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Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa

Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be delivered subcutaneously (s.c.), with clinical outcomes similar of those obtained with i.v.-del...

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Autores principales: Ozawa, Yohei, Hicks, Kristin C., Minnar, Christine M., Knudson, Karin M., Schlom, Jeffrey, Gameiro, Sofia R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096334/
https://www.ncbi.nlm.nih.gov/pubmed/33996267
http://dx.doi.org/10.1080/2162402X.2021.1915561
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author Ozawa, Yohei
Hicks, Kristin C.
Minnar, Christine M.
Knudson, Karin M.
Schlom, Jeffrey
Gameiro, Sofia R.
author_facet Ozawa, Yohei
Hicks, Kristin C.
Minnar, Christine M.
Knudson, Karin M.
Schlom, Jeffrey
Gameiro, Sofia R.
author_sort Ozawa, Yohei
collection PubMed
description Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be delivered subcutaneously (s.c.), with clinical outcomes similar of those obtained with i.v.-delivered agents. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) fused to the heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti-PDL1), was designed to target two key immunosuppressive pathways in the tumor microenvironment (TME). Bintrafusp alfa is currently being administered i.v. in clinical studies. The studies reported here demonstrate that systemic or s.c. delivery of bintrafusp alfa, each administered at five different doses, induces similar anti-tumor effects in breast and colorectal carcinoma models. An interrogation of the TME for CD8(+) and CD4(+) T cells, regulatory T cells (Tregs), monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic (G) MDSCs showed similar levels and phenotype of each cell subset when bintrafusp alfa was given systemically or s.c. Subcutaneous administration of bintrafusp alfa also sequestered TGFβ in the periphery at similar levels seen with systemic delivery. To our knowledge, this is the most comprehensive preclinical evaluation of any checkpoint inhibitor MAb given s.c. vs systemically, and the first to demonstrate this phenomenon using a bifunctional agent. These studies provide preclinical rationale to explore s.c. approaches for bintrafusp alfa in the clinic.
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spelling pubmed-80963342021-05-13 Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa Ozawa, Yohei Hicks, Kristin C. Minnar, Christine M. Knudson, Karin M. Schlom, Jeffrey Gameiro, Sofia R. Oncoimmunology Original Research Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be delivered subcutaneously (s.c.), with clinical outcomes similar of those obtained with i.v.-delivered agents. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) fused to the heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti-PDL1), was designed to target two key immunosuppressive pathways in the tumor microenvironment (TME). Bintrafusp alfa is currently being administered i.v. in clinical studies. The studies reported here demonstrate that systemic or s.c. delivery of bintrafusp alfa, each administered at five different doses, induces similar anti-tumor effects in breast and colorectal carcinoma models. An interrogation of the TME for CD8(+) and CD4(+) T cells, regulatory T cells (Tregs), monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic (G) MDSCs showed similar levels and phenotype of each cell subset when bintrafusp alfa was given systemically or s.c. Subcutaneous administration of bintrafusp alfa also sequestered TGFβ in the periphery at similar levels seen with systemic delivery. To our knowledge, this is the most comprehensive preclinical evaluation of any checkpoint inhibitor MAb given s.c. vs systemically, and the first to demonstrate this phenomenon using a bifunctional agent. These studies provide preclinical rationale to explore s.c. approaches for bintrafusp alfa in the clinic. Taylor & Francis 2021-05-03 /pmc/articles/PMC8096334/ /pubmed/33996267 http://dx.doi.org/10.1080/2162402X.2021.1915561 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Ozawa, Yohei
Hicks, Kristin C.
Minnar, Christine M.
Knudson, Karin M.
Schlom, Jeffrey
Gameiro, Sofia R.
Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title_full Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title_fullStr Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title_full_unstemmed Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title_short Analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
title_sort analysis of the tumor microenvironment and anti-tumor efficacy of subcutaneous vs systemic delivery of the bifunctional agent bintrafusp alfa
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096334/
https://www.ncbi.nlm.nih.gov/pubmed/33996267
http://dx.doi.org/10.1080/2162402X.2021.1915561
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