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CAMBRIDGE, Mass., Feb. 18, 2014 (GLOBE NEWSWIRE) -- Merrimack Pharmaceuticals, Inc. (Nasdaq:MACK) today announced that the manuscript "MM-141, an IGF-1R- and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-1R Inhibitors" has been published in
Molecular Cancer Therapeutics and selected for the Highlights section in the current issue (Volume 13, Issue 2).
This publication describes the preclinical development of Merrimack's MM-141, a novel bispecific tetravalent antibody that binds to IGF-1R and ErbB3 receptors. With this mechanism, MM-141 is able to inhibit oncogenic signaling through the PI3K/AKT/mTOR pathway, which is a driving force behind cell growth. MM-141 recently completed the monotherapy portion of a Phase 1 study in the United States and Europe. It is currently being investigated in a Phase 1 combination study and is expected to enter Phase 2 development in 2014.
"We are excited that
Molecular Cancer Therapeutics has highlighted how Merrimack's proprietary systems biology approach can guide the design of novel therapeutics that overcome redundancies in tumor cell resistance," said Alexey A. Lugovskoy, Ph.D., Vice President of Therapeutics at Merrimack. "MM-141 is a first-in-class molecule that is an excellent example of our approach, as it can arrest tumor cell growth in two ways: it blocks multiple inputs into the major tumor survival pathway and also depletes receptor complexes containing IGF-1R and ErbB3, which would normally allow cancer cells to proliferate."
IGF-1R, the receptor activated by insulin-like growth factor 1, has the ability to induce cellular growth and proliferation. Thus, it has been implicated in promoting resistance to both chemotherapies and targeted therapies. However, the effectiveness of current IGF-1R inhibitors in the clinic has been limited, as cancer cells have the ability to develop resistance to therapies by signaling through alternative pathways.
Through a systems biology-based methodology, Merrimack researchers have found that cancer cells can develop resistance to IGF-1R that is mediated through ErbB3. Therefore, dual inhibition of IGF-1R and ErbB3 pathways would be necessary to block the PI3K/AKT/mTOR pathway, resulting in the arrest of tumor cell growth. In preclinical
in vitro and
in vivo models, MM-141 was more active than a combination of anti-ErbB3 and anti-IGF-1R monoclonal antibodies. MM-141 was able to inhibit PI3K/AKT/mTOR signaling and potentiated the activity of cytotoxic and targeted therapies, supporting its ongoing clinical development.
MM-141 is fully human tetravalent antibody that targets signaling of the PI3K/AKT/mTOR pathway driven through activation of IGF-1R and ErbB3/HER3. The PI3K/AKT/mTOR is a major pro-survival pathway that tumor cells use as a resistance mechanism to anti-cancer therapies. MM-141 is designed to interfere with this pathway by blocking ligand-induced signaling through the IGF-1R and ErbB3 receptors. A Phase 1 clinical study of MM-141 for the treatment of advanced solid tumors is currently underway. MM-141 is Merrimack's sixth oncology candidate to enter clinical development.