Selective toxicity of neocarzinostatin-monoclonal antibody conjugates to the antigen-bearing human melanoma cell line in vitro.
Monoclonal antibodies (IgG1) against high molecular weight antigen A-1-43 on human melanoma cell line A-375 were successfully linked to the anti-tumour protein neocarzinostatin (NCS) using the heterobifunctional reagent N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP). The conjugate retained both the reactivity of the antibody and the toxicity of the drug. The antigen-bearing cell line A-375, antigen-lacking cell line MeWo and normal skin fibroblasts were exposed to NCS-monoclonal antibody conjugates. As negative control, cells were also treated with free NCS and NCS coupled to normal mouse IgG1 antibodies. Inhibition of 3H-thymidine uptake after treatment was used to measure the biological activity of the cytotoxic drug complex or substance, respectively. Comparing the inhibition dose for 50% uptake (ID50) it was found that the monoclonal antibody-drug complex is about 100 times more toxic for the antigen-bearing cell line than free NCS or normal mouse IgG1-NCS. This high toxicity is due to a local increase of drug concentration on these cells. With the two cell lines lacking the appropriate antigen no significant differences in the ID50 values were observed. A selectivity factor of 40-50 was obtained by comparing the cytotoxic effect of the monoclonal antibody-NCS conjugate upon the antigen-bearing as opposed to the antigen-lacking cell type. These data demonstrate, that the toxicity of NCS can be directed by monoclonal antibodies to human tumour cells carrying the corresponding surface antigen.
Lüders
G
G
Köhnlein
W
W
Sorg
C
C
Brüggen
J
J
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000627:therapeutic use*; D002455:Cell Division; D003432:Cross-Linking Reagents; D006801:Humans; D007074:Immunoglobulin G / Q000302:isolation & purification; D007167:Immunotherapy; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D009353:Zinostatin / Q000008:administration & dosage*
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D007074:Immunoglobulin G; D009353:Zinostatin