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Research interests
Leucocyte Membrane Molecules
I am interested in the molecules on the plasma membranes of human leucocytes, particularly the dendritic cells and other cells of the myeloid lineage. The cell surface landscape provides clues into how each cell interacts with its environment. Regulation of immune cell surface phenotypes is crucial to directing cell interactions. Our group has a long history in describing and developing unique monoclonal antibodies to the molecules on the surface of human dendritic cells. We have characterised a number of human cell surface molecules including the CD300 family or immune regulatory molecules, DC activation molecules such as CD83 and the C-type lectin molecules CD205 and CD302.
Our knowledge of the DC cell surface has provided us with opportunities to harness the power of monoclonal antibodies to investigate the function of specific molecules – including the checkpoint inhibitors, and to use them to develop strategies for cancer immunotherapy.
Papers:Clark et al Trends in Immunology 2009, Ju et al Blood 2008, Lo et al JI 2016, Ju et al JI 2016
Human Dendritic Cell Subsets
Dendritic cells orchestrate the immune response; they stimulate responses to danger signals fighting infections and dampen response to self antigen. When things go awry, DC fail to dampen a response contributing to chronic inflammation and autoimmunity to failing to recognise a neoantigen or tumor antigen resulting in cancers. Immunotherapy approaches using blood DC to vaccinate against cancers has long been thought to have great potential but the many clinical trials in a range of cancers have met limited success. DC are a rare cell population and whilst human peripheral blood provides the most easily accessible human DC, using monocytes to derive a DC like cell “in vitro” has been the preferred source of DC in most clinical trials. Our group has concentrated on understanding the blood DC populations, their sparsity and how best to enrich for them to be able to use the “gold standard” blood DC in clinical trial. We have combined our expertise of the DC cell surface landscape to help identify different functional subpopulations of DC from human blood to ensure that we know which DC population should be targeted for a therapeutic outcome.
Link MacDonald Paper, the surface antigen paper 2018
Strategies to use monoclonal antibodies to DC surface molecules as therapeutics
1. DC Immunotherapy
We have developed a platform for the purification of blood DC from apheresis sample provided by patients that will allow us to trial DC immunotherapy for prostate cancer and glioma. A vaccine will be prepared from blood DC enriched from the patient’s apheresis sample and loaded with tumor antigen in the form of mRNA in a process that will take less than 24 hours. Enough vaccine will be prepared for between 5-10 doses. We are currently working to determine the best antigens to load into the DC. Tumor environments are often immunosuppressive. Combining DC vaccines with checkpoint inhibitors are predicted to enhance the efficacy of DC vaccines and we are determining the best combination.
Papers: Fromm paper, Hsu paper
2. Targeting DC
Whilst purifying DC is one approach to tumour immunotherapy, directly targeting antigen to a DC in vivo would have many advantages. A number of our mAbs target molecules that are expressed primarily by DC, are able to be internalised and are thus potential DC targeting mAbs. We have made chimeric versions of these mAbs to test their efficacy as antigen loading therapeutics.
3. Antibody drug conjugates
Acute Myeloid Leukemia (AML) is an aggressive leukemia with poor overall survival. We have identified a number of mAbs that target molecules expressed on leukemic blast cells from a high percentage of AML patients. We are developing these mAbs into antibody drug conjugates able to deliver toxins specifically to the leukemic cells and investigating strategies to safely use these conjugates without compromising the haematopoietic system of the patient.
Leucocyte Membrane Molecules
I am interested in the molecules on the plasma membranes of human leucocytes, particularly the dendritic cells and other cells of the myeloid lineage. The cell surface landscape provides clues into how each cell interacts with its environment. Regulation of immune cell surface phenotypes is crucial to directing cell interactions. Our group has a long history in describing and developing unique monoclonal antibodies to the molecules on the surface of human dendritic cells. We have characterised a number of human cell surface molecules including the CD300 family or immune regulatory molecules, DC activation molecules such as CD83 and the C-type lectin molecules CD205 and CD302.
Our knowledge of the DC cell surface has provided us with opportunities to harness the power of monoclonal antibodies to investigate the function of specific molecules – including the checkpoint inhibitors, and to use them to develop strategies for cancer immunotherapy.
Papers:Clark et al Trends in Immunology 2009, Ju et al Blood 2008, Lo et al JI 2016, Ju et al JI 2016
Human Dendritic Cell Subsets
Dendritic cells orchestrate the immune response; they stimulate responses to danger signals fighting infections and dampen response to self antigen. When things go awry, DC fail to dampen a response contributing to chronic inflammation and autoimmunity to failing to recognise a neoantigen or tumor antigen resulting in cancers. Immunotherapy approaches using blood DC to vaccinate against cancers has long been thought to have great potential but the many clinical trials in a range of cancers have met limited success. DC are a rare cell population and whilst human peripheral blood provides the most easily accessible human DC, using monocytes to derive a DC like cell “in vitro” has been the preferred source of DC in most clinical trials. Our group has concentrated on understanding the blood DC populations, their sparsity and how best to enrich for them to be able to use the “gold standard” blood DC in clinical trial. We have combined our expertise of the DC cell surface landscape to help identify different functional subpopulations of DC from human blood to ensure that we know which DC population should be targeted for a therapeutic outcome.
Link MacDonald Paper, the surface antigen paper 2018
Strategies to use monoclonal antibodies to DC surface molecules as therapeutics
1. DC Immunotherapy
We have developed a platform for the purification of blood DC from apheresis sample provided by patients that will allow us to trial DC immunotherapy for prostate cancer and glioma. A vaccine will be prepared from blood DC enriched from the patient’s apheresis sample and loaded with tumor antigen in the form of mRNA in a process that will take less than 24 hours. Enough vaccine will be prepared for between 5-10 doses. We are currently working to determine the best antigens to load into the DC. Tumor environments are often immunosuppressive. Combining DC vaccines with checkpoint inhibitors are predicted to enhance the efficacy of DC vaccines and we are determining the best combination.
Papers: Fromm paper, Hsu paper
2. Targeting DC
Whilst purifying DC is one approach to tumour immunotherapy, directly targeting antigen to a DC in vivo would have many advantages. A number of our mAbs target molecules that are expressed primarily by DC, are able to be internalised and are thus potential DC targeting mAbs. We have made chimeric versions of these mAbs to test their efficacy as antigen loading therapeutics.
3. Antibody drug conjugates
Acute Myeloid Leukemia (AML) is an aggressive leukemia with poor overall survival. We have identified a number of mAbs that target molecules expressed on leukemic blast cells from a high percentage of AML patients. We are developing these mAbs into antibody drug conjugates able to deliver toxins specifically to the leukemic cells and investigating strategies to safely use these conjugates without compromising the haematopoietic system of the patient.
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The Prostate (2024)
Kate L Mahon,Sarah Im Sutherland,Hui Ming Lin,Martin R Stockler,Howard Gurney,Girish Mallesara, Karen Briscoe,Gavin Marx,Celestia S Higano, Johann S de Bono,Kim N Chi,Georgina Clark,
The Prostate (2024)
Journal of Thoracic Oncologyno. 11 (2023): S388-S388
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