The clinical application of murine monoclonal antibodies has been hindered by their immunogenicity, pharmacokinetics and limited biologic activity. This project will characterize (both in vitro and in vivo) chimeric mouse human monoclonal antibodies made up of the variable region of 17-1A (mouse monoclonal antibody to colon cancer) and each of the human IgG subclass constant regions. These chimeric antibodies will be isolated and purified by immunoaffinity columns and be analyzed as regards quantitation of antibody binding to tumor cells, epitope specificity and binding affinity as compared to native murine 17-1A. Each subclass will be carefully analyzed in regard to its ability to interact with human complement (C) including C' mediated tumor cell lysis, C' 3 activation on the tumor cell surface and aggregate-induced C' consumption. Each subclass will be further analyzed in regard to Fc receptor interaction including mediation of leukocyte ADCC, competitive inhibition of standard ADCC reactions and non-specific mediating of Fc receptor binding. In nude mice, the antibodies will be tested for their ability to image colon cancer implants and to prevent tumor growth using a Winne assay system. In man, the chi- meric antibodies will be characterized as regard the pharmacokinetics of varying doses, pharmacokinetics of repetitive doses, characterization of the immune response to chimeric antibody administration and characterization of anti-idiotype and anti-anti- idiotype response. These observations may be extended to other chimeric antibodies as they are developed. These studies should provide vital laboratory information for the successful implementation of chimeric antibodies in human studies. They will also shed light on basic questions relevant to human immunoglobulin subclass function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045232-02
Application #
3188283
Study Section
Experimental Immunology Study Section (EI)
Project Start
1988-02-01
Project End
1991-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Saleh, M N; Khazaeli, M B; Wheeler, R H et al. (1995) Phase II trial of murine monoclonal antibody D612 combined with recombinant human monocyte colony-stimulating factor (rhM-CSF) in patients with metastatic gastrointestinal cancer. Cancer Res 55:4339-46
Cartner, A M; Conry, R M; Safavy, A et al. (1993) An animal model to predict the immunogenicity of murine V regions in humans. Hum Antibodies Hybridomas 4:174-80
Saleh, M N; Khazaeli, M B; Grizzle, W E et al. (1993) A phase I clinical trial of murine monoclonal antibody D612 in patients with metastatic gastrointestinal cancer. Cancer Res 53:4555-62
Meredith, R F; Khazaeli, M B; Grizzle, W E et al. (1993) Direct localization comparison of murine and chimeric B72.3 antibodies in patients with colon cancer. Hum Antibodies Hybridomas 4:190-7
Conry, R M; Khazaeli, M B; LoBuglio, A F (1992) Lack of T-cell immunity in humans with preexisting anti-mouse immunoglobulin reactivity. Cancer Res 52:6979-82
Khazaeli, M B; Saleh, M N; Liu, T et al. (1992) Frequent anti-V-region immune response to mouse B72.3 monoclonal antibody. J Clin Immunol 12:116-21
Meredith, R F; Khazaeli, M B; Plott, W E et al. (1992) Phase I trial of iodine-131-chimeric B72.3 (human IgG4) in metastatic colorectal cancer. J Nucl Med 33:23-9
Meredith, R F; LoBuglio, A F; Plott, W E et al. (1991) Pharmacokinetics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/human IgG1,k 17-1A monoclonal antibody. J Nucl Med 32:1162-8
Khazaeli, M B; Wheeler, R; Rogers, K et al. (1990) Initial evaluation of a human immunoglobulin M monoclonal antibody (HA-1A) in humans. J Biol Response Mod 9:178-84
Saleh, M N; LoBuglio, A F; Wheeler, R H et al. (1990) A phase II trial of murine monoclonal antibody 17-1A and interferon-gamma: clinical and immunological data. Cancer Immunol Immunother 32:185-90

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