PMID- 35769484
OWN - NLM
STAT- MEDLINE
DCOM- 20220701
LR  - 20240102
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity.
PG  - 888274
LID - 10.3389/fimmu.2022.888274 [doi]
LID - 888274
AB  - Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable 
      interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins 
      of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of 
      regulatory T cells and therapeutic activity could be demonstrated in various 
      autoinflammatory diseases, including graft-versus-host disease (GvHD), 
      experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis 
      (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF 
      fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 
      molecule as an oligomerizing building block and generated a new TNFR2 agonist 
      with improved serum retention and superior in vivo activity. METHODS: 
      Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the 
      C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation 
      which avoids/minimizes interaction with Fcgamma-receptors (FcgammaRs). The fusion protein 
      obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based 
      agonist of TNF receptor 2), was analyzed with respect to activity, productivity, 
      serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or 
      selective TNF-based agonist of TNF receptor 2), a well-established highly active 
      nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in 
      various in vitro and in vivo systems. RESULTS: STAR2 (TNC-sc(mu)TNF80) and 
      NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The 
      novel domain architecture of NewSTAR2 significantly improved serum retention 
      compared to STAR2, which correlated with efficient binding to FcRn. A single 
      injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and 
      increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers 
      remained as high as 200% for about 10 days. Furthermore, a single in vivo 
      treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and 
      other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more 
      suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) 
      proliferation and expression of activation markers in vitro. Finally, singular 
      preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell 
      transplantation (allo-HCT) protected mice from acute GvHD. CONCLUSIONS: NewSTAR2 
      represents a next generation ligand-based TNFR2 agonist, which is efficiently 
      produced, exhibits improved pharmacokinetic properties and high serum retention 
      with superior in vivo activity exerting powerful protective effects against acute 
      GvHD.
CI  - Copyright (c) 2022 Vargas, Wagner, Shaikh, Lang, Medler, Anany, Steinfatt, Mosca, 
      Haack, Dahlhoff, Buttner-Herold, Graf, Viera, Einsele, Wajant and Beilhack.
FAU - Vargas, Juan Gamboa
AU  - Vargas JG
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
AD  - Graduate School of Life Sciences, Wurzburg University, Wurzburg, Germany.
FAU - Wagner, Jennifer
AU  - Wagner J
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
FAU - Shaikh, Haroon
AU  - Shaikh H
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
AD  - Graduate School of Life Sciences, Wurzburg University, Wurzburg, Germany.
FAU - Lang, Isabell
AU  - Lang I
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
FAU - Medler, Juliane
AU  - Medler J
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
FAU - Anany, Mohamed
AU  - Anany M
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
AD  - Department of Microbial Biotechnology, Institute of Biotechnology, Giza, Egypt.
FAU - Steinfatt, Tim
AU  - Steinfatt T
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Mosca, Josefina Pena
AU  - Mosca JP
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
AD  - Graduate School of Life Sciences, Wurzburg University, Wurzburg, Germany.
FAU - Haack, Stephanie
AU  - Haack S
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Dahlhoff, Julia
AU  - Dahlhoff J
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Buttner-Herold, Maike
AU  - Buttner-Herold M
AD  - Department of Nephropathology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Graf, Carolin
AU  - Graf C
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Viera, Estibaliz Arellano
AU  - Viera EA
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Einsele, Hermann
AU  - Einsele H
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
FAU - Wajant, Harald
AU  - Wajant H
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
FAU - Beilhack, Andreas
AU  - Beilhack A
AD  - Interdisciplinary Center for Clinical Research Laboratory, Department of Internal 
      Medicine II, University Hospital Wurzburg, Wurzburg, Germany.
AD  - Graduate School of Life Sciences, Wurzburg University, Wurzburg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220613
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
SB  - IM
EIN - Front Immunol. 2023 Dec 18;14:1352525. PMID: 38164131
MH  - Animals
MH  - *Encephalomyelitis, Autoimmune, Experimental/metabolism
MH  - *Graft vs Host Disease
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Immunoglobulin G/metabolism
MH  - Mice
MH  - Receptors, Tumor Necrosis Factor, Type II/metabolism
MH  - T-Lymphocytes, Regulatory
PMC - PMC9234581
OTO - NOTNLM
OT  - GvHD
OT  - TNF
OT  - TNFR2
OT  - agonist
OT  - regulatory T cells
OT  - serum retention
COIS- The University of Wurzburg has filed a patent concerning the construction of 
      TNFR2 agonists. The authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2022/07/01 06:00
MHDA- 2022/07/02 06:00
PMCR- 2022/01/01
CRDT- 2022/06/30 02:35
PHST- 2022/03/02 00:00 [received]
PHST- 2022/05/10 00:00 [accepted]
PHST- 2022/06/30 02:35 [entrez]
PHST- 2022/07/01 06:00 [pubmed]
PHST- 2022/07/02 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.888274 [doi]
PST - epublish
SO  - Front Immunol. 2022 Jun 13;13:888274. doi: 10.3389/fimmu.2022.888274. eCollection 
      2022.