In vivo administration of lymphocyte-specific monoclonal antibodies in nonhuman primates. In vivo stability of disulfide-linked immunotoxin conjugates.
The stability in vivo and circulatory clearance of immunotoxins were assessed in rhesus monkeys. The immunotoxins studied were T cell-specific monoclonal anti-T11 antibodies conjugated by disulfide linkage to ribosome-inactivating toxins. Intact immunotoxin was detectable in the circulation of the monkeys following a single intravenous infusion. This was demonstrated by quantitative flow-cytometric analysis, gel-filtration, and sodium dodecyl sulfate-gel electrophoresis. This intact conjugate was shown to be functional in the plasma of the infused animals in an in vitro cytotoxicity assay. However, a number of factors contributed to bring the level of circulating immunotoxin to a less than optimal level. When conjugated to a ribosome-inactivating toxin, the antibody was cleared more rapidly than was the native antibody. Furthermore, following infusion, some breakdown of the conjugate occurred, resulting in the generation of detectable levels of circulating free antibody. The present data indicate the feasibility of using immunotoxins as therapeutic tools in man.
Letvin
N L
NL
Goldmacher
V S
VS
Ritz
J
J
Yetz
J M
JM
Schlossman
S F
SF
Lambert
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface / Q000276:immunology*; D004220:Disulfides; D000922:Immunotoxins; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage*; D054789:Ribosome Inactivating Proteins, Type 1; D012270:Ribosomes / Q000187:drug effects*; D000076985:Saporins; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D004220:Disulfides; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum; D009699:N-Glycosyl Hydrolases; D000076985:Saporins