Abstract
This perspective highlights the history and challenges of developing CD3-based bispecific T-cell engagers (TCEs) as cancer therapeutics as well as considerations and potential strategies for designing the next generation TCE molecules. The goal of this article is to raise awareness of natural T-cell biology and how to best harness the tumor cell killing capacity of cytotoxic T-cells with TCEs. In light of 30 years of concerted efforts to advance TCEs in early clinical development, many of the first-generation bispecific antibodies have exhibited lackluster safety, efficacy, and manufacturability profiles. As of January 2020, blinatumomab remains the only approved TCE. Many of the current set-backs in early clinical trials implicate the high-affinity CD3 binding domains employed and the respective bispecific platforms as potential culprits. The underlying conviction of the authors is that by taking corrective measures, TCEs can transform cancer therapy. Through openness, transparency, and much needed feedback from ongoing clinical studies, the field can continuously improve the design and effectiveness of next generation T-cell redirecting therapeutics.
Highlights
HEEDING NATURE’S DESIGNWhen considering the design of T-cell engagers (TCEs), it is important to appreciate the characteristics of immune-recognition and the biology of T-cells which we aim to redirect
Complementing peptide-human leukocyte antigen complexes (pHLA):T-cell receptors (TCR) complex signaling, both costimulatory and coinhibitory T-cell receptor pathways modulate the balance of controlled T-cell activation
It was through the understanding of these pathways that a Designing T-cell Engagers number of therapeutics were developed to modulate T-cell activation against cancers expressing neoantigens and overcome the immune-suppressive microenvironment of tumors [7, 8]
Summary
When considering the design of TCEs, it is important to appreciate the characteristics of immune-recognition and the biology of T-cells which we aim to redirect. Biotech companies like CytomX (South San Francisco, CA), Maverick Therapeutics (Brisbane, CA), and Amunix (South San Francisco, CA) have introduced proteolytic sites in their therapeutic molecules whereby local tumor cell proteases can cleave and conditionally activate the respective highly potent TCEs at the site of the tumor, potentially minimizing systemic toxicities These various formats are currently in preclinical stages of development and undergoing IND-enabling studies. Unlike the first generation anti-CD3 TCEs, F2 family-based TCEs do not upregulate Tcell inhibitory receptors such as PD1 and CTLA4, which are hallmarks of T-cell exhaustion and/or anergy (unpublished data) This unique attribute of the F2 family binders is likely due to signaling intensity driven by CD3 affinity and the distinct binding epitope on CD3δε.
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