The potential of
antibodies, especially for the
bispecific antibodies, are limited by high cost and complex technical process of development and manufacturing. A cost-effective and rapid platform for the endogenous
antibodies expression via using the in vitro transcription (IVT) technique to produce
nucleoside-modified
mRNA and then encapsulated into
lipid nanoparticle (LNP) may turn the body to a manufactory. Coinhibitory pathway of
programmed death ligand 1 (PD-L1) and
programmed cell death protein 1 receptor (PD-1) could suppress the T-cell mediated immunity. We hypothesized that the coblocking of PD-L1 and PD-1 via
bispecific antibodies may achieve more potential antitumor efficacies compare with the monospecific ones. Here, we described the application of
mRNA to encode a bispecific antibody with ablated Fc immune effector functions that targets both human PD-L1 and PD-1, termed XA-1, which was further assessed the in vitro functional activities and in vivo antitumor efficacies. The in vitro
mRNA-encoded XA-1 held comparable abilities to fully block the PD-1/PD-L1 pathway as well as to enhance functional T cell activation compared to XA-1
protein from CHO cell source. Pharmacokinetic tests showed enhanced area under curve (AUC) of
mRNA-encoded XA-1 compared with XA-1 at same dose. Chronic treatment of LNP-encapsulated XA-1
mRNA in the mouse
tumor models which were reconstituted with human immune cells effectively induced promising antitumor efficacies compared to XA-1
protein. Current results collectively demonstrated that LNP-encapsulated
mRNA represents the viable delivery platform for treating
cancer and hold potential to be applied in the treatment of many diseases.Abbreviations: IVT: in vitro transcription; LNP:
lipid nanoparticle; hPD-1: human PD-1; hPD-L1: human PD-L1; ITS-G:
Insulin-
Transferrin-
Selenium; Pen/Strep:
penicillin-
streptomycin; FBS:
fetal bovine serum; TGI:
tumor growth inhibition; IE1: cytomegalovirus immediate early 1; SP:
signal peptide; hIgLC: human
immunoglobulin kappa light chain; hIgHC: human
IgG1 heavy chain; AUC: area under the curve; Cl: serum clearance; Vss: steady-state distributed volume; MLR: mixed lymphocyte reaction.