AgonOx entered into an exclusive, global partnership with MedImmune to develop agonists using its OX40 platform. MedImmune will lead further preclinical and clinical studies of this tumor-specific T-cell immunity stimulator for the potential treatment of cancer.
MedImmune will also support further OX40 research at Providence Cancer Center, where the foundational preclinical and clinical development of the compound has been conducted. OX40 is a protein transiently expressed on the surface of effector T cells but only after activation of the T cells by immune-stimulating antigens, AgonOx explains. Binding OX40 with either anti-OX40 antibodies or OX40 ligand compositions has been shown to inhibit apoptosis in such T cells, causing T-cell proliferation, immune attack on tumors, and sometimes very distinct tumor-specific therapeutic responses.
AgonOx’ lead agents include a soluble form of OX40 ligand (OX40L) that complexes two OX40L trimers and a humanized antihuman OX40 mAb. Both are designed to bind OX40 and generate the same activation signal produced by the binding of OX40L to OX40 on T cells in the body.
The anti-OX40 mAb has been studied in patients with advanced solid tumors. A 30-patient, dose-ranging clinical trial was completed and showed a strong connection between immune system activation by OX40 and signs of tumor shrinkage.
Additional clinical trials of the anti-OX40 monoclonal antibody are in progress, including a trial in men with advanced prostate cancer. Men in this trial will be treated with the chemotherapy agent cyclophosphamide and with radiation in order to promote shedding of tumor antigens and then will be treated with anti-OX40 for promotion of tumor-specific T-cell responses.
AgonOx is also particularly interested in combination therapies that couple OX40 agonists with cytotoxic agents, other immunologic modifiers, and tumor ablation techniques and devices. "Typically, the first line of defense against cancer in the body is the immune system," said Walter Urba, M.D., Ph.D., director of cancer research at the Robert W. Franz Cancer Research Center.
"OX40 agonists have shown very intriguing preclinical and clinical behavior in specific activation of T-cells to attack tumors, and I am pleased to have MedImmune engaged in moving OX40 forward into additional human studies."
Activated T cells express OX40 and cytotoxic T lymphocyte antigen 4 (CTLA-4) on their cell surface. Engagement of OX40 on T cells by OX40L on APCs leads to increased proliferation and expansion of effector cells, increased cytokine receptor and cytokine production, and increased survival of memory T cells, according to AgonOx. In the absence of OX40 engagement, there is decreased cell survival and the majority of cells die by activation induced cell death (AICD), and fewer memory T cells develop.
Ligation of OX40 on activated T cells leads to signaling through tumor-necrosis factor receptor-associated factor 2 (TRAF-2). Induction of TRAF-2 activates the transcription factor nuclear factor-kappa-B (NF-kB), which activates downstream target gene transcription. Engagement by OX40 also leads to sustained PKB/AKT activation and this has been shown to be important for cell survival. Additionally, OX40-mediated effects on survival are attributed to increased levels of the anti-apoptotic proteins, BCL-2, BCL-XL, and BFL1.