Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET

Our plain-English summary of Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET, by A.G. Terwisscha van Scheltinga, A. Ogasawara, G. Pacheco, et al (Molecular Cancer Therapeutics, 2017).

The study

• Authors: A.G. Terwisscha van Scheltinga, A. Ogasawara, G. Pacheco, A.N. Vanderbilt, J.N. Tinianow, N. Gupta, D. Li, R. Firestein, J. Marik, S.J. Scales, S.P. Williams
• Journal: Molecular Cancer Therapeutics
• Published: 2017;16(1):134-142
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Antibody-drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3×2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134-42. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

In this study in mice, the authors tested whether a PET scan could predict the effect of an experimental drug on tumors carrying a protein called mesothelin. The drug, AMA-MMAE, is an anti-mesothelin antibody linked to a cell-killing agent. Mice carried human tumors grown from six cell lines: one ovarian, four pancreatic and one mesothelioma (MSTO-211H). Mice received a single 5 mg/kg dose of the drug or of a non-targeting control. Other mice received the same antibody tagged with radioactive zirconium-89 for scanning. The drug slowed growth most in the ovarian line and two pancreatic lines (Capan-2, HPAC). These three tumors took up significantly more tagged antibody than control antibody (ovarian tumors at day 6: 10.4 versus 4.9 percent of injected dose per gram). In the other three, including the mesothelioma line, the drug showed marginal or no specific effect and uptake was similar to control, although tissue staining confirmed mesothelin was present. The authors concluded that scan results correlated with drug effect in these models. They noted that mouse tumors differ from human ones.

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 animal experiment: tumor growth inhibition studies and PET imaging in mice carrying human tumor xenografts
• Who was studied: Female immunocompromised mice, 4-5 months old, carrying flank tumors grown from six human cell lines: ovarian cancer OVCAR-3X2.1, pancreatic cancers Capan-2, HPAC, AsPC-1 and HPAF-II, and mesothelioma MSTO-211H. Groups were 5-8 mice for efficacy and 4-5 mice for imaging. All authors are current or former Genentech employees.
• Exposure: No asbestos exposure was studied. Mice received a single intravenous dose of 5 mg/kg of the anti-mesothelin antibody-drug conjugate AMA-MMAE (DMOT4039A) or of a non-targeting control conjugate (anti-gD-MMAE). Some models were also tested at 3 and 10 mg/kg, and OVCAR-3X2.1 at 5 and 20 mg/kg. Separate mice received zirconium-89-labeled antibodies at 5 mg/kg for PET imaging.
• Main results:
  • In OVCAR-3X2.1 tumors, growth inhibition was significantly greater with AMA-MMAE than with the control conjugate. Some differential effect was also seen in Capan-2 and HPAC tumors.
  • AsPC-1, HPAF-II and MSTO-211H (mesothelioma) tumors showed marginal or no differential efficacy of AMA-MMAE at the 5 mg/kg dose.
  • At day 6, OVCAR-3X2.1 tumor uptake was 10.4 plus or minus 0.8 percent of injected dose per gram for the mesothelin-targeted tracer versus 4.9 plus or minus 0.7 for the control tracer (p less than or equal to 0.05).
  • Mesothelin-targeted tracer uptake was 8.8 plus or minus 1.0 percent of injected dose per gram in Capan-2 tumors and 6.0 plus or minus 1.2 in HPAC tumors. In all three responsive models, uptake was significantly higher than with the control tracer (p less than 0.05).
  • In the non-responsive AsPC-1, HPAF-II and MSTO-211H tumors, uptake of the mesothelin-targeted tracer was measurable but similar to non-specific control uptake.
  • Immunohistochemistry confirmed mesothelin in all six xenografts: OVCAR-3X2.1, AsPC-1 and HPAC were 3+, Capan-2 was 2-3+, HPAF-II was 2+ and MSTO-211H was 1+.
  • A correlation plot of tumor growth inhibition versus specific uptake (ratio of targeted to control tracer) gave r2 = 0.823.
  • In repeat studies at 3 and 10 mg/kg (9 mice per group), Capan-2 tumors showed dose-dependent efficacy while AsPC-1 tumors did not.
  • Blood levels of the drug were similar in Capan-2 and AsPC-1 mice, so they did not explain the difference in efficacy.
• The authors' conclusion: The authors concluded that quantitative immunoPET measurements of relative antibody uptake correlated with tumor growth inhibition by the AMA-MMAE drug in these preclinical models. They suggested imaging may help confirm the prerequisites for efficacy.
• Limitations the authors state:
  • The cell lines were pre-screened for sensitivity to the cell-killing agent MMAE, so some patient tumors may be resistant.
  • In mice, the zirconium-89 signal accumulates in actively remodeling bone.
  • The mouse models lack the full human tumor immune infiltrate.
  • Uniform xenograft tumors differ from varied human tumors, particularly dense-stroma pancreatic cancers.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Monoclonal, Ovarian Cancer, Mesothelioma, Immunohistochemistry.

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