IDO Pathway Inhibitors

Our IDO Pathway Inhibitor Technology

Natural killer (NK) cells. Immunofluorescent light micrograph of human natural killer cells (small cells, center) attacking cultured cancer cells (unstained except for large blue nuclei).

We believe that immune system failure is a fundamental reason for the inability of the human body to successfully fight cancer cells. Research indicates that tumors can induce the human immune system to tolerate the existence of the tumor. This immune tolerance and suppression is a major barrier to successful treatment of cancer and is a significant target for new therapeutics.

Indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitors, including NLG8189 (d-1-methyltryptophan, or D-1MT), represent a potential breakthrough approach to cancer therapy using small‑molecule, anti-toleragenic product candidates intended to combat the mechanisms by which tumors evade immune-mediated destruction. IDO is an enzyme that regulates immune response by suppressing effector T-cell function through depletion of the essential amino acid tryptophan. Recent studies have demonstrated that IDO is overexpressed in many cancer types, both 1) within tumor cells,where it may act as a direct defense against T-cell attack, and 2) within dendritic antigen presenting cells in the lymph nodes draining the tumor, thereby promoting peripheral tolerance to tumor-associated antigens (TAAs). When hijacked by tumors in this manner,IDO may facilitate the survival, growth, invasion, and metastasis of malignant cells expressing TAAs that might otherwise be recognized and attacked by the immune system as foreign.

The ability to eliminate the tumor-protective IDO mechanism by administering IDO pathway inhibitor drugs, such as NLG8189, may provide a therapeutic window in which to break tolerance in tumors and reverse the inhibition of immune cells.

We believe our IDO pathway inhibitor technology has the following potential advantages:

  • Potential to break immune tolerance. Immune tolerance to tumor cells is a key barrier to the treatment of cancer. To date, few available therapies have addressed the immune escape mechanisms of cancer. We believe inhibition of the IDO pathway has the potential to block this escape and significantly enhance patient outcomes.
  • Tolerability. In early stage clinical development, we have observed an encouraging safety profile. We believe inhibition of the IDO pathway will selectively enhance the immune response against cancer cells given the limited expression of IDO in normal cells.
  • Oral bioavailability. Unlike many cancer therapies which require intravenous administration, our NLG8189 IDO pathway inhibitor is orally bioavailable, a significant advantage in ease of administration for patients and physicians.
  • Synergy with existing cancer therapies. Inhibiting the IDO pathway in conjunction with chemotherapy has the potential to enhance the therapeutic effect of chemotherapy by delaying or disrupting the reacquisition of immune tolerance to tumor antigens during the period following chemotherapy. We believe our IDO pathway inhibitors could also have therapeutic synergy with targeted therapeutics, radiation and immunotherapy.