Mersana Therapeutics, Inc., 840 Memorial Drive, Cambridge, Massachusetts 02139, United States.
3-Dimensional Consulting, 134 Franklin Avenue, Quincy, Massachusetts 02170, United States.
J Med Chem. 2023 Aug 10;66(15):10715-10733. doi: 10.1021/acs.jmedchem.3c00907. Epub 2023 Jul 24.
While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
虽然 STING 激动剂已被证明在临床前具有抗肿瘤作用，但这些有前途的结果尚未在临床上得到转化。STING 激动剂抗体药物偶联物（ADC）可以通过提高肿瘤的可及性来克服当前的限制，从而允许系统给药以及肿瘤局部激活 STING，以实现更高的抗肿瘤活性和更好的耐受性。基于这一努力，通过系统优化基于多种因素的有效载荷、接头和支架，包括在体外和体内评估中的效力和特异性，确定了 STING 激动剂 ADC 平台。该平台采用了一种有效的非环二核苷酸 STING 激动剂、一种可裂解的酯基接头和一种亲水的 PEG8-双葡糖胺支架。使用由此产生的 STING 激动剂平台构建的肿瘤靶向 ADC 诱导了强大和持久的抗肿瘤活性，并在非临床物种中表现出高稳定性和良好的药代动力学特性。
