Technology

Technology 2017-06-29T13:12:10+00:00

Cell-based assays are important tools used by the world’s pharmaceutical industries in drug discovery research. They are primarily used to determine the activity of drugs and drug candidates to improve the efficacy, safety and help validate drug candidates before they progress to human trials.

Receptor-Heteromer Investigation Technology

Dimerix’s patented cell-based assay, known as Receptor-HIT (heteromer investigation technology), can be applied to a number of stages of the drug development process. The company’s core technology allows identification of pairs of different receptors that function in a joint manner (interact) when ligands, small molecule drugs, peptides or antibodies, bind to them. Functionally interacting receptors of this type are known as heteromers. If these receptors are drug targets then this could potentially result in a unique pharmacology and therefore biological function.

Compared with the traditional analysis of single target receptors in isolation, Dimerix is able to identify differences in signalling behaviour when receptors interact as heteromers, as expected in vivo.

Dimerix is applying its technology to receptors such as G-protein coupled receptors (GPCR’s); a large and important family of drug targets that play a central role in many biological processes and are linked to a wide variety of diseases.

Commercial Applications

Commercial applications for the HIT technology include:

De-orphanisation of G-protein coupled receptors (GPCR's)

Profiling compounds to identify the signalling effects and identify potential unwanted effects

Differentiate between protein interactions of the heteromer complex to optimise the drug performance.

The leading discovery and demonstration/validation of our Receptor-HIT technology is the functional interaction identified between the receptors AT1R (angiotensin II receptor type 1) and CCR2 (Chemokine (C-C motif) Receptor 2). CCR2, or C-C chemokine receptor 2 is member of the family of chemokine receptors often associated with inflammatory disorders, and themselves part of the large family of GPCRs.

Identification of the AT1R/CCR2 heteromer resulted in the company’s lead candidate, called DMX-200, as a novel combination of two existing drugs that are approved and on the market and which is currently in clinical trial for chronic kidney disease (see Clinical Program).

DMX-200 constitutes Irbesartan, an angiotensin II type I receptor blocker and Propagermanium, a chemokine receptor (CCR2) blocker.

The repurposing of existing drugs, based on new biology elucidated using Receptor-HIT, has the potential to be repeated for other receptor combinations already identified by Dimerix resulting in a pipeline of potential near term clinical programs. In addition the heteromer biology can be used to design or select heteromer specific new molecules.

Pipeline

In addition to our lead program in chronic kidney disease, Dimerix has a pipeline of multiple surface receptors shown to functionally interact. These so called “heteromers” have resulted in several additional programs in our pipeline including for the treatment of conditions such as:

NASH (fatty liver disease)

Pre-clinical development

Ocular diseases

Early stage opportunity

Cancer fatigue

Early stage opportunity

Multiple sclerosis

Early stage opportunity

Intellectual Property

Dimerix was granted an Australian patent for its DMX-200 combination therapy in June 2015, in the US in April 2016, and in Japan in early 2017. The patent is also being examined in Europe, Japan and other key markets. The international filing date of the patent applications was in January 2012.

Dimerix also has several granted and pending patent applications protecting its innovative Receptor-HIT technology.

We are committed to the ongoing expansion, broadening and development of our intellectual property portfolio.

Scientific Publications

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Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KDG and Devi LA (2016) G Protein-Coupled Receptor Heteromers. Annual Review of Pharmacology and Toxicology 56:403-425 [Full Text – Free]

Ayoub MA, Zhang Y, Kelly RS, See HB, Johnstone EKM, McCall EA, Williams JH, Kelly DJ and Pfleger KDG (2015) Functional Interaction between Angiotensin II Receptor Type 1 and Chemokine (C-C Motif) Receptor 2 with Implications for Chronic Kidney Disease. PLOS ONE 10(3): e0119803 [Full Text – Free]

Jaeger WC, Armstrong SP, Hill SJ and Pfleger KDG (2014) Biophysical detection of diversity and bias in GPCR function. Frontiers in Endocrinology 5:26
[Full Text – Free]

Ayoub MA, See HB, Seeber RM, Armstrong SP and Pfleger KDG (2013) Profiling epidermal growth factor receptor and heregulin receptor 3 heteromerization using Receptor Tyrosine Kinase Heteromer Investigation Technology. PLOS ONE 8:e64672
[Full Text – Free]

Watts AO, van Lipzig MMH, Jaeger WC, Seeber RM, van Zwam M, Vinet J, van der Lee, Siderius M, Zaman GJR, Boddeke HWGM, Smit MJ, Pfleger KDG, Leurs R and Vischer HF (2013) Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes. British Journal of Pharmacology 168:1662-1674
[NCBI PubMed Entry]

Mustafa S, See HB, Seeber RM, Armstrong SP, White CW, Ventura S, Ayoub MA and Pfleger KDG (2012) Identification and profiling of a novel α1A-adrenoceptor-CXC chemokine receptor 2 heteromer. Journal of Biological Chemistry 287:12952-12965
[NCBI PubMed Entry] [Full Text – Free]

Johnstone KM and Pfleger KDG (2012) Receptor-Heteromer Investigation Technology and its application using BRET. Frontiers in Endocrinology 3:101
[NCBI PubMed Entry] [Full Text – Free]

Porrello ER, Pfleger KDG, Seeber RM, Qian H, Oro C, Abogadie F, Delbridge LMD and Thomas WG (2011) Heteromerization of angiotensin receptors changes trafficking and arrestin recruitment profiles. Cellular Signalling 23:1767-1776
[NCBI PubMed Entry]

See HB, Seeber RM, Kocan M, Eidne KA and Pfleger KDG (2011) Application of G Protein-Coupled Receptor Heteromer Identification Technology to monitor b-arrestin recruitment to G protein-coupled receptor heteromers. Assay & Drug Development Technologies 9:21-30
[NCBI PubMed Entry] [Full Text – Free]

Mustafa S and Pfleger KDG (2011) G protein-coupled receptor heteromer identification technology: identification and profiling of GPCR heteromers. Journal of Laboratory Automation 16:285-291
[NCBI PubMed Entry] [Full Text – Free]

Mustafa S, Ayoub MA and Pfleger KDG (2010) Uncovering GPCR heteromer-biased ligands. Drug Discovery Today: Technologies 7:e77-e85
[Full Text]

Ayoub MA and Pfleger KDG (2010) Recent advances in bioluminescence resonance energy transfer technologies to study GPCR heteromerization. Current Opinion in Pharmacology 10:44-52
[NCBI PubMed Entry]

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Dimerix Scientific Publications CoverList of Dimerix Scientific Publications (PDF, 80Kb)