TRX518, a novel, first-in-class immunomodulatory agent demonstrates anti-tumor activity in data presented at the Keystone Symposia ?Antibodies as Drugs? meeting held fromFebruary 6 – 11, 2011 in Keystone, Colorado.

TRX518 is an investigational monoclonal antibody reactive withthe glucocorticoid-induced tumor necrosis factor receptor (GITR) and is designed to enhance the immune system’s anti-tumor response by enabling T cells to more effectively attack cancer cells. GITR plays a role in directing the anti-tumor immune response via a multifaceted mechanism of action that includes activating tumor antigen-specific T effector cells, abrogating the suppression induced by T regulatory cells, and activating NK cells.

Ongoing Trials

In preclinical studies thefully humanized Fc-disabled anti-human GITR IgG1 mAb achieved its effect without compromising normal immune function, and preclinical models suggest TRX518 to have a favorable safety profile.

To further assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of the new drug candidate, an open label, non-randomized single group assignment, Phase I single dose escalation study in adults with biopsy proven unresectable in stage III or stage IV melanoma (TRXMel-1 NCT01239134)has been initiated.

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Activating and Sustaining Effect

TRX518 is designed to have activating and sustaining effects on T cells for enhancing the immune system’s responses against cancer cells, including responses that may occur with TRX518 alone, as well as complementary responses in combination with other cancer therapies including vaccines.

The investigational drug candidate is being developed by Tolerx, Inc. Cambridge, MA (USA), a biopharmaceutical company developing novel therapies to treat autoimmune diseases and cancer by normalizing the immune response.The results presented from preclinical studies with TRX518 were presented as a poster and invited talk. The presentation included a range of data from preclinical studies of TRX518 and details of the fully humanized TRX518 antibody. The data showed that a murine analog of TRX518 showed anti-tumor activity as a monotherapy and, when used as a combination therapy with standard chemotherapeutics, prevented the establishment of tumors, induced complete and partial remission of established tumors, and prolonged survival in animal models of human cancer.

Specific Immune Responses

The enhancement of the anti-tumor response afforded by anti-GITR combination therapy was shown to target specific immune responses, because these animal models were resistant to tumor re-challenge while other antigenically distinct tumors grew normally. TRX518 blocked the interaction of GITR with its ligand, enhanced the cytotoxicity of natural human killer cells, downmodulated GITR on peripheral blood lymphocytes, did not induce appreciable cytokine release, and was well tolerated and safe at high doses in non-human primates.

“We are very excited about the anti-GITR program, notably the unique and multifaceted mechanism of action and its promising safety profile,” said Tony deFougerolles, Tolerx Chief Scientific Officer. “The preclinical data indicate that TRX518 has tremendous potential for enhancing anti-tumor responses, regardless of tumor type, and for also improving the effectiveness of other cancer therapies including chemotherapeutics and cancer vaccines.”

For more information:
Clinical Trial NCT01239134:
Trial of TRX518 (Anti-GITR mAb) in Unresectable Stage III or Stage IV Malignant Melanoma.

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