CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.
Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.
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B 细胞成熟抗原（BCMA）在多发性骨髓瘤中发挥病理生物学作用，是一个经过验证的靶点，已有五种 BCMA 特异性治疗药物获批用于复发/难治性疾病。
然而，这些药物并非治愈性，且在分子定义的高危疾病患者中疗效较差，包括涉及抑癌基因 TP53 缺失的 17p 缺失（del17p）患者，这支持需要进一步开发药物。在其他肿瘤类型中，del17p 与 RNA 聚合酶 II 亚基 alpha（POLR2A）拷贝数减少和基因表达降低相关。
因此，我们研究了 HDP-101——一种携带 POLR2A 毒素 α-鹅膏蕈碱的抗 BCMA 抗体药物偶联物（ADC）——是否可能成为骨髓瘤中有吸引力的药物，尤其是在 del17p 情况下。HDP-101 降低了代表不同分子疾病亚型的骨髓瘤细胞系的活力，并克服了黏附介导的耐药以及传统和新型药物耐药。在确认公开可用的骨髓瘤患者数据库中 del17p 与 POLR2A 水平降低相关后，我们对 TP53 野生型细胞进行了 TP53 敲除（KO）、POLR2A 敲低（KD）或两者兼有的工程化改造，后者用于模拟 del17p。HDP-101 对所有测试细胞系均显示出强效抗骨髓瘤活性，并对 POLR2A KD 和 TP53 KO/POLR2A KD 双敲细胞发挥增强的疗效。机制研究显示，HDP-101 上调未折叠蛋白反应、激活凋亡并诱导免疫原性细胞死亡。
值得注意的是，HDP-101 影响 CD138 阳性原代细胞但不影响 CD138 阴性原代细胞，对醛脱氢酶阳性克隆形成细胞显示出强效疗效，并在体内细胞系来源异种移植（CDX）中根除骨髓瘤。有趣的是，在CDX模型中，先前使用HDP-101治疗可阻止随后肿瘤细胞系再挑战时的植入，这种方式似乎部分依赖于NK 细胞和巨噬细胞。
最后，在体外针对细胞系和原代骨髓瘤细胞以及体内CDX中，HDP-101优于靶向BCMA的ADC belantamab mafodotin。
总之，这些数据支持将HDP-101转化至临床的依据，目前它正在进行I期试验，并表明它可能成为一种更有效的骨髓瘤ADC，尤其对高风险del17p骨髓瘤亚型具有特别有趣的活性。
B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease.
However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53 , supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha ( POLR2A ) in other tumor types.
We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance.
After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death.
Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages.
Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro , and in an in vivo CDX.
Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.
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