Druggability of intracellular targets: a challenging, but highly rewarded goal for emerging technologies to generate TCR fusion proteins, TCRL antibodies and cell-permeating biologics

STUTTGART, Germany I January 25, 2018 I A tissue-based map of the human proteome suggests that about 75 % are intracellular or secreted targets not accessible for conventional monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy (Uhlen et al., Science, 2015). Thus, the large pool of intracellular protein targets, including overexpressed oncogenic proteins, mutated tumor suppressors and gene products of translocation, remains untapped so far. Part of the intracellular antigen proteins are degraded to protein fragments that are eventually presented on the cell surface as a composite antigen comprised of a variable linear sequence peptide (typically 9-10 amino acids in length) buried within a major histocompatibility complex (MHC) molecule, also referred to as human leukocyte antigen (HLA) class I, for recognition by T-cell receptors.

Emerging technologies addressing intracellular targets presented as p/MHC epitopes on the cell surface include TCR-engineered T-cells and recombinant TCR fusion proteins, in addition to TCR-like (TCRL) or TCR mimic antibodies. Cell-penetrating biologics are directly addressing targets located within the cell, or even in the nucleus, especially protein-protein interactions.

At present, only one recombinant TCR fusion protein and one cell-penetrating peptide have advanced to clinical testing reflecting the high technological hurdles. However, in 2015, the leader in the field of recombinant TCR fusion proteins completed Europe’s largest ever financing round by a private life sciences company, raising US$ 320 mln, indicating that high rewards are waiting for those who establish and validate technologies to untap the intracellular target pool.

Technologies to access intracellular targets include intracellular target discovery platforms and the complementary TCR discovery technologies, a suitable format for a recombinant TCR fusion protein and the appropriate presentation of p/MHC targets to raise TCR-like antibodies. For intracellularly located targets, the therapeutic modality first has to pass the cell membrane without being degraded and then being able to target complex intracellular targets such as beta-catenin, MDM2/X or KRAS.

Presentation of Target	Target Examples	Therapeutic Modality	Effector Function
On cell surface as peptide-MHC class I complex	Neoantigens Gp100; NY-ESO-1; MAGE-A, PRAME; WT1; MART-1	TCR fusion protein TCR-like antibody	Fc-enhanced Bispecific (T-cell recruiting) Drug Conjugate
Intracellular; Intranuclear Protein-protein interaction (PPI)	Beta-catenin; Myc; Ras	Cell penetrating peptide, miniprotein or antibody incl. shuttle	Inhibition

In a new report released by La Merie Publishing the competitive landscape of target and TCR disovery technologies and of the new therapeutic modalities TCR fusion proteins, TCR-like antibodies and cell-penetrating biologics is described and analyzed.

This report „Intracellular Targets made druggable by TCR-like Antibodies, TCR Fusion Proteins & Cell-Penetrating Biologics 2018: an industry analysis of technologies, stakeholders, deals & trends“ brings you up-to-date regarding key technologies

• for identification and validation of intracellular targets,
• for generation of T-cell receptors (TCR) and TCR fusion proteins,
• for discovery of TCR-like antibodies, and
• for construction of cell-penetrating peptides, proteins and antibodies.

The report furthermore describes the profiles of leading product candidates created by these technologies. The technology companies are presented and analyzed. Deals between Big Pharma and technology companies as well as collaboration and licensing deals between technology companies are highlighted. The value of technologies and product candidates are discussed regarding company acquisition prices, economic deal terms and financing rounds.

About La Merie

La Merie Publishing is a Business Intelligence enterprise fully dedicated to provide high quality R&D information to the biopharmaceutical industry. La Merie offers individual consultancy services and publishes reports and periodicals. For more information visit www.lamerie.com and www.PipelineReview.com, the Biologics News Center and Online Store of La Merie Publishing.

SOURCE: La Merie Publishing