PF-06804103, A Site-specific Anti-HER2 Antibody-Drug Conjugate for the Treatment of HER2-expressing Breast, Gastric, and Lung Cancers
PF-06804103, A Site-specific Anti-HER2 Antibody-Drug Conjugate for the Treatment of HER2-expressing Breast, Gastric, and Lung Cancers
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DOI：
10.1158/1535-7163.mct-20-0237
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发表时间：
2020-10-01
影响因子：
5.7
通讯作者：
Sapra, Puja
中科院分区：
文献类型：
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作者：
Graziani, Edmund, I;Sung, Matthew;Sapra, Puja
ado-曲妥珠单抗emtansine （T-DM1）被批准用于治疗HER2阳性转移性乳腺癌，证实了HER2是HER2特异性抗体-药物偶联物（ADC）的靶点。尽管具有临床疗效，但T-DM1的某些固有特性阻碍了该化合物在adc靶向表达her2的实体瘤中发挥全部潜力。在这里，我们详细介绍了PF-06804103的发现，这是一种与T-DM1相比具有更宽治疗窗口的抗her2 ADC。我们利用经验偶联位点筛选活动来鉴定工程的kK183C和K290C残基，这些残基可以最大限度地提高四药抗体比（DAR） ADC的体内稳定性、有效性和安全性。PF-06804103结合了以下新颖的设计元素：(i)具有优化药效学特性的新型aurisatin有效载荷，（ii）具有优化有效载荷释放和增强抗肿瘤功效的可切割连接体，以及（iii）工程半胱氨酸位点特异性偶联方法，克服了传统偶联物的传统安全性缺陷，产生了DAR为4的同质药物产品。PF-06804103显示出(i)对低her2表达的乳腺、胃和肺肿瘤模型的疗效增强，（ii）克服体外和体内获得性T-DM1耐药性，以及（iii）通过增强ADC稳定性、药代动力学参数和减少脱靶毒性来改善安全性。在此，我们展示了优化ADC设计的平台方法，从而生成了抗her2 ADC PF-06804103。本研究中使用的识别新偶联位点的设计元素可作为开发针对其他肿瘤特异性靶点的优化adc的平台。
The approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2specific antibody-drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential of targeting HER2expressing solid tumors with ADCs. Here, we detail the discovery of PF-06804103, an anti-HER2 ADC designed to have a widened therapeutic window compared with T-DM1. We utilized an empirical conjugation site screening campaign to identify the engineered kK183C and K290C residues as those that maximized in vivo ADC stability, efficacy, and safety for a four drug-antibody ratio (DAR) ADC with this linker-payload combination. PF-06804103 incorporates the following novel design elements: (i) a new auristatin payload with optimized pharmacodynamic properties, (ii) a cleavable linker for optimized payload release and enhanced antitumor efficacy, and (iii) an engineered cysteine site-specific conjugation approach that overcomes the traditional safety liabilities of conventional conjugates and generates a homogenous drug product with a DAR of 4. PF-06804103 shows (i) an enhanced efficacy against low HER2-expressing breast, gastric, and lung tumor models, (ii) overcomes in vitro- and in vivo-acquired T-DM1 resistance, and (iii) an improved safety profile by enhancing ADC stability, pharmacokinetic parameters, and reducing off-target toxicities. Herein, we showcase our platform approach in optimizing ADC design, resulting in the generation of the antiHER2 ADC, PF-06804103. The design elements of identifying novel sites of conjugation employed in this study serve as a platform for developing optimized ADCs against other tumor-specific targets.