N-terminal selective conjugation method widens the therapeutic window of antibody-drug conjugates by improving tolerability and stability

被引：7

作者：

Ko, Min Ji ^{[1
]}

Song, Daehae ^{[1
]}

Kim, Juhee ^{[1
]}

Kim, Jae Yong ^{[2
]}

Eom, Jaehyun ^{[1
]}

Sung, Byungje ^{[1
]}

Son, Yong-Gyu ^{[1
]}

Kim, Young Min ^{[3
]}

Lee, Sang Hoon ^{[1
]}

You, Weon-Kyoo ^{[1
]}

Jung, Jinwon ^{[1
]}

机构：

[1] ABL Bio Inc, Seongnam Si, South Korea

[2] Samsung Biol, Global Support Ctr, Incheon, South Korea

[3] Reyon Pharmaceut Co Ltd, BIO Business Div, Seoul, South Korea

来源：

MABS | 2021年 / 13卷 / 01期

关键词：

Antibody– drug conjugate; N-terminal conjugation; therapeutic window; toxicity; stability; trastuzumab; monomethyl auristatin-F;

D O I：

10.1080/19420862.2021.1914885

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable in vitro and in vivo than the thiol-conjugated and the lysine-conjugated ADCs. The NTERM-conjugated ADC showed lower toxicity compared to other ADCs, whereas its efficacy was comparable to that of the thiol-conjugated ADC and better than that of the lysine-conjugated ADC. These results suggest that the NTERM conjugation method could widen the therapeutic window of ADCs by enhancing its stability and reducing toxicity.

引用

页数：15

共 25 条

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