting to cancer cells that express both receptors. We employed computational physicochemical modeling to guide the kinetic optimization of the monovalent binding affinities to the ErbB2 and ErbB3 receptors to increase the potency and specificity of MM-111 for tumor cells. We have demonstrated that MM-111 inhibits activation of the phosphatidylinositol 3-kinase pathway in vitro and in vivo , resulting in attenuation of tumor proliferation. Inhibition of growth by MM-111 has been observed in several murine xenograft models including BT474 and MDA-MB-361 breast tumors. While the antitumor activity of MM-111 is positively correlated with ErbB2 expression levels, MM-1119s potent inhibition of ErbB3 phosphorylation and signaling downstream from this receptor differs markedly from currently available therapies targeting ErbB2 over-expressing breast tumors and thus provides a novel approach to treatment for these malignancies. In conclusion, our data demonstrate that the combination of computational biology with antibody engineering has resulted in the development of a promising, novel therapeutic, MM-111, that has potent antitumor activity in malignancies driven by the ErbB2/3 oncogenic unit. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4166.