Mathematical Biology Seminar Ulrik Nielsen, PhD Merrimack Pharmaceuticals Wednesday, May 13, 2009 3:05pm in LCB 215 A systems biology approach to developing targeted therapies Abstract: Quantitative, data-driven computational modeling of signal transduction networks can be used to identify targets, to design better therapeutics and to help guide the selection of indications or biomarkers. Using the ErbB signaling network as an example, we will discuss how this systems approach helped to identify ErbB3 as a critical node in the pathway. We will present simulations suggesting that an anti-ErbB3 monoclonal antibody can effectively inhibit signaling in the ligand dependent setting and a bispecific antibody using ErbB2 (a.k.a. HER2) as a targeting arm and ErbB3 as a therapeutic arm can effectively inhibit signaling in the ErbB2 amplified setting. We will present data consistent with simulations showing that MM-121, an anti-ErbB3 monoclonal antibody, and MM-111, a bispecific antibody to ErbB2/3, inhibit the ErbB pathway and prevent the outgrowth of tumors in xenografted mice in either the ligand dependent or ErbB2 amplified setting. Taken together, we show how a systems approach helped us to identify the critical role of ErbB3, a previously under appreciated target, and allowed us to develop two different therapeutics showing efficacy in different disease settings. The approach may be applied to other disease areas such as regenerative medicine where complex growth factor interactions determine cell fate.