Enhanced Activity of Monomethylauristatin F through Monoclonal Antibody Delivery: Effects of Linker Technology on Efficacy and Toxicity
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- 作者：Svetlana O. Doronina ; Brian A. Mendelsohn ; Tim D. Bovee ; Charles G. Cerveny ; Stephen C. Alley ; Damon L. Meyer ; Ezogelin Oflazoglu ; Brian E. Toki ; Russell J. Sanderson ; Roger F. Zabinski ; Alan F. Wahl
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：January 2006
- 年：2006
- 卷：17
- 期：1
- 页码：114 - 124
- 全文大小：532K
- 年卷期：v.17,no.1(January 2006)
- ISSN：1520-4812
文摘
We have previously shown that antibody-drug conjugates (ADCs) consisting of cAC10 (anti-CD30) linked tothe antimitotic agent monomethylauristatin E (MMAE) lead to potent in vitro and in vivo activities against antigenpositive tumor models. MMAF is a new antimitotic auristatin derivative with a charged C-terminal phenylalanineresidue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE, most likely due toimpaired intracellular access. In vitro cytotoxicity studies indicated that mAb-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-MMAF (mAb-L1-MMAF) conjugates were >2200-fold more potent than freeMMAF on a large panel of CD30 positive hematologic cell lines. As with cAC10-L1-MMAE, the correspondingMMAF ADC induced cures and regressions of established xenograft tumors at well tolerated doses. To furtheroptimize the ADC, several new linkers were generated in which various components within the L1 linker wereeither altered or deleted. One of the most promising linkers contained a noncleavable maleimidocaproyl (L4)spacer between the drug and the mAb. cAC10-L4-MMAF was approximately as potent in vitro as cAC10-L1-MMAF against a large panel of cell lines and was equally potent in vivo. Importantly, cAC10-L4-MMAFwas tolerated at >3 times the MTD of cAC10-L1-MMAF. LCMS studies indicated that drug released fromcAC10-L4-MMAF was the cysteine-L4-MMAF adduct, which likely arises from mAb degradation withinthe lysosomes of target cells. This new linker technology appears to be ideally suited for drugs that are bothrelatively cell-impermeable and tolerant of substitution with amino acids. Thus, alterations of the linker havepronounced impacts on toxicity and lead to new ADCs with greatly improved therapeutic indices.