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Updated: Jun 13, 2026
Identification of Mouse and Human Antibody Repertoires by Next-Generation Sequencing
Published on: March 15, 2019
Potential aggregation-prone regions in complementarity-determining regions of antibodies and their contribution
Xiaoling Wang1, Satish K Singh, Sandeep Kumar
1Pharmaceutical Research and Development BioTherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA.
Purpose:
To analyze contribution of short aggregation-prone regions (APRs), which may self-associate via cross-beta motif and were earlier identified in therapeutic mAbs, towards antigen recognition via structural analyses of antibody-antigen complexes.
Methods:
A dataset of 29 publically available high-resolution crystal structures of Fab-antigen complexes was collected. Contribution of APRs towards the surface areas of the Fabs buried by the cognate antigens was computed. Propensities of amino acids to occur in APRs and to be involved in antigen binding were compared. Coincidence between APRs and individual CDR loops was examined.
Results:
All Fabs in the dataset contain at least one APR in CDR loops and adjacent framework beta-strands. The average contribution of APRs towards buried surface area of Fabs is 16.0 +/- 10.7%. Aggregation and antigen recognition may be coupled via aromatic residues (Tyr, Trp), which occur with high propensities in both APRs and antigen binding sites. APRs are infrequent in the heavy chain CDR 3 (H3) loops (7%), but are frequent in H2 loops (45%).
Conclusions:
Co-incidence of APRs with antigen recognition sites can potentially lead to the loss of function upon aggregation. Rational structure-based design or selection strategies are suggested for biotherapeutics with improved druggability while maintaining potency.
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