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 & 4 others Shu-Dong Zhang, Yeoh Khay Guan, Jimmy So, Qi Zeng

Research output: Contribution to journalArticle

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.
LanguageEnglish
JournalJCI Insight
Volume1
Issue number9
DOIs
Publication statusPublished - 16 Jun 2016

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Antibodies, Monoclonal, Humanized
Neoplasms
Stomach Neoplasms
Therapeutics
Stomach
Fluorouracil
Tumor Microenvironment
Antibodies
Drug Discovery
Phosphoric Monoester Hydrolases
Immunotherapy

Keywords

  • Gastroenterology
  • Therapeutics
  • PRL3-zumab
  • humanized antibody
  • cancer therapy

Cite this

Thura, M., Al-Aidaroos, A. Q. O., Yong, W. P., Kono, K., Gupta, A., Lin, Y. B., ... Zeng, Q. (2016). PRL3-zumab, a first-in-class humanized antibody for cancer therapy. JCI Insight, 1(9). https://doi.org/10.1172/jci.insight.87607
Thura, Min ; Al-Aidaroos, Abdul Qader Omer ; Yong, Wei Peng ; Kono, Koji ; Gupta, Abhishek ; Lin, You Bin ; Mimura, Kousaku ; Thiery, Jean Paul ; Goh, Boon Cher ; Tan, Patrick ; Soo, Ross ; Hong, Cheng William ; Wang, Lingzhi ; Lin, Suling Joyce ; Chen, Elya ; Rha, Sun Young ; Chung, Hyun Cheol ; Li, Jie ; Nandi, Sayantani ; Yuen, Hiu Fung ; Zhang, Shu-Dong ; Guan, Yeoh Khay ; So, Jimmy ; Zeng, Qi. / PRL3-zumab, a first-in-class humanized antibody for cancer therapy. In: JCI Insight. 2016 ; Vol. 1, No. 9.
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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.",
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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, S-D, Guan, YK, So, J & Zeng, Q 2016, 'PRL3-zumab, a first-in-class humanized antibody for cancer therapy', JCI Insight, vol. 1, no. 9. https://doi.org/10.1172/jci.insight.87607

PRL3-zumab, a first-in-class humanized antibody for cancer therapy. / Thura, Min; Al-Aidaroos, Abdul Qader Omer; Yong, Wei Peng; Kono, Koji; Gupta, Abhishek; Lin, You Bin; Mimura, Kousaku; Thiery, Jean Paul; Goh, Boon Cher; Tan, Patrick; Soo, Ross; Hong, Cheng William; Wang, Lingzhi; Lin, Suling Joyce; Chen, Elya; Rha, Sun Young; Chung, Hyun Cheol; Li, Jie; Nandi, Sayantani; Yuen, Hiu Fung; Zhang, Shu-Dong; Guan, Yeoh Khay; So, Jimmy; Zeng, Qi.

In: JCI Insight, Vol. 1, No. 9, 16.06.2016.

Research output: Contribution to journalArticle

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

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.

KW - Gastroenterology

KW - Therapeutics

KW - PRL3-zumab

KW - humanized antibody

KW - cancer therapy

U2 - 10.1172/jci.insight.87607

DO - 10.1172/jci.insight.87607

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Thura M, Al-Aidaroos AQO, Yong WP, Kono K, Gupta A, Lin YB et al. PRL3-zumab, a first-in-class humanized antibody for cancer therapy. JCI Insight. 2016 Jun 16;1(9). https://doi.org/10.1172/jci.insight.87607