Generalizable Design Parameters for Soluble T Cell Receptor-based T Cell Engagers

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2022 Mar 9

PMID 35260435

Authors

Karen J Froning

Arlene Sereno

Flora Huang

Stephen J Demarest

Affiliations

Soon will be listed here.

Abstract

While most biological and cellular immunotherapies recognize extracellular targets, T cell receptor (TCR) therapeutics are unique in their ability to recognize the much larger pool of intracellular antigens found on virus-infected or cancerous cells. Recombinant T cell receptor (rTCR)-based therapeutics are gaining momentum both preclinically and clinically highlighted by recent positive phase III human clinical trial results for a TCR/CD3 bifunctional protein in uveal melanoma. Unlike antibody-based T cell engagers whose molecular formats have been widely and extensively evaluated, little data exist describing the putative activities of varied bifunctional formats using rTCRs. Here we generate rTCR/anti-CD3 bifunctionals directed toward NY-ESO-1 or MAGE-A3 with a variety of molecular formats. We show that inducing strong redirected lysis activity against tumors displaying either NY-ESO-1 or MAGE-A3 is highly restricted to small, tandem binding formats with an rTCR/antiCD3 Fab demonstrating the highest potency, rTCR/anti-CD3 single chain variable domain fragment showing similar but consistently weaker potency, and IgG-like or IgG-Fc-containing molecules demonstrating poor activity. We believe this is a universal trait of rTCR bifunctionals, given the canonical TCR/human leukocyte antigen structural paradigm.

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PMID: 37420174 PMC: 10401791. DOI: 10.1186/s12943-023-01807-w.

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