2:41 PM
Jul 20, 2017
 |  BC Innovations  |  Product R&D

Eureka moment for TCR mimics

How Eureka is developing high affinity TCR-like antibodies

Editor's Note: This article was updated on Jul 20, 2017 at 3:23 PM PDT

In the race to access the wealth of intracellular molecular targets once considered undruggable, Eureka Therapeutics Inc. is pioneering TCR-like antibodies that capitalize on the ability of TCRs to recognize tumor antigens. But the company will need to satisfy concerns about off-target binding that sank earlier TCR-based therapies against the same class of antigens.

Last month, Eureka and its partners at Memorial Sloan Kettering Cancer Center published a study in the Journal of Clinical Investigation demonstrating that its TCR-mimicking (TCRm) antibodies can recognize and kill cancer cells expressing the intracellular PRAME tumor antigen in mice.

While most approaches to hitting intracellular targets involve cell-penetrating compounds, TCRms work from outside the cell, recognizing and binding intracellular tumor antigens after they are broken down and presented on the cell surface by MHC molecules (see "Toxic Presentation").

Figure: Toxic presentation

Eureka Therapeutics Inc. is one of the first companies to use TCR mimic (TCRm) antibodies to target intracellular tumor antigens without needing to enter the cell. Like chimeric antigen receptor (CAR) and engineered TCR therapies, the TCRm technique hijacks antigen presentation -- the body’s natural mechanism for flagging pathogen-infected cells -- to specifically kill tumors.

Within the cytosol of the cancer cell, intracellular proteins including tumor antigens are systematically broken down by the proteasome into short peptide fragments about nine amino acids in length. The short peptides are then transported to the endoplasmic reticulum and bound to MHCI molecules, which are transported as an MHCI-peptide complex to the cell membrane, where MHCI presents the peptides to T cells for immune surveillance. When an abnormal or pathogenic peptide sequence is detected, the T cells eliminate the abnormal or infected cell.

To increase T cell-mediated antitumor immunity, at least eight companies have engineered TCRs that recognize specific intracellular tumor antigen-MHCI complexes, including PRAME, WT1, MAGEA10 or NY-ESO-1 peptides.

A. Eureka and at least three other companies are designing antibodies, instead of cell therapies, that target the same intracellular tumor antigen-MHCI complexes to specifically mark cancer cells for death. When a TCRm recognizes and binds the peptide-MHCI complex, it stimulates antibody-dependent cell cytotoxicity (ADCC) that causes various effector cells recruited to the antibody-coated cancer cell to secrete cytotoxic granules (green circles) that kill it.

B. Eureka has also incorporated the single chain variable fragment (scFv) of its TCRms into a CAR design to direct CAR T cells to the tumor cell. In contrast to the engineered TCR T cells in development against the intracellular tumor antigens, Eureka believes its CAR T cells benefit from easier CMC and better clinical validation.

MAGEA10 - Melanoma-associated antigen A10; MHCI - Major histocompatibility complex class I; NY-ESO-1 (CTAG1B) - Cancer/testis antigen 1B; PRAME - Preferentially expressed antigen in melanoma; TCR - T cell receptor; WT1 - Wilms tumor 1

Eureka CEO Cheng Liu told BioCentury the antibodies are referred to as TCR mimics because they recognize the same epitope as T cells -- 9- or 10-amino acid peptides presented on the cell surface in complex with MHCI. “We're taking advantage of a mechanism that the immune system has evolved to identify antigens from pathogens that have invaded our cells," said Liu.

Indeed, most work in the field has focused on infectious disease, where viral antigens presented on the surface can be attacked by the TCR-mimicking antibodies.

But for cancer, there has been less activity. MorphoSys AG and Pure MHC LLC have TCRm programs against undisclosed targets, and academic groups at the University of Texas MD Anderson Cancer Center and Texas Tech University Health Sciences Center have reported TCRms against HER2 or TMEM37 -- two extracellular targets.

Liu said that despite the apparent simplicity of the idea, success in the field has been hampered by the tiny size of the epitopes, which are dwarfed by the large...

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