Neutrophil and complement attracting anti-cancer monoclonal antibody conjugates:

Immunexcite, Inc., Lexington MA

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Abstract

DESCRIPTION (provided by applicant): The introduction of therapeutic monoclonal antibodies (mAbs) in cancer has come of age with mAbs now approved for various cancer types including breast cancer. Unmodified mAbs tend to have moderate efficacy in eliminating metastatic tumors even when combined with chemotherapeutic agents. Drug/Toxin mAb conjugates may bring additional clinical benefit but are expensive to manufacture and may be associated with long-terms toxicity and resistance concerns. An approach which leverages on the exquisite specificity of mAbs coupled with improved immune activity is needed. One arm of the immune system that has not been extensively exploited in cancer therapeutics is the innate immune system. Innate immunity is the first line of defense against infectious agents such as fungi and bacteria. This arm employs the powerful cytotoxic armament associated with neutrophils, the most abundant white blood cell. The challenge has been to capture this effector function in a tumor specific manner. A unique fungal cell wall polysaccharide, beta-1,6-glucan, has been identified as a key molecule in attracting neutrophils to the site of fungal infection. By attaching this saccharide to mAbs which target breast cancer cells, complete tumor destruction has been demonstrated. Herceptin (trastuzumab) is a mAb used to treat breast cancer patients whose tumors display the HER2 molecule. In mouse xenograft models of human breast cancer, treatment of Herceptin resistant tumors with the Herceptin-beta-1,6-glucan conjugate resulted in tumor destruction and elimination compared to naked Herceptin. These experiments were performed in standard cancer mouse models lacking a complete immune system to allow human tumor growth in mice without rejection. Herceptin will go out of patent in 2014 in the EU and 2016-2019 in the rest of the world, and therefore, it would be possible to progress a superior Herceptin conjugate toward the clinic. As in any immunotherapeutic approaches, additional studies employing immune competent mice are needed to explore how the beta-1,6-glucan technology might interact in an intact immune environment. In addition, any toxicity associated with this approach can best be addressed in this model. ImmuneXcite's unique approach has substantial benefits over antibody drug/toxin conjugates (ADCs): If indeed the beta-1,6-glucan approach is able to co-opt the powerful killing mechanism of neutrophils in clinical setting with minimal toxicity, a powerful new monotherapy may be possible and significantly impact treatment of HER2 positive metastatic breast cancer patients in the clinic.