Development of a novel antibody-drug conjugate for treating T-cell lymphoma.

摘要 T细胞淋巴瘤占所有非霍奇金淋巴瘤的15%。这些复杂 血液癌症的集群具有很强的侵袭性，五年存活率很低（<50%）。固有的 这些癌症的分子异质性阻碍了治疗方法的发展， 对这些血癌具有持久反应的靶向治疗剂少得惊人。在 初步研究中，我们确定了一种细胞表面蛋白，存在于所有T细胞淋巴瘤患者 这表明它可能是一种新的治疗靶点。因此，我们开发了 抗体-药物偶联物（ADC）对这种新靶点具有特异性，并发现这种ADC高度 有效地在体外选择性杀死T淋巴瘤细胞并缩小已经发展的肿瘤 在T细胞淋巴瘤的临床前模型中体内。我们还对 使用在我们的初步研究中使用的单克隆抗体（mAb）来产生ADC的小鼠版本。 尽管亲本mAb和人源化mAb都显示出皮摩尔级的针对人源化mAb的亲和力，但它们都不表达人源化mAb。 在靶点处，我们注意到人源化mAb亲和力下降约2倍。在第一阶段的申请中， 神农生物科技和克利夫兰诊所将合作开发人性化和 嵌合ADC，测试其治疗功效，并在两个临床前研究中探索其安全性特征。 T细胞淋巴瘤的模型。这些研究将确定发展局的未来发展方向， 提供所需的概念验证，以将其推进到II期研究，最终目标是 为T细胞淋巴瘤患者生产急需的新药。

Abstract T-cell lymphomas comprise up to 15% of all Non-Hodgkin’s lymphoma. These complex clusters of blood cancers are very aggressive with poor (<50%) five-year survival. The inherent molecular heterogeneity of these cancers impedes therapeutics development and as a result, targeted therapeutics with durable responses against these blood cancers are alarmingly few. In pilot studies, we identified a cell surface protein that is present on all T-cell lymphoma patient specimens examined, suggesting that it could be a novel therapeutic target. We thus developed an antibody-drug conjugate (ADC) specific for this new target and found that this ADC is highly effective in selectively killing T lymphoma cells in vitro and shrinking already developed tumors in vivo in a preclinical model of T-cell lymphoma. We have also sequenced and humanized the monoclonal antibody (mAb) used in our pilot studies to generate the mouse version of the ADC. Even though both the parent mAb and the humanized mAbs showed picomolar affinities against the target, we noticed a ~2 –fold drop of humanized mAb affinity. In this Phase I application, Shennong Biotech and Cleveland Clinic will collaborate to develop both the humanized and chimeric ADCs, test their treatment efficacies, and explore their safety profiles in two preclinical models of T-cell lymphoma. These studies will identify the ADC for future development and provide the required proof-of-concept to advance it into Phase II studies with the ultimate goal of producing a much-needed new drug for patients with T cell lymphoma.