An Anti-hTNF-α Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira® in a Transgenic Mouse Autoimmune Polyarthritis Disease Model

Obinna C. Ubah (Corresponding Author), John Steven, Andrew J. Porter, Caroline J. Barelle

Research output: Contribution to journalArticle

1 Citation (Scopus)
5 Downloads (Pure)

Abstract

Tumour necrosis factor-alpha (TNF-α), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Here, we report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunised nurse shark. Two anti-TNF-α VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X™) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-α ‘best in class’ therapy, Adalimumab (Humira®). Both VNAR formats bind and neutralise anti-TNF-α through an epitope that appears to be different from those recognised by other anti-TNF biologics used clinically. All doses of Quad-X™, from 0.5 mg/kg to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X™, the arthritis score was improved by 76% and the histopathology score by 63%. At 3 mg/kg Quad-X™, control of disease was almost complete at 90% (arthritis) and 88% (histopathology). In marked contrast, 1 mg/kg Humira® saw profound disease breakthrough with scores of 39% and 16 % respectively, increasing to a respectable 82% and 86% inhibition at 10 mg/kg Humira®. We have previously reported the superior potency of anti-TNF-α VNARs in vitro and in these studies translate this superiority into an in vivo setting and demonstrate the potential of VNAR formats to meet the requirements of next-generation anti-TNF-α therapies.
Original languageEnglish
Article number526
Number of pages12
JournalFrontiers in Immunology
Volume10
Early online date22 Mar 2019
DOIs
Publication statusPublished - Mar 2019

Fingerprint

Antigen Receptors
Transgenic Mice
Autoimmune Diseases
Arthritis
Tumor Necrosis Factor-alpha
Adalimumab
Sharks
Therapeutics
Biological Products
Health Care Costs
Epitopes
Immune System
Chronic Disease
Nurses
Cytokines
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Keywords

  • variable new antigen receptors (VNARs)
  • chronic inflammation
  • shark IgNAR
  • anti-TNF biologics
  • rheumatoid arthritis
  • autoimmune disease
  • TNF-alpha
  • RHEUMATOID-ARTHRITIS
  • ADALIMUMAB
  • THERAPEUTIC ANTIBODIES
  • KNOCKOUT MICE
  • DOSE-ESCALATION
  • MURINE MODEL
  • IMMUNOGENICITY
  • TUMOR-NECROSIS-FACTOR
  • TRANSMEMBRANE TNF-ALPHA
  • MONOCLONAL-ANTIBODIES

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

An Anti-hTNF-α Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira® in a Transgenic Mouse Autoimmune Polyarthritis Disease Model. / Ubah, Obinna C. (Corresponding Author); Steven, John; Porter, Andrew J.; Barelle, Caroline J.

In: Frontiers in Immunology, Vol. 10, 526, 03.2019.

Research output: Contribution to journalArticle

@article{918010a854aa4fca86821a04e1402bd8,
title = "An Anti-hTNF-α Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira{\circledR} in a Transgenic Mouse Autoimmune Polyarthritis Disease Model",
abstract = "Tumour necrosis factor-alpha (TNF-α), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Here, we report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunised nurse shark. Two anti-TNF-α VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X™) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-α ‘best in class’ therapy, Adalimumab (Humira{\circledR}). Both VNAR formats bind and neutralise anti-TNF-α through an epitope that appears to be different from those recognised by other anti-TNF biologics used clinically. All doses of Quad-X™, from 0.5 mg/kg to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X™, the arthritis score was improved by 76{\%} and the histopathology score by 63{\%}. At 3 mg/kg Quad-X™, control of disease was almost complete at 90{\%} (arthritis) and 88{\%} (histopathology). In marked contrast, 1 mg/kg Humira{\circledR} saw profound disease breakthrough with scores of 39{\%} and 16 {\%} respectively, increasing to a respectable 82{\%} and 86{\%} inhibition at 10 mg/kg Humira{\circledR}. We have previously reported the superior potency of anti-TNF-α VNARs in vitro and in these studies translate this superiority into an in vivo setting and demonstrate the potential of VNAR formats to meet the requirements of next-generation anti-TNF-α therapies.",
keywords = "variable new antigen receptors (VNARs), chronic inflammation, shark IgNAR, anti-TNF biologics, rheumatoid arthritis, autoimmune disease, TNF-alpha, RHEUMATOID-ARTHRITIS, ADALIMUMAB, THERAPEUTIC ANTIBODIES, KNOCKOUT MICE, DOSE-ESCALATION, MURINE MODEL, IMMUNOGENICITY, TUMOR-NECROSIS-FACTOR, TRANSMEMBRANE TNF-ALPHA, MONOCLONAL-ANTIBODIES",
author = "Ubah, {Obinna C.} and John Steven and Porter, {Andrew J.} and Barelle, {Caroline J.}",
note = "Funding The Biotechnology and Biological Sciences Research Council (BB/K010905/1), Scottish Enterprise (VNAR_001 (2012), Innovate UK (102865). Acknowledgments The authors wish to acknowledge the funding support for this work from Scottish Enterprise (SE), the Biotechnology and Biological Sciences Research Council (BBSRC), and Innovate UK.",
year = "2019",
month = "3",
doi = "10.3389/fimmu.2019.00526",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - An Anti-hTNF-α Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira® in a Transgenic Mouse Autoimmune Polyarthritis Disease Model

