Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma.
Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma.
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抗ICAM 1抗体-药物偶联物对多发性骨髓瘤的有效活性。
DOI：
10.1158/1078-0432.ccr-20-0400
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发表时间：
2020-11-15
期刊：
影响因子：
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通讯作者：
Liu B
中科院分区：
文献类型：
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作者：
Sherbenou DW;Su Y;Behrens CR;Aftab BT;Perez de Acha O;Murnane M;Bearrows SC;Hann BC;Wolf JL;Martin TG;Liu B
新的治疗方法已经改变了多发性骨髓瘤患者的前景，但对于目前批准的药物类别难治性或复发的患者需要新的药物。新的免疫疗法开发需要CD 38和BCMA以外的新靶点，因为对达雷妥尤单抗和新兴抗BCMA方法的耐药性似乎不可避免。骨髓瘤中一个潜在的目标是ICAM 1。裸抗ICAM 1抗体在骨髓瘤的临床前模型中是有活性的，并且在患者中是安全的，但是显示出有限的临床功效。在这里，我们试图用抗ICAM 1抗体-药物缀合物实现对多发性骨髓瘤的改进的靶向。将我们的抗ICAM 1人单克隆抗体与澳瑞他汀衍生物缀合，并在体外针对多发性骨髓瘤细胞系、体内原位异种移植物和离体患者样品进行测试。还通过定量流式细胞术测量了从诊断到达雷妥单抗难治性状态的患者中ICAM 1的表达。抗ICAM 1抗体-药物偶联物在体外和体内显示出有效的抗骨髓瘤细胞毒性。此外，我们已经证实，ICAM 1是高度表达的骨髓瘤细胞，并表明其表达进一步加剧了骨髓微环境因素的存在。在原代样本中，与正常细胞相比，多发性骨髓瘤细胞上ICAM 1差异性过表达，包括CD 38降低的达雷妥尤单抗难治性患者。此外，ICAM 1-ADC在多发性骨髓瘤原发性样品中显示出选择性细胞毒性。我们建议，抗ICAM 1抗体-药物偶联物应进一步研究毒性，如果安全，应测试复发或难治性多发性骨髓瘤患者的临床疗效。
New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate. Our anti-ICAM1 human monoclonal antibody was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. The anti-ICAM1 antibody-drug conjugate displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared to normal cells, including daratumumab refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. We propose that anti-ICAM1 antibody-drug conjugate should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.