SITA: Predicting site-specific immunogenicity for therapeutic antibodies.
10.1016/j.jpha.2025.101316
- Author:
Yewei CUN
1
;
Hao DING
1
;
Tiantian MAO
2
;
Yuan WANG
2
;
Caicui WANG
2
;
Jiajun LI
1
;
Zihao LI
1
;
Mengdie HU
1
;
Zhiwei CAO
1
;
Tianyi QIU
3
Author Information
1. School of Life Sciences, Fudan University, Shanghai, 200433, China.
2. School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
3. Institute of Clinical Science, Zhongshan Hospital Shanghai Institute of Infectious Disease and Biosecurity Intelligent Medicine Institute Fudan University, Shanghai, 200032, China.
- Publication Type:Journal Article
- Keywords:
Humanization;
Immunogenicity;
Machine learning;
Therapeutic antibody
- From:
Journal of Pharmaceutical Analysis
2025;15(6):101316-101316
- CountryChina
- Language:English
-
Abstract:
Antibody (Ab) humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic Abs originated from animal models. Computational suggestions have long been desired, but available tools focused on immunogenicity calculation of whole Ab sequences and sequence segments, missing the individual residue sites. This study introduces Site-specific Immunogenicity for Therapeutic Antibody (SITA), a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody, but also individual residues, based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures. A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Ab-Ab structural complexes. On an independent testing dataset derived from 13 Ab-Ab structural complexes, SITA successfully predicted the epitope sites for Ab-Ab structures with a receiver operating characteristic (ROC)-area unver the ROC curve (AUC) of 0.85 and a precision-recall (PR)-AUC of 0.305 at the residue level. Furthermore, the SITA score can significantly distinguish immunogenicity levels of whole human Abs, therapeutic Abs and non-human-derived Abs. More importantly, analysis of an additional 25 therapeutic Abs revealed that over 70% of them were detected with decreased immunogenicity after modification compared to their parent variants. Among these, nearly 66% Abs successfully identified actual modification sites from the top five sites with the highest SITA scores, suggesting the ability of SITA scores for guide the humanization of antibody. Overall, these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.
