Antitumor activity of adriamycin (hydrazone-linked) immunoconjugates compared with free adriamycin and specificity of tumor cell killing.
Adriamycin (ADM) was chemically coupled to two monoclonal antibodies (MAb) expressed on human B-cell lymphomas. Immunoconjugates were prepared by linking to the MAb an ADM derivative, Adriamycin 13-[3-(2-pyridyldithio)propionyl]hydrazone (ADM-HZN), which releases ADM under mild acidic conditions (see preceding article). The (ADM-HZN) conjugates were tested for antitumor activity on two human B-lymphoma xenografts, Daudi and Ramos, which were growing as solid tumors in athymic mice. The conjugates, injected i.p., significantly inhibited tumor growth when antibody protein doses were greater than or equal to 500 mg/kg (approximately 10 mg/mouse). At these input antibody doses, (ADM-HZN) conjugates were more potent and had greater antitumor activity than free ADM given at an optimized dose and schedule. MAb-conjugated ADM was also tolerated to much higher levels than unconjugated drug. Antitumor activity was not obtained using mixtures of MAb plus free drug or with MAb-drug conjugates that did not bind to the tumor target cell. Thus, the antitumor activity of the immunoconjugate was directed by binding of the MAb portion of the conjugate to target tumor cells.
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, Connecticut.
G R
GR
Braslawsky
M A
MA
Edson
W
W
Pearce
T
T
Kaneko
R S
RS
Greenfield
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D006835:Hydrazones; D000922:Immunotoxins / Q000627:therapeutic use*; D008223:Lymphoma / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D006835:Hydrazones; D000922:Immunotoxins; D004317:Doxorubicin