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

开发用于治疗 T 细胞淋巴瘤的新型抗体-药物缀合物。

• 批准号: 10545523
• 负责人: FENG C LIN
• 金额: $ 40.27万
• 依托单位: ABCON THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545523
• 关键词: Affinity; Antibody Affinity; Antibody-drug conjugates; Autoimmune Diseases; Biotechnology; CD6 antigen; Cancerous; Cell Line; Cell Surface Proteins; Cells; Clinic; Clinical Trials; Complex; Development; Dose; Drops; FDA approved; Future; Goals; Hematopoietic Neoplasms; Human; Immune system; Immunoglobulin G; In Vitro; Knockout Mice; Lymphoma cell; Medical; Mitotic; Modeling; Molecular; Monoclonal Antibodies; Mus; Non-Hodgkin' s Lymphoma; Parents; Pathogenicity; Patients; Phase; Physiological; Pilot Projects; Pre-Clinical Model; Proliferating; Research; Safety; Small Business Technology Transfer Research; Specimen; Surface; T cell response; T-Cell Lymphoma; T-Lymphocyte; Testing; Therapeutic; Tissue Microarray; Tissues; Toxin; Treatment Efficacy; Work; cancer heterogeneity; cancer therapy; chimeric antibody; clinical development; design; drug candidate; effective therapy; humanized antibody; humanized monoclonal antibodies; humanized mouse; in vivo; new technology; new therapeutic target; novel; novel therapeutics; patient derived xenograft model; phase 2 study; pre-clinical; programs; response; side effect; subcutaneous; success; targeted treatment; therapeutic development; treatment comparison; tumor

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.

摘要 T细胞淋巴瘤占所有非霍奇金淋巴瘤的15%。这些复合体 成群的血癌侵袭性很强，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技术的发展，因此， 针对这些血癌具有持久疗效的靶向治疗药物少得惊人。在……里面 初步研究发现，所有T细胞淋巴瘤患者身上都存在一种细胞表面蛋白 对标本进行了检查，表明它可能是一个新的治疗靶点。我们就这样发展起来了 一种针对这个新靶点的抗体-药物结合物(ADC)，并发现这种ADC高度 在体外选择性杀伤T淋巴瘤细胞和缩小已发展的肿瘤 体内T细胞淋巴瘤的临床前模型。我们还将其排序和人性化 在我们的试点研究中使用的单抗(MAb)来产生小鼠版本的ADC。 即使亲本单抗和人源化单抗都表现出对 作为靶点，我们注意到人源化mAb亲和力下降了~2倍。在此阶段I应用中， 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，测试它们的治疗效果，并在两个临床前研究中探索它们的安全性 T细胞淋巴瘤模型。这些研究将确定香港艺术发展局的未来发展方向和 提供所需的概念验证以将其推进到第二阶段研究，最终目标是 为T细胞淋巴瘤患者生产一种急需的新药。