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Published on: May 16, 2020
Fully human antagonistic antibodies targeting FPR2 through dual extracellular-loop engagement for gastric cancer
Min Su Kim1,2, Tae Hyun Kang1,2,3,4
1Department of Biopharmaceutical Chemistry, Kookmin University, Seoul, 02707, Republic of Korea.
Background:
Gastric cancer (GC) remains a major cause of cancer mortality worldwide, particularly in metastatic stages. N-formyl peptide receptor 2 (FPR2), a class A G protein-coupled receptor activated by the Helicobacter pylori-derived peptide Hp(2-20), promotes GC progression by stimulating oncogenic signaling pathways. However, no clinically applicable agents selectively targeting FPR2 have been developed.
Methods:
We generated fully human antagonistic antibodies targeting FPR2 using a two-step discovery strategy. A CDR-H3-focused synthetic single-chain variable fragment library was screened against an extracellular loop 3 (ECL3) peptide, followed by light-chain engineering to confer dual engagement of extracellular loop 2 (ECL2).
Results:
The engineered antibody exhibited dose-dependent binding to both ECL2 and ECL3 peptides, selectively recognized FPR2 over other FPR family members, and showed nanomolar binding to FPR2-expressing cancer cells. The antibody inhibited Hp(2-20)-induced calcium mobilization and suppressed migration and invasion of Adenocarcinoma Gastric (AGS) gastric cancer cells. Structural modeling indicated a lid-like binding mode occluding the orthosteric pocket.
Conclusions:
We developed a fully human antagonistic antibody that selectively binds and inhibits FPR2 through dual extracellular-loop engagement. The antibody potentially suppresses FPR2-driven signaling and invasive behaviors in gastric cancer cells, supporting its development for therapeutic application. Further assessment of its efficacy in vivo is warranted.
Insights
Researchers developed a novel antibody targeting N-formyl peptide receptor 2 (FPR2) to combat gastric cancer. This antibody inhibits cancer cell invasion, offering a potential new therapeutic strategy for this deadly disease.
Area of Science:
- Oncology
- Immunology
- Gastroenterology
Background:
- Gastric cancer (GC) is a leading cause of cancer mortality, especially in metastatic stages.
- N-formyl peptide receptor 2 (FPR2), activated by *Helicobacter pylori* peptide Hp(2-20), drives GC progression via oncogenic signaling.
- Currently, no clinically effective agents selectively target FPR2 for GC treatment.
Purpose of the Study:
- To develop fully human antagonistic antibodies targeting FPR2 for potential gastric cancer therapy.
- To engineer an antibody with dual engagement of FPR2 extracellular loops (ECL2 and ECL3).
- To evaluate the antibody's efficacy in inhibiting FPR2-mediated signaling and cancer cell invasion.
Main Methods:
- Generated fully human antagonistic antibodies against FPR2 using a two-step strategy.
- Screened a synthetic single-chain variable fragment library against an ECL3 peptide.
- Engineered light chains for dual engagement of FPR2 ECL2 and ECL3.
Main Results:
- The engineered antibody demonstrated dose-dependent binding to FPR2 ECL2 and ECL3 peptides.
- The antibody selectively recognized FPR2 with nanomolar affinity for FPR2-expressing cancer cells.
- Inhibition of Hp(2-20)-induced calcium mobilization and suppression of gastric cancer cell migration and invasion were observed.
Conclusions:
- A fully human antagonistic antibody targeting FPR2 via dual extracellular-loop engagement was successfully developed.
- The antibody shows potential in suppressing FPR2-driven signaling and invasive phenotypes in gastric cancer cells.
- Further *in vivo* studies are warranted to assess the therapeutic efficacy of this antibody.
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