ADRIAMYCIN(HYDRAZONE)-ANTIBODY CONJUGATES REQUIRE INTERNALIZATION AND INTRACELLULAR ACID-HYDROLYSIS FOR ANTITUMOR-ACTIVITY

被引：73

作者：

BRASLAWSKY, GR ^{[1
]}

KADOW, K ^{[1
]}

KNIPE, J ^{[1
]}

MCGOFF, K ^{[1
]}

EDSON, M ^{[1
]}

KANEKO, T ^{[1
]}

GREENFIELD, RS ^{[1
]}

机构：

[1] PFIZER INC,CENT CHEM,GROTON,CT 06340

来源：

CANCER IMMUNOLOGY IMMUNOTHERAPY | 1991年 / 33卷 / 06期

关键词：

MONOCLONAL ANTIBODIES; IMMUNOCONJUGATES; ADRIAMYCIN;

D O I：

10.1007/BF01741596

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Adriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with a oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.

引用

页码：367 / 374

页数：8

共 33 条

[1] TUMOR BOUND IMMUNOGLOBULINS - RELATIONSHIP BETWEEN INVIVO COATING OF TUMOR-CELLS BY POTENTIALLY CYTOTOXIC ANTI-TUMOR ANTIBODIES, AND EXPRESSION OF IMMUNE-COMPLEX RECEPTORS [J].