Integrating molecular dynamics simulation with small- and wide-angle X-ray scattering to unravel the flexibility, antigen-blocking, and protease-restoring functions in a hindrance-based pro-antibody.

ABSTRACT: Spatial hindrance-based pro-antibodies (pro-Abs) are engineered antibodies to reduce monoclonal antibodies' (mAbs) on-target toxicity using universal designed blocking segments that mask mAb antigen-binding sites through spatial hindrance. By linking through protease substrates and linkers, these blocking segments can be removed site-specifically. Although many types of blocking segments have been developed, such as coiled-coil and hinge-based Ab locks, the molecular structure of the pro-Ab, particularly the region showing how the blocking fragment blocks the mAb, has not been elucidated by X-ray crystallography or cryo-EM. To achieve maximal effect, a pro-Ab must have high antigen-blocking and protease-restoring efficiencies, but the unclear structure limits its further optimization. Here

SUBMITTER: Liao JM 

PROVIDER: S-EPMC11325194 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature