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Our lab is broadly interested in the discovery and preclinical/clinical development of enzymes andantibodies for therapeutic purposes, especially cancer. We employ integrated approach to thedevelopment of protein therapeutics that begins with the invention of platform technologies tofacilitate discovery, continues with tissue and animal testing of efficacy and then with bioprocessdevelopment, GMP production and toxicology, as required for clinical studies. Examples of our recentstudies in protein therapeutics will be discussed: 1) Enzyme therapeutics: The use of enzymes to systemically deplete metabolites required for thegrowth of tumor cells but not of normal tissues, has been pursued for many years. However thistherapeutic approach had been stymied by poor therapeutic properties and immunogenicity of theenzymes investigated. We have engineered and validated in xenograft models: (i) human arginasefor L-Arg depletion therapy for the treatment of hepatocellular carcinomas, metastatic melanomasand other L-Arg auxotrophic tumors. A phase I clinical trial of this drug is scheduled to begin in July2012. (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 innateimmune cells to destroy pathogens or diseased cells is critical for the therapeutic action of severalantibodies. The potency of ADCC depends on very subtle molecular effects that dictate the bindingof the antibody to inhibitory or activating receptors on immune cells. We have succeeded inengineering antibodies that engage exclusively (or preferentially) the activating receptors only andthus, display unique abilities to induce the efficient killing of cancer cells. Remarkably, theseengineered antibodies are aglycosylated, i.e. they lack the normally invariant carbohydrate chainwithin 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 themonoclonal antibodies that comprise the antigen-specific immunoglobulin pool in serum. We havenow developed a technology that enables the identification and relative quantitation of specificantibodies in serum samples from patients. This technology can guide the discovery of noveltherapeutic antibodies to infectious agents and other diseases, via the mining of the serum responsesthat have overcome the disease.