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, Mary Ann Go, Alexander N. Vanderbilt, Herman S. Gill, Li Miao, Joshua Goldsmith, Bonnee Rubinfeld, Weiguang Mao, Ron Firestein, Shang-Fan Yu, Jan Marik, Anton G.T.Terwisscha van Scheltinga

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)25103-25112
Number of pages10
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - 3 May 2016
Externally publishedYes

Keywords

  • Antibody-drug conjugates
  • ImmunoPET
  • STEAP1
  • TENB2
  • Zirconium-89

Cite this

Williams, S-P., Ogasawara, A., Tinianow, J. N., Flores, J. E., Kan, D., Lau, J., ... van Scheltinga, A. G. T. T. (2016). ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. Oncotarget, 7(18), 25103-25112. https://doi.org/10.18632/oncotarget.8390
Williams, Simon-Peter ; Ogasawara, Annie ; Tinianow, Jeff N. ; Flores, Judith E. ; Kan, David ; Lau, Jeffrey ; Go, Mary Ann ; Vanderbilt, Alexander N. ; Gill, Herman S. ; Miao, Li ; Goldsmith, Joshua ; Rubinfeld, Bonnee ; Mao, Weiguang ; Firestein, Ron ; Yu, Shang-Fan ; Marik, Jan ; van Scheltinga, Anton G.T.Terwisscha. / ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. In: Oncotarget. 2016 ; Vol. 7, No. 18. pp. 25103-25112.
@article{410c63973c65478b8c81a7beb1251cdf,
title = "ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1",
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.",
keywords = "Antibody-drug conjugates, ImmunoPET, STEAP1, TENB2, Zirconium-89",
author = "Simon-Peter Williams and Annie Ogasawara and Tinianow, {Jeff N.} and Flores, {Judith E.} and David Kan and Jeffrey Lau and Go, {Mary Ann} and Vanderbilt, {Alexander N.} and Gill, {Herman S.} and Li Miao and Joshua Goldsmith and Bonnee Rubinfeld and Weiguang Mao and Ron Firestein and Shang-Fan Yu and Jan Marik and {van Scheltinga}, {Anton G.T.Terwisscha}",
year = "2016",
month = "5",
day = "3",
doi = "10.18632/oncotarget.8390",
language = "English",
volume = "7",
pages = "25103--25112",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "18",

}

Williams, S-P, Ogasawara, A, Tinianow, JN, Flores, JE, Kan, D, Lau, J, Go, MA, Vanderbilt, AN, Gill, HS, Miao, L, Goldsmith, J, Rubinfeld, B, Mao, W, Firestein, R, Yu, S-F, Marik, J & van Scheltinga, AGTT 2016, 'ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1', Oncotarget, vol. 7, no. 18, pp. 25103-25112. https://doi.org/10.18632/oncotarget.8390

ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. / Williams, Simon-Peter; Ogasawara, Annie; Tinianow, Jeff N.; Flores, Judith E.; Kan, David; Lau, Jeffrey; Go, Mary Ann; Vanderbilt, Alexander N.; Gill, Herman S.; Miao, Li; Goldsmith, Joshua; Rubinfeld, Bonnee; Mao, Weiguang; Firestein, Ron; Yu, Shang-Fan; Marik, Jan; van Scheltinga, Anton G.T.Terwisscha.

In: Oncotarget, Vol. 7, No. 18, 03.05.2016, p. 25103-25112.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1

AU - Williams, Simon-Peter

AU - Ogasawara, Annie

AU - Tinianow, Jeff N.

AU - Flores, Judith E.

AU - Kan, David

AU - Lau, Jeffrey

AU - Go, Mary Ann

AU - Vanderbilt, Alexander N.

AU - Gill, Herman S.

AU - Miao, Li

AU - Goldsmith, Joshua

AU - Rubinfeld, Bonnee

AU - Mao, Weiguang

AU - Firestein, Ron

AU - Yu, Shang-Fan

AU - Marik, Jan

AU - van Scheltinga, Anton G.T.Terwisscha

PY - 2016/5/3

Y1 - 2016/5/3

N2 - 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.

AB - 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.

KW - Antibody-drug conjugates

KW - ImmunoPET

KW - STEAP1

KW - TENB2

KW - Zirconium-89

UR - http://www.scopus.com/inward/record.url?scp=84966929786&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.8390

DO - 10.18632/oncotarget.8390

M3 - Article

AN - SCOPUS:84966929786

VL - 7

SP - 25103

EP - 25112

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 18

ER -

Williams S-P, Ogasawara A, Tinianow JN, Flores JE, Kan D, Lau J et al. ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. Oncotarget. 2016 May 3;7(18):25103-25112. https://doi.org/10.18632/oncotarget.8390