A human T cell line engineered to secrete chimeric monoclonal antibody.
Both monoclonal antibodies (MAbs) and human T cells have been used in human tumor immunotherapy protocols. Tumor-infiltrating lymphocytes (TILs) and MAbs that can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) via human effector cells have shown antitumor effects in both animal models and clinical trials. One potential novel approach would be to combine these two modalities in the creation of a T cell capable of secreting antitumor immunoglobulins (Ig), in essence, creating an antitumor Ig "factory" at the tumor site. In the studies reported here, we have cloned the D612 MAb Ig genes and generated a chimeric D612 IgG1 containing the murine variable region and human constant region. D612 MAb has been shown to mediate lysis of human colon carcinomas via effector cell-mediated ADCC. We have demonstrated that following transfection, chimeric D612 can be expressed and secreted by the human T-cell line MOLT-4 at a rate of 0.25 micrograms/ml per 10(6) cells in 72 hours. The secreted Ig retained its antigen-binding properties as assayed by competition radioimmunoassay and also its ability to mediate ADCC against human tumor cells. To our knowledge, this is the first demonstration of the production of a chimeric IgG by human T cells and opens the possibility of a therapeutic approach in which TILs secrete humanized antitumor MAb capable of mediating ADCC at the tumor site.
Tsang
K Y
KY
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Kashmiri
S V
SV
De Filippi
R
R
Qi
C F
CF
Calvo
B
B
Shu
L
L
Nieroda
C A
CA
Greiner
J W
JW
Schlom
J
J
D000911:Antibodies, Monoclonal / Q000235:genetics*; D001667:Binding, Competitive / Q000276:immunology; D015153:Blotting, Western; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D005818:Genetic Engineering; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D016130:Immunophenotyping; D008957:Models, Genetic; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007136:Immunoglobulins