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Structure and Function

Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It 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 tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The Fc domain is glycosylated 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 and facing the solvent. 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 can be conquered by introducing a serine-to-proline mutation at amino acid 228, which prevents Fab-arm exchange and stabilizes the molecule.

Pembrolizumab/PD-1 Interaction

PemFab/PD-1 Interaction

PemFv/PD-1 Interaction

Mechanism

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