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Modulating Antibody–Drug Conjugate Payload Metabolism by Conjugation Site and Linker Modification
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2018-02-26 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00785
Dian Su 1 , Katherine R. Kozak 1 , Jack Sadowsky 1 , Shang-Fan Yu 1 , Aimee Fourie-O’Donohue 1 , Christopher Nelson 1 , Richard Vandlen 1 , Rachana Ohri 1 , Luna Liu 1 , Carl Ng 1 , Jintang He 1 , Helen Davis 1 , Jeff Lau 1 , Geoffrey Del Rosario 1 , Ely Cosino 1 , Josefa dela Cruz-Chuh 1 , Yong Ma 1 , Donglu Zhang 1 , Martine Darwish 1 , Wenwen Cai 2 , Chunjiao Chen 2 , Hongxiang Zhou 2 , Jiawei Lu 2 , Yichin Liu 1 , Surinder Kaur 1 , Keyang Xu 1 , Thomas H. Pillow 1
Affiliation  

Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized linkers provided optimal stability and reduction of payloads metabolism in circulation in vivo.

中文翻译:

通过结合位点和接头修饰来调节抗体-药物结合的有效负载代谢

由于相对稳定的有效负载(如美登素),以前对抗体-药物偶联物(ADC)稳定性的研究集中在通过接头解偶联产生的药物释放上。ADC的最新发展一直集中在探索生产同类ADC的技术和新型有效载荷上,以扩展所输送药物的作用机制。某些新的ADC有效负载在与抗体连接时可能会经历循环代谢,因此会影响ADC的稳定性,药代动力学以及功效和毒性。在这里,我们专门研究有效载荷的稳定性,并寻求解决有效载荷代谢的一般准则,从而提高总体ADC的稳定性。对具有不同功能(例如PNU-159682类似物,微管溶素,隐藻霉素,和紫杉醇)在THIOMAB抗体上使用不同的结合位点(HC-A118C,LC-K149C和HC-A140C)。我们能够通过采用最佳的偶联位点(LC-K149C和HC-A140C)来减少THIOMAB抗体-药物偶联物的有效载荷的代谢和失活。此外,通过优化链接器,进一步提高了负载的稳定性。用优化的接头偶联相对稳定的位点可提供最佳的稳定性,并减少体内循环中有效载荷的代谢。
更新日期:2018-02-26
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