Effectiveness of Anti-Erythropoietin Producing Hepatocellular Receptor Type-A2 Antibody in Pancreatic Cancer Treatment

Background: Related to the pathogenesis of cancers in humans, the interaction between erythropoietin-producing hepatocyte receptors and ephrins (Ephs/ephrins) affects and regulates various biological functions. Erythropoietin-producing hepatocyte receptor type A2 (EphA2) is a tyrosine kinase that binds to ephrins (e.g., ephrin-A1) to initiate bidirectional signaling between cells. The binding of EphA2 and ephrin-A1 leads to the inhibition of Ras-MAPK activity and tumor growth. During tumorigenesis, the normal interaction between EphA2 and ephrin-A1 is hindered, which leads to the overexpression of EphA2 and induces cancer. The overexpression of EphA2 has been identified as a notable tumor marker in the diagnosis and treatment of pancreatic cancer. Results In this study, we used phage display to isolate specific antibodies against the active site of EphA2 molecules by using a discontinuous recombinant epitope for immunization. The therapeutic efficacy and inhibition mechanism of the generated antibody against pancreatic cancer was validated and clarified. The generated antibodies were bound to the conformational epitope of endogenous EphA2 on cancer cells, thus inducing cellular endocytosis and causing EphA2 degradation. Molecule signals pAKT, pERK, pFAK, and pSTAT3 were weakened, thereby inhibiting the proliferation and migration of pancreatic cancer cells. The humanized antibody hSD5 could effectively inhibit the growth of the xenograft pancreatic cancer tumor cells BxPc-3 and Mia PaCa-2 in mice, respectively. When antibody hSD5 was administered in combination with gemcitabine, significantly synergistic effects on tumor growth inhibition (reach 79.3%) were observed. Conclusions On the basis of the efficacy of the IgG hSD5 antibody, clinical administration of the hSD5 antibody is likely to suppress tumors in patients with pancreatic cancer and abnormal activation or overexpression of EphA2 signaling.