Comparison of Recombinant and Synthetically Formed Monoclonal Antibody--Lactamase Conjugates for Anticancer Prodrug A
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- 作者：David E. Kerr ; Vivekananda M. Vrudhula ; Hå ; kan P. Svensson ; Nathan O. Siemers ; and Peter D. Senter
- 刊名：Bioconjugate Chemistry
- 出版年：1999
- 出版时间：November 1999
- 年：1999
- 卷：10
- 期：6
- 页码：1084 - 1089
- 全文大小：89K
- 年卷期：v.10,no.6(November 1999)
- ISSN：1520-4812
文摘
Conjugates of the L49 monoclonal antibody (binds to the p97 antigen on melanomas and carcinomas)were formed by attaching Enterobacter cloacae 
-lactamase (bL) to the L49-Fab' fragment using aheterobifunctional cross-linking reagent or by linking the enzyme to L49-sFv using DNA recombinanttechnology. The conjugates thus formed, L49-Fab'-bL and L49-sFv-bL, were designed to activatecephalosporin containing anticancer prodrugs at the surfaces of antigen positive tumor cells. Resultsfrom in vitro experiments using two lung carcinoma cell lines demonstrated that the conjugates wereequally active in effecting the release of phenylenediamine mustard from the cephalosporin nitrogenmustard prodrug CCM. While treatment with either of the conjugates combined with the maximumtolerated doses of CCM led to cures of established SN12P renal cell carcinoma tumors in nude mice,only the L49-sFv-bL conjugate maintained its ability to do so at 1/4 the maximum tolerated dose ofCCM. L49-sFv-bL was also superior to L49-Fab'-bL in the 1934J renal cell carcinoma tumor modeland was shown to be quite active in two in vivo models of human lung carcinoma. These resultsdemonstrate that the recombinant fusion protein leads to more pronounced therapeutic windows thanthe chemical conjugate and is active in an array of human tumor models.
-lactamase (bL) to the L49-Fab' fragment using aheterobifunctional cross-linking reagent or by linking the enzyme to L49-sFv using DNA recombinanttechnology. The conjugates thus formed, L49-Fab'-bL and L49-sFv-bL, were designed to activatecephalosporin containing anticancer prodrugs at the surfaces of antigen positive tumor cells. Resultsfrom in vitro experiments using two lung carcinoma cell lines demonstrated that the conjugates wereequally active in effecting the release of phenylenediamine mustard from the cephalosporin nitrogenmustard prodrug CCM. While treatment with either of the conjugates combined with the maximumtolerated doses of CCM led to cures of established SN12P renal cell carcinoma tumors in nude mice,only the L49-sFv-bL conjugate maintained its ability to do so at 1/4 the maximum tolerated dose ofCCM. L49-sFv-bL was also superior to L49-Fab'-bL in the 1934J renal cell carcinoma tumor modeland was shown to be quite active in two in vivo models of human lung carcinoma. These resultsdemonstrate that the recombinant fusion protein leads to more pronounced therapeutic windows thanthe chemical conjugate and is active in an array of human tumor models.