TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide–HLA Complex

Coles, C.H.; Mulvaney, R.; Malla, S.; Walker, Andrew; Smith, Kathrine J.; Lloyd, Alun G.; Lowe, Kate L.; McCully, Michelle L.; Hague, R. Martinez; Aleksic, Milos; Harper, Jane; Paston, Samantha; Donnellan, Zoe; Chester, F.; Wiederhold, K.; Robinson, R.A.; Knox, Andrew Alexander; Stacey, Andrea; Dukes, Joseph; Baston, Emma; Griffin, Sue T.; Jakobsen, Bent K.; Vuidepot, Annelise; Harper, Stephen

doi:10.4049/jimmunol.1900915

Cited by 37 publications

(41 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although like conformation, the alanine scan profile and MagPix analysis revealed lower levels of peptide selectivity compared with the affinity-enhanced TCRs. To probe this discrepancy further, we developed an approach for the characterization of TCR peptide degeneracy using randomized pHLA libraries displayed on phage (50). We used this system to identify peptide motif preferences for the affinity-enhanced TCRs and TCR mimics that recognized W5 was selected by 3M4E5_T2 and 3M4E5_T3, it was not the dominant amino acid preference at this position, with phenylalanine (F) being preferred by both reagents (Figure 3, E-F).…”

Section: Resultsmentioning

confidence: 99%

“…Panning using scHLA libraries. scHLA libraries were generated as previously described (50). Biotinylated affinity-enhanced TCRs (1G4_α 5 β 100 , 1G4_α 5 β 51 , and 1G4_α 58 β 61 ) and TCR-mimic antibodies (3M4E5, 3M4E5_T2, and 3M4E5_T3) were captured on streptavidincoated paramagnetic beads and incubated with the library of purified phage particles preblocked in 3% MPBS buffer.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Holland¹,

Crean²,

Pentier³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Holland¹,

Crean²,

Pentier³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…In any case, it is likely that computational tools will sit alongside other experimental approaches to ensure that therapeutically deployed aeTCRs maintain peptide selectivity relative to their WT parent TCR. 46 …”

Section: Discussionmentioning

confidence: 99%

Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy

Crean

MacLachlan

Madura

et al. 2020

Molecular Therapy - Oncolytics

Self Cite

View full text Add to dashboard Cite

Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition of peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface. However, because natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. In this study, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with those of their wild-type progenitors. Additionally, we performed molecular dynamics simulations to better understand the energetic mechanisms driving the affinity enhancements. These data demonstrate that supra-physiological binding affinities can be achieved without altering native TCR-pHLA binding modes via relatively subtle modifications to the interface contacts, often driven through the addition of buried hydrophobic residues. Individual energetic components of the TCR-pHLA interaction governing affinity enhancements were distinct and highly variable for each TCR, often resulting from additive, or knock-on, effects beyond the mutated residues. This comprehensive analysis of affinity-enhanced TCRs has important implications for the future rational design of engineered TCRs as efficacious and safe drugs for cancer treatment.

show abstract

“…NY-ESO-1 157−165 (peptide sequence SLLMWITQC) has been demonstrated to be a safe and effective human leukocyte antigen (HLA)-A2 restricted antigenic epitope with therapeutic potency, which can be recognized by specific T cells (12). Several studies have identified and characterized the function of NY-ESO-1 157−165 specific TCRs (13)(14)(15), and >30% of TCR-T cell clinical trials have targeted NY-ESO-1 157−165 (16). Among these TCRs, 1G4, which has been extensively investigated, with clear recognition mechanisms with NY-ESO-1 157−165 (17,18), is currently undergoing multiple clinical trials for a range of advanced solid tumors (11), and striking clinical responses have been observed in patients with advanced multiple myeloma and synovial cell sarcoma (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Identification of NY-ESO-1157–165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy

et al. 2021

View full text Add to dashboard Cite

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1157−165 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1157−165 epitope-specific murine TCRs obtained from HLA-A*0201 transgenic mice. NY-ESO-1157−165 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1157−165/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1157−165/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1157−165 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1157−165/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1157−165, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.

show abstract

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide–HLA Complex

Cited by 37 publications

References 68 publications

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy

Identification of NY-ESO-1157–165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy

Contact Info

Product

Resources

About