Immed S.L., Immunological and Medicinal Products, Madrid, Spain.
Catapult Therapeutics, Lelystad, The Netherlands.
MAbs. 2021 Jan-Dec;13(1):1917484. doi: 10.1080/19420862.2021.1917484.
Lymph node (LN) is a key tissue in the pathophysiology of mature blood cancers, especially for chronic lymphocytic leukemia (CLL). Within the multiple de-regulated pathways affecting CLL homeostasis, the CC-chemokine receptor 7 (CCR7) grants homing of CLL cells into the LN where protective environments foster tumor progression. To cover the lack of specific therapies targeting the CCR7-dependence of CLL to enter into the LN, and aiming to displace the disease from LN, we generated CAP-100, an antibody that specifically binds to hCCR7 and neutralizes its ligand-binding site and signaling. In various and i preclinical models CAP-100 strongly inhibited CCR7-induced migration, extravasation, homing, and survival in CLL samples. Moreover, it triggered potent tumor cell killing, mediated by host immune mechanisms, and was effective in xenograft models of high-risk disease. Additionally, CAP-100 showed a favorable toxicity profile on relevant hematopoietic subsets. Our results validated CAP-100 as a novel therapeutic tool to prevent the access of CLL cells, and other neoplasia with nodal-dependence, into the LN niches, thus hitting a central hub in the pathogenesis of cancer. The first-in-human clinical trial (NCT04704323), which will evaluate this novel therapeutic approach in CLL patients, is pending.
淋巴结（LN）是成熟血液癌症发病机制中的关键组织，特别是对于慢性淋巴细胞白血病（CLL）。在影响 CLL 动态平衡的多个失调途径中，CC-趋化因子受体 7（CCR7）赋予 CLL 细胞归巢到 LN 的能力，在 LN 中保护性环境促进肿瘤进展。为了弥补缺乏针对 CLL 进入 LN 对 CCR7 依赖性的特异性治疗方法，并旨在将疾病从 LN 中转移，我们生成了 CAP-100，这是一种特异性结合 hCCR7 并中和其配体结合位点和信号的抗体。在各种体内和体外临床前模型中，CAP-100 强烈抑制 CCR7 诱导的 CLL 样本中的迁移、渗出、归巢和存活。此外，它通过宿主免疫机制触发有效的肿瘤细胞杀伤作用，并在高危疾病的异种移植模型中有效。此外，CAP-100 在相关造血亚群中显示出有利的毒性特征。我们的研究结果验证了 CAP-100 作为一种新型治疗工具的潜力，用于阻止 CLL 细胞和其他依赖淋巴结的肿瘤进入 LN 龛位，从而打击癌症发病机制中的中心枢纽。正在等待评估该新型治疗方法在 CLL 患者中的首次人体临床试验（NCT04704323）。
