PAR2 Antagonists

Novel, selective, orally active small molecule antagonists (and agonists) of the human protease-activated receptor 2 (PAR2) have been developed for the potential treatment of inflammatory diseases, metabolic syndrome and cancer.

Key Features

  • Novel small molecules
  • Orally active
  • Effective in models of acute and chronic inflammation, IBD and obesity
  • Selective and potent
  • Novel target and unique mechanism of action.


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Endocytosis inhibitors to improve anti-cancer monoclonal antibody immunotherapy responses

Many oncology patients receiving monoclonal antibody immunotherapy receive no therapeutic benefit, or rapidly develop resistance to therapy. Direct killing of tumour cells by antibodies (antibody dependent cell cytotoxicity, ADCC) requires strong engagement between antibodies bound to tumour cell surface receptors and NK cells. In studies with the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab at the University of Queensland, head and neck cancer patients who have dysfunctional EGFR receptor internalisation (and hence have EGFR clustered on the tumour surface) respond to cetuximab treatment. However, those with normal EGFR receptor biology do not respond. Clustering of receptors on the tumour surface increases NK-antibody interactions, and hence ADCC, resulting in increased tumour cell killing.

Inhibition of dynamin (a key enzyme involved in internalisation of receptors such are EGFR, PD-L1, HER2 and VEGF) leads to receptor enrichment and clustering on the cell membrane. Specific dynamin inhibitors or the anti-nausea drug prochlorperazine (Stemetil),  a dopamine receptor antagonist with off target activity as a dynamin inhibitor, inhibit dynamin activity in vitro, leading to receptor clustering and in the presence of a therapeutic antibody (e.g. avelumab, cetuximab or trastuzumab), leading to enhanced NK-cell mediated antibody dependent cell cytotoxicity (ADCC). In mouse tumour models published in Cell (Mar 2020) prochlorperazine treatment in combination with either avelumab or cetuximab resulted in tumour clearance and reduced metastases. In addition, treated mice became resistant to the same tumour.

A clinical proof of mechanism study in head and neck cancer patients demonstrated that high dose i.v. prochlorperazine is able to cluster receptors on tumours. A phase 1b combination safety study of cetuximab and prochlorperazine is ongoing.

Key features

  • Dynamin inhibition enhances the ability of anti-cancer antibodies that target tumour cell surface proteins to kill tumour cells by ADCC, increasing efficacy, reducing target heterogeneity and overcoming resistance.
  • In vitro, in vivo and clinical data demonstrate that co-administration of prochlorperazine with a therapeutic mAb has the potential to be a transformative oncology treatment strategy.


Further information:

Cell:

Media release:

New drug combination could support better cancer treatments – The University of Queensland, 6 March, 2020

Media coverage:

Hopes one-two punch cancer treatment will prove knockout blow – Brisbane Times, 6 March 2020

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UniQuest is seeking licensing, collaborative partners or investment for preclinical and clinical development of dynamin inhibitors (reformulated prochlorperazine and NCEs) to be used in combination with any existing and future monoclonal antibody therapies that mediate tumour killing via ADCC and target appropriate receptor to increase their efficacy and patient response rates.

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Hematopoietic prostaglandin D2 synthase (HPGD2S) inhibitors for inflammatory disease including DMD and asthma

Small molecule inhibitors of hematopoietic prostaglandin D2 synthase (HPGD2S) for inflammatory disease including DMD and asthma.

Key Features

  • Potent, selective and orally administrable small molecule compounds
  • Down-regulates multiple clinically validated targets
  • Selective expression resulting in improved safety – HPGD2S is primarily expressed peripheral tissues (mast and Th2 cells)
  • First in class opportunity for the treatment of asthma and allergic rhinitis


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C3a receptor modulators

Diseases driven by chronic inflammation are major health burdens and controlling inflammation is an important preventative and therapeutic goal. A network of over 40 ‘Complement’ proteins is produced in blood and on cell surfaces in response to infection/injury. Complement protein C3 is a central mediator of all avenues of complement activation leading to pathogen destruction and elimination. However, blocking C3 also blocks beneficial roles of complement cascade in fighting infection.

University of Queensland (UQ) researchers have developed multiple series of novel, potent and selective, small organic molecules that mimic C3a (agonists) or inhibit its action (antagonists).

