An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models

Our plain-English summary of An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models, by S.J. Scales, N. Gupta, G. Pacheco, et al (Molecular Cancer Therapeutics, 2014).

The study

• Authors: S.J. Scales, N. Gupta, G. Pacheco, R. Firestein, D.M. French, H. Koeppen, L. Rangell, V. Barry-Hamilton, E. Luis, J. Chuh, Y. Zhang, G.S. Ingle, A. Fourie-O'Donohue, K.R. Kozak, S. Ross, M.S. Dennis, S.D. Spencer
• Journal: Molecular Cancer Therapeutics
• Published: 2014;13(11):2630-40
• Cited by: 60 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubule-disrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, αMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of αMSLN-MMAE profoundly inhibited or regressed tumor growth in a dose-dependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of αMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial.

©2014 American Association for Cancer Research.

In plain English

This laboratory and mouse study of an experimental cancer drug did not examine asbestos exposure. The authors attached antibodies against mesothelin, a protein on many ovarian, pancreatic and mesothelioma cancer cells, to a cell-killing drug, MMAE. In cultured HT1080 cells engineered with mesothelin, the humanized version had an average IC50 of 0.32 nmol/L. In OVCAR3-x2.1 ovarian cells, which make mesothelin naturally, the IC50 was substantially higher (20.3 nmol/L). Human tumor staining showed mesothelin in 85% of 86 ovarian adenocarcinomas, 75% of 196 pancreatic ductal adenocarcinomas and 45% of 29 mesotheliomas (4 of 12 pleural, 6 of 13 peritoneal, 3 of 4 pericardial). In mice carrying human tumors, single doses slowed or shrank tumors, more so at higher doses. In H226-x2 mesothelioma tumors, 10 mg/kg stopped growth (102% inhibition) for 3 weeks. In low-mesothelin MSTO-211H mesothelioma tumors, the response was shorter, and a non-targeted control also showed some activity. The authors concluded the drug was highly active in mesothelin-positive mouse models. They noted the mesothelioma samples may be unrepresentative and the minimum mesothelin level needed for activity remains undetermined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: development of an antibody-drug conjugate, cell culture experiments, staining (immunohistochemistry) of human tumor tissue microarrays, and treatment experiments in mice carrying human tumor xenografts
• Who was studied: Human tumor tissue microarrays: 86 ovarian adenocarcinomas, 196 pancreatic ductal adenocarcinomas and 29 mesotheliomas (12 pleural, 13 peritoneal, 4 pericardial). Human cancer cell lines. Female mice carrying six xenograft models in groups of 8 to 11 mice: ovarian OVCAR3-x2.1 and OVXF1023, pancreatic HPAC and PAXF1657, and mesothelioma H226-x2 and MSTO-211H.
• Exposure: No asbestos exposure was studied. The exposure was an experimental antibody-drug conjugate: a humanized antimesothelin antibody (h7D9.v3) linked to monomethyl auristatin E (MMAE) through a cleavable valine-citrulline linker. It was given to mice as single doses of 1 to 20 mg/kg and compared with a non-targeted control conjugate, the unconjugated antibody, and vehicle.
• Main results:
  • With an earlier version of the drug in the OVCAR3 ovarian xenograft model, a single 3 mg/kg dose of the MMAE conjugate (7D9-mc-vc-PAB-MMAE) was more effective than two MMAF conjugates.
  • In cell culture, the humanized conjugate killed mesothelin-transfected gD-MSLN-HT1080 cells with an average IC50 of 0.32 nmol/L across three independent experiments. The positive control conjugate had an IC50 of 2.2 nmol/L in the same cells.
  • In OVCAR3-x2.1 cells, which express less mesothelin and express it naturally (40,000 copies per cell), the IC50 of the conjugate was substantially higher: 20.3 nmol/L (data not shown).
  • In human tumor tissue microarrays stained with antibody 19C3, 85% of 86 ovarian adenocarcinomas were mesothelin positive.
  • 75% of 196 pancreatic ductal adenocarcinomas were mesothelin positive.
  • 45% of 29 mesotheliomas were mesothelin positive: 4 of 12 pleural, 6 of 13 peritoneal and 3 of 4 pericardial. The authors noted this was far fewer than the 86% for pleural mesothelioma reported in the literature.
  • Mesothelin increased when cancer cell lines were grown as tumors in mice. In OVCAR3-x2.1 ovarian cells it rose about 6.5-fold.
  • In the OVCAR3-x2.1 ovarian model, 10 mg/kg produced almost complete regressions (108% tumor growth inhibition). Mean tumor-doubling time increased from 4.5 days with vehicle to 83 days.
  • In the primary ovarian OVXF1023 model, 10 mg/kg achieved only 53% tumor growth inhibition after 3 weeks. A second dose achieved 78% inhibition by 84 days.
  • In pancreatic models, HPAC xenografts strongly regressed at 10 to 15 mg/kg. PAXF1657 tumors shrank at 10 mg/kg (104% inhibition). At 20 mg/kg there were 9 of 10 complete responses, but significant nonspecific activity occurred at that dose.
  • In the H226-x2 mesothelioma model, 10 mg/kg produced tumor stasis (102% inhibition) for 3 weeks and delayed tumor doubling to 34 days.
  • In the low-mesothelin MSTO-211H mesothelioma model, the drug caused stasis (96% inhibition), but the response was shorter. The non-targeted control conjugate also showed some activity in this model.
  • The antibody without the attached drug had no activity at 15 mg/kg in any model tested.
• The authors' conclusion: The authors concluded that the conjugate was highly active at inhibiting or shrinking tumor growth in mesothelin-positive mouse models, and that its preclinical efficacy justified the ongoing phase I clinical trial.
• Limitations the authors state:
  • The mesothelioma tissue microarray may not have been representative, because histologic subtypes were not specified.
  • The 10% staining cutoff was a hypothesis. The actual mesothelin threshold and intensity needed for an antitumor response remain to be determined.
  • Further work is required to determine the minimum mesothelin level needed for activity, and other factors likely also play a role.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelin, Immunohistochemistry, Clinical Trial.

Related studies

• Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models — K. Wickstroem, U.B. Hagemann, et al. (2019)
• A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface — Z. Tang, M. Feng, et al. (2013)
• Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer — A. Cerise, T.K. Bera, et al. (2019)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells — K. Kobayashi, T. Sasaki, et al. (2015)
• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)

Browse more research in Molecular Cancer Therapeutics, or return to medical research.