Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy.

Abstract

The IDO pathway mediates immunosuppressive effects through the metabolization of tryptophan (Trp) to kynurenine (Kyn), triggering downstream signaling through GCN2, mTOR and AHR that can affect differentiation and proliferation of T cells. Expression of the IDO1 gene by tumor cells or host APCs can inhibit tumor-specific effector CD8+ T cells and enhance the suppressor activity of Tregs, and high expression of IDO correlates with worse clinical prognosis in patients with a variety of malignancies. Therefore, targeting the IDO pathway via inhibition of the IDO enzyme or blocking its downstream signaling effects is a prime target for small-molecule immunomodulatory drugs in cancer. Here we describe the pharmacological and biological properties of NLG919, a novel small-molecule IDO-pathway inhibitor. NLG919 potently inhibits this pathway in vitro and in cell based assays (Ki=7 nM; EC50 =75 nM). It is orally bioavailable (F>70%); and has a favorable pharmacokinetic and toxicity profile. In mice, a single oral administration of NLG919 reduces the concentration of plasma and tissue Kyn by ∼ 50%. Using IDO-expressing human monocyte-derived DCs in allogeneic MLR reactions, NLG919 potently blocked IDO-induced T cell suppression and restored robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, NLG919 abrogated IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50=120 nM. In vivo, in mice bearing large established B16F10 tumors, administration of NLG919 markedly enhanced the anti-tumor responses of naïve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, NLG919 plus pmel 1/vaccine produced a dramatic collapse of tumor size within 4 days of vaccination (∼95% reduction in tumor volume compared to control animals receiving pmel-1/vaccine alone without NLG919). In conclusion, NLG919 is a potent IDO pathway inhibitor with desirable pharmacological properties, suitable for the treatment of immunosuppression associated with cancer. Citation Format: Mario R. Mautino, Firoz A. Jaipuri, Jesse Waldo, Sanjeev Kumar, James Adams, Clarissa Van Allen, Agnieszka Marcinowicz-Flick, David Munn, Nicholas Vahanian, Charles J. Link. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2013-491

Discovery of IDO1 Inhibitors: From Bench to Bedside

“…Later development of an imidazoisoindole series incorporated some of these insights but also yielded novel information incorporated into the clinical lead navoximod (92, 93) (Figure 6E). X-ray structural information shows that the ring planes of the PI and imidazoisoindole series assume similar but not identical positions in the active site (94).…”

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…Preclinical studies of GDC-0919 illustrate its potency as an IDO1 inhibitor with EC50=75 nM in cell-based assays and a 10–20-fold selectivity against TDO (Mautino et al , 2013). GDC-0919 is orally bioavailable and has a favorable pharmacokinetic and toxicity profile.…”

Trial watch: IDO inhibitors in cancer therapy

“…1,67,109 Relatively recently, these findings convinced some oncologists on the possibility to test the safety and therapeutic potential of 1methyl-D-tryptophan (also known as indoximod and NLG8189), second-generation IDO1 inhibitors (such as the orally available agent INCB024360 and NLG919), and IDO1targeting vaccines in cancer patients. 74,75,[110][111][112][113][114][115][116][117][118][119][120] So far, the pharmacological profile of several other IDO1 inhibitors-including 1-methyl-L-tryptophan, methylthiohydantoin tryptophan, brassinin and derivatives, annulin B and derivatives, exiguamine A and derivatives, as well as INCB023843-appears to be suboptimal for clinical development. 1,20,67,112,[121][122][123][124][125][126] The first-in-man Phase I clinical trial involving indoximod enrolled a total of 48 adults with refractory solid malignancies (NCT00567931).…”