50 Years of Antibody Numbering Schemes: A Statistical and Structural Evaluation Reveals Key Differences and...

Area of Science:

• Immunology
• Structural Biology
• Bioinformatics

Background:

• Antibody complementarity-determining regions (CDRs) are crucial for immune responses due to their high sequence and structural diversity.
• Multiple antibody CDR numbering schemes exist, leading to potential confusion and a lack of comprehensive evaluation.
• Understanding CDR variations is essential for antibody research and development.

Purpose of the Study:

• To statistically quantify and compare the diversity of antibody CDRs across different numbering schemes.
• To evaluate the consistency and accuracy of existing CDR definitions.
• To identify discrepancies and propose refinements for antibody CDR delineation.

Main Methods:

• Statistical analyses were employed to quantify CDR diversity relative to antibody framework regions.
• Comparative analyses were performed across established antibody numbering schemes (Kabat, AbM, Chothia, IMGT).
• Identification of critical structural residues within CDR loops was conducted.

Main Results:

• Significant variations in CDR definitions were observed among different numbering schemes.
• Kabat and AbM schemes include more conserved residues, while Chothia and IMGT schemes show greater diversity, sometimes omitting loop residues.
• A critical residue L29 in kappa light chain CDR1 was identified, with topological equivalents differing across schemes, indicating a need for refinement.

Conclusions:

• Findings reveal regional sequence and structural conservation within antibody databases, alongside discrepancies from numbering schemes.
• The study provides guidelines for precise CDR delineation and antibody repertoire design.
• These insights have practical implications for developing novel antibody-based therapeutics and diagnostics.