title: Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab.
abstract: Immunoglobulin G4 antibodies exhibit unusual properties with important biological consequences. We report the structure of the human full-length IgG4 S228P anti-PD1 antibody pembrolizumab, solved to 2.3-Å resolution. Pembrolizumab is a compact molecule, consistent with the presence of a short hinge region. The Fc domain is glycosylated at the CH2 domain on both chains, but one CH2 domain is rotated 120° with respect to the conformation observed in all reported structures to date, and its glycan chain faces the solvent. We speculate that this new conformation is driven by the shorter hinge. The structure suggests a role for the S228P mutation in preventing the IgG4 arm exchange. In addition, this unusual Fc conformation suggests possible structural diversity between IgG subclasses and shows that use of isolated antibody fragments could mask potentially important interactions, owing to molecular flexibility.
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.affiliation: Biologics and Vaccines Formulation, Analytical Method Development, Merck &Co, Inc., Kenilworth, New Jersey, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Winifred W
authors.initials: WW
authors.lastname: Prosise
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McCoy
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Reichert
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Johnston
authors.affiliation: Bioprocess Technology and Expression, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Kashi
authors.affiliation: Structural Chemistry, Merck &Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab