Abstract

The objective of this study is to develop human monoclonal antibodies to ganglioside antigens and to determine their potential usefulness in the treatment of cancer. Gangliosides are glycosphingolipids bearing sialic acid and are synthesized at high levels by malignant tissues of neuroectodermal origin (ie., melanoma and neuroblastoma). Gangliosides are usually located on the cell surface. Human melanoma have been shown to express several ganglioside molecules which are uncommon to their normal counterpart. These unique gangliosides include GM2, GD2, O-acetyl gangliosides, N-glycolyl (NeuGc) containing gangliosides, and GD3. Murine monoclonal antibodies to these gangliosides have been developed by other investigators. Over the past grant periods, we developed human monoclonal antibodies to two of these gangliosides, GM2 and GD2, and recently we demonstrated their clinical usefulness through intralesional injection into recurrent cutaneous melanoma. In these clinical studies, we found that ganglioside negative melanoma tissues were not effected by treatment, and that ganglioside expression was widely heterogeneous among melanoma. It thus appears that development of human monoclonal antibodies to other ganglioside antigens is essential for an effective passive immunotherapy for this type of tumor. In this renewal application, we will develop human monoclonal antibody to GD3, and NeuGc containing gangliosides and other melanoma associated gangliosides not yet defined. Epstein-Barr virus transformation, hybridoma and cDNA technology will be utilized to develop both IgM and IgG antibodies. The former two techniques are well established in this laboratory while the construction of human-human IgG chimeric antibodies will be done by collaborative research with a molecular biologist. We will evaluate these newly developed human monoclonal antibodies for their potential therapeutic application in cancer. Tissue distribution of ganglioside antigens defined by the new HuMAbs, binding and cytotoxic ability of the antibodies will be determined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030647-09
Application #
3169337
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-08-01
Project End
1991-05-31
Budget Start
1989-08-14
Budget End
1990-05-31
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Irie, Reiko F; Ollila, David W; O'Day, Steven et al. (2004) Phase I pilot clinical trial of human IgM monoclonal antibody to ganglioside GM3 in patients with metastatic melanoma. Cancer Immunol Immunother 53:110-7
Takahashi, T; Johnson, T D; Nishinaka, Y et al. (1999) IgM anti-ganglioside antibodies induced by melanoma cell vaccine correlate with survival of melanoma patients. J Invest Dermatol 112:205-9
Takahashi, T; Conforti, A; Kikumoto, Y et al. (1998) Augmentation of IgM antibody to gp43 tumor-associated antigen peptide by melanoma cell vaccine. J Clin Immunol 18:299-305
Zhang, Z; Irie, R F; Chi, D D et al. (1998) Cellular immuno-PCR. Detection of a carbohydrate tumor marker. Am J Pathol 152:1427-32
Nishinaka, Y; Hoon, D S; Irie, R F (1998) Human IgM antibodies to tumor-associated gangliosides share VHIII (V3-23) and VKIV family subgroups. Immunogenetics 48:73-5
Takahashi, T; Irie, R F; Morton, D L et al. (1997) Recognition of gp43 tumor-associated antigen peptide by both HLA-A2 restricted CTL lines and antibodies from melanoma patients. Cell Immunol 178:162-71
Nishinaka, Y; Ravindranath, M H; Irie, R F (1996) Development of a human monoclonal antibody to ganglioside G(M2) with potential for cancer treatment. Cancer Res 56:5666-71
Kikumoto, Y; Oka, T; Cao, J N et al. (1995) Peptides with carboxyl-terminal sequence of alanine-proline: detection by a human monoclonal antibody. Hybridoma 14:45-50
Morioka, N; Kikumoto, Y; Hoon, D S et al. (1995) Cytotoxic T cell recognition of a human melanoma derived peptide with a carboxyl-terminal alanine-proline sequence. Mol Immunol 32:573-81
Oka, T; Kikumoto, Y; Itakura, K et al. (1994) Human monoclonal antibody identified an immunoreactive tetrapeptide sequence (Lys-Tyr-Gln-Ile) in M(r) 43,000 protein of human melanoma. Cancer Res 54:3511-5

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