The research projects proposed are to elucidate - directly or indirectly - the molecular mechanisms of a novel concept of inducing tumor cell killing: the target-specific activation by a potent biological response modifier of one of the body's own cytotoxic mechanism: complement. We synthesized hybrid proteins consisting of the complement-activating cobra venom factor (CVF) and monoclonal antibodies to tumor associated antigens. By themselves non-toxic, the hybrid proteins became a specific and efficient cytolytic agent for human tumor cells in the presence of serum complement in vitro and in vivo. The proposed research projects include: 1) Analysis of the molecular mechanisms of monoclonal antibody-induced and hybrid-induced complement-mediated killing of tumor cells including resistance phenomena and their manipulation by metabolic inhibitors. 2) Synthesis of hybrid proteins with different heterobifunctional crosslinking reagents to select the optimal crosslinker. 3) Studies of the effect of hybrid proteins in normal animals including clearence from the circulation and non-specific localization into tissues. 4) Studies of the effect of hybrid proteins in athymic animals bearing human tumors including localization into the tumors and their tumor-suppressive activity. 5) Studies to elucidate the structural differences between CVF and C3 in order to generate a human C3 derivative with CVF-line activity which migth replace CVF in hybrid proteins. This approach would result in a target-specific, non-toxic and non-immunogenic cytotoxic agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Modified Research Career Development Award (K04)
Project #
5K04CA001039-04
Application #
3071609
Study Section
Experimental Immunology Study Section (EI)
Project Start
1985-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
School of Medicine & Dentistry
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Lu, Christine Y; Ross-Degnan, Dennis; Soumerai, Stephen B et al. (2008) Interventions designed to improve the quality and efficiency of medication use in managed care: a critical review of the literature - 2001-2007. BMC Health Serv Res 8:75
Vogel, Carl-Wilhelm (2004) Preparation of immunoconjugates using antibody oligosaccharide moieties. Methods Mol Biol 283:87-108
Gowda, D C; Glushka, J; Halbeek Hv et al. (2001) N-linked oligosaccharides of cobra venom factor contain novel alpha(1-3)galactosylated Le(x) structures. Glycobiology 11:195-208
Juhl, H; Petrella, E C; Cheung, N K et al. (1997) Additive cytotoxicity of different monoclonal antibody-cobra venom factor conjugates for human neuroblastoma cells. Immunobiology 197:444-59
Vogel, C W; Bredehorst, R; Fritzinger, D C et al. (1996) Structure and function of cobra venom factor, the complement-activating protein in cobra venom. Adv Exp Med Biol 391:97-114
Zara, J; Pomato, N; McCabe, R P et al. (1995) Cobra venom factor immunoconjugates: effects of carbohydrate-directed versus amino group-directed conjugation. Bioconjug Chem 6:367-72
Gowda, D C; Petrella, E C; Raj, T T et al. (1994) Immunoreactivity and function of oligosaccharides in cobra venom factor. J Immunol 152:2977-86
Fritzinger, D C; Bredehorst, R; Vogel, C W (1994) Molecular cloning and derived primary structure of cobra venom factor. Proc Natl Acad Sci U S A 91:12775-9
Ollert, M W; Kadlec, J V; David, K et al. (1994) Antibody-mediated complement activation on nucleated cells. A quantitative analysis of the individual reaction steps. J Immunol 153:2213-21
Ollert, M W; Kadlec, J V; Petrella, E C et al. (1993) Molecular basis of complement resistance of human melanoma cells expressing the C3-cleaving membrane protease p65. Cancer Res 53:592-9

Showing the most recent 10 out of 26 publications