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New therapy for rheumatoid arthritis
TEL AVIV, Israel—Compugen Ltd., a leading predictive drug discovery company, disclosed in an oral presentation at the 2015 ACR/ARHP Annual Meeting held in San Francisco recently results from a translational study supporting the potential treatment of rheumatoid arthritis (RA) with CGEN-15001. CGEN-15001 is an Fc fusion protein based on one of the multiple novel immune checkpoint candidates discovered by the company.
Compugen uses computational tools to predict the biological function and therapeutic relevance of novel proteins it discovers, which were not previously considered as drug target candidates, notes Dr. Eyal Neria, vice president of R&D planning and control. “For over a decade, we have been developing predictive platforms for a variety of biological processes and phenomena that are continuously being improved and diversified to address the need for novel targets in areas of interest to the industry. An example is CGEN-15001T that we have discovered using our predictive tools and which is being used both as a target for therapeutic antibodies development in immuno-oncology and forms the basis for the CGEN-15001 Fc fusion protein for autoimmune diseases.”
Fc fusion is an engineered recombinant protein built by fusing a protein of interest to the Fc domain of an antibody, Neria explains. The Fc provides antibody-like properties such as a long half-life in the body and ease of production, making Fc fusion proteins an attractive approach for biologic drugs. Several Fc fusions are already approved and in clinical use, including, for example, the blockbusters Enbrel and Orencia indicated for the treatment of RA and other conditions.
The translational study, conducted in collaboration with Prof. Iain B. McInnes from the University of Glasgow, was designed to evaluate the potential to translate the efficacy of CGEN-15001, previously observed in animal models of the disease, to human patients. McInnes is a well-known clinician and scientist in the field of rheumatology and a member of Compugen’s scientific advisory board.
The study’s experimental design utilizes co-cultures of immune cells from individual RA patients that mimic the deleterious interaction of these cells within the joints of RA patients. This interaction drives secretion of pro-inflammatory proteins known as cytokines that have a major role in RA pathology, leading to chronic progressive joint inflammation and damage. Thus, these co-cultures provide a translational tool to evaluate the effect of potential drugs for treatment of RA.
In the reported results, CGEN-15001 was shown to inhibit the secretion of various RA-related inflammatory cytokines in these co-cultures, including for example TNFα, IFNγ and GM-CSF, pointing to the mechanism by which this drug can potentially treat RA. The anti-inflammatory effect was observed initially in healthy donors’ cells and was then successfully reproduced in cells from RA patients, thereby confirming that the CGEN-15001 pathway is functional and responsive in these autoimmune patients.
“We are very excited to collaborate with Compugen on this promising drug candidate for autoimmune diseases,” said McInnes, the Muirhead Chair of Medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow. “The results for CGEN-15001 obtained in my laboratory using a translational experimental system that capitalizes on near patient immune analysis of samples from RA patient cells show that CGEN-15001 is capable of modulating the underlying immune processes that promote inflammation in joints of people with RA. CGEN-15001’s unique mode of action has a potential to induce long-term responses in patients and thus to become an important addition to the armamentarium of autoimmune disease therapeutics, allowing patients to live healthier and more productive lives.”
“Inhibiting immune checkpoints using antibodies to unleash the power of the immune system is already transforming cancer therapy, and Compugen is a clear leader in the discovery of novel immune checkpoint drug targets,” said Dr. Anat Cohen-Dayag, Compugen’s president and CEO. “Furthermore, the potential for an additional major pharmaceutical opportunity exists for immune checkpoints in the treatment of autoimmune diseases through the use of fusion proteins based on them to inhibit immune system activity. These important recent results for CGEN-15001, from this patient-based translational assay performed at a world-leading center, demonstrate that CGEN-15001 has the potential to provide relief to autoimmune patients, thus presenting a promising therapeutic approach for RA and other autoimmune diseases. Therefore, while maintaining our current commitment to focus our internal R&D operations on immuno-oncology, we are now examining various alternatives to advance CGEN-15001 as an autoimmune product candidate.”
CGEN-15001 is a novel Fc fusion protein drug candidate for autoimmune diseases, consisting of the fusion of the extracellular region of CGEN-15001T to an IgG Fc domain. CGEN-15001T is a novel immune checkpoint discovered by Compugen through its predictive discovery infrastructure. CGEN-15001 was shown to be effective in treating several autoimmune diseases in animal models, including models of multiple sclerosis, rheumatoid arthritis, psoriasis and type 1 diabetes. In these models, CGEN-15001 treatment has been shown to induce a durable long-term response suggestive of immune tolerance restoration, and has also promoted graft survival in a model of bone marrow transplantation. Further research demonstrated that CGEN-15001 has an immune modulatory function attenuating inflammatory responses and promoting regulatory anti-inflammatory activity, including the promotion of regulatory T cells.