Key Features

  • Novel small molecule modulators of C3aR
  • Potent and selective for human/mouse C3aR
  • Orally active in inflammatory disease models
  • Distinct ‘Complement’ target and mechanism of action.

Potential applications

The C3aR antagonists have potential as treatments for inflammation-related diseases where C3aR has been implicated as important, including but not limited to:

  • Asthma, allergies, respiratory diseases
  • Arthritis, diseases of musculoskeletal system
  • Metabolic Syndrome (including obesity, diabetes and cardiovascular disease)
  • Inflammatory Bowel Disease (IBD), ulcerative colitis
  • Autoimmune diseases (e.g. lupus, multiple sclerosis)
  • Neurodegenerative diseases
  • Cancers.


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Enhanced antibiotics for MDR/XDR gram-negative infections

UQ researchers have identified a novel class of octapeptin derivatives with improved activity against multiple gram-negative bacteria strains that cannot be treated by any other tested antibiotic.

Key features
  • Novel lipopeptide antibiotics that target multi and extensively drug resistant (MDR, XDR) gram negative bacteria
  • Greater efficacy with significantly reduced nephrotoxicity compared to current standard of care
  • Targets the most critical pathogens identified by WHO: Carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae
  • Potential for these novel lipopeptides as a “resistance breaker” to synergise with existing antibiotics to potentiate their activity against MDR/XDR bacteria.

BioCurate Award - Best Translational Research

Winning pitch

'Octapeptin X – a novel antibiotic for Gram-negative bacterial infections' claimed the 2020 BioCurate Award for Best Translational Research Pitch at the recent AusBiotech Early Stage Investment Forum.

Congratulations to Dr Tamsin Terry for presenting the winning pitch from a field of 13 early stage technologies in the area of human therapeutics, medical devices and diagnostics, digital health and enabling technologies.

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To enquire about this technology, please contact Dr Tamsin Terry.

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ASITI Therapeutic Tolerance

ASITI (Antigen Specific Immune Tolerance Induction) nanoparticle technology in Phase 1b study and subsequent reverse translation studies elucidate dosing strategy to optimize the expansion of regulatory T cells for tolerance.

Targets self-antigen which is the underlying cause of the autoimmune disease rather than treating the symptoms alone and hampering the immune system’s ability to fight infections.  UniQuest is seeking a partner to help prioritise and develop one or more therapeutic programs such as type 1 diabetes, rheumatoid arthritis and other autoimmune diseases.


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Novel constructs for flavivirus vaccines and diagnostics

Researchers at The University of Queensland have developed a new chimeric virus platform suitable for use in flavivirus vaccine and diagnostic applications.

Key features

  • Chimeras combining an insect-specific flavivirus (ISF) genomic backbone with specific antigenic elements of a vertebrate-infecting flavivirus (VIF)
  • ISF chimeras replicate only in mosquito cells and are expected to be safe to administer to humans and can be prepared with minimal biocontainment
  • Data shows diagnostic and vaccine applications with strong antigenic authenticity
  • ISF chimeras successfully designed to display the antigens from a range of flavivirus pathogens including dengue fever and Zika.

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Methylscape cancer diagnostic

A rapid method for identifying and isolating cancer genomic and cell free DNA.

It is well recognised that changes in the DNA methylation landscape are a hallmark of cancer. This epigenetic reprogramming creates a methylation landscape, distinct from that of normal DNA, characterized by clustered methylation at regulatory promoter regions separated by large tracks of hypomethylated regions. While this process is well characterized, most DNA methylation cancer diagnostics focus on differences in DNA methylation at a few specific loci, and thus are only able to identify a few cancer sub-types.

Researchers at the University of Queensland have developed a method that steps away from the current “specific loci” approach and looks at the DNA molecule more globally, detecting the overall changes in the levels and patterns in DNA methylation, which are the consequence of cancer.

Key features

  • Fast method for differentiating cancer DNA from normal DNA based on physicochemical properties imparted by global DNA methylation profile
  • No Bisulphite conversion or PCR amplification required
  • Works on genomic DNA from tumour and cfDNA from plasma
  • Potential to be used as fast (10 mins) enrichment process for downstream PCR or sequencing assays to reduce signal to noise ratio
  • Validated on over 70 tumour samples taken from breast, prostate and lymph node; and over 280 plasma samples from patients with breast and colorectal cancer.


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