The humanness of macaque antibody sequences

Area of Science:

• Immunology
• Biotechnology
• Bioinformatics

Background:

• Therapeutic antibodies aim to reduce immunogenicity through increased human character.
• Antibody variable regions (V-regions) humanness is a key factor in predicting immunogenicity.
• Macaque antibody sequences are of interest due to their perceived human-like characteristics.

Purpose of the Study:

• To objectively assess the humanness of macaque antibody V-regions compared to human counterparts.
• To introduce and validate a new parameter, the G-score, for evaluating antibody V-region humanness.
• To investigate the impact of germline humanization on macaque V-region humanness.

Main Methods:

• Statistical comparison of H-scores between macaque and human antibody V-regions.
• Derivation of the G-score from the H-score to mitigate family size influence.
• Re-analysis of macaque V-region sequences using both H-score and G-score.

Main Results:

• H-score analysis revealed macaque V-regions are not fully human, with results influenced by human family relatedness.
• The G-score demonstrated that macaque heavy chain V-regions are not human-like, whereas light chain humanness is variable.
• Germline humanization of macaque V-regions improved their humanness as assessed by both H-score and G-score.

Conclusions:

• The H-score and G-score provide objective measures for antibody V-region humanness.
• Macaque antibody heavy chains are distinct from human sequences, while light chains show variability.
• Germline humanization is a viable strategy to enhance the humanness of macaque-derived antibody V-regions for therapeutic development.