Riptide Bioscience, Inc., announces the publication in Science Translational Medicine of a seminal article establishing a novel immune checkpoint, potentially useful in the treatment of both cancer and fibrosis.
The article is entitled "Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and immune antitumor immune responses." (https://stm.sciencemag.org/content/12/530/eaax6337). Riptide originated the development program and collaborated with Tuskegee University’s Cancer Research Center and the National Institutes of Health under separate research agreements. First author, Dr. Jesse Jaynes, Professor of Integrative Biosciences at Tuskegee, was joined by 42 co-authors from the National Cancer Institute, the National Center for Advancing Translational Sciences, and Tuskegee in this publication.
The article documents extensive research to evaluate the efficacy and confirm the mechanism of Riptide drug candidate RP-182. RP-182 is the first of several engineered peptides emerging from a years-long effort to enhance the activity of naturally occurring host defense peptides (HDPs) with immunomodulatory properties.
HDPs have the capacity to directly kill invasive microbes by forming pores in their membranes. However, certain HDPs also activate the immune system to fight the invaders – an activity which Riptide scientists discovered could be turned against "non-self" cancer cells.
Jaynes commented, "We did an extensive search for the cellular target of these peptides. Surprisingly it turned out to be CD206, the canonical biomarker for M2-polarized tumor-associated macrophages (TAMs). That made these small proteins really promising as potential drugs, since CD206 is many times more highly expressed on M2 macrophages than on any other somatic cell type."
TAMs are the most common immune cells in the tumor microenvironment, often outnumbering cancer cells themselves in solid tumors. TAMs produce a tumor-promoting tissue environment. Riptide scientists demonstrated that engaging a specific set of amino acids in a particular domain of CD206, returned the macrophage population from M2-dominant to M1-dominant, restoring a tumor-inhibiting microenvironment.
Jaynes’ colleague, Dr. Clayton Yates, Director of Tuskegee’s Cancer Research Center, added, "CD206 is a perfect narrow target for an exquisitely specific therapy. Our team was the first to show that this receptor could serve as a ‘toggle switch’ between macrophage phenotypes. We think it’s accurate to consider it a novel immune checkpoint – a completely natural mechanism that can have a profound effect on tumor etiology, without significant toxicity."
Yates continued, "We demonstrated that both in vitro and in vivo, the RP class of peptides are able to repolarize the macrophage population, and that once repolarized, the macrophages return to phagocytic activity and begin consuming cancer cells. They also send downstream signals to the T-cell, NK-cell and B-cell populations to attack the tumor."
Riptide President Dr. George Martin commented, "The results in animal models of organ cancers have been spectacular. RP-182, administered in combination with gemcitabine, produced the best results ever shown in NCI’s KRAS-p16 pancreatic cancer model. Also, with its distinctive mechanism, it has been shown to powerfully complement both chemotherapy and checkpoint inhibitor immunotherapy."
Dr. Martin continued, "Riptide has built very solid intellectual property around this program, and following the promising early work with RP-182, has developed two other peptide candidates with even better efficacy and excellent pharmacokinetics. These have demonstrated striking results in preclinical models of colon, breast, prostate, and skin cancers."
Riptide Executive Vice President Dr. Henry Lopez added, "Also, since M2 macrophages are important in the progress of certain fibroses, including scleroderma and IPF, we anticipated – and have recently confirmed – potent efficacy in animal models of those diseases."
Dr. Martin concluded, "We’re now engaging with larger pharmaceutical companies to move this important program into clinic. I see a real opportunity, similar in many ways to the discovery of the first checkpoint inhibitors, to make a major impact on clinical practice."
Riptide Bioscience, Inc., with laboratories in Vallejo, California, maintains an intensive program of research into peptide-based therapeutics.
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