De-immun ized and F unctional T herapeutic (DeFT) versions of a long lasting recombinant alpha interferon for antiviral therapy

T-Cell Dependent Immunogenicity of Protein Therapeutics Pre-clinical Assessment and Mitigation–Updated Consensus and Review 2020

“…Extensive validation in vitro assays may be cost-prohibitive, thus current practice is to initiate the analysis with advanced in silico tools (127). Following in silico analysis, HLA binding and T cell assays can be performed or outsourced to commercial research organizations.…”

“…Direct ranking of a new biologic drug products against other known non-immunogenic and immunogenic products is possible using a normalized "immunogenicity scale." The toolkit also features novel algorithms to search for epitope that are "human-like" (see next section) and therefore less likely to engage activated T cells, and methods for deimmunization and tolerization that can be performed directly in silico (127).…”

“…All other factors being equal, the greater the burden of T cell epitopes contained in a given protein, the more likely it is that the protein will induce an immune response. The comparison of one biologic to another is possible to accomplish by normalizing epitope content scores across HLA alleles and adjusting for sequence lengths, as is done on the ISPRI toolkit (47,127). Regional epitope density can also drive immune responses.…”

Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity

“…Accordingly, developing the capacity to predict potential immunogenicity, affording strategies to decrease the potential immunogenicity of protein drugs, has been the subject of intense investigation . Several groups, including De Groot and co‐workers, have worked on this subject and produced valuable contributions …”

“…1 groups, including De Groot and co-workers, have worked on this subject and produced valuable contributions. [26][27][28][29] Several different variables affect protein immunogenicity, including their propensity to form aggregates, the degree of difference from self, uptake by antigen-presenting cells and, as it is well established that HLA class II binding is a necessary (although not sufficient) condition for T-cell immunogenicity, their content in terms of HLA-binding epitopes. CD4 T-cell responses are mediated by HLA class II molecules and are involved in responses to exogenously administered proteins.…”