Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis

Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved ef...

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Main Authors:	Kanakaraj, Palanisamy, Puffer, Bridget A., Yao, Xiao-Tao, Kankanala, Spandana, Boyd, Ernest, Shah, Rutul R., Wang, Geping, Patel, Dimki, Krishnamurthy, Rajesh, Kaithamana, Shashi, Smith, Rodger G., LaFleur, David W., Barbas III, Carlos F., Hilbert, David M., Kiener, Peter A., Roschke, Viktor V.
Format:	Online
Language:	English
Published:	Landes Bioscience 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499301/

id	pubmed-3499301
recordtype	oai_dc
spelling	pubmed-34993012012-11-23 Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis Kanakaraj, Palanisamy Puffer, Bridget A. Yao, Xiao-Tao Kankanala, Spandana Boyd, Ernest Shah, Rutul R. Wang, Geping Patel, Dimki Krishnamurthy, Rajesh Kaithamana, Shashi Smith, Rodger G. LaFleur, David W. Barbas III, Carlos F. Hilbert, David M. Kiener, Peter A. Roschke, Viktor V. Report Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone. Landes Bioscience 2012-09-01 /pmc/articles/PMC3499301/ /pubmed/22864384 http://dx.doi.org/10.4161/mabs.21227 Text en Copyright © 2012 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kanakaraj, Palanisamy Puffer, Bridget A. Yao, Xiao-Tao Kankanala, Spandana Boyd, Ernest Shah, Rutul R. Wang, Geping Patel, Dimki Krishnamurthy, Rajesh Kaithamana, Shashi Smith, Rodger G. LaFleur, David W. Barbas III, Carlos F. Hilbert, David M. Kiener, Peter A. Roschke, Viktor V.
spellingShingle	Kanakaraj, Palanisamy Puffer, Bridget A. Yao, Xiao-Tao Kankanala, Spandana Boyd, Ernest Shah, Rutul R. Wang, Geping Patel, Dimki Krishnamurthy, Rajesh Kaithamana, Shashi Smith, Rodger G. LaFleur, David W. Barbas III, Carlos F. Hilbert, David M. Kiener, Peter A. Roschke, Viktor V. Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
author_facet	Kanakaraj, Palanisamy Puffer, Bridget A. Yao, Xiao-Tao Kankanala, Spandana Boyd, Ernest Shah, Rutul R. Wang, Geping Patel, Dimki Krishnamurthy, Rajesh Kaithamana, Shashi Smith, Rodger G. LaFleur, David W. Barbas III, Carlos F. Hilbert, David M. Kiener, Peter A. Roschke, Viktor V.
author_sort	Kanakaraj, Palanisamy
title	Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
title_short	Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
title_full	Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
title_fullStr	Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
title_full_unstemmed	Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
title_sort	simultaneous targeting of tnf and ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis
description	Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone.
publisher	Landes Bioscience
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499301/
_version_	1611924510540300288

Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis

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