This project is directed toward the design and synthesis of immunogens, vaccine constructs, immunomodulators and biological response modifiers for collaborative studies of both basic and applied nature. Much of this work has been focused upon (1) studying immune responses to Brucella abortus conjugated with antigenic peptides or proteins derived from intracellular pathogens, with the goal of developing therapeutic vaccines, (2) studying the effects cross-linking antigen receptors on B cells with multivalent antibody-polymer conjugates, (3) developing novel polymer-peptide conjugates that inhibit tumor and endothelial cell growth with potential for the treatment of malignant tumors. Emphasis has been placed on studying the effects, in vitro and in vivo, of polyvalent presentation of biologically active molecules (peptides, lipopolysaccharides, ligands, haptens, etc.), covalently linked to soluble high molecular weight polymer or protein carriers. Conjugates of HIV-1-derived peptides covalently linked to heat-inactivated B. abortus have been found by collaborative investigators at CBER, FDA to elicit virus neutralizing (syncytia inhibiting) antibodies, predominantly of IgG2a isotype, as well as peptide-specific cytotoxic T cells (Th1 type responses), even in mice severely depleted of CD4+ helper T cells. These constructs are being actively investigated as potential therapeutic vaccines for treating AIDS patients. In a collaborative study with Dr. Patricia Mongini (New York Univ.), we have prepared a number of conjugates of high molecular weight dextran with affinity diverse monoclonal antibodies against B cell surface immunoglobulin M. These constructs allow cross-linking of multiples of antigen receptors in much the same manner as do polyvalent antigens. Studies have defined the interrelationships between valence, affinity and dose for the productive activation versus apoptosis of resting B cells. Collaborative studies are being carried out with investigators in the Laboratory of Pathology, NCI, on biological responses to synthetic peptide analogs and their conjugates with polymer carriers, such as polysucrose (FicollTM). In vivo experiments have shown that stable oligomers of some of these peptide analogs are potent inhibitors of tumor cell growth in a mouse-human breast cancer model; thus, such materials may be useful in blocking metastatic growth of breast cancer and other solid tumors. A US patent has been filed based on these findings.
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