Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET

Anton G.T. Van Terwisscha Scheltinga, Annie Ogasawara, Glenn Pacheco, Alexander N. Vanderbilt, Jeff N. Tinianow, Nidhi Gupta, Dongwei Li, Ron Firestein, Jan Marik, Suzie J. Scales, Simon-Peter Williams

Research output: Contribution to journalArticleResearchpeer-review

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 (98Zr)-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-32.1, 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-32.1, 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.

Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalMolecular Cancer Therapeutics
Volume16
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Cite this

Van Terwisscha Scheltinga, A. G. T., Ogasawara, A., Pacheco, G., Vanderbilt, A. N., Tinianow, J. N., Gupta, N., ... Williams, S-P. (2017). Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET. Molecular Cancer Therapeutics, 16(1), 134-142. https://doi.org/10.1158/1535-7163.MCT-16-0449
Van Terwisscha Scheltinga, Anton G.T. ; Ogasawara, Annie ; Pacheco, Glenn ; Vanderbilt, Alexander N. ; Tinianow, Jeff N. ; Gupta, Nidhi ; Li, Dongwei ; Firestein, Ron ; Marik, Jan ; Scales, Suzie J. ; Williams, Simon-Peter. / Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 1. pp. 134-142.
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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 (98Zr)-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-32.1, 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-32.1, 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.",
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Van Terwisscha Scheltinga, AGT, Ogasawara, A, Pacheco, G, Vanderbilt, AN, Tinianow, JN, Gupta, N, Li, D, Firestein, R, Marik, J, Scales, SJ & Williams, S-P 2017, 'Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET' Molecular Cancer Therapeutics, vol. 16, no. 1, pp. 134-142. https://doi.org/10.1158/1535-7163.MCT-16-0449

Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET. / Van Terwisscha Scheltinga, Anton G.T.; Ogasawara, Annie; Pacheco, Glenn; Vanderbilt, Alexander N.; Tinianow, Jeff N.; Gupta, Nidhi; Li, Dongwei; Firestein, Ron; Marik, Jan; Scales, Suzie J.; Williams, Simon-Peter.

In: Molecular Cancer Therapeutics, Vol. 16, No. 1, 01.01.2017, p. 134-142.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Van Terwisscha Scheltinga, Anton G.T.

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AU - Pacheco, Glenn

AU - Vanderbilt, Alexander N.

AU - Tinianow, Jeff N.

AU - Gupta, Nidhi

AU - Li, Dongwei

AU - Firestein, Ron

AU - Marik, Jan

AU - Scales, Suzie J.

AU - Williams, Simon-Peter

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Van Terwisscha Scheltinga AGT, Ogasawara A, Pacheco G, Vanderbilt AN, Tinianow JN, Gupta N et al. Preclinical efficacy of an antibody-drug conjugate targeting mesothelin correlates with quantitative89 Zr-ImmunoPET. Molecular Cancer Therapeutics. 2017 Jan 1;16(1):134-142. https://doi.org/10.1158/1535-7163.MCT-16-0449