Discovery and Preclinical Development of Therapeutic Enzymes and Antibodies

George Georgiou, University of Texas

Our lab is broadly interested in the discovery and preclinical/clinical development of enzymes and antibodies for therapeutic purposes, especially cancer.  We employ integrated approach to the development of protein therapeutics that begins with the invention of platform technologies to facilitate discovery, continues with tissue and animal testing of efficacy and then with bioprocess development, GMP production and toxicology, as required for clinical studies.  Examples of our recent studies in protein therapeutics will be discussed: 

1) Enzyme therapeutics:  The use of enzymes to systemically deplete metabolites required for the growth of tumor cells but not of normal tissues, has been pursued for many years.  However this therapeutic approach had been stymied by poor therapeutic properties and immunogenicity of the enzymes investigated.    We have engineered and validated in xenograft models:  (i) human arginase for L-Arg depletion therapy for the treatment of hepatocellular carcinomas, metastatic melanomas and other L-Arg auxotrophic tumors.  A phase I clinical trial of this drug is scheduled to begin in July 2012. (ii) A human methionine g-lyase for L-Met restriction in tumors of neurological origin.

2) Engineered aglycosylated antibodies displaying novel effector functions and enhanced ADCC: Antibody-Dependent Cell Cytotoxicity (ADCC), i.e. the ability of the antibodies to activate innate immune cells to destroy pathogens or diseased cells is critical for the therapeutic action of several antibodies.    The potency of ADCC depends on very subtle molecular effects that dictate the binding of the antibody to inhibitory or activating receptors on immune cells.  We have succeeded in engineering antibodies that engage exclusively (or preferentially) the activating receptors only and thus, display unique abilities to induce the efficient killing of cancer cells.    Remarkably, these engineered antibodies are aglycosylated, i.e. they lack the normally invariant carbohydrate chain within the Fc domain, a property that greatly facilitates bioprocessing.

3) Deconvolution of the monoclonal antibodies that comprise the polyclonal serum response:   Remarkably, after 100 years of intense research in immunology, there is nothing known about the monoclonal antibodies that comprise the antigen-specific immunoglobulin pool in serum.  We have now developed a technology that enables the identification and relative quantitation of specific antibodies in serum samples from patients.  This technology can guide the discovery of novel therapeutic antibodies to infectious agents and other diseases, via the mining of the serum responses that have overcome the disease.