The low uptake of an abrin A-chain immunotoxin by rat hepatic cells in vivo and in vitro.
The therapeutic value of antibody-ricin A-chain conjugates (immunotoxins) as antineoplastic agents is limited by their rapid removal from the circulation, primarily by cells of the liver which take up the immunotoxin through receptor mediated recognition of mannose-containing oligosaccharides in the toxin A-chain. We have therefore examined the uptake by rat hepatic cells of a monoclonal antibody (LICR-LOND Fib 75) conjugate assembled with the ricin related, but carbohydrate free, A-chain of the plant toxin abrin. The abrin A-chain immunotoxin was very poorly taken up in vivo and in vitro by both hepatic parenchymal and non parenchymal cells whereas a comparable conjugate assembled with ricin A-chain was actively accumulated by liver cells particularly the hepatic non-parenchymal cells. Furthermore, the abrin A-chain immunotoxin uptake by non-parenchymal cells in vitro was unaffected by mannose and the immunotoxin bound less readily to liver cells than did the ricin A-chain conjugate, consistent with a proposal that its accumulation by hepatic cells is brought about by endocytosis following non-specific binding or by fluid phase pinocytosis. These results suggest abrin A-chain immunotoxins might be further explored as anti-cancer agents since in some cases they could have an improved therapeutic efficacy over immunotoxins constructed with ricin A-chains.
Skilleter
D N
DN
MRC Toxicology Unit, Medical Research Council Laboratories, Carshalton, Surrey, U.K.
Price
R J
RJ
Parnell
G D
GD
Cumber
A J
AJ
D000036:Abrin / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D006601:Hexoses / Q000494:pharmacology; D000922:Immunotoxins / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010940:Plant Proteins / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D012276:Ricin / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006601:Hexoses; D000922:Immunotoxins; D010940:Plant Proteins; D000036:Abrin; D012276:Ricin