title: Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein.
abstract: 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.
authors.affiliation: Scios Inc., 6500 Paseo Padre Pkway, Fremont, CA 94555, USA. ifica99@yahoo.com <ifica99@yahoo.com>
authors.forename: E
authors.initials: E
authors.lastname: Koren
authors.forename: A S
authors.initials: AS
authors.lastname: De Groot
authors.forename: V
authors.initials: V
authors.lastname: Jawa
authors.forename: K D
authors.initials: KD
authors.lastname: Beck
authors.forename: T
authors.initials: T
authors.lastname: Boone
authors.forename: D
authors.initials: D
authors.lastname: Rivera
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: D
authors.initials: D
authors.lastname: Mytych
authors.forename: M
authors.initials: M
authors.lastname: Koscec
authors.forename: D
authors.initials: D
authors.lastname: Weeraratne
authors.forename: S
authors.initials: S
authors.lastname: Swanson
authors.forename: W
authors.initials: W
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000917:Antibody Formation / Q000276:immunology; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D008958:Models, Molecular; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D011993:Recombinant Fusion Proteins