HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells
HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells
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DOI：
10.1158/1535-7163.mct-20-0287
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发表时间：
2021-02-01
影响因子：
5.7
通讯作者：
Raab, Marc S.
中科院分区：
文献类型：
--
作者：
Figueroa-Vazquez, Vianihuini;Ko, Jonathan;Raab, Marc S.
尽管近年来治疗取得了重大进展，但多发性骨髓瘤患者不可避免地会复发。RNA聚合酶II复合体已被确定为增殖和休眠癌细胞的有希望的治疗靶点。α -amanitin是一种毒素，由于肝毒性高，迄今没有临床应用，它能特异性抑制这种复合物。在这里，我们描述了HDP-101的发展，这是一种抗b细胞成熟抗原（BCMA）抗体，结合了一种amanitin衍生物。HDP-101在体外对增殖性和静止性骨髓瘤细胞均显示出高疗效，保留bcma阴性细胞。在皮下和播散的小鼠异种移植模型中，低剂量的HDP-101诱导肿瘤消退，包括单次静脉注射后持久的完全缓解。在食蟹猴中，HDP-101耐受性良好，具有良好的治疗指标。总之，HDP-101安全、选择性地将amanitin传递给骨髓瘤细胞，为克服这种疾病的耐药性提供了一种新的治疗方法。
Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.