5VH5

Crystal Structure of Fc fragment of anti-TNFa antibody infliximab

Summary for 5VH5

• Entry DOI: 10.2210/pdb5vh5/pdb
• Related: 5VH3 5VH4
• Descriptor: Infliximab Fc, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[beta-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (5 entities in total)
• Functional Keywords: antibody, fc, biosimilar, infliximab, tnfa, anti-tnfa, immune system
• Biological source: Mus musculus, Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 30038.82

Authors

Mayclin, S.J.,Edwards, T.E.,Lerch, T.F.,Conlan, H.,Sharpe, P. (deposition date: 2017-04-12, release date: 2017-05-03, Last modification date: 2024-10-23)

Primary citation

Lerch, T.F.,Sharpe, P.,Mayclin, S.J.,Edwards, T.E.,Lee, E.,Conlon, H.D.,Polleck, S.,Rouse, J.C.,Luo, Y.,Zou, Q.
Infliximab crystal structures reveal insights into self-association.
MAbs, 9:874-883, 2017

PubMed Abstract: Aggregation and self-association in protein-based biotherapeutics are critical quality attributes that are tightly controlled by the manufacturing process. Aggregates have the potential to elicit immune reactions, including neutralizing anti-drug antibodies, which can diminish the drug's efficacy upon subsequent dosing. The structural basis of reversible self-association, a form of non-covalent aggregation in the native state, is only beginning to emerge for many biologics and is often unique to a given molecule. In the present study, crystal structures of the infliximab (Remicade) Fc and Fab domains were determined. The Fab domain structures are the first to be reported in the absence of the antigen (i.e., tumor necrosis factor), and are consistent with a mostly rigid complementarity-determining region loop structure and rotational flexibility between variable and constant regions. A potential self-association interface is conserved in two distinct crystal forms of the Fab domain, and solution studies further demonstrate that reversible self-association of infliximab is mediated by the Fab domain. The crystal structures and corresponding solution studies help rationalize the propensity for infliximab to self-associate and provide insights for the design of improved control strategies in biotherapeutics development.

PubMed: 28421849
DOI: 10.1080/19420862.2017.1320463

Experimental method

X-RAY DIFFRACTION (1.75 Å)