Pharmacokinetics and mechanism of action of a doxorubicin-monoclonal antibody 9.2.27 conjugate directed to a human melanoma proteoglycan.
Doxorubicin (DXR) conjugated to a monoclonal antibody (MAb), 9.2.27, which recognizes a human melanoma-associated proteoglycan, effectively suppresses the growth of human melanoma xenografts and prolongs the life span of tumor-bearing athymic nude (nu/nu) mice. We have investigated further the mechanism(s) of this in vivo antitumor activity. Our results indicate that following iv injection, the DXR-MAb 9.2.27 conjugate is cleared from the circulation with typical biphasic kinetics, similar to the clearance process of the unconjugated MAb 9.2.27. In contrast, less than 10% of injected dose per milliliter of blood is found in the circulation at any given time after ip injection. Toxicity studies further indicate that DXR-MAb 9.2.27 conjugate is less toxic in vivo than the freely administered DXR, which is known to cause considerable cardiotoxic effects. Direct autoradiography demonstrates that the DXR-MAb 9.2.27 conjugate binds specifically to the tissue sections derived from a human melanoma xenograft of a nude mouse. A critical evaluation is given of the relevance of these findings and their impact on the design of future strategies for the immunochemotherapy of malignant melanoma.
Yang
H M
HM
Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
Reisfeld
R A
RA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001345:Autoradiography; D004317:Doxorubicin / Q000008:administration & dosage*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism* / Q000633:toxicity; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000032:analysis / Q000276:immunology*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D011509:Proteoglycans; D004317:Doxorubicin