Opportunities and challenges for TCR mimic antibodies in cancer therapy

ABSTRACT

Introduction: Monoclonal antibodies (mAbs) are potent cancer therapeutic agents, but exclusively recognize cell-surface targets whereas most cancer-associated proteins are found intracellularly. Hence, potential cancer therapy targets such as over expressed self-proteins, activated oncogenes, mutated tumor suppressors, and translocated gene products are not accessible to traditional mAb therapy. An emerging approach to target these epitopes is the use of TCR mimic mAbs (TCRm) that recognize epitopes similar to those of T cell receptors (TCR).

Areas covered: TCRm antigens are composed of a linear peptide sequence derived from degraded proteins and presented in the context of cell-surface MHC molecules. We discuss how the nature of the TCRm epitopes provides both advantages (absolute tumor specificity and access to a new universe of important targets) and disadvantages (low density, MHC restriction, MHC down-regulation, and cross-reactive linear epitopes) to conventional mAb therapy. We will also discuss potential solutions to these obstacles.

Expert opinion: TCRm combine the specificity of TCR recognition with the potency, pharmacologic properties, and versatility of mAbs. The structure and presentation of a TCRm epitope has important consequences related to the choice of targets, mAb design, available peptides and MHC subtype restrictions, possible cross-reactivity, and therapeutic activity.

KEYWORDS:

• Monoclonal antibody
• TCR mimic
• TCR
• oncofetal antigen
• cancer-testis antigen
• neoantigen
• oncogene
• phage display

Article highlights

• Traditional monoclonal antibodies (mAbs) exclusively recognize cell-surface targets.

• Most cancer-specific targets are not accessible to traditional mAb therapy.

• TCR mimic mAbs (TCRm) recognize epitopes similar to those of T cell receptors (TCR) derived from proteins inside the cell.

• TCRm combine the specificity of TCR recognition with the potency, pharmacologic properties, and versatility of mAbs.

• TCRm epitopes provide advantages in tumor specificity and access to a new universe of important targets.

• However, TCRm epitopes are characterized by low density, MHC restriction, potential MHC down-regulation, and cross-reactive linear epitopes.

• The structure and presentation of a TCRm epitope has important consequences related to target choice, mAb design, peptide and MHC restrictions, and possible cross-reactivity.

This box summarizes key points contained in the article.

Declaration of interests

Funding has been received from the NIH/NCI and the Leukemia Lymphoma Society. D Scheinberg and T Dao’s institution, MSKCC, has licensed IP for the ESK antibody to Novartis on their behalf. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.