Effectiveness of an adriamycin immunoconjugate that recognizes the C-erbB-2 product on breast cancer cell lines.
Adriamycin (ADM) was chemically conjugated to a murine monoclonal antibody, A0011, which recognizes the c-erbB-2 product, via a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolane (2-IT). The molar ratio of ADM to the monoclonal antibody ranged from 15:1 to 25:1 and enzyme-linked immunosorbent assay (ELISA) showed that the binding activity of the conjugate was almost retained. We compared the efficacy of A0011 alone, ADM alone, the A0011-ADM conjugate, against the human breast cancer cell lines SK-BR-3, MDA-MB-361, MCF-7, and BT-20. The A0011-ADM conjugate was observed to be ten times more cytotoxic to the cell lines overexpressing the c-erbB-2 product, namely, SK-BR-3 and MDA-MB-361, than free ADM, but it showed weak cytotoxicity against the cell lines with a low level of c-erbB-2 product expression, namely, MCF-7 and BT-20. However, free A0011 and nonspecific murine IgM-ADM conjugate showed no cytotoxicity toward any of the four cell lines, while the addition of a tenfold molar excess of A0011 inhibited conjugate cytotoxicity. These data suggest that conjugate cytotoxicity is antibody-mediated. Moreover, conjugate cytotoxicity at 10(-6)M was correlated with antigen volume, and the data were fitted to the regression equation y = -11.63logX + 116.38 where the correlation coefficient = 0.950. Our results indicate that targeting therapy aiming at the c-erbB-2 product may be useful in the treatment of breast cancers overexpressing the c-erbB-2 product.
Jinno
H
H
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Ueda
M
M
Enomoto
K
K
Ikeda
T
T
Kyriakos
P
P
Kitajima
M
M
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D002460:Cell Line; D004317:Doxorubicin / Q000008:administration & dosage*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D004317:Doxorubicin; D018796:Immunoconjugates; D018719:Erb-b2 Receptor Tyrosine Kinases