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An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to a...

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Autores principales: Di Nitto, Cesare, Gilardoni, Ettore, Mock, Jacqueline, Nadal, Lisa, Weiss, Tobias, Weller, Michael, Seehusen, Frauke, Libbra, Chiara, Puca, Emanuele, Neri, Dario, De Luca, Roberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964878/
https://www.ncbi.nlm.nih.gov/pubmed/36839699
http://dx.doi.org/10.3390/pharmaceutics15020377
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author Di Nitto, Cesare
Gilardoni, Ettore
Mock, Jacqueline
Nadal, Lisa
Weiss, Tobias
Weller, Michael
Seehusen, Frauke
Libbra, Chiara
Puca, Emanuele
Neri, Dario
De Luca, Roberto
author_facet Di Nitto, Cesare
Gilardoni, Ettore
Mock, Jacqueline
Nadal, Lisa
Weiss, Tobias
Weller, Michael
Seehusen, Frauke
Libbra, Chiara
Puca, Emanuele
Neri, Dario
De Luca, Roberto
author_sort Di Nitto, Cesare
collection PubMed
description Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.
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spelling pubmed-99648782023-02-26 An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties Di Nitto, Cesare Gilardoni, Ettore Mock, Jacqueline Nadal, Lisa Weiss, Tobias Weller, Michael Seehusen, Frauke Libbra, Chiara Puca, Emanuele Neri, Dario De Luca, Roberto Pharmaceutics Article Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1. MDPI 2023-01-22 /pmc/articles/PMC9964878/ /pubmed/36839699 http://dx.doi.org/10.3390/pharmaceutics15020377 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Nitto, Cesare
Gilardoni, Ettore
Mock, Jacqueline
Nadal, Lisa
Weiss, Tobias
Weller, Michael
Seehusen, Frauke
Libbra, Chiara
Puca, Emanuele
Neri, Dario
De Luca, Roberto
An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title_full An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title_fullStr An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title_full_unstemmed An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title_short An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties
title_sort engineered ifnγ-antibody fusion protein with improved tumor-homing properties
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964878/
https://www.ncbi.nlm.nih.gov/pubmed/36839699
http://dx.doi.org/10.3390/pharmaceutics15020377
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