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Updated: Dec 10, 2025
Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin
Raffit Hassan1, Christine Alewine2, Idrees Mian1
1Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Lay Summary:
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.
Insights
The maximum tolerated dose for LMB-100, an antibody-toxin conjugate targeting mesothelin, was determined to be 140 µg/kg. While showing some efficacy in mesothelioma, LMB-100 developed antidrug antibodies, limiting its use as a single agent.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Mesothelin is a promising cancer target due to its limited expression in normal tissues and high expression in various cancers.
- LMB-100 is a novel antibody-toxin conjugate designed to target mesothelin-expressing tumors.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and safety profile of LMB-100 in a first-in-human phase 1 study.
- To evaluate the pharmacokinetics and immunogenicity of LMB-100 in patients with advanced solid tumors.
Main Methods:
- Patients with advanced solid tumors expressing mesothelin received LMB-100 intravenously at escalating doses (40–250 µg/kg) over 21-day cycles.
- Dose-limiting toxicities were recorded to establish the MTD.
- Plasma concentrations and antidrug antibody development were monitored.
Main Results:
- The MTD of LMB-100 was established at 140 µg/kg. Dose-limiting toxicities included capillary leak syndrome and creatinine increase.
- Among 10 mesothelioma patients treated at 140 or 170 µg/kg, 8 had stable disease.
- Antidrug antibodies developed in 38% of patients by cycle 2 and 81.8% by cycle 3, impacting drug levels.
Conclusions:
- The MTD for single-agent LMB-100 is 140 µg/kg given every other day for 3 doses every 3 weeks.
- Despite reduced immunogenicity compared to SS1P, LMB-100 demonstrated limited antitumor efficacy as a single agent due to antidrug antibody development.
- Phase 2 trials combining LMB-100 with pembrolizumab are ongoing for mesothelioma and lung cancer.
