A stable, engineered TL1A ligand co-stimulates T cells via specific binding to DR3

Adam Zwolak; Szeman Ruby Chan; Paul Harvilla; Sally Mahady; Anthony A Armstrong; Leopoldo Luistro; Ninkka Tamot; Douglas Yamada; Mehabaw Derebe; Steven Pomerantz; Mark Chiu; Rajkumar Ganesan; Partha Chowdhury

doi:10.1038/s41598-022-24984-y

A stable, engineered TL1A ligand co-stimulates T cells via specific binding to DR3

Sci Rep. 2022 Nov 29;12(1):20538. doi: 10.1038/s41598-022-24984-y.

Authors

Affiliations

¹ Biologics Discovery, Janssen Research & Development, LLC, Spring House, PA, 19477, USA. azwolak1@its.jnj.com.
² Oncology Discovery, Janssen Research & Development, LLC, Spring House, PA, 19477, USA.
³ Biologics Discovery, Janssen Research & Development, LLC, Spring House, PA, 19477, USA.
⁴ Merck Research Laboratories, Discovery Biologics, Protein Sciences, South San Francisco, CA, USA.
⁵ Tavotek Biotherapeutics, Spring House, PA, USA.
⁶ Immunotherapeutics, Amgen, South San Francisco, CA, USA.
⁷ Cell Engineering and Early Development, Janssen Research & Development, Spring House, PA, USA.

^# Contributed equally.

Abstract

TL1A (TNFSF15) is a TNF superfamily ligand which can bind the TNFRSF member death receptor 3 (DR3) on T cells and the soluble decoy receptor DcR3. Engagement of DR3 on CD4+ or CD8+ effector T cells by TL1A induces downstream signaling, leading to proliferation and an increase in secretion of inflammatory cytokines. We designed a stable recombinant TL1A molecule that (1) displays high monodispersity and stability, (2) displays the ability to activate T cells in vitro and in vivo, and (3) lacks binding to DcR3 while retaining functional activity via DR3. Together these results suggest the TL1A ligand can be amenable to therapeutic development on its own or paired with a tumor-targeting moiety.

MeSH terms

Lymphocyte Count
Signal Transduction
T-Lymphocytes*
Tumor Necrosis Factor Ligand Superfamily Member 15* / genetics

Substances

Tumor Necrosis Factor Ligand Superfamily Member 15