Implications of available design space for identification of non-immunogenic protein therapeutics |
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Authors: | " target="_blank">Stephen Craig Lee |
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Institution: | (1) Department of Biomedical Engineering, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA;(2) Departments of Cellular and Molecular Biochemistry, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA;(3) Chemical and Biomolecular Engineering, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA;(4) Davis Heart & Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA;(5) College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA |
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Abstract: | Immunogenicity/antibody responses are major issues for parenteral proteins and nanotherapeutics (nanovectors, diagnostics,
theranostics, etc.), and robust antibody responses require T-helper epitopes. T-helper epitopes consist of specific amino
acids at specific positions (anchor positions) in immunogens which contact the major histocompatibility complex (MHC), provide
most of the energy for MHC binding and constitute the binding motif for the corresponding MHC alleles. We developed an algorithm
that considers motifs to design vaccines lacking unwanted T-cell epitopes, and found numbers of such vaccines can be astronomical
(Lee et al. 2009). The algorithm can be used to design reduced immunogenicity proteins, and numbers of predicted proteins are also immense.
Reducing T-helper epitope content reduces protein immunogenicity, but the depth of mutagensis needed to eliminate immunogenicity
is commonly assumed to be too great for retention of protein bioactivity. However, very deep, but successful substitution,
insertion and deletion mutagenesis have been reported. These reports and design space the algorithm reveals suggest development
of non-immunogenic therapeutics might be more feasible than commonly assumed. |
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