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Generation and in vivo validation of an IL-12 fusion protein based on a novel anti-human FAP monoclonal antibody


Nadal, Lisa; Peissert, Frederik; Elsayed, Abdullah; Weiss, Tobias; Look, Thomas; Weller, Michael; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Matasci, Mattia; Favalli, Nicholas; Corbellari, Riccardo; Di Nitto, Cesare; Prodi, Eleonora; Libbra, Chiara; Galeazzi, Simone; Carotenuto, Claudiopietro; Halin, Cornelia; Puca, Emanuele; Neri, Dario; De Luca, Roberto (2022). Generation and in vivo validation of an IL-12 fusion protein based on a novel anti-human FAP monoclonal antibody. Journal for ImmunoTherapy of Cancer, 10(9):e005282.

Abstract

BACKGROUND

In this study, we describe the generation of a fully human monoclonal antibody (named '7NP2') targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.

METHODS

7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in Cynomolgus monkeys.

RESULTS

Biodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.

CONCLUSIONS

The results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.

Abstract

BACKGROUND

In this study, we describe the generation of a fully human monoclonal antibody (named '7NP2') targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.

METHODS

7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in Cynomolgus monkeys.

RESULTS

Biodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.

CONCLUSIONS

The results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Life Sciences > Molecular Medicine
Health Sciences > Oncology
Life Sciences > Pharmacology
Life Sciences > Cancer Research
Language:English
Date:September 2022
Deposited On:06 Oct 2022 16:27
Last Modified:29 Jan 2024 02:44
Publisher:BioMed Central
ISSN:2051-1426
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1136/jitc-2022-005282
PubMed ID:36104101
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)