ASITI Therapeutic Tolerance

Background
Autoimmune diseases develop and persist due to the failure of immune self-tolerance mechanisms, which regulate inflammatory responses to injury or infection.

The team, led by Professor Ranjeny Thomas, discovered that the body’s immune response could be “re-educated” to turn-off, rather than promote inflammation in response to self-antigens driving an autoimmune disease. This discovery led to the development of two drug formats for rheumatoid arthritis (RA) that have progressed to Phase 1 clinical trials. The first was an ex vivo antigen-exposed tolerising dendritic cell therapy, followed by an injectable antigen-encapsulated tolerising liposome formulation which has since been the focus of translation and commercialisation. The antigen specific immune tolerance induction (ASITI) technology addresses the immunological cause of autoimmune disease by re-establishing disease-specific tolerance in patients, without impairing normal immunity and the ability to fight infections.

The technology
ASITI therapy comprises subcutaneously administered liposome nanoparticles which co-deliver NF-kB inhibitor (calcitriol) and autoantigenic peptide to dendritic cells (DCs). After s.c. administration, liposomes draining to the lymph node are taken up by and inhibit NF-kB in dendritic cells, which present encapsulated antigen to T cells. Antigen and dendritic cell NF-kB inhibition promote the expansion of antigen-specific CD4+ T cells in draining lymph node that can be measured in blood. These T cells:

1. become anergic and regulatory when further exposed to their antigen in the diseased tissue and tissue draining lymph nodes;
2. regulate tissue antigen-experienced memory T cells and suppress autoreactive B cells; and
3. induce bystander regulation by suppressing dendritic cells presenting multiple self-antigens in diseased tissue-draining lymph nodes.

ASITI therapeutic development
Preclinical POC has been demonstrated in animal models of rheumatoid arthritis (ovalbumin, PGIA, CIA), Goodpasture’s vasculitis, experimental autoimmune uveoretinitis (EAU), and type 1 diabetes (multiple epitopes tested in NOD mouse model).

Our first antigen-encapsulated liposome for clinical studies was DEN-181 for RA patients. It proceeded through preclinical development, manufacturing and a Phase 1b single ascending dose trial in patients.

The first-in-human study found that a single dose of DEN-181 was safe and, at low doses suited to tolerance, expanded antigen-specific T lymphocytes specific for RA joint proteins collagen II and citrullinated-vimentin. These T cells were enriched in PD1 and the lymph node homing receptor CCR7 respectively. T-cell expansion persisted for 28 days and was associated with clinical remission. Subsequent studies comparing patients with RA and type 1 diabetes patients achieving long remission demonstrated similar expansion of lymph node-homing self-antigen specific T cells. In reverse translation studies this expanded population became anergic and regulatory upon re-exposure to antigen in diseased tissue and tissue draining lymph nodes. These studies identify a peripheral blood companion biomarker strategy by which the dose of liposomes that expands tolerance-inducing antigen-specific T cells can be optimised in clinical trials.

DEN-181 had shelf-life stability of beyond 24 months. However, because it showed evidence of payload instability in plasma, we optimised our second-generation liposome formulation for stability and specific delivery to the skin draining lymph node. This novel second-generation liposome composition is being applied to each of our therapeutic programs including type 1 diabetes and rheumatoid arthritis.

Our lead program in Type 1 Diabetes (T1D) targets beta cell preservation in children and adults with stage 2 or stage 3 T1D, where there is beta-cell function but glucose imbalance, to restore glycaemic control and extend insulin-independence (remission). It recently entered a phase 1b SAD clinical trial in adults with T1D (first-dosing cohort completed) supported by non-diluting grants from JDRF, Helmsley and CUREator.

Our RA program targets recent-onset RA patients, with goal to consolidate drug-free remission. Compelling preclinical data shows that ASITI can achieve extended drug-free suppression of the mouse PGIA model following withdrawal of standard of care RA treatment (methotrexate and/or steroid). The ASITI RA program is commencing scale-up for GMP manufacturing and IND enabling studies in advance of entering a Phase 1b clinical in 2026, supported by an $11.53 million MRFF Frontiers grant.

Intellectual property

1. PCT/AU2024/051401 underpins novel second-generation liposome formulation used in each therapeutic program​.
2. Australian patent application number 2025902146 underpins novel combination and induction therapy regimens for ASITI-RA​
3. Broad foundational patents granted in US, CN, CA, IN, EP and AU. US patent term until 2031​.
4. Clear strategy to extend patent portfolio with further filings planned.

Commercialisation opportunity
UniQuest spin-out Andara Therapeutics was recently formed in partnership with an experienced European management team to advance the ASITI technology. Andara Therapeutics is seeking €35 million in a syndicated Series A round to fund clinical advancement, manufacturing scale-up, and strategic platform expansion into additional autoimmune indications.

We are also seeking partners to help advance our therapeutic development programs in rheumatoid arthritis, type 1 diabetes and other autoimmune diseases. Other tractable diseases include those with accessible biopsies and well-characterised or emerging epitopes (e.g. Jo1-positive polymyositis), or where antigens are known, but epitope discovery is required (e.g. systemic lupus erythematosus).

Selected Publications

• Sonigra et al., Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis. DOI: 10.1172/jci.insight.160964
• Benham et al., Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med. 2015;7(290):290ra87
• Galea et al., PD-L-1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease. JCI Insight. 2019;4(18):126025.
• Bergot et al., Regulatory T cells induced by single peptide liposome immunotherapy suppress islet-specific T cell responses to multiple antigens and protect from autoimmune diabetes. J Immunol 2020, DOI: 10.4049/jimmunol.1901128
• Musthaffa et al., Proinsulin-specific T-cell responses correlate with estimated c-peptide and predict partial remission duration in type 1 diabetes. Clin Transl Immunol 2021;10:r1315

Research leader

Professor Ranjeny Thomas AM (MBBS, FRACP, MD) is the Arthritis Qld Chair of Rheumatology at the University of Queensland, The Frazer Institute, consultant Rheumatologist at Princess Alexandra Hospital and fellow of the Australian Academy of Health and Medical Sciences. Professor Thomas’ research is focused on the study of the biology and clinical use of human dendritic cells in autoimmune disease.  She is a co-inventor of the ASITI technology and has an extensive track record of conducting industry-funded research projects. She has been a keynote speaker at the American College of Rheumatology and European League of Rheumatology Annual Meetings and is a member of Abbvie’s Immunology Reflection Panel. She leads the RESET RA project of 14 international academic partners.