An engineered 4-1BBL fusion protein with "activity on demand".
4-1BB Ligand
/ administration & dosage
Animals
Antigens, Neoplasm
/ administration & dosage
Cell Line, Tumor
/ transplantation
Disease Models, Animal
Female
Fibronectins
/ genetics
Humans
Mice
Neoplasms
/ drug therapy
Protein Domains
/ genetics
Protein Engineering
Recombinant Fusion Proteins
/ administration & dosage
4-1BB
armed antibody
cancer immunotherapy
protein engineering
tumor targeting
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
15 12 2020
15 12 2020
Historique:
pubmed:
27
11
2020
medline:
30
1
2021
entrez:
26
11
2020
Statut:
ppublish
Résumé
Engineered cytokines are gaining importance in cancer therapy, but these products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein, termed F8-4-1BBL, that does not exhibit cytokine activity in solution but regains biological activity on antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent antitumor activity in various mouse models of cancer without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display "activity on demand" properties at the site of disease on antigen binding and reduce toxicity to normal tissues.
Identifiants
pubmed: 33239441
pii: 2013615117
doi: 10.1073/pnas.2013615117
pmc: PMC7749310
doi:
Substances chimiques
4-1BB Ligand
0
Antigens, Neoplasm
0
Fibronectins
0
Recombinant Fusion Proteins
0
Tnfsf9 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
31780-31788Déclaration de conflit d'intérêts
Competing interest statement: D.N. is a cofounder and shareholder of Philogen S.p.A., the company that owns the F8 and L19 antibodies.
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