CAMBRIDGE, Mass.—Merrimack Pharmaceuticals Inc. recently gained some press to go with its progress, as a paper covering one of its clinical candidates was published in the latest issue of Molecular Cancer Therapeutics. The manuscript, “MM-141, an IGF-1R- and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-1R Inhibitors,” details the preclinical study results of its MM-141 compound.
MM-141 is a fully human, tetravalent monoclonal antibody that inhibits signaling of the PI3K/AKT/mTOR pathway driven through activation of IGF-1R and ErbB3/HER3. The PI3K/AKT/mTOR pathway is a major pro-survival pathway that tumor cells exploit as a resistance mechanism to anticancer therapies. The compound interferes with this pathway by blocking ligand-induced signaling through the IGF-1R and ErbB3 receptors.
“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,” Dr. Alexey A. Lugovskoy, vice president of therapeutics at Merrimack, said in a news release. “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.”
Merrimack is currently conducting a Phase 1 clinical study of MM-141 as a treatment for advanced solid tumors in order to determine the compound’s safety and tolerability as a monotherapy and in combination with everolimus and docetaxel. While the monotherapy portion was recently completed in the United States and Europe, the combination portion is still underway. The trial is also seeking to determine the maximum tolerated dose and the recommended Phase 2 dose. Merrimack expects to advance the compound into Phase 2 development sometime this year.
As for which cancer types MM-141 might be most effective in treating, Ulrik Nielsen, chief scientific officer at Merrimack, notes that they have “observed the potential for redundant IGF1-R/ErbB3 signaling across most solid tumors studied to date,” though the Phase 1 trial has been focused on breast, lung, hepatocellular carcinoma (liver cancer) and pancreatic tumors.
Merrimack’s systems biology approach played a significant role in the discovery and development of MM-141, in helping them identify ErbB3 as a significant node in the pathway and in “determining that a tetravalent antibody design was optimal relative to a mixture of antibodies or other bispecific antibody formats,” says Nielsen.
“Systems biology at Merrimack integrates the fields of biology, computing and engineering,” he adds. “We use these tools to gain a more comprehensive understanding of the dynamics of cancer. Rather than focus on individual molecules, our discovery efforts seek to encompass the complexity of entire biological networks. Our foundation is data-driven. We build predictive computational models of tumor biology and using simulation to drive the productivity and precision of our research.”
Targeting both the IGF-1R and ErbB3 receptors, says Nielsen, offers two advantages: “We achieve greater potency through increased avidity of binding, and the antibody induces dramatic down-regulation of both receptors.”
IGF-1R is the receptor activated by insulin-like growth factor 1, and it has the ability to induce cell growth and proliferation, which has implicated it in promoting resistance to chemotherapies and targeted cancer therapies. While other IGF-1R inhibitors exist, their effectiveness has been limited since cancer cells can develop resistance to such therapies by signaling through alternative pathways. Researchers at Merrimack have discovered that cancer cells are capable of developing resistance to IGF-1R mediated through ErbB3, which is why dual inhibition of both the IGF-1R and ErbB3 pathways is required to block the PI3K/AKT/mTOR pathway. Preclinical in-vitro and in-vivo models have shown MM-141 to be more active than a combination of anti-ErbB3 and anti-IGF-1R monoclonal antibodies, capable of inhibiting PI3K/AKT/mTOR signaling and potentiating the activity of cytotoxic and targeted therapies.