Oncotarget

Research Papers:

ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1

Simon-Peter Williams _, Annie Ogasawara, Jeff N. Tinianow, Judith E. Flores, David Kan, Jeffrey Lau, MaryAnn Go, Alexander N. Vanderbilt, Herman S. Gill, Li Miao, Joshua Goldsmith, Bonnee Rubinfeld, Weiguang Mao, Ron Firestein, Shang-Fan Yu, Jan Marik and Anton Terwisscha van G.T. Scheltinga

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Oncotarget. 2016; 7:25103-25112. https://doi.org/10.18632/oncotarget.8390

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Abstract

Simon-Peter Williams1, Annie Ogasawara1, Jeff N. Tinianow1, Judith E. Flores1, David Kan1, Jeffrey Lau1, MaryAnn Go1, Alexander N. Vanderbilt1, Herman S. Gill1, Li Miao1, Joshua Goldsmith1, Bonnee Rubinfeld1, Weiguang Mao1, Ron Firestein1, Shang-Fan Yu1, Jan Marik1, Anton G.T. Terwisscha van Scheltinga1,2

1Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA

2Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, 9700RB, The Netherlands

Correspondence to:

Simon-Peter Williams, e-mail: [email protected]

Keywords: antibody-drug conjugates, immunoPET, TENB2, STEAP1, zirconium-89

Received: December 10, 2015    Accepted: March 04, 2016    Published: March 26, 2016

ABSTRACT

The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with 111In-mAbs and gamma counting or with 89Zr-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that 89Zr-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload.


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