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Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-12-03 , DOI: 10.1021/acsmedchemlett.9b00468 Alexei S Karpov 1 , Cristina M Nieto-Oberhuber 1 , Tinya Abrams 2 , Edwige Beng-Louka 1 , Enrique Blanco 1 , Sylvie Chamoin 1 , Patrick Chene 1 , Isabelle Dacquignies 1 , Dylan Daniel 3 , Michael P Dillon 2 , Lionel Doumampouom-Metoul 1 , Nikolaos Drosos 1, 2, 3 , Pavel Fedoseev 1 , Markus Furegati 1 , Brian Granda 2 , Robert M Grotzfeld 1 , Suzanna Hess Clark 2 , Emilie Joly 1 , Darryl Jones 1 , Marion Lacaud-Baumlin 1 , Stephanie Lagasse-Guerro 1 , Edward G Lorenzana 3 , William Mallet 3 , Piotr Martyniuk 1 , Andreas L Marzinzik 1 , Yannick Mesrouze 1 , Sandro Nocito 1 , Yoko Oei 3 , Francesca Perruccio 1 , Grazia Piizzi 1 , Etienne Richard 1 , Patrick J Rudewicz 3 , Patrick Schindler 1 , Mélanie Velay 1 , Kristine Venstrom 3 , Peiyin Wang 3 , Mauro Zurini 1 , Marc Lafrance 1, 2
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-12-03 , DOI: 10.1021/acsmedchemlett.9b00468 Alexei S Karpov 1 , Cristina M Nieto-Oberhuber 1 , Tinya Abrams 2 , Edwige Beng-Louka 1 , Enrique Blanco 1 , Sylvie Chamoin 1 , Patrick Chene 1 , Isabelle Dacquignies 1 , Dylan Daniel 3 , Michael P Dillon 2 , Lionel Doumampouom-Metoul 1 , Nikolaos Drosos 1, 2, 3 , Pavel Fedoseev 1 , Markus Furegati 1 , Brian Granda 2 , Robert M Grotzfeld 1 , Suzanna Hess Clark 2 , Emilie Joly 1 , Darryl Jones 1 , Marion Lacaud-Baumlin 1 , Stephanie Lagasse-Guerro 1 , Edward G Lorenzana 3 , William Mallet 3 , Piotr Martyniuk 1 , Andreas L Marzinzik 1 , Yannick Mesrouze 1 , Sandro Nocito 1 , Yoko Oei 3 , Francesca Perruccio 1 , Grazia Piizzi 1 , Etienne Richard 1 , Patrick J Rudewicz 3 , Patrick Schindler 1 , Mélanie Velay 1 , Kristine Venstrom 3 , Peiyin Wang 3 , Mauro Zurini 1 , Marc Lafrance 1, 2
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Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.
中文翻译：
通过连接子和有效负载优化，发现具有Eg5抑制剂的强效和选择性抗体药物共轭物。
靶向抗有丝分裂剂是一种有前途的抗癌治疗方法。在这里，我们描述了一种有效的和选择性的基于抗有丝分裂的Eg5抑制剂的抗体-药物偶联物（ADC）的开发。使用专有的Eg5抑制剂进行了初步研究，使用马来酰亚胺基己酰基缬氨酸-瓜氨酸对氨基苯甲氨基甲酸酯或MC-VC-PABC可裂解的接头将其结合到HER2靶向抗体上。但是，所得的ADC在体内缺乏抗原特异性，这可能是由于有效载荷的过早释放所致。然后使用不可裂解的接头开发了第二代ADC，得到的结合物（ADC-4和ADC-10）在表达HER-2的小鼠（SK-OV-3ip）小鼠异种移植模型中产生体内功效，而ADC-11在靶标依赖性方式下，可产生抗c-KIT（NCI-H526）小鼠异种移植模型的体内功效。
更新日期：2019-12-05
中文翻译：
通过连接子和有效负载优化，发现具有Eg5抑制剂的强效和选择性抗体药物共轭物。
靶向抗有丝分裂剂是一种有前途的抗癌治疗方法。在这里，我们描述了一种有效的和选择性的基于抗有丝分裂的Eg5抑制剂的抗体-药物偶联物（ADC）的开发。使用专有的Eg5抑制剂进行了初步研究，使用马来酰亚胺基己酰基缬氨酸-瓜氨酸对氨基苯甲氨基甲酸酯或MC-VC-PABC可裂解的接头将其结合到HER2靶向抗体上。但是，所得的ADC在体内缺乏抗原特异性，这可能是由于有效载荷的过早释放所致。然后使用不可裂解的接头开发了第二代ADC，得到的结合物（ADC-4和ADC-10）在表达HER-2的小鼠（SK-OV-3ip）小鼠异种移植模型中产生体内功效，而ADC-11在靶标依赖性方式下，可产生抗c-KIT（NCI-H526）小鼠异种移植模型的体内功效。
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