Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1784896617860562944 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9964878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT dinittocesare anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT gilardoniettore anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT mockjacqueline anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT nadallisa anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT weisstobias anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT wellermichael anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT seehusenfrauke anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT libbrachiara anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT pucaemanuele anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT neridario anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT delucaroberto anengineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT dinittocesare engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT gilardoniettore engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT mockjacqueline engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT nadallisa engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT weisstobias engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT wellermichael engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT seehusenfrauke engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT libbrachiara engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT pucaemanuele engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT neridario engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties AT delucaroberto engineeredifngantibodyfusionproteinwithimprovedtumorhomingproperties |