T cell epitope: Friend or Foe? Immunogenicity of biologics in context☆

Abstract

Like vaccines, biologic proteins can be very immunogenic for reasons including route of administration, dose frequency and the underlying antigenicity of the therapeutic protein. Because the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening. T cell epitopes are at the root of the immunogenicity issue. Through their presentation to T cells, they activate the process of anti-drug antibody development. Preclinical screening for T cell epitopes can be performed in silico, followed by in vitro and in vivo validation. Importantly, screening for immunogenicity is complicated by the discovery of regulatory T cell epitopes, which suggests that immunogenicity testing must now take regulatory T cells into consideration. In this review, we address the application of computational tools for preclinical immunogenicity assessment, the implication of the discovery of regulatory T cell epitopes, and experimental validation of those assessments.

Engineering the variable region of therapeutic IgG antibodies

“…91 The most common N-glycosylation site in the variable region is CDR2 of the heavy chain, but other potential Recently, De Groot and colleagues reported a novel concept of regulatory T-cell epitope (Tregitope) in the Fc and variable region of the antibody as a suppressor of immune response. 132,133 They suggested that introducing a Tregitope sequence into the immunogenic antibodies might be an alternative deimmunization strategy.…”

In silico Design of Discontinuous Peptides Representative of B and T-cell Epitopes from HER2-ECD as Potential Novel Cancer Peptide Vaccines

“…While B cells and antibodies generally recognize conformational epitopes from surface proteins, T cells recognize linear epitopes derived from proteins that are processed by APCs (Weber et al, 2009). In addition, the presentation of T-cell epitopes in the context of MHC is critical to the recognition of self vs. foreign proteins and to the development of both cellular and humoral immune responses (De Groot et al, 2010).…”

The role of the tumour microenvironment in immunotherapy

“…Most neoantigens arising from passenger mutations are not related to the tumourigenesis process and are therefore likely to be unique to every patient. The development of algorithms to predict candidate neoantigens and immunogenicity of peptides with higher precision are the topic of intense current research efforts in academia and the private sector (Weber et al 2009, Zhang et al 2015. Such algorithms will be invaluable for the design of peptide vaccines and chimeric antigen receptor (CAR) T cell technology, where chimeras are generated by combining side-chain variable fragments with the ζ subunit of CD3, CD28 or CD137 to artificially link tumour surface antigen specificity with activation signal transmission in T cells upon antigen binding (Delitto et al 2016).…”