Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

Abstract

The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse. Mol Cancer Ther; 11(3); 582-93. Ó2012 AACR.

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

“…We have previously used network biology simulations to identify a single optimal target and the monospecific and bispecific methods of inhibiting that target (32,46). Here, we extend our simulation approach to guide the therapeutic design of a new class of multispecific antibody-like molecules that optimally coinhibit two signaling receptors.…”

A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells

“…MM-111 (Merrimack) is the first dual-targeting agent based on dual blockage of proliferation-promoting signals to have entered clinical trials. 30 This bispecific scFv-fusion protein blocks the EGFR-HER3 signaling unit. MM-141, a dual-specific antibody simultaneously targeting the growth factor receptors Erb-B3 and Igf1-R functions along similar principles.…”

Role of HSGAGs in Regulation of FGF Signaling Pathway: Insights from Mathematical Modeling

“…Accordingly, one would expect that cellular responses to signaling pathway activation also follow Michaelis-Menten type kinetics. This is indeed the case for signaling pathways like ErbB and IGFR at physiological ligand concentrations [1][2][3][4][5][6].…”