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 gp 120 or V3-loop peptides derived from human immunodeficiency virus (HIV-1) strains, with the goal of developing a therapeutic vaccine, (2) developing novel polymer-peptide conjugates that inhibit tumor and endothelial cell growth with potential for the treatment of disease conditions that depend on neovascularization, such as melanomas, breast carcinoma, Kaposi's sarcoma and diabetic retinopathies. 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. New reagents and methods have been developed in this section for synthesizing novel conjugates used for these studies. 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, even in mice severely depleted of CD4+ helper T cells. These constructs are being actively investigated as potential therapeutic vaccines for treating AIDS patients. Collaborative studies are being carried out with investigators in the Laboratory of Pathology, NCI, on biological responses to synthetic peptides linked to soluble polymer carriers. The sequences are taken from the extracellular matrix protein, thrombospondin-1. A number of variants of a peptide from the type 1 repeat unit have been synthesized and covalently coupled to highly branched polysucrose (FicollTM). In vitro and in vivo experiments have shown that many of these conjugates are potent inhibitors of endothelial and tumor cell growth; and thus, they may be useful in blocking metastatic growth of solid tumors. A US patent has recently been filed based on these findings.
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| Golding, Basil; Eller, Nancy; Levy, Lily et al. (2002) Mucosal immunity in mice immunized with HIV-1 peptide conjugated to Brucella abortus. Vaccine 20:1445-50 |
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