Novel CXCR2 antibodies exhibit enhanced anti-tumor activity in pancreatic cancer.

G protein-coupled receptors (GPCRs) are crucial in several physiological and pathological processes and are associated with numerous diseases across all therapeutic areas. Antibodies are well-established therapeutics with better selectivity, stability, and half-life than small molecules and peptides. CXC motif chemokine receptor 2 (CXCR2) and its ligands play functional roles in the progression and metastasis of tumors and activation and trafficking of inflammatory mediators. Several chemical-based antagonists that inhibit the CXCLs/CXCR2 signaling axis are under clinical study in cancer or inflammatory disease research; however, therapeutic antibodies have not yet been successfully established. In this study, we used phage display technology to identify single-chain variable fragment proteins that target the N-terminal domain of human CXCR2. Subsequently, we performed an enzyme-linked immunosorbent assay to validate the interaction of these IgG1 candidates and bio-layer interferometry to determine their affinity. The association of these antibodies, IgG18 and IgG56, with stable HEK293 cell lines expressing hCXCR2 and various cancer cell lines, including pancreatic cancer cells, was further analyzed. We found that IgG18 and IgG56 antibodies antagonized CXCL8-induced CXCR2 signaling, suppressed CXCL8-mediated cell proliferation and migration, and induced apoptosis in pancreatic cancer cells. In a xenograft model of pancreatic cancer, CXCR2 antibodies, IgG18 and IgG56, decreased tumor growth and induced apoptosis in vivo. Our results indicate that CXCR2 inhibitory antibodies attenuate tumor progression and may be potential candidates for anti-tumor therapeutics.