Recombinant ricin toxin A chain cytotoxicity against carcinoembryonic antigen expressing tumour cells mediated by a bispecific monoclonal antibody and its potentiation by ricin toxin B chain.
A bispecific monoclonal antibody recognising both carcinoembryonic antigen (CEA) and ricin toxin A chain (RTA) was tested for its ability to target recombinant RTA (r-RTA) to CEA-expressing tumour cells, alone and in combination with ricin B chain (RTB). The antibody, 636 (Robins et al., 1990), induced significant RTA cytotoxicity against MKN45 gastric carcinoma cells which express high levels of CEA, using the r-RTA at a concentration below that known to be intrinsically cytotoxic. The addition of ricin toxin B chain (RTB) also potentiated cytotoxicity of r-RTA, and there was an additive increase in potentiation against CEA-positive cells when both RTB and 636 were included. The bispecific antibody restored potentiation by RTB after blocking of its binding site with excess galactose, and also the cytotoxic activity of whole ricin which had been blocked with galactose. It was concluded that the 636 bispecific antibody was highly effective in targeting the toxic moiety of the molecule to CEA-expressing cells, and allowed exploitation of the additional ability of the B chain to facilitate cellular incorporation. The facilitating function of the B chain was equally effective whether or not its lectin site was active.
Embleton
M J
MJ
Cancer Research Campaign Laboratories, University of Nottingham, University Park, UK.
Charleston
A
A
Robins
R A
RA
Pimm
M V
MV
Baldwin
R W
RW
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D004357:Drug Synergism; D005690:Galactose / Q000494:pharmacology; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D012276:Ricin / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000276:immunology / Q000628:therapy; D014407:Tumor Cells, Cultured / Q000276:immunology
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D011994:Recombinant Proteins; D012276:Ricin; D005690:Galactose