Monoclonal antibody-targeted superantigens: a different class of anti-tumor agents.
The bacterial superantigen staphylococcal enterotoxin (SE) A (SEA) directs cytotoxic T lymphocytes (CTLs) expressing particular sequences of the T-cell receptor (TCR) beta chain to lyse tumor cells expressing major histocompatibility complex (MHC) class II molecules, which serve as receptors for SEs. We now report that chemical conjugates of SEA and the colon carcinoma-reactive monoclonal antibodies (mAbs) C215 or C242 mediate T cell-dependent destruction of colon carcinoma cells lacking MHC class II molecules. SEA was covalently linked to the mAbs C215 and C242 via a PEG-based hydrophilic spacer. The C215-SEA conjugate targeted CD4+ as well as CD8+ CTLs to lyse a panel of colon carcinoma cells lacking MHC class II molecules. T-cell recognition of mAb-SEA conjugates was SEA specific, since SEB-selective T-cell lines with potent cytotoxic activity towards Raji cells coated with SEB did not respond to the C215-SEA conjugate. Unconjugated SEA did not induce T-cell lysis of MHC class II- colon carcinoma cells but efficiently directed CTLs against MHC class II+ Raji cells and certain interferon-treated MHC class II+ colon carcinoma cells. These results suggest that SEA-mAb conjugates retain the SEA-related selectivity for certain TCR beta-chain variable region (V beta) sequences but, in contrast to unconjugated SEA, mediate the TCR interaction in a MHC class II-independent manner. The cytotoxic activity mediated by C215-SEA and C242-SEA conjugates was blocked by excess of C215 mAb and C242 mAb, respectively, showing that the specificity in the targeting of mAb-SEA conjugates is defined by the antigen reactivity of the mAb. These results demonstrate that bacterial superantigens may be successfully conjugated to mAb with preserved T cell-activating capacity. The circumvention of MHC class II binding of SEs by conjugation to mAb suggests that such conjugates may find general application as antitumor agents, taking advantage of the extreme T cell-activating potency of superantigens.
Kabi Pharmacia Therapeutics AB, Lund, Sweden.
M
M
Dohlsten
G
G
Hedlund
E
E
Akerblom
P A
PA
Lando
T
T
Kalland
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D003110:Colonic Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004768:Enterotoxins / Q000494:pharmacology*; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D000922:Immunotoxins; D016393:Lymphoma, B-Cell / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D004768:Enterotoxins; D006681:HLA-D Antigens; D000922:Immunotoxins; D011994:Recombinant Proteins; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal