A Macropinocytosis-Intensifying Albumin Domain-Based scFv Antibody and Its Conjugate Directed against K-Ras Mutant Pancreatic Cancer.

Abstract

Enhanced macropinocytosis has been found in K-Ras mutant pancreatic cancer cells, through which albumin can massively enter into the K-Ras-driven cancer cells, suggesting its role in serving as a macropinocytosis-intensifying drug delivery carrier. In the present study, a novel recombinant protein Fv-LDP-D3 and its reconstituted analogue Fv-LDP-D3-AE were designed and prepared. Fv is the fragment of an anti-EGFR antibody, D3 is the domain III of human serum albumin (HSA), LDP is the apoprotein of the antitumor antibiotic lidamycin (LDM), and AE is an extremely cytotoxic enediyne chromophore derived from LDM. As shown, the recombinant protein Fv-LDP-D3 presented intensive and selective binding capacity to pancreatic cancer cells and inhibited cell proliferation by blocking EGFR signaling. Moreover, Fv-LDP-D3 showed prominent tumor imaging in pancreatic carcinoma xenograft. The reconstituted, enediyne-integrated analogue Fv-LDP-D3-AE displayed highly potent cytotoxicity to pancreatic cancer cells through apoptosis induction and G2/M arrest. Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the tumor growth of the pancreatic carcinoma AsPC-1 xenograft. Study results indicated that the novel recombinant protein displays both EGFR-targeting and macropinocytosis-intensifying attributes, presenting a new format of scFv antibody that integrates with albumin domain III. It might be a feasible strategy to develop targeted drugs for K-Ras mutant pancreatic cancer.