Keytruda: Difference between revisions

Pembrolizumab, trade name Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding occurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated at Asp297</scene> at both CH₂ domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.