Protease Activated Receptor 2 Antagonist In Inflammatory Disease
Funder
National Health and Medical Research Council
Funding Amount
$621,347.00
Summary
The immune response to infection involves a network of proteins that produce an inflammatory response. Sometimes this response is prolonged or uncontrolled and can lead to a large number of inflammatory and other diseases. We have discovered a class of drugs that can bind to a particular protein on the surface of human cells and control this inflammatory response. This property has the potential to treat a wide range of inflammatory and other diseases in humans.
Development And Biological Evaluation Of Cytokine Macrophage-migration Inhibitor (MIF) Non-Steroidal Antagonists
Funder
National Health and Medical Research Council
Funding Amount
$85,000.00
Summary
The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhi ....The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other inflammatory diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray crystal structure of MIF has been published and the putative active site fully characterised. We have deduced structural features of MIF that reveal aspects of the structural complementarity of host-guest affinity. This information has been used in the synthesis of new compounds to antagonise MIF. We have designed, synthesised and tested several classes of compounds, which have shown activity from milli to nano-molar levels in novel in-house in vitro bioassays.Read moreRead less
Development Of A Highly Potent, Fully Human Anti-GM-CSF Monoclonal Antibody
Funder
National Health and Medical Research Council
Funding Amount
$334,000.00
Summary
Many diseases, such as arthritis, have unwanted inflammatory reactions. Better drugs are needed to control inflammation. A powerful antibody to a significant pro-inflammatory cytokine will be generated; this antibody will be especially designed so that it will not be rejected by patients. Because of its properties it will cost the community less than similar therapeutics. Because inflammatory diseases are common many patients will benefit from our therapeutic.
Development Of An Anti-GM-CSF Antibody For Treatment Of Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
The aim of this project is to develop assays for the evaluation of the efficacy and safety of an anti-GMCSF neutralizing antibody in a Australian first-in-man clinical trial in patients with severe rheumatoid arthritis (RA). This chimeric antibody has been developed by the Ludwig Institute for Cancer Research, Melbourne Branch, in conjunction with KaloBios Pharmaceuticals, Inc., USA. It is intended to use the assays developed in this project to facilitate commercial development of this antibody, ....The aim of this project is to develop assays for the evaluation of the efficacy and safety of an anti-GMCSF neutralizing antibody in a Australian first-in-man clinical trial in patients with severe rheumatoid arthritis (RA). This chimeric antibody has been developed by the Ludwig Institute for Cancer Research, Melbourne Branch, in conjunction with KaloBios Pharmaceuticals, Inc., USA. It is intended to use the assays developed in this project to facilitate commercial development of this antibody, and result in the development of an improved treatment for this devastating disease.Read moreRead less
Development And Evaluation Of Novel Anti-inflammatory Products Derived From An Indigenous Medicinal Plant
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
This collaborative project between researchers at the University of South Australia and Indigenous traditional owners from Northern Kaanju homelands (Cape York Peninsula, Qld) will develop and evaluate products derived from the Northern Kaanju medicinal plant Dodonaea polyandra. Extracts of the plant and novel compounds isolated from it have anti-inflammatory activity. These have the potential to be used in inflammatory diseases such as dermatitis, arthritis and inflammatory bowel disease.
There is an unmet need for safe and effective anti-inflammatory drugs. Because P38 MAPK intracellular signalling modulates multiple pro-inflammatory cytokine actions, it appears to be an ideal candidate pathway. P38 inhibitors have been limited by their toxicity within hepatocytes. The aim of this program therefore is to develop agents with enhanced P38 MAPK inhibitory effects as well as reduced liver toxicity based on known structure activity relationships.
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Phase 1 Clinical Trial Of Autologous Dendritic Cells To Induce Antigen-specific Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$165,125.00
Summary
We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their ....We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with rheumatoid arthritis taking drugs for their diseaseRead moreRead less
Preclinical Development Of A Humanised Antibody To C5aR.
Funder
National Health and Medical Research Council
Funding Amount
$124,875.00
Summary
Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) ....Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the antibody, safety, the most effective dose, timing and route of administration. These studies are a necessary prelude to human clinical trials, which we hope to perform in approximately 24 months.Read moreRead less
Development And Pre-clinical Evaluation Of G-DSF Inhibitors For Inflammatory Joint Disease
Funder
National Health and Medical Research Council
Funding Amount
$88,329.00
Summary
G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in expe ....G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in experimental models of inflammatory joint disease. We propose to develop inhibitors of G-CSF as a novel form of anti-cytokine therapy for inflammatory joint disorders, such as rheumatoid arthritis.Read moreRead less