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

Jawa, Vibha; Terry, Frances; Gokemeijer, Jochem; Mitra-Kaushik, Shibani; Roberts, Brian; Tourdot, Sophie; Groot, Anne S. De

doi:10.3389/fimmu.2020.01301

Cited by 90 publications

(70 citation statements)

References 170 publications

(230 reference statements)

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“…Of these, HLA-DR is the most polymorphic [16], and is usually expressed at higher levels [17,18]. It is unclear why antiantibody (or anti-idiotype) immune responses are not highly prevalent due to the very high diversity of somatically mutated human antibodies, including the substantial untemplated diversity of CDR3 regions, although highly homologous antibody sequences (including T regulatory cell epitopes, or Tregitopes) have been suggested to play a role in reducing anti-antibody immunity [19][20][21]. Methods for computational MHC binding prediction have continually improved in recent years, particularly for HLA-DR [22], and recent high-throughput proteomic elution data have provided large experimental datasets as benchmarks to enhance prediction accuracy [23,24].…”

Section: Introductionmentioning

confidence: 99%

Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Gutiérrez-González

Nanaware

et al. 2021

Preprint

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SummaryHuman antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of class-switched sequences and serum proteomic data revealed that MHC-II epitope deletion is associated with antibody class switching and long-term secretion into serum. These data suggest that the MHC-II peptide epitope content of a BCR is an important determinant of antibody maturation that shapes the composition and durability of humoral immunity.HighlightsAntibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors.Antibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching.MHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum.MHC-II genotype provides a personalized selection pressure on human antibody development.

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Section: Introductionmentioning

confidence: 99%

Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Gutiérrez-González

Nanaware

et al. 2021

Preprint

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“…While many T cell epitope induces immunogenic effector T cell responses, some may instead engage regulatory T cells (Tregs) leading to tolerance and immunosuppression 25 – 27 . Treg epitopes, or Tregitopes, have been documented in both biologics and pathogens 10 , 11 , 28 , 29 . Mutations generating Treg neoepitopes, or neo-Tregitopes, may camouflage tumors from the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…1 ). These tools have been well validated in the biologics and infectious disease fields 10 – 12 , 14 , 29 – 31 , and have been employed in tumor associated antigen and neoantigen-based vaccine studies 16 , 32 . Analysis of genomic data from the TCGA BLCA cohort with Ancer found that both Ancer HLA class I and HLA class II neoepitope loads were strongly correlated with patient TMB (Fig.…”

Section: Discussionmentioning

confidence: 99%

Multi-step screening of neoantigens’ HLA- and TCR-interfaces improves prediction of survival

Richard

Groot

Steinberg³

et al. 2021

Sci Rep

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Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

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“…T cells recognize and bind this peptide-HLA-II complex with the T cell receptor (TCR), which provides an initial stimulatory signal to the T cell. 15 , 16 To achieve T cell activation, proliferation, and cytokine production by an antigen, costimulatory signals delivered by CD28 on T cells and its ligands CD80 or CD86 on APCs are also needed. 17 Additional T cell costimulatory receptors belonging to the tumor necrosis factor receptor superfamily (TNFRSF), such as CD134 (also known as OX40) and CD137 (also known as 4–1BB), with their corresponding ligands on APCs (OX40L and 4–1BBL, respectively) are also important for full antigen-dependent T cell activation.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells

Cohen¹,

Myneni²,

Batt³

et al. 2021

mAbs

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Biotherapeutics, which are biologic medications that are natural or bioengineered products of living cells, have revolutionized the treatment of many diseases. However, unwanted immune responses still present a major challenge to their widespread adoption. Many patients treated with biotherapeutics develop antigen-specific anti-drug antibodies (ADAs) that may reduce the efficacy of the therapy or cross-react with the endogenous counterpart of a protein therapeutic, or both. Here, we describe an in vitro method for assessing the immunogenic risk of a biotherapeutic. We found a correlation between clinical immunogenicity and the frequency with which a biotherapeutic stimulated an increase in CD134, CD137, or both cell surface markers on CD4 + T cells. Using high-throughput flow cytometry, we examined the effects of 14 biotherapeutics with diverse rates of clinical immunogenicity on peripheral blood mononuclear cells from 120 donors with diverse human leukocyte antigen class II-encoding alleles. Biotherapeutics with high rates of ADA development in the clinic had higher proportions of CD4 + T cells positive for CD134 or CD137 than biotherapeutics with low clinical immunogenicity. This method provides a rapid and simple preclinical test of the immunogenic potential of a new candidate biotherapeutic or biosimilar. Implementation of this approach during biotherapeutic research and development enables rapid elimination of candidates that are likely to cause ADA-related adverse events and detrimental consequences.

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

Cited by 90 publications

References 170 publications

Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Multi-step screening of neoantigens’ HLA- and TCR-interfaces improves prediction of survival

Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells

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