PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Min Thura; Abdul Qader Omer Al-Aidaroos; Wei Peng Yong; Koji Kono; Abhishek Gupta; You Bin Lin; Kousaku Mimura; Jean Paul Thiery; Boon Cher Goh; Patrick Tan; Ross Soo; Cheng William Hong; Lingzhi Wang; Suling Joyce Lin; Elya Chen; Sun Young Rha; Hyun Cheol Chung; Jie Li; Sayantani Nandi; Hiu Fung Yuen; Shu Dong Zhang; Yeoh Khay Guan; Jimmy So; Qi Zeng

doi:10.1172/jci.insight.87607

PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Min Thura, Abdul Qader Omer Al-Aidaroos, Wei Peng Yong, Koji Kono, Abhishek Gupta, You Bin Lin, Kousaku Mimura, Jean Paul Thiery, Boon Cher Goh, Patrick Tan, Ross Soo, Cheng William Hong, Lingzhi Wang, Suling Joyce Lin, Elya Chen, Sun Young Rha, Hyun Cheol Chung, Jie Li, Sayantani Nandi, Hiu Fung YuenShu Dong Zhang, Yeoh Khay Guan, Jimmy So, Qi Zeng

Department of Internal Medicine

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

15 Citations (Scopus)

Abstract

Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3⁺, but not PRL-3^–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3⁺ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.

Original language	English
Article number	e87607
Journal	JCI insight
Volume	1
Issue number	9
DOIs	https://doi.org/10.1172/jci.insight.87607
Publication status	Published - 2016 Jun 16

Bibliographical note

Funding Information:
This work was supported by research grants from A*STAR. We are especially grateful to Bert Vogelstein, Soldano Ferrone, and Michel Tremblay for their encouragement and continuous support for our unconventional antibody therapies. We also thank Eng Chon Boon and Rajeev Singh from the National University Hospital–National University of Singapore Tissue Repository for their help in providing clinical samples.

Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.

All Science Journal Classification (ASJC) codes

Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/jci.insight.87607

Cite this

Thura, M., Al-Aidaroos, A. Q. O., Yong, W. P., Kono, K., Gupta, A., Lin, Y. B., Mimura, K., Thiery, J. P., Goh, B. C., Tan, P., Soo, R., Hong, C. W., Wang, L., Lin, S. J., Chen, E., Rha, S. Y., Chung, H. C., Li, J., Nandi, S., ... Zeng, Q. (2016). PRL3-zumab, a first-in-class humanized antibody for cancer therapy. JCI insight, 1(9), [e87607]. https://doi.org/10.1172/jci.insight.87607

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title = "PRL3-zumab, a first-in-class humanized antibody for cancer therapy",

abstract = "Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.",

author = "Min Thura and Al-Aidaroos, {Abdul Qader Omer} and Yong, {Wei Peng} and Koji Kono and Abhishek Gupta and Lin, {You Bin} and Kousaku Mimura and Thiery, {Jean Paul} and Goh, {Boon Cher} and Patrick Tan and Ross Soo and Hong, {Cheng William} and Lingzhi Wang and Lin, {Suling Joyce} and Elya Chen and Rha, {Sun Young} and Chung, {Hyun Cheol} and Jie Li and Sayantani Nandi and Yuen, {Hiu Fung} and Zhang, {Shu Dong} and Guan, {Yeoh Khay} and Jimmy So and Qi Zeng",

note = "Funding Information: This work was supported by research grants from A*STAR. We are especially grateful to Bert Vogelstein, Soldano Ferrone, and Michel Tremblay for their encouragement and continuous support for our unconventional antibody therapies. We also thank Eng Chon Boon and Rajeev Singh from the National University Hospital–National University of Singapore Tissue Repository for their help in providing clinical samples. Publisher Copyright: {\textcopyright} 2016 American Society for Clinical Investigation. All rights reserved.",

year = "2016",

month = jun,

day = "16",

doi = "10.1172/jci.insight.87607",

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Thura, M, Al-Aidaroos, AQO, Yong, WP, Kono, K, Gupta, A, Lin, YB, Mimura, K, Thiery, JP, Goh, BC, Tan, P, Soo, R, Hong, CW, Wang, L, Lin, SJ, Chen, E, Rha, SY , Chung, HC, Li, J, Nandi, S, Yuen, HF, Zhang, SD, Guan, YK, So, J & Zeng, Q 2016, 'PRL3-zumab, a first-in-class humanized antibody for cancer therapy', JCI insight, vol. 1, no. 9, e87607. https://doi.org/10.1172/jci.insight.87607

TY - JOUR

T1 - PRL3-zumab, a first-in-class humanized antibody for cancer therapy

AU - Thura, Min

AU - Al-Aidaroos, Abdul Qader Omer

AU - Yong, Wei Peng

AU - Kono, Koji

AU - Gupta, Abhishek

AU - Lin, You Bin

AU - Mimura, Kousaku

AU - Thiery, Jean Paul

AU - Goh, Boon Cher

AU - Tan, Patrick

AU - Soo, Ross

AU - Hong, Cheng William

AU - Wang, Lingzhi

AU - Lin, Suling Joyce

AU - Chen, Elya

AU - Rha, Sun Young

AU - Chung, Hyun Cheol

AU - Li, Jie

AU - Nandi, Sayantani

AU - Yuen, Hiu Fung

AU - Zhang, Shu Dong

AU - Guan, Yeoh Khay

AU - So, Jimmy

AU - Zeng, Qi

N1 - Funding Information: This work was supported by research grants from A*STAR. We are especially grateful to Bert Vogelstein, Soldano Ferrone, and Michel Tremblay for their encouragement and continuous support for our unconventional antibody therapies. We also thank Eng Chon Boon and Rajeev Singh from the National University Hospital–National University of Singapore Tissue Repository for their help in providing clinical samples. Publisher Copyright: © 2016 American Society for Clinical Investigation. All rights reserved.

PY - 2016/6/16

Y1 - 2016/6/16

N2 - Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.

AB - Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.

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PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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