Removing T-cell epitopes with computational protein design.
Immune responses can make protein therapeutics ineffective or even dangerous. We describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method recapitulates previous experimental results on immunogenicity reduction, and we use it to disrupt T-cell epitopes in GFP and Pseudomonas exotoxin A without disrupting function.
Institute for Protein Design, Department of Biochemistry and chrisk1@uw.edu.
Chris
C
King
Department of Immunology, University of Washington, Seattle, WA 98195; and.
Esteban N
EN
Garza
National Cancer Institute and.
Ronit
R
Mazor
National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892.
Jonathan L
JL
Linehan
National Cancer Institute and.
Ira
I
Pastan
Department of Immunology, University of Washington, Seattle, WA 98195; and.
Marion
M
Pepper
Institute for Protein Design, Department of Biochemistry and.
David
D
Baker
D036002:ADP Ribose Transferases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D017076:Computer-Aided Design; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005098:Exotoxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D000922:Immunotoxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence; D060388:Support Vector Machine; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D018984:Epitopes, T-Lymphocyte; D005098:Exotoxins; D049452:Green Fluorescent Proteins; D006680:HLA Antigens; D000922:Immunotoxins; D011506:Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
Rosetta; biotherapeutics; deimmunization; immunotoxin; machine learning