Stabilization of soluble high‐affinity T‐cell receptor with <i>de novo</i> disulfide bonds

Sádio, Flávio; Stadlmayr, Gerhard; Stadlbauer, Katharina; Gräf, Maximilian; Scharrer, Agnes; Rüker, Florian; Wozniak‐Knopp, Gordana

doi:10.1002/1873-3468.13616

Cited by 7 publications

(3 citation statements)

References 54 publications

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“…Alternatively, fusion of the Ig constant domain to the TCRα and TCRβ extracellular domain, jun-fos leucine zipper fusion to the TCR C terminus, or novel addition of the interchain disulfide-bridge were found to improve soluble TCR stability [50]. Several different soluble TCR molecules, mutated with an intradomain disulfide bond, showed superior stability in comparison with non-mutated soluble TCRs and maintained binding specificity toward pMHC-expressing target cells [51].…”

Section: Tcrl-and Tcr-based Soluble Non-armed Moleculesmentioning

confidence: 99%

The Intracellular Proteome as a Source for Novel Targets in CAR-T and T-Cell Engagers-Based Immunotherapy

Arman

Haus-Cohen

Reiter

2022

Cells

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The impressive clinical success of cancer immunotherapy has motivated the continued search for new targets that may serve to guide potent effector functions in an attempt to efficiently kill malignant cells. The intracellular proteome is an interesting source for such new targets, such as neo-antigens and others, with growing interest in their application for cell-based immunotherapies. These intracellular-derived targets are peptides presented by MHC class I molecules on the cell surface of malignant cells. These disease-specific class I HLA–peptide complexes can be targeted by specific TCRs or by antibodies that mimic TCR-specificity, termed TCR-like (TCRL) antibodies. Adoptive cell transfer of TCR engineered T cells and T-cell-receptor-like based CAR-T cells, targeted against a peptide-MHC of interest, are currently tested as cancer therapeutic agents in pre-clinical and clinical trials, along with soluble TCR- and TCRL-based agents, such as immunotoxins and bi-specific T cell engagers. Targeting the intracellular proteome using TCRL- and TCR-based molecules shows promising results in cancer immunotherapy, as exemplified by the success of the anti-gp100/HLA-A2 TCR-based T cell engager, recently approved by the FDA for the treatment of unresectable or metastatic uveal melanoma. This review is focused on the selection and isolation processes of TCR- and TCRL-based targeting moieties, with a spotlight on pre-clinical and clinical studies, examining peptide-MHC targeting agents in cancer immunotherapy.

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Section: Tcrl-and Tcr-based Soluble Non-armed Moleculesmentioning

confidence: 99%

The Intracellular Proteome as a Source for Novel Targets in CAR-T and T-Cell Engagers-Based Immunotherapy

Arman

Haus-Cohen

Reiter

2022

Cells

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“…Whereas individual mutations predicted to improve overall stability only resulted in small gains in resistance to thermal denaturation and mammalian expression titres, combining several mutations resulted in significant improvements, with the best full‐length TCR gaining 8.5 °C in melting point. Another study building on a scaffold already containing the Boulter disulfide algorithmically identified potential additional disulfide bonds that could be placed within the TCR C domains or at the V‐C interface based on existing crystal structure data [ 58 ]. Although the addition of these extra disulfide bonds showed only incremental improvements in thermal stability (+1‐3 °C determined using differential scanning calorimetry), the approach highlights the additional potential for fine‐tuning of certain Vα‐Vβ pairs.…”

Section: Engineering Stable Soluble Tcrsmentioning

confidence: 99%

Engineering soluble T‐cell receptors for therapy

et al. 2021

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Immunotherapy approaches that target peptide-human leukocyte antigen (pHLA) complexes are becoming highly attractive because of their potential to access virtually all foreign and cellular proteins. For this reason, there has been considerable interest in the development of the natural ligand for pHLA, the T-cell receptor (TCR), as a soluble drug to target disease-associated pHLA presented at the cell surface. However, native TCR stability is suboptimal for soluble drug development, and natural TCRs generally have weak affinities for pHLAs, limiting their potential to reach efficacious receptor occupancy levels as soluble drugs. To overcome these limitations and make full use of the TCR as a soluble drug platform, several protein engineering solutions have been applied to TCRs to enhance both their stability and affinity, with a focus on retaining target specificity and selectivity. Here, we review these advances and look to the future for the next generation of soluble TCR-based therapies that can target monomorphic HLA-like proteins presenting both peptide and nonpeptide antigens.

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“…Although native TCR inhibition is a simple way to reduce TCR mispairing, other strategies tackle the stability of the transgenic TCR and, by doing so, they reduce TCR mispairing ( Figure 2 ). Thus, TCRs for genetic engineering of T cells have been modified with extra disulfide bonds [ 101 , 102 , 103 ], which has recently been employed in high-affinity soluble TCRs [ 104 ]. This is achieved by introducing cysteines in both the TCR alpha and beta chains.…”

Section: Improvement Of Tcr-engineered T-cell Antitumor Responsesmentioning

confidence: 99%

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

Campillo-Davò

Flumens

Lion

2020

Cells

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Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR–peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells.

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Stabilization of soluble high‐affinity T‐cell receptor with de novo disulfide bonds

Cited by 7 publications

References 54 publications

The Intracellular Proteome as a Source for Novel Targets in CAR-T and T-Cell Engagers-Based Immunotherapy

The Intracellular Proteome as a Source for Novel Targets in CAR-T and T-Cell Engagers-Based Immunotherapy

Engineering soluble T‐cell receptors for therapy

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

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