Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Cancer. 2020 Nov 15;126(22):4936-4947. doi: 10.1002/cncr.33145. Epub 2020 Sep 1.
LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.
Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle.
Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.
The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.
Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.
LMB-100 是一种抗体 - 毒素偶联物，它将抗间皮素 Fab 与突变降低免疫原性的 24kDa 部分假单胞菌外毒素 A 连接起来。目前这项首次人体的 I 期研究的目的是确定在表达间皮素的晚期实体瘤患者中，最大耐受剂量（MTD）和安全性。
7 个剂量组的 1 至 7 名患者接受静脉内 LMB-100，剂量为 40μg/kg 至 250μg/kg，在 21 天周期的第 1、3 和 5 天静脉内给药。
25 名入组患者中，17 名患有间皮瘤，3 名分别患有卵巢癌或胰腺癌，2 名患有胃癌。在 250μg/kg 剂量组的 4 名患者中（毛细血管渗漏综合征）和在 170μg/kg 剂量组的 7 名患者中（肌酐增加）出现剂量限制毒性。LMB-100 的 MTD 为 140μg/kg。在接受 170μg/kg 或 140μg/kg 剂量治疗的 10 名间皮瘤患者中，8 名病情稳定，2 名病情进展。在第 1 周期中，LMB-100 血浆浓度的峰值与剂量呈依赖性。在接受第 2 周期和第 3 周期的 21 名患者中的 8 名（38%）和 11 名患者中的 9 名（81.8%）中，抗药物抗体的产生降低了 LMB-100 的血药水平。
单药 LMB-100 的 MTD 确定为每 3 周每 2 天给药，剂量为 140μg/kg，共 3 个剂量。尽管 LMB-100 比第一代抗间皮素免疫毒素 SS1P 的免疫原性低，但大多数患者在 2 个周期后产生了抗药物抗体，表明 LMB-100 作为单一药物的抗肿瘤疗效有限。目前正在进行 LMB-100 联合 pembrolizumab 治疗间皮瘤和肺癌患者的 II 期临床试验。
Lay Summary：间皮素是一种细胞表面抗原，因其在正常人类组织中的有限表达和在许多人类癌症中的高表达，是癌症治疗的一个有吸引力的靶点。LMB-100 是一种重组抗间皮素免疫毒素，由与人源化抗间皮素抗体片段融合的截短假单胞菌外毒素 A 组成。在目前的研究中，作者确定了 LMB-100 的安全性、最大耐受剂量、药代动力学以及抗药物抗体的产生。正在进行的 II 期临床试验正在评估 LMB-100 联合 pembrolizumab 治疗难治性间皮瘤和非小细胞肺癌患者的疗效。
