Generalizable design parameters for soluble T cell receptor-based T cell engagers
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 therapeu...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004281.full |
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| Summary: | 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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| ISSN: | 2051-1426 |