AU - Ubah, Obinna C.

AU - Steven, John

AU - Porter, Andrew J.

AU - Barelle, Caroline J.

N1 - Funding The Biotechnology and Biological Sciences Research Council (BB/K010905/1), Scottish Enterprise (VNAR_001 (2012), Innovate UK (102865). Acknowledgments The authors wish to acknowledge the funding support for this work from Scottish Enterprise (SE), the Biotechnology and Biological Sciences Research Council (BBSRC), and Innovate UK.

PY - 2019/3

Y1 - 2019/3

N2 - Tumour necrosis factor-alpha (TNF-α), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Here, we report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunised nurse shark. Two anti-TNF-α VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X™) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-α ‘best in class’ therapy, Adalimumab (Humira®). Both VNAR formats bind and neutralise anti-TNF-α through an epitope that appears to be different from those recognised by other anti-TNF biologics used clinically. All doses of Quad-X™, from 0.5 mg/kg to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X™, the arthritis score was improved by 76% and the histopathology score by 63%. At 3 mg/kg Quad-X™, control of disease was almost complete at 90% (arthritis) and 88% (histopathology). In marked contrast, 1 mg/kg Humira® saw profound disease breakthrough with scores of 39% and 16 % respectively, increasing to a respectable 82% and 86% inhibition at 10 mg/kg Humira®. We have previously reported the superior potency of anti-TNF-α VNARs in vitro and in these studies translate this superiority into an in vivo setting and demonstrate the potential of VNAR formats to meet the requirements of next-generation anti-TNF-α therapies.

AB - Tumour necrosis factor-alpha (TNF-α), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Here, we report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunised nurse shark. Two anti-TNF-α VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X™) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-α ‘best in class’ therapy, Adalimumab (Humira®). Both VNAR formats bind and neutralise anti-TNF-α through an epitope that appears to be different from those recognised by other anti-TNF biologics used clinically. All doses of Quad-X™, from 0.5 mg/kg to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X™, the arthritis score was improved by 76% and the histopathology score by 63%. At 3 mg/kg Quad-X™, control of disease was almost complete at 90% (arthritis) and 88% (histopathology). In marked contrast, 1 mg/kg Humira® saw profound disease breakthrough with scores of 39% and 16 % respectively, increasing to a respectable 82% and 86% inhibition at 10 mg/kg Humira®. We have previously reported the superior potency of anti-TNF-α VNARs in vitro and in these studies translate this superiority into an in vivo setting and demonstrate the potential of VNAR formats to meet the requirements of next-generation anti-TNF-α therapies.

KW - variable new antigen receptors (VNARs)

KW - chronic inflammation

KW - shark IgNAR

KW - anti-TNF biologics

KW - rheumatoid arthritis

KW - autoimmune disease

KW - TNF-alpha

KW - RHEUMATOID-ARTHRITIS

KW - ADALIMUMAB

KW - THERAPEUTIC ANTIBODIES

KW - KNOCKOUT MICE

KW - DOSE-ESCALATION

KW - MURINE MODEL

KW - IMMUNOGENICITY

KW - TUMOR-NECROSIS-FACTOR

KW - TRANSMEMBRANE TNF-ALPHA

KW - MONOCLONAL-ANTIBODIES

UR - http://www.scopus.com/inward/record.url?scp=85064721344&partnerID=8YFLogxK

UR - https://www.frontiersin.org/article/10.3389/fimmu.2019.00526/full

UR - http://www.mendeley.com/research/antihtnf%CE%B1-variable-new-antigen-receptor-format-demonstrates-superior-vivo-preclinical-efficacy-humir

U2 - 10.3389/fimmu.2019.00526

DO - 10.3389/fimmu.2019.00526

M3 - Article

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 526

ER -