The overall goal of this NCDDG is to develop our lymphoid cancer targeting peptidomimetic leads into useful therapeutic and imaging agents. Through combinatorial chemistry, we have identified a series of peptidomimetic compounds that bind to activated alpha4beta1 of lymphoid malignancies. These compounds contain an organic moiety, D-amino acids, and unnatural amino acids, and therefore they are expected to be resistant to proteolysis. They bind to both T- and B-lymphoma cell lines as well as fresh leukemia cells derived from patients with acute lymphocytic leukemia, but they do not bind to normal human peripheral blood. Furthermore, they bind strongly to dog lymphoma cells. These peptidomimetic leads have great potential to be developed into therapeutic and imaging agents for both human and canine lymphoid malignancies. This NCDDG application has three programs and two cores. Program 1 is responsible for further optimization and characterization of these peptidomimetic leads. Computational chemistry and combinatorial chemistry will be used for lead optimization. Program 2 involves the use of a series of CHO cells, that have been stably transfected with wild type or mutant alpha4 and/or beta1 integrin genes, to evaluate the molecular interactions between alpha4beta1 integrin and the targeting agents developed in Program 1. This study will enable us to map the binding site, and to develop high affinity ligand analogues that can overcome the mutation of the critical residues on the integrin. Program 3 involves in vivo evaluation of the targeting agents, developed in Program 1 and synthesized by Core B. DOTA-labeled targeting agents will be loaded with 64Cu for PET imaging and 90Y for therapeutics studies in nude mice with human lymphoma xenograft, and in spontaneous canine lymphoma in companion dog. The synthetic chemistry core (Core B), with input from corresponding programs, will be responsible for the design and synthesis of compound-bead libaries, targeting agents, and any other chemical conjugates required by all three programs. Program 1, 2, and 3 as well as Core B are highly interactive and synergistic. Our goal is to fully optimize and evaluate the targeting potential of our radio-targeting agents for lymphoid malignancies by the end of year 5, at which time one targeting agent will be selected for clinical development.
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