Engineering of tandem bispecific IL-7 receptor agonist antibody promoting selective T cell expansion

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ID: 320048
2026
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Abstract
Interleukin-7 (IL-7) is indispensable for T cell development and homeostasis, and clinical studies have demonstrated its ability to restore T cell numbers in lymphopenic conditions. However, the therapeutic application of IL-7 has been limited by its short half-life and potential immunogenicity of recombinant variants. To overcome these challenges, we engineered a fully human tandem bispecific antibody, TB4, that functions as a potent IL-7 receptor agonist by cis-targeting IL-7 receptor alpha (IL-7Rα) and the common γ chain (γc). The tetravalent tandem scFv-Fc architecture, coupled with optimized linker length, conferred markedly enhanced binding affinity and avidity compared to the knobs-into-holes bispecific format, with domain orientation designed to limit unintended γc binding. At the cellular level, TB4 engaged both receptor subunits and exhibited reduced internalization dynamics, features that are likely to contribute to the sustained STAT5 phosphorylation observed in primary human T cells. Functionally, TB4 supported long-term T cell survival and expansion, but selectively promoted the expansion of CD4+ memory subsets, especially effector memory cells re-expressing CD45RA populations, in contrast to the broader effects of native IL-7. Transcriptomic profiling further revealed that while both TB4 and IL-7 activated proliferative gene programs, TB4 uniquely drove an antiviral and innate immune signature. Collectively, these findings establish TB4 as a next-generation IL-7R agonist antibody with a differentiated mechanism of action and potential as a precision immunomodulator that can selectively expand and reprogram T cells.
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openalex_W7167690543 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Jun-Kook Park, Inseong Jung, Seunghyun Lee, Junsu Kim, Sanghee Shin, Jiwon Shin, Soojeong Noh, Dahye Kwon, Chaerin Nam, Hyunwook Kim, Hongsoo Choi, Kyungmoo Yea
Journal Protein Engineering Design and Selection
Year 2026
DOI
10.1093/protein/gzag017
URL
https://doi.org/10.1093/protein/gzag017
Keywords Keywords not found

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