Monoclonal antibodies reactive with tumor associated antigens are being studied for their utility for cancer therapy, either alone as an immunologic mediator of cytotoxicity, or conjugated to a drug, toxin, or radionuclide. A significant problem with radiolabeled MAbs is their relative inaccessibility to all regions of a tumor in adequate quantities. Because of the large size of the MAb-conjugates, endothelial and reticuloendothelial tissues act as restrictive barriers limiting the egress from the intravascular space of these large molecules. For this reason, the ability to transiently increase vascular permeability is receiving considerable attention as a way of enhancing tumor uptake of highly specific MAbs from the blood. The investigators involved in this research initiative have developed a panel of stable conformationally constrained decapeptide agonists corresponding to the C-terminal """"""""effector"""""""" region of human C5a that have the ability to increase vascular permeability. This project will investigate methods of conjugation of the C5a decapeptides to MAb B72.3 without loss of the vasoactivity of the agonist peptides or the specificity/ avidity of the MAb. Furthermore, the in vivo use of the Mab-C5a peptide constructs will be studied to determine the optimal decapeptide and linker combination to improve the tumor distribution of radiolabeled MAbs. These studies will lead to the preparation of clinical grade materials for future clinical radioimmunotherapy studies.
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