Clinical validation of the “ in silico” prediction of immunogenicity of a human recombinant therapeutic protein

• Published in: Clinical Immunology Vol. 124; no. 1; pp. 26 - 32
• Main Authors: Koren, E., De Groot, A.S., Jawa, V., Beck, K.D., Boone, T., Rivera, D., Li, L., Mytych, D., Koscec, M., Weeraratne, D., Swanson, S., Martin, W.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.07.2007; Elsevier
• Subjects: Adolescent; Adult; Algorithms; Allergy and Immunology; Antibody Formation - immunology; Antibody response; Biological and medical sciences; Combinatorial Chemistry Techniques; Computational Biology - methods; Computer Simulation; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - trends; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HLA; Humans; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; Immunogenicity prediction; Immunoinformatics; Male; Medical sciences; Middle Aged; Models, Immunological; Models, Molecular; Predictive Value of Tests; Quantitative Structure-Activity Relationship; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T-cell epitope; T-Lymphocytes, Helper-Inducer - immunology; HLA; Immunogenicity prediction; T-cell epitope; Antibody response; Immunoinformatics; Human; Validation; Immunopathology; Immune response; Antigenic determinant; Antibody; Prediction; Protein A; Medicine; Immunology; Treatment; Immunogenicity; T-Lymphocyte; Recombinant protein; Predictive factor; Humoral immunity
• ISSN: 1521-6616; 1521-7035; 1365-2567
• DOI: 10.1016/j.clim.2007.03.544

Antibodies elicited by protein therapeutics can cause serious side effects in humans. We studied immunogenicity of a recombinant fusion protein (FPX) consisting of two identical, biologically active, peptides attached to human Fc fragment. EpiMatrix, an in silico epitope-mapping tool, predicted promiscuous T-cell epitope(s) within the 14-amino-acid carboxy-terminal region of the peptide portion of FPX. On administration of FPX in 76 healthy human subjects, 37% developed antibodies after a single injection. A memory T-cell response against the above carboxy-terminus of the peptide was observed in antibody-positive but not in antibody-negative subjects. Promiscuity of the predicted T-cell epitope(s) was confirmed by representation of all common HLA alleles in antibody-positive subjects. As predicted by EpiMatrix, HLA haplotype DRB1*0701/1501 was associated with the highest T-cell and antibody response. In conclusion, in silico prediction can be successfully used to identify Class II restricted T-cell epitopes within therapeutic proteins and predict immunogenicity thereof in humans.