Abstract A38: MM-141, a novel tetravalent bispecific antibody directed at IGF-1R and ErbB3 that inhibits pancreatic tumor cell growth and potentiates the effects of gemcitabine.

Purpose: Overall 5-year survival rates for patients diagnosed with pancreatic cancer is approximately 5.5% and most patients do not show durable responses to therapy. While monoclonal antibodies have significantly advanced our ability to treat cancer, their potential in pancreatic cancer is yet to be realized. We believe that targeted therapeutic strategies focused on the identification and blockade of redundant growth factor signaling pathways critical for tumor cell survival will result in the discovery of novel antibody therapies for treatment of patients with pancreatic cancer. Methods and Summary: Cancer cell lines frequently rely on insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling to support their survival and proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel tetravalent bispecific antibody, MM-141, for co-targeting of IGF-1R and ErbB3. MM141 blocks IGF-1, IGF-2, and HRG-induced signaling through IGF-1R and ErbB3, and causes downregulation of these receptors. MM-141 also downregulates IGF-1R-InsR hybrid receptors as well as ErbB1:ErbB3 and ErbB2:ErbB3 heterodimers. MM-141 does not bind other ErbB family receptors or homodimers of insulin receptor, thus reducing the risk of side effects. MM-141 inhibits phosphorylation of IGF-1R and ErbB3 receptors as well as downstream activation of the PI3K/Akt/mTOR pathway. In our preclinical tests, MM-141 displays inhibitory activity in the presence of single or multiple ligands, over a broad range of receptor profiles. Inhibition of cell growth by MM-141 has been observed in vitro as well as in vivo in multiple xenograft models including human pancreatic cancer (BxPC-3). Importantly, we show stronger activity of MM-141 compared to combinations of monospecific antibodies targeting IGF-1R and/or ErbB3. This appears to be due to the ability of MM-141 to block additional feedback loops through autocrine HRG signaling, FoxO-mediated upregulation of RTKs, or feedback activation of Akt by ribosomal S6 kinase (S6K) and insulin receptor substrate 1 (IRS-1). Additionally, we have performed pharmacodynamic and efficacy studies with MM-141 and gemcitabine in both monotherapy and combination therapy preclinical settings. We find that MM-141 potentiates the response to gemcitabine with respect to both downstream signaling effects on the PI3K/Akt/mTOR axis in short-term studies, as well as activity in long-term studies. Conclusions: Our in vitro and in vivo preclinical studies show that MM-141 has favorable pharmaceutical properties and pharmacokinetic profiles and shows activity in xenograft models of pancreatic cancer. These results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors including, but not limited to, pancreatic cancer. Citation Format: Bryan Johnson, Yang Jiao, Birgit Schoeberl, Ulrik Nielsen, Jonathan Fitzgerald, Alexey Lugovskoy, Sharlene Adams, Jason Baum, Jian Tang, Sergio Iadevaia, Neeraj Kohli, Rachel Rennard, Pragalath Sundararajan, Lihui Xu. MM-141, a novel tetravalent bispecific antibody directed at IGF-1R and ErbB3 that inhibits pancreatic tumor cell growth and potentiates the effects of gemcitabine. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A38.