Developing the next-gen therapeutic monoclonal antibodies: new insights by targeting and manipulating human FcR: antibody dependant functions

Hogarth PM1,2,3, Chenoweth AM1, Wines BD1, Trist HM1 and Esparon SE1

  1. Immune Therapies Group, Burnet Institute, Melbourne. VIC.
  2. Clinical Pathology, University of Melbourne, Parkville VIC.
  3. Immunology and Pathology Monash University, Melbourne.

The potency of many therapeutic antibodies, particularly in cancer and immune agonism, requires antibody interaction with human Fc receptors. The FcR are specific, cell surface receptors for immunoglobulins which provide a potent, system of activation and regulation of cell-based effector responses used by therapeutic antibodies. These Fc-dependant reposes include antibody dependent cell mediated cytotoxicity, phagocytosis, potent degranulation and mediator release. In addition to therapeutic potency, the Fc:FcR interaction of antibodies or Fc fusions can also induce unwanted adverse reactions. Manipulation of the antibody Fc will provide the next generation therapeutic mabs and Fc fusions with more potent and specific actions i.e. cell or virus killing in anti-cancer mAbs or inhibitory anti-inflammatory modulation in autoimmunity and allergy or the ablation of FcR-dependant function to avoid adverse effects. Our therapeutic biologicals program uses our pioneering studies of antibody and Fc receptor structure and function of human, and non-human primates, as the basis for the engineering of next generation therapeutic antibodies for profoundly altered function and specificity. This will include our work on (i) Fc receptors forms and roles in antibody effector function. (ii)Manipulation of mAbs and Fc receptors for antibody therapy (iii)Novel methods of evaluation of antibody:FcR effector functions in immune therapy. (iv) Challenges in using non-human primates as models of human antibody function. WWW