Cited by 198Protein purification and stabilityMonoclonal and Polyclonal Antibodies ResearchProtein Structure and Dynamics

Potential aggregation prone regions in biotherapeutics: A survey of commercial monoclonal antibodies

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Wang, Xiaoling, Das, Tapan K., Singh, Satish K., Kumar, Sandeep·2009·mAbs

Abstract

Aggregation of a biotherapeutic is of significant concern and judicious process and formulation development is required to minimize aggregate levels in the final product. Aggregation of a protein in solution is driven by intrinsic and extrinsic factors. In this work we have focused on aggregation as an intrinsic property of the molecule. We have studied the sequences and Fab structures of commercial and non-commercial antibody sequences for their vulnerability towards aggregation by using sequence based computational tools to identify potential aggregation-prone motifs or regions. The mAbs in our dataset contain 2 to 8 aggregation-prone motifs per heavy and light chain pair. Some of these motifs are located in variable domains, primarily in CDRs. Most aggregation-prone motifs are rich in beta branched aliphatic and aromatic residues. Hydroxyl-containing Ser/Thr residues are also found in several aggregation-prone motifs while charged residues are rare. The motifs found in light chain CDR3 are glutamine (Q)/asparagine (N) rich. These motifs are similar to the reported aggregation promoting regions found in prion and amyloidogenic proteins that are also rich in Q/N, aliphatic and aromatic residues. The implication is that one possible mechanism for aggregation of mAbs may be through formation of cross-beta structures and fibrils. Mapping on the available Fab-receptor/antigen complex structures reveals that these motifs in CDRs might also contribute significantly towards receptor/antigen binding. Our analysis identifies the opportunity and tools for simultaneous optimization of the therapeutic protein sequence for potency and specificity while reducing vulnerability towards aggregation.

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Crossref · 10.4161/mabs.1.3.8035

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  • Wang and co-workers examined molecular sequences of commercially available mAb drug products and showed that they contain multiple well defined aggregation prone motifs often located in their CDRs.

    “Wang and co-workers have examined molecular sequences of commercially available mAb drug products and shown that they contain multiple well defined aggregation prone motifs often located in their CDRs [206].”

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Authors
Wang, X., Das, T. K., Singh, S. K., & Kumar, S.
Affiliations
Pfizer (United States) (US)
Corresponding author
Kumar, Sandeep
Venue
mAbs
Published
2009-05
Volume
1
Issue
3
Pages
254-267
ISSN
  • 1942-0862 (ISSN-L)
  • 1942-0870
OpenAlex
W1597806993
Cited by
198
References
104
Citations by year
2026: 1 · 2025: 5 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 11 · 2020: 20 · 2019: 15 · 2018: 11 · 2017: 16 · 2016: 10 · 2015: 15 · 2014: 14 · 2013: 20 · 2012: 14
FWCI
5.50
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • mAbs (publishedVersion, public-domain)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Pfizer
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
antibody aggregation, aggregation-prone regions, monoclonal antibodies, hypervariable region, cross-β structure, fibril formation
MeSH terms
Amyloid, Animals, Antibodies, Monoclonal, Antigen-Antibody Complex, Humans, Immunoglobulin Fab Fragments, Immunotherapy, Prions, Protein Binding, Software, Protein Structure, Secondary, Amino Acid Motifs, Databases, Genetic, Protein Multimerization

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