Our current and future research utilizes antibody technology for the generation of a large naive human Fab library in a newly designed phage display vector. This phage display library has become an important source for the generation of human monoclonal antibodies (mAbs) to targets of relevance for hematologic malignancies. In FY05, we selected human mAb KYK-1.0 to human NKG2D from this library. NKG2D is expressed on NK cells which mediate the perhaps most important activity mechanism of antibodies, i.e. antibody-dependent cellular cytotoxicity (ADCC). In FY06, we further evolved KYK-1.0 through sequential affinity maturation based on phage display technology. The matured antibody (termed KYK-2.0) now binds human NKG2D with subnanomolar affinity. Since FY07, we have been evaluating KYK-2.0 (i) as diagnostic and therapeutic targeting device for NK-cell and T-cell lymphoma and leukemia, (ii) for the generation of bispecific antibodies designed to recruit NKG2D+ NK cells and NKG2D+ CD8+ T cells to the tumor site, and (iii) for interfering with autoimmune processes mediated by NK-cells and T-cells. Complementing our efforts for generating human monoclonal antibodies, we are continuing the mining of rabbit antibody repertoires by phage display. A target of interest in this regard is receptor tyrosine kinase ROR1 which we have found to be uniquely expressed on the surface of B-CLL cells. Another aspect of our antibody engineering efforts is the development of new antibody conjugation technologies. In this area we are closely collaborating with chemists from the Laboratory of Medicinal Chemistry, CCR, NCI, NIH in Frederick, MD. In particular, we are exploring new technologies at the interface of monoclonal antibodies and small synthetic molecules, resulting in uniquely defined immunoconjugates in which the biological and chemical components are endowed with pharmacological advantages. Our focus has been on the 21st natural amino acid selenocysteine as interface between biological and chemical components.
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