Anti-tumor × anti-CD3 heteroconjugates direct human peripheral blood lymphocytes to lyse colon tumor cells

Heidi Nelson, David J. McKean, Lindsey A. Kerr, John H. Donohue

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

T lymphocytes normally recognize antigens through the antigen receptor complex (TCR/CD3) but can be redirected to bind and lyse unrecognized tumor cells by anti-tumor X anti-CD3 heteroconjugates. Chemical coupling of an antibody directed against the T cell receptor complex and an antibody directed against tumor antigen produces a conjugated antibody that activates the T cell lytic mechanism and bridges the T cell and tumor cell. We tested the lytic activity of heteroconjugate-treated cultured human peripheral blood lymphocytes (PBLs) in 4-h radioactive chromium release assays with human colon tumor cell targets. PBLs were enriched for T cells by the depletion of Leu11a+ and Leu19+ cells, prior to culture in rIL-2 and anti-CD3. Cultured human PBLs depleted of Leu11a+ and Leu19+ cells produced low levels of tumor cell lysis in the absence of antibodies. Anti-tumor X anti-CD3 heteroconjugates significantly enhanced tumor cell lysis by cultured PBLs when tested against four different colon tumor cell lines (P < 0.005), but, heteroconjugates in the absence of PBLs did not augment tumor cell lysis. Cultured PBLs treated with monoclonal anti-tumor antibody, with monoclonal anti-CD3 antibody, or with irrelevant heteroconjugate did not enhance tumor cell lysis. We conclude that heteroconjugate-directed lysis is mediated by PBLs and that both the antitumor antibody and the anti-CD3 antibody are essential for heteroconjugate function. In addition, heteroconjugate-enhanced tumor cell lysis is mediated through a mechanism other than antibody-dependent cellular cytotoxicity or nonspecific T cell receptor crosslinking. Anti-tumor X anti-CD3 heteroconjugates augment lysis of colon cancer cell lines of diverse origin and antigen expression and represent a potential approach to tumor-specific immunotherapy.

Original languageEnglish (US)
Pages (from-to)284-290
Number of pages7
JournalJournal of Surgical Research
Volume48
Issue number4
DOIs
StatePublished - 1990

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Colon
Lymphocytes
Neoplasms
Antibodies
T-Lymphocytes
Anti-Idiotypic Antibodies
T-Cell Antigen Receptor
T-Cell Antigen Receptor-CD3 Complex
Monoclonal Antibodies
Cultured Tumor Cells
Neoplasm Antibodies
Antigens
Antigen Receptors
Neoplasm Antigens
Chromium
Tumor Cell Line
Immunotherapy
Colonic Neoplasms
Cell Line

ASJC Scopus subject areas

  • Surgery

Cite this

Anti-tumor × anti-CD3 heteroconjugates direct human peripheral blood lymphocytes to lyse colon tumor cells. / Nelson, Heidi; McKean, David J.; Kerr, Lindsey A.; Donohue, John H.

In: Journal of Surgical Research, Vol. 48, No. 4, 1990, p. 284-290.

Research output: Contribution to journalArticle

Nelson, Heidi ; McKean, David J. ; Kerr, Lindsey A. ; Donohue, John H. / Anti-tumor × anti-CD3 heteroconjugates direct human peripheral blood lymphocytes to lyse colon tumor cells. In: Journal of Surgical Research. 1990 ; Vol. 48, No. 4. pp. 284-290.
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abstract = "T lymphocytes normally recognize antigens through the antigen receptor complex (TCR/CD3) but can be redirected to bind and lyse unrecognized tumor cells by anti-tumor X anti-CD3 heteroconjugates. Chemical coupling of an antibody directed against the T cell receptor complex and an antibody directed against tumor antigen produces a conjugated antibody that activates the T cell lytic mechanism and bridges the T cell and tumor cell. We tested the lytic activity of heteroconjugate-treated cultured human peripheral blood lymphocytes (PBLs) in 4-h radioactive chromium release assays with human colon tumor cell targets. PBLs were enriched for T cells by the depletion of Leu11a+ and Leu19+ cells, prior to culture in rIL-2 and anti-CD3. Cultured human PBLs depleted of Leu11a+ and Leu19+ cells produced low levels of tumor cell lysis in the absence of antibodies. Anti-tumor X anti-CD3 heteroconjugates significantly enhanced tumor cell lysis by cultured PBLs when tested against four different colon tumor cell lines (P < 0.005), but, heteroconjugates in the absence of PBLs did not augment tumor cell lysis. Cultured PBLs treated with monoclonal anti-tumor antibody, with monoclonal anti-CD3 antibody, or with irrelevant heteroconjugate did not enhance tumor cell lysis. We conclude that heteroconjugate-directed lysis is mediated by PBLs and that both the antitumor antibody and the anti-CD3 antibody are essential for heteroconjugate function. In addition, heteroconjugate-enhanced tumor cell lysis is mediated through a mechanism other than antibody-dependent cellular cytotoxicity or nonspecific T cell receptor crosslinking. Anti-tumor X anti-CD3 heteroconjugates augment lysis of colon cancer cell lines of diverse origin and antigen expression and represent a potential approach to tumor-specific immunotherapy.",
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AB - T lymphocytes normally recognize antigens through the antigen receptor complex (TCR/CD3) but can be redirected to bind and lyse unrecognized tumor cells by anti-tumor X anti-CD3 heteroconjugates. Chemical coupling of an antibody directed against the T cell receptor complex and an antibody directed against tumor antigen produces a conjugated antibody that activates the T cell lytic mechanism and bridges the T cell and tumor cell. We tested the lytic activity of heteroconjugate-treated cultured human peripheral blood lymphocytes (PBLs) in 4-h radioactive chromium release assays with human colon tumor cell targets. PBLs were enriched for T cells by the depletion of Leu11a+ and Leu19+ cells, prior to culture in rIL-2 and anti-CD3. Cultured human PBLs depleted of Leu11a+ and Leu19+ cells produced low levels of tumor cell lysis in the absence of antibodies. Anti-tumor X anti-CD3 heteroconjugates significantly enhanced tumor cell lysis by cultured PBLs when tested against four different colon tumor cell lines (P < 0.005), but, heteroconjugates in the absence of PBLs did not augment tumor cell lysis. Cultured PBLs treated with monoclonal anti-tumor antibody, with monoclonal anti-CD3 antibody, or with irrelevant heteroconjugate did not enhance tumor cell lysis. We conclude that heteroconjugate-directed lysis is mediated by PBLs and that both the antitumor antibody and the anti-CD3 antibody are essential for heteroconjugate function. In addition, heteroconjugate-enhanced tumor cell lysis is mediated through a mechanism other than antibody-dependent cellular cytotoxicity or nonspecific T cell receptor crosslinking. Anti-tumor X anti-CD3 heteroconjugates augment lysis of colon cancer cell lines of diverse origin and antigen expression and represent a potential approach to tumor-specific immunotherapy.

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