Characterization of a re‐engineered, mesothelin‐targeted<i>Pseudomonas</i>exotoxin fusion protein for lung cancer therapy

Bauss, Frieder; Lechmann, Martin; Krippendorff, Ben‐Fillippo; Staack, Roland F.; Herting, Frank; Festag, Matthias; Imhof-Jung, Sabine; Hesse, Friederike; Pompiati, Marc; Kollmorgen, Gwendlyn; Seidl, Rita da Silva Mateus; Bossenmaier, Birgit; Lau, Wilma; Schantz, Christian; Stracke, Jan Olaf; Brinkmann, Ulrich; Onda, Masanori; Pastan, Ira; Bosslet, Klaus; Niederfellner, Gerhard

doi:10.1016/j.molonc.2016.07.003

Cited by 48 publications

(60 citation statements)

References 47 publications

(62 reference statements)

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“…Several therapies targeting mesothelinexpressing tumors have been developed and are currently undergoing clinical translation (15). Preclinical studies using RG7787, a recombinant immunotoxin, in combination with chemotherapy showed complete remission of mesothelin-expressing tumor xenografts in mice (21). Phase I clinical trials of RG7787 for treatment of mesothelioma have opened (22).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer

et al. 2018

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Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triplenegative breast cancer not responding to trastuzumab or hormonebased therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99m Tc-A1 and 99m Tc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99m Tc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triplenegative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99m Tc-A1 and 99m Tc-C6 bound mesothelin with high affinity in vitro, with 99m Tc-A1 affinity being 2.4-fold higher than that of 99m Tc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P , 0.05). 99m Tc-A1 and 99m Tc-C6 remained stable in vivo in murine blood (.80% at 2 h) and ex vivo in human blood (.90% at 6 h). In vivo 99m Tc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99m Tc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P , 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99m Tc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99m Tc-A1 and 99m Tc-C6. Considering its superior characteristics, 99m Tc-A1 was selected as the most suitable tool for further clinical translation.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer

et al. 2018

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“…LMB-100 and SVP-R. LMB-100 was manufactured by Roche as described previously (45) and provided for these studies through a Collaborative Research and Development Agreement (2791). SVP-R was manufactured by Selecta Bioscience as described previously, with a rapamycin content of 500 μg/mL (19).…”

Section: Methodsmentioning

confidence: 99%

Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity

Mazor

King

Onda

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Protein-based drugs are very active in treating cancer, but their efficacy can be limited by the formation of neutralizing antidrug antibodies (ADAs). Recombinant immunotoxins are proteins that are very effective in patients with leukemia, where immunity is suppressed, but induce ADAs, which compromise their activity, in patients with intact immunity. Here we induced a specific, durable, and transferable immune tolerance to recombinant immunotoxins by combining them with nanoparticles containing rapamycin (SVP-R). SVP-R mitigated the formation of inhibitory ADAs in naïve and sensitized mice, resulting in restoration of antitumor activity. The immune tolerance is mediated by colocalization of the SVP-R and immunotoxin to dendritic cells and macrophages in the spleen and is abrogated by depletion of regulatory T cells. Tolerance induced by SVPs was not blocked by checkpoint inhibitors or costimulatory agonist monoclonal antibodies that by themselves enhance ADA formation.

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“…16 LMB-100 contains a modified Pseudomonas exotoxin A (PE) payload. 1,2,17 PE kills cells by irreversibly modifying eukaryotic elongation factor 2 to halt protein synthesis and induce apoptosis, a unique mechanism of action among anticancer agents. PE activity requires toxin internalization by the target cell through binding to a surface receptor.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin

Hassan

Alewine

Mian

et al. 2020

Cancer

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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-inhuman 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. Cancer 2020;126:4936-4947.

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Characterization of a re‐engineered, mesothelin‐targetedPseudomonasexotoxin fusion protein for lung cancer therapy

Cited by 48 publications

References 47 publications

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer

Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity

Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin

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