Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis

Daniel L.J. Thorek; Philip A. Watson; Sang Gyu Lee; Anson T. Ku; Stylianos Bournazos; Katharina Braun; Kwanghee Kim; Kjell Sjostrom; Michael G. Doran; Urpo Lamminmaki; Elmer Santos; Darren Veach; Mesruh Turkekul; Emily Casey; Jason S. Lewis; Diane S. Abou; Marise R.H. Van Voss; Peter T. Scardino; Sven Erik Strand; Mary L. Alpaugh; Howard I. Scher; Hans Lilja; Steven M. Larson; David Ulmert

doi:10.1126/scitranslmed.aaf2335

Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis

Daniel L.J. Thorek, Philip A. Watson, Sang Gyu Lee, Anson T. Ku, Stylianos Bournazos, Katharina Braun, Kwanghee Kim, Kjell Sjostrom, Michael G. Doran, Urpo Lamminmaki, Elmer Santos, Darren Veach, Mesruh Turkekul, Emily Casey, Jason S. Lewis, Diane S. Abou, Marise R.H. Van Voss, Peter T. Scardino, Sven Erik Strand, Mary L. AlpaughHoward I. Scher, Hans Lilja, Steven M. Larson, David Ulmert

School of Medicine

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.

Original language	English (US)
Article number	367ra167
Journal	Science translational medicine
Volume	8
Issue number	367
DOIs	https://doi.org/10.1126/scitranslmed.aaf2335
State	Published - Nov 30 2016

ASJC Scopus subject areas

General Medicine

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Thorek, D. L. J., Watson, P. A., Lee, S. G., Ku, A. T., Bournazos, S., Braun, K., Kim, K., Sjostrom, K., Doran, M. G., Lamminmaki, U., Santos, E., Veach, D., Turkekul, M., Casey, E., Lewis, J. S., Abou, D. S., Van Voss, M. R. H., Scardino, P. T., Strand, S. E., ... Ulmert, D. (2016). Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis. Science translational medicine, 8(367), Article 367ra167. https://doi.org/10.1126/scitranslmed.aaf2335

Thorek, DLJ, Watson, PA, Lee, SG, Ku, AT, Bournazos, S, Braun, K, Kim, K, Sjostrom, K, Doran, MG, Lamminmaki, U, Santos, E, Veach, D, Turkekul, M, Casey, E, Lewis, JS, Abou, DS, Van Voss, MRH, Scardino, PT, Strand, SE, Alpaugh, ML, Scher, HI, Lilja, H, Larson, SM & Ulmert, D 2016, 'Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis', Science translational medicine, vol. 8, no. 367, 367ra167. https://doi.org/10.1126/scitranslmed.aaf2335

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abstract = "Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.",

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AU - Thorek, Daniel L.J.

AU - Watson, Philip A.

AU - Lee, Sang Gyu

AU - Ku, Anson T.

AU - Bournazos, Stylianos

AU - Braun, Katharina

AU - Kim, Kwanghee

AU - Sjostrom, Kjell

AU - Doran, Michael G.

AU - Lamminmaki, Urpo

AU - Santos, Elmer

AU - Veach, Darren

AU - Turkekul, Mesruh

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AU - Lewis, Jason S.

AU - Abou, Diane S.

AU - Van Voss, Marise R.H.

AU - Scardino, Peter T.

AU - Strand, Sven Erik

AU - Alpaugh, Mary L.

AU - Scher, Howard I.

AU - Lilja, Hans

AU - Larson, Steven M.

AU - Ulmert, David

PY - 2016/11/30

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N2 - Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.

AB - Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.

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Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis

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