Nicholas Huntington

Discovering the dominant factors that regulate NK cell development, differentiation and homeostasis in order to exploit such pathways in disease. Recent discoveries: Nature Immunology 2024 Feb;25(2):240-255. doi: 10.1038/s41590-023-01718-4 "IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development" Optimisation of a primary human CAR-NK cell manufacturing pipeline. Clin Transl Immunology. 2024 May 2;13(5):e1507. Cell Reports 2024 Jun 25;43(6):114333 "DOT1L maintains NK cell phenotype and function for optimal tumor control" Cancer Immunology Research 2022 Sep 1;10(9):1047-1054 "TGFβ and CIS Inhibition Overcomes NK-cell Suppression to Restore Antitumor Immunity"

Audax Bio was founded by internationally recognised NK cell biologist, Professor Nicholas Huntington and his colleague Dr Jai Rautela. The group has established a unique immuno-oncology drug discovery platform which has resulted in partnering deals with Gilead Sciences and Kite Pharma along with the discovery and progression of multiple internal programs. The discovery platform leverages the group’s unparalleled knowledge in primary human immune cell CRISPR and chemical library phenotypic screens, along with its’ advanced in-vivo tumor microenvironment immune cell CRISPR screening platform. Pipeline: IL-12v-ABD-Fc (DAX-044): Our 4th generation IL-12 program: An optimized potency IL-12v-Fc has been coupled to a unique T cell binder (enriched in tumor microenvironment and distinct from PD1) and addresses all the concerns with previous IL-12 approaches (therapeutic index, half-life, systemic IFNg toxicity, tachyphylaxis). In tumor-bearing mice, we see no spike in peripheral IFNg and no signs of toxicity, but our molecule retains potent solid tumor regression and cures. Currently 95% CRs with DAX-044 molecules versus 40% CRs with aPD1. Importantly we don't observe tachyphalaxis with our binder-IL-12v-Fc and the half-life is extended to 1 week. IL-15 pathway SMI (DAX-037): Most CD8 T cell therapies aim to enhance signals 1 and 2 (TCR/Co-Stim), whereas signal 3 (e.g. IL-15R) is typically weak in solid tumor microenvironments. To address this, we have developed a SMI of an enzyme that regulates the expression of IL-15R/CD122 on CD8 T cells and NK cells. Target inhibition results in higher IL-15R expression and enhanced IL-15/STAT5 signaling resulting in improved metabolism, resistance to immunosuppression, increased polyfunctional-cytokine production and serial killing. This target pathway is orthogonal to anti-PD1 and thus demonstrates clear additive solid tumor immunity when DAX-037 and PD1 are inhibited in vivo. DAX-037 is at hit-to-lead candidate stage.

A/Prof in Immunology division leading the Cancer Immunotherapy Laboratory. Established myself as an opinion leader on natural killer (NK) cell biology and NK cell immunotherapy following notably discoveries on regulatory mechanisms of IL-15 signalling, identification of human and murine NK cell differentiation pathways and identification of multiple checkpoint in NK cell activation and tumour immunity. For 8 years I led a research program aimed at deciphering the regulatory networks that control NK cell immunity and a drug discovery program using cutting-edge in vivo screens for novel checkpoints in NK cell activation for targeting in cancer immunotherapy. In this role I published 82 peer-reviewed research articles and was granted 2 patents that were licensed by international Biotech/Pharma companies. I was awarded the 2019 Australian Academy of Science Jacques Miller Medal, 2018 NFMRI John Dixon Hughes Medal and the 2016 Burnet Prize for these discoveries.

Human Frontiers Science Program Fellow in the Di Santo Laboratory. During this post-doc I published 23 papers on the role of IL-15 in human NK cell and T cell development and function using human immune system mice models that I developed as part of a Bill and Melinda Gates GC4 grant team. In 2009, I was granted a patent WO2010071836 which was licensed. My 2009 paper "IL-15 trans-presentation promotes human NK cell development and differentiation in vivo" in JEM has been cited over 600 times.

Thesis projects: CD45 links the B cell receptor with cell survival and is required for the persistence of germinal centers A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. I was fortunate to have 3 PhD supervisors David Tarlinton, Stephen Nutt and Andreas Strasser. I published 2 Nature Immunology, 1 JEM and 1 JI first author papers during this PhD. I was awarded The Menzies Foundation RG Menzies Award in 2007 and a High Commendation for the Victorian Premier’s Award in 2006

Honours project on the role of BAFF (B cell activating factor) in pre-clinical model of Multiple Sclerosis. B-cell-activating factor (BAFF) is a member of the tumour-necrosis factor (TNF) family. BAFF is a trimeric membrane-bound or soluble factor that binds to three receptors — BCMA (B-cell maturation antigen), TACI (transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor) and BAFF-R (BAFF receptor) all are expressed on B cells.