____^ _. This proposal focuses on two related themes in order to achieve selective prevention and treatment of primary tumors and metastasis of human cancers: (1) Novel cell-targeting antibody (Ab) constructs derived from the non-targeting catalytic aldolase monoclonal Abs (mAbs) are developed;and (2) Integrins avb3 and avb5 are evaluated as targets of the proposed therapy. In the proposed research, we will test the hypotheses that a cell-targeting Ab construct can be prepared from a small molecule inhibitor of the cancer-associated extracellular receptors, such as integrins avb3 and avb5 antagonists, reacting selectively and covalently with the binding sites of a catalytic aldolase mAb, such as 38C2;the construct would target its receptor and discern its activity more efficiently than the antagonist or the non-targeting Ab alone;and the construct would deliver a cytotoxic drug selectively to cancer cells. This combination will be extremely efficient for the treatment of the primary tumors and metastasis of various cancers. These hypotheses utilize a unique property of the catalytic aldolase mAbs because they possess a pair of reactive lysine residues in their binding sites that can react selectively and efficiently with diketone or vinylketone compounds. In principle, the aldolase mAb can be directed to any receptor of choice that will depend upon specificity of the antagonist (or targeting agents) used. With the development of our approach at the interface of chemistry and biology: One can use different low molecular weight targeting agents to selectively target the same antibody to different sites for different uses, thereby breaking the one antibody-one target axiom. This strategy has the advantage that only a single antibody is required for a multiplicity of tasks and it taps into the unlimited chemical diversity and the specificity that can be engendered by organic synthesis.
