Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer.
Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer.
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DOI：
10.1038/s41416-020-01046-6
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发表时间：
2020-11
影响因子：
8.8
通讯作者：
Scott CJ
中科院分区：
文献类型：
--
作者：
Greene MK;Chen T;Robinson E;Straubinger NL;Minx C;Chan DKW;Wang J;Burrows JF;Van Schaeybroeck S;Baker JR;Caddick S;Longley DB;Mager DE;Straubinger RM;Chudasama V;Scott CJ
抗体-药物缀合物（ADC）的构建提出了限制临床进展的许多挑战。特别地，常见的生物缀合方法对药物偶联至抗体的位点提供最小的控制。在此，通过将西妥昔单抗（CTX）的链间二硫化物与带有奥瑞他汀的哒嗪二酮再桥接来克服这些困难，以产生高度精制的抗表皮生长因子受体（EGFR）ADC。在已知对CTX疗法具有抗性的KRAS突变胰腺癌（PaCa）模型中进行ADC活性的体外和体内评估。采用计算建模定量预测肿瘤对各种ADC给药方案的反应。澳瑞他汀与CTX的位点选择性偶联产生平均药物：抗体比率（DAR）为3.9的ADC，其在体外以亚纳摩尔效力引起浓度和EGFR依赖性细胞毒性。在人类异种移植物中，ADC抑制肿瘤生长并延长生存期，没有明显的毒性迹象。通过一个强大的数学框架，包括与肿瘤细胞上的抗原密度相关的靶介导的处置效应，获得了对ADC疗效控制因素的关键见解。总之，我们的研究结果为CTX在PaCa治疗中的应用带来了新的希望，表明它可以重新格式化为下一代ADC，并与预测建模工具相结合来指导成功的翻译。
Antibody-drug conjugate (ADC) construction poses numerous challenges that limit clinical progress. In particular, common bioconjugation methods afford minimal control over the site of drug coupling to antibodies. Here, such difficulties are overcome through re-bridging of the inter-chain disulfides of cetuximab (CTX) with auristatin-bearing pyridazinediones, to yield a highly refined anti-epidermal growth factor receptor (EGFR) ADC. In vitro and in vivo assessment of ADC activity was performed in KRAS mutant pancreatic cancer (PaCa) models with known resistance to CTX therapy. Computational modelling was employed for quantitative prediction of tumour response to various ADC dosing regimens. Site-selective coupling of an auristatin to CTX yielded an ADC with an average drug:antibody ratio (DAR) of 3.9, which elicited concentration- and EGFR-dependent cytotoxicity at sub-nanomolar potency in vitro. In human xenografts, the ADC inhibited tumour growth and prolonged survival, with no overt signs of toxicity. Key insights into factors governing ADC efficacy were obtained through a robust mathematical framework, including target-mediated dispositional effects relating to antigen density on tumour cells. Together, our findings offer renewed hope for CTX in PaCa therapy, demonstrating that it may be reformatted as a next-generation ADC and combined with a predictive modelling tool to guide successful translation.
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影响因子：
8.4
作者：
Lee MTW;Maruani A;Richards DA;Baker JR;Caddick S;Chudasama V
通讯作者：
Chudasama V
影响因子：
4.7
作者：
Agarwal, Paresh;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
DOI：
10.1016/j.ddtec.2018.09.004
发表时间：
2018-12-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Forte, Nafsika;Chudasama, Vijay;Baker, James R
通讯作者：
Baker, James R
影响因子：
46.9
作者：
Lyon, Robert P.;Setter, Jocelyn R.;Senter, Peter D.
通讯作者：
Senter, Peter D.
影响因子：
5.7
作者：
Roy Chaudhuri T;Straubinger NL;Pitoniak RF;Hylander BL;Repasky EA;Ma WW;Straubinger RM
通讯作者：
Straubinger RM