Overview

Research and development of new immunomodulatory therapeutics for autoimmune diseases such as rheumatoid arthritis and lupus; treatments of blood cancers; and vaccines in infections such as HIV and malaria.

There is a significant unmet need for the treatment of several intractable, neglected or incurable diseases. These include some of the blood cancers and solid tumours; several chronic inflammatory diseases such as rheumatoid arthritis and lupus; and infectious diseases including malaria, HIV and chronic bacterial infection.

Antibodies are the critical blood proteins of the immune system which, in normal immunity, protect against infection and they are the major reason why vaccines work. Pathological inflammation in some autoimmune diseases aberrant antibodies induce uncontrolled, powerful inflammatory responses that result in tissue destruction.

We are studying how antibodies protect against infection for the development of better vaccines and at the same time we are attempting to design new ways to prevent the tissue destruction seen in autoimmunity. Finally because antibodies are so naturally potent, we are developing new biological drugs called monoclonal antibodies to treat disease.

Our primary goal is to discover new ways to treat disease by manipulating the immune system.

We are studying the structure and function of leucocyte cell surface molecules, especially Fc-receptors, or FcR which bind antibodies IgG, IgA or IgE. These Fc-receptors are implicated in immune protection against pathogenic microorganisms and in the aetiology of autoimmune disease. Antibodies complexed to antigen can cluster Fc-receptors, regulating potent effector cell responses including the release of immune polarising inflammatory cytokines, antibody dependant cellular cytotoxicity and phagocytosis of cells or pathogens. Targeting these receptors with monoclonal antibodies or designed drugs may neutralise inflammation and prevent or treat several major diseases. Moreover monoclonal antibodies can also be engineered to harness the FcRs of innate immune cells to eliminate cancer or infection.

Understanding how Fc receptor signalling leads to diverse different outcomes is crucial for the development of novel interventions in human health. By studying the structure and function of Fc-receptors in diverse inflammatory settings, we aim to discover new therapeutic targets for the treatment of autoimmune diseases and infection.

Diseases we study

Because of the broad role of antibodies in normal immunity and in disease, our work is very relevant in a number of major human diseases:

Inflammatory Autoimmune Disease:
These include rheumatoid arthritis and its related diseases lupus, antiphospholipid syndrome, vasculitis in Wegener’s granulomatosus and vitaligo. We are targeting Fc receptors and also have discovery programs to identify new molecular targets on Th17 and Th1 inflammatory cells.

Cancer:
There has been much speculation about the role of inflammation in both protecting against or enhancing the development of various cancers. We are identifying surface molecules associated with inflammation that are also present on cancer cells, especially blood cancers and some solid tumours. We aim to target these with genetically engineered monoclonal antibodies.

Infection:
Since antibodies are critical to the success of vaccines, we are identifying how they function to resist infection and how microbes attempt to avoid antibodies. We are particularly interested in neutralising antibodies in HIV, and the role of antibodies in malaria immunity and staphylococcal infection.

Major techniques employed in our laboratory

• Antibody engineering and monoclonal antibody production
• Protein structure and function analysis
• Molecular cloning
• Protein purification and characterisation
• Isolation and expansion of human T cell subsets
• Characterisation of Fc Receptor function inflammatory and innate immune cell function
• Flow cytometric analysis of cellular subsets
• Proteomics
• Animal models of inflammation especially arthritis and cancer.

Objectives

• To understand how antibodies interact with Fc receptors and drive inflammatory cell activation in tissue destruction in some autoimmune diseases such as lupus, rheumatoid arthritis and related diseases. Of major importance is understanding the basis of immune complex hypersensitivity in disease development

• To understand the role of Th17 cells in FcgRIIa transgenic (Tg) mice, which spontaneously develop destructive arthritis mimicking human rheumatoid arthritis and lupus

• To discover targets for the treatment of cancer with new therapeutic anti-cancer monoclonal antibodies allowing us to harness the “potent” activating potential of FcR

• To understand the relationship between inflammation and cancer

• To define how bacterial pathogens avoid antibody destruction

• To discover new markers of Th17 cells for the treatment of inflammatory diseases and blood cancers (with CRC-BMD)

• To study how FcgR engagement modifies the innate immune response to the malaria parasite, Plasmodium falciparum.

Projects

• A unique approach to anti-inflammatory immune therapy
  Next Generation monoclonal antibody therapies targeting the inhibitory FcR.
• Antibody mAbs to destroy infection: engineering the next generation treatments
  Applying discoveries from our cancer mAb program to neutralize and destroy pathogens.
• Broadly neutralising anti-HIV antibodies and Fc Receptor function
  Defining the properties of anti-HIV antibodies for vaccine development and protection of pregnant women.
• Discovery of new cell surface biomarkers of Th17 and Th1 cells
  We are researching the cause of inflammation associated with rheumatoid arthritis.
• Discovery of new treatments for myeloma and myelogenous leukemia
  We are developing monoclonal antibodies against new biomakers to treat blood cancers.
• FcgR Function in cellular responses to malaria parasites
  Understanding how antibodies protect against malaria is crucial to vaccine development.
• IgA and staphyloccocal aureus immune evasion
  Staphylococcus aureus, or the golden staph, is a major pathogen of humans. We are investigating how this bug evades the immune system.
• New approaches to the treatment of lupus
  Research into an early intervention diagnostic test for Lupus, which is particularly dangerous to women.
• Predicting quality and potency of monoclonal and natural antibodies
  Rapid, simple and scalable assays for predicting antibody potency.
• Understanding the connection between inflammation and cancer
  Defining the relationship between inflammation and cancer with the aim of developing new therapies.