Technology

What is an ImmTAC® molecule?

ImmTAC® (Immune mobilising monoclonal TCRs against cancer) molecules are a new class of bi-specific biologics designed to overcome the limitations of other immuno-oncology agents by combining a T cell receptor (TCR)-targeting system with an anti-CD3 effector function to activate a highly potent and specific T cell response to cancer cells.

Engineering an ImmTAC® molecule

The process of making an ImmTAC® molecule begins with a natural human TCR specific for a validated target and involves three proprietary engineering steps.

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1. TCR affinity enhancement

The TCR is affinity-enhanced up to several millionfold (µM to pM) using phage display technology. Affinity enhancement allows ImmTAC® molecules to overcome limitations of the natural immune system and recognise cancer cells presenting low numbers of peptide HLA.

eng_immtac_molecule_diagram_02.png

2. Creating soluble and stable TCRs

A major barrier to the use of TCRs as therapeutics is their instability as soluble proteins. ImmTAC® molecules are stabilised in a soluble form through the incorporation of a novel interchain disulphide bond buried within the core of the TCR.

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3. T cell-redirecting effector function

ImmTAC® molecules engage the natural T cell activation pathway via an anti-CD3 antibody fragment (scFv), fused to the TCR via a flexible linker. The anti-CD3 effector function mediates potent redirection of T cells to target cells expressing as low as 5-10 pHLA complexes (Liddy et al., 2012).

How do ImmTAC® molecules work?


ImmTAC® molecules initiate potent T cell redirection and cancer cell killing

Step 1: Soluble ImmTAC® molecules are infused.

Step 2: The TCR end of the bi-specific ImmTAC® molecule recognises the target peptide HLA complex on the cancer cell. The anti-CD3 effector function engages the CD3 receptor on T cells.

Step 3: The T cells are activated and release lytic granules, killing the cancer cell.


Visualising ImmTAC®-redirected T cell killing of antigen-positive cells in vitro

These videos shows real cancer cells being killed by ImmTAC®-redirected T cells.

Blue

Antigen-positive target cell (e.g. cancer cell)

Grey

Antigen-negative cell (e.g. normal cell)

Yellow

Effector T cell

Green

Cell death marker

ImmTAC® molecules have the potential to access >90% of target antigens

One of the greatest challenges in immunotherapy is the identification of new and safe target antigens. Antibody-based therapies, including bi-specifics and CAR-T cells, recognise cell surface antigens, which account for as low as ~10% of potential disease targets.

TCRs are naturally optimised to recognise intracellular antigens presented on the cell surface as peptide-HLA complexes, permitting access to potentially nine-fold more targets than antibody-based therapies.

TCRs diagram

  • ImmTAC® molecules; Immune mobilising monoclonal TCRs Against Cancer
  • TILs; Tumour Infiltrating Lymphocytes
  • CAR-T cell; Chimeric Antigen Receptor T cell
  • T and Ab; Tetravalent bi-specific Ab
  • DART; Dual Affinity Re-Targeting Ab
  • BiTE; bi-specific T cell engager
  • HLA; Human Leukocyte Antigen

Soluble ImmTAC® molecules also offer advantages in manufacturing and administration over cellular TCR-based platforms. 

Publications / Abstracts

Categories:

Authors

Title

Links/Downloads

Harper J, et al.

An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules (2018). PLOS One.

Patel M et al.

iS-CellR: a user-friendly tool for analyzing and visualizing single-cell RNA sequencing data (2018). Bioinformatics.

Sato T, et al.

Redirected T cell lysis in patients with metastatic uveal melanoma with gp100-direct TCR IMCgp100: Overall survival findings (2018) ASCO.

Sato T, et al.

Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T cell based toxicity and preliminary efficacy in advanced uveal melanoma (2017) ASCO.

Boudousquie C. et al.

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells (2017) Immunology. 152(3):425-438.

Carvajal, R, et al.

Safety, efficacy and biology of the gp100 TCR-based bispecific T cell redirector, IMCgp100 in advanced uveal melanoma in two Phase 1 trials (2017) SITC.

Hickman, E. S. et al.

Antigen Selection for Enhanced Affinity T-Cell Receptor-Based Cancer Therapies. (2016) J Biomol Screen. 21(8):769-85.

Middleton, R M.

Safety, pharmacokinetics and efficacy of IMCgp100, a first-in-class soluble TCR-antiCD3 bispecific T cell redirector with solid tumour activity: Results from the FIH study in melanoma (2016) ASCO.

Raman, M. C. et al.

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. (2016) Sci Rep 6. 18851.

Yang H. et al.

Elimination of latently HIV-infected cells from antiretroviral therapy-suppressed subjects by engineered immune mobilising T cell receptors. (2016) Molecular Therapy. 24(11):1913-1925.

Oates J. et al.

ImmTACs for targeted cancer therapy: Why, what, how, and which (2015) Mol Immunol. 67(2 Pt A):67-74.

Bossi G. et al.

ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells. (2014) Cancer Immunol Immunother. 63(5):437-48.

Oates J. and Jakobsen B.K.

ImmTACs: Novel bi-specific agents for targeted cancer therapy. (2013) Oncoimmunology 2(2):1-2.

McCormack E. et al.

Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors. (2013) Cancer Immunol Immunother 62(4):773-85.

Bossi G. et al.

Examining the presentation of tumor-associated antigens on peptide-pulsed T2 cells. (2013) Oncoimmunology. Nov 1;2(11):e26840.

Lissin N. et al.

High-Affinity Monoclonal T-cell receptor (mTCR) Fusions. Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges. (2013).

Cameron B.J. et al.

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. (2013) Sci Trans Med Aug 7;5(197):197ra103.

Hassan N.J. and Oates J.

The T Cell Promise. (2013) European Biopharmaceutical Review (Summer 2013).

Liddy N. et al.

Monoclonal TCR-redirected tumor cell killing. (2012) Nat Med 18(6):980-7.

Aleksic M. et al.

Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. (2012) Eur J Immunol 42(12):3174-9.

Liddy N. et al.

Production of a soluble disulfide bond-linked TCR in the cytoplasm of Escherichia coli trxB gor mutants. (2010) Mol Biotechnol 45(2):140-9.

Sami M. et al.

Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry. (2007) Protein Eng Des Sel 20(8):397-403.

Dunn S.M. et al.

Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity. (2006) Protein Sci 15(4):710-21.

Purbhoo M.A. et al.

Quantifying and imaging NY-ESO-1/LAGE-1-derived epitopes on tumor cells using high affinity T cell receptors. (2006) J Immunol 176(12):7308-16.

Ashfield R. and Jakobsen B.K.

Making high-affinity T-cell receptors: a new class of targeted therapeutics. (2006) IDrugs 9(8):554-9.

Li Y. et al.

Directed evolution of human T-cell receptors with picomolar affinities by phage display. (2005) Nat Biotechnol 23(3):349-54.

Boulter J.M. and Jakobsen B.K.

Stable, soluble, high-affinity, engineered T cell receptors: novel antibody-like proteins for specific targeting of peptide antigens. (2005) Clin Exp Immunol 142(3):454-60.

Boulter J.M. et al.

Stable, soluble T-cell receptor molecules for crystallization and therapeutics. (2003) Protein Eng 16(9):707-11.

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