APPLICATION OF MONOCLONAL-ANTIBODIES AGAINST CYTOSINE DEAMINASE FOR THE IN-VIVO CLEARANCE OF A CYTOSINE DEAMINASE IMMUNOCONJUGATE

被引:28
作者
KERR, DE
GARRIGUES, US
WALLACE, PM
HELLSTROM, KE
HELLSTROM, I
SENTER, PD
机构
[1] Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121
关键词
D O I
10.1021/bc00023a008
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The selective delivery of anticancer drugs to tumors vs normal tissue using targeted antibody-enzyme conjugates for prodrug activation is limited by the amount of drug generated by blood-borne enzyme. Clearance of non-tumor-associated conjugate would increase the tumor/blood conjugate ratio, and enable larger amounts of prodrugs to be administered. A method for clearing the monoclonal antibody (mAb) conjugate L6-cytosine deaminase (L6-CD) was established by using an antibody raised against CD. The mAb 102-26 was obtained by immunizing BALB/C mice with CD conjugated to keyhole limpet hemocyanin. 102-26 was able to precipitate purified CD from solution as assessed by radioimmune precipitation and recognized CD in Western blot analyses. Similar studies were used to establish that 102-26 also recognized CD when conjugated to the L6 and 1F5 mAbs. Selective removal of L6-CD from the circulation of nude mice bearing H2981 human lung adenocarcinoma (L6-antigen positive) was achieved by injecting 102-26 24 h after L6-CD administration. High T/B ratios were obtained by clearance of a L6-CD (38:1 compared to 1.3:1 without clearance).
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页码:353 / 357
页数:5
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