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
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
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Research Article Gastroenterology Therapeutics

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.

Authors

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

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Figure 4

PRL3-zumab is more effective as a monotherapy rather than when coadministered with 5-fluorouracil or 5-fluorouracil alone.

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PRL3-zumab is more effective as a monotherapy rather than when coadminis...
Four treatment groups were used to treat PRL-3+ SNU-484 orthotopic tumors: placebo (group 1), PRL3-zumab monotherapy (group 2), PRL3-zumab and 5-fluorouracil (5-FU) combination therapy (group 3), or 5-FU alone (group 4). (A) Excised stomachs from each group of mice at day 28, with orthotopic tumor areas framed with black lines, and mean gastric tumor volumes in each group at day 28. Scale bar: 10 mm. n = 5 per group; P < 0.001, 1-way ANOVA; data represent mean ± SEM. (B) Representative images of Giemsa-stained blood smears from each group before the start of therapy (day 0) and at the end of the experiment (day 28) and mean wbc count from blood smears from each mouse at day 28. wbc are stained blue. Scale bar: 40 μm. n = 5 per group; P < 0.001, 1-way ANOVA; data represent mean ± SEM.