A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

Chang, Amy; Dao, Tao; Gejman, Ron S.; Jarvis, Casey A.; Scott, Andrew; Dubrovsky, Leonid; Mathias, Melissa; Korontsvit, Tatyana; Zakhaleva, Victoriya; Curcio, Michael; Hendrickson, Ronald C.; Liu, Cheng; Scheinberg, David A.

doi:10.1172/jci92335

Cited by 75 publications

(58 citation statements)

References 61 publications

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“…Specificity analysis of a TCR-mimic antibody to PRAME 300-309 -HLA-A*02:01 was inconclusive. The molecule delivered mixed results in in vitro cellular assays with good specificity towards a panel of cell lines and whole blood but had a high degree of tolerance for alanine substitution at all peptide positions with the exception of positions 8 and 9 (indicating a potential for cross reactivity) [66]. More promising was the report describing a TCR-mimic antibody towards the EBV 426-434 CLGGLLTMV-HLA-A*0201 antigen, which displayed a bellshaped distribution of contacts across the peptide backbone.…”

Section: Targeting Intracellular Antigensmentioning

confidence: 99%

Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours

Lowe

Cole

Kenefeck

et al. 2019

Cancer Treatment Reviews

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Immunotherapeutic strategies have revolutionised cancer therapy in recent years, bringing meaningful improvements in outcomes for patients with previously intractable conditions. These successes have, however, been largely limited to certain types of liquid tumours and a small subset of solid tumours that are known to be particularly immunogenic. Broadening these advances across the majority of tumour indications, which are characterised by an immune-excluded, immune-deserted or immune-suppressed ('cold') phenotype, will require alternative approaches that are able to specifically address this unique biological environment. Several newer therapeutic modalities, including adoptive cell therapy and T cell redirecting bispecific molecules, are considered to hold particular promise and are being investigated in early phase clinical trials across various solid tumour indications. ImmTAC molecules are a novel class of T cell redirecting bispecific biologics that exploit TCR-based targeting of tumour cells; providing potent and highly specific access to the vast landscape of intracellular targets. The first of these reagents to reach the clinic, tebentafusp (IMCgp100), has generated demonstrable clinical efficacy in an immunologically cold solid tumour with a high unmet need. Here, we highlight the key elements of the ImmTAC platform that make it ideally positioned to overcome the cold tumour microenvironment in an off-the-shelf format.

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Section: Targeting Intracellular Antigensmentioning

confidence: 99%

Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours

Lowe

Cole

Kenefeck

et al. 2019

Cancer Treatment Reviews

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“…These attributes enable ImmTAC molecules to elicit antitumor responses at picomolar concentrations against cells expressing very low levels of pHLA on the cell surface. In comparison, bispecific T cell engagers (BiTEs) can utilize antibodies to target pHLA (TCR-mimic antibodies) as soluble T cell-engaging bispecific molecules (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Antibodies, unlike TCRs that are anchored in the cell membrane, can exist naturally as soluble effector molecules (and as such, are easier to engineer as soluble reagents) and typically have a strong affinity for their antigen (nanomolar range), making them attractive for development as soluble therapeutics (21).…”

Section: Resultsmentioning

confidence: 99%

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

Holland¹,

Crean²,

Pentier³

et al. 2020

Journal of Clinical Investigation

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“…An antibody recognizing a complex of PRAME-derived peptide/HLA class I was investigated. 34 The other one would be PR1, which was clinically investigated as a peptide vaccine in patients with AML. 35 Receptorredirected CAR-T or TCR-T cells targeting these antigens could be promising.…”

Section: Discussionmentioning

confidence: 99%

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

Tawara¹,

Kageyama

Miyahara

et al. 2017

Blood

144

115

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Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.

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A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

Cited by 75 publications

References 61 publications

Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours

Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours

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

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

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