April 12, 2011
Systems-guided development of a bispecific antibody against the ErbB receptor network
While the importance of ErbB2 in cancer is well known, the equally important oncogenic role of its preferred dimerization partner, the kinase-dead ErbB3, has only recently been appreciated. To develop therapeutics against the ErbB2/3 oncogenic unit, we have developed a mechanistic model of heregulin (HRG) activation of the ErbB receptor signaling network. Simulating the inhibition of HRG-induced signaling indicated that a bispecific antibody targeting ErbB2 and ErbB3 is a highly effective strategy for antagonizing the ErbB2/3 oncogenic unit in the presence of high levels of ErbB2. Using this insight, we have developed MM-111, which inhibits ligand-induced phosphorylation of ErbB3 by exploiting the overexpression of its dimerization partner, ErbB2, for specific targeting to cancer cells that display both receptors. We developed an in silico MM-111 representation and used it to select optimal binding affinities for the ErbB2 and ErbB3 arms. Computational analysis predicted that avid, bivalent binding of MM-111 is required for molecular potency, a result which was confirmed experimentally. Additionally, by introducing this virtual inhibitor into our ErbB computational model, we have quantitatively predicted the dependence of MM-111 in vitro and in vivo response on a wide range of ErbB1, ErbB2, and ErbB3 expression levels.
About Merrimack Pharmaceuticals
Merrimack Pharmaceuticals is dedicated to the creation of innovative targeted therapies that enable prospective medicine in cancer. Its Network Biology research engine applies insights from quantitative dynamic models of biochemical signaling networks to drive innovation and efficiency in topics spanning the entire spectrum of pre-clinical and clinical drug discovery and development activities. Dr. Harms joined Merrimack in 2004 as a computational biologist after obtaining a doctorate at MIT with Douglas Lauffenburger. His work at Merrimack encompasses the use of computational modeling and quantitative cell biology for target identification, mechanism-based drug design, and biomarker selection. As a Principal Scientist, Dr. Harms currently leads a multidisciplinary team at Merrimack responsible for lead molecule design and selection for a novel, systems biology-inspired oncology drug.