A Novel Type of PD-L1 Inhibitor rU1 snRNPA From Human-Derived Protein Scaffolds Library

Abstract

Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to the PD-1 binding domain of PD-L1. The RNA binding domain of U1 snRNPA was selected as one of potential binders because it had the most favorable binding energies with PD-L1 and conformed to pre-established biological criteria for the screening of candidates. The recombinant U1 snRNPA (rU1 snRNPA) in Escherichia coli exhibits anti-cancer activity in melanoma and breast cancer by reactivating tumor-suppressed T cells in vitro and anti-melanoma activity in vivo. Considering hydrophobic and electrostatic interactions, three residues were mutated on the interface of U1 snRNPA and PD-L1 complex, and the ranked variants by PatchDock and A32D showed an increased active phenotype. The screening of human-derived protein scaffolds may become the potential development of therapeutic agents.

Targeted Therapy and Immunotherapy for Heterogeneous Breast Cancer

“…However, some researchers pointed out that almost all anti-PD-L1 antibodies on the market have serious side effects due to their high immunogenicity [ 121 , 122 ]. Therefore, Ma et al [ 123 ] screened a human-derived protein scaffold, U1, small nuclear ribonucleoprotein polypeptide A (snRNPA), which is complementary in shape to the domain of the PD-L1 binding receptor, by constructing a library and found that this combination inhibited PD-1/PD-L1 interaction. Compared to antibodies, the human-derived protein scaffold has a longer half-life and better permeability because of its lower molecular weight and immunogenicity since this protein scaffold exerts anti-tumor activity by reactivating tumor-suppressed T cells and is unable to coordinate direct cytocidal effects.…”