The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8
Animals
Antibodies, Monoclonal
/ administration & dosage
Antineoplastic Agents, Immunological
/ pharmacology
Apoptosis
CD8-Positive T-Lymphocytes
/ drug effects
Carcinoma, Lewis Lung
/ drug therapy
Cell Proliferation
Colonic Neoplasms
/ drug therapy
Drug Synergism
Female
Fibronectins
/ immunology
Humans
Interleukin-12
/ administration & dosage
Killer Cells, Natural
/ drug effects
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating
/ drug effects
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Sarcoma
/ drug therapy
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
EDB domain of fibronectin
antibody-cytokine fusions
immune checkpoint blockade
immunotherapy
interleukin-12
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 05 2020
01 05 2020
Historique:
received:
18
12
2018
revised:
03
07
2019
accepted:
17
07
2019
pubmed:
3
8
2019
medline:
1
7
2020
entrez:
3
8
2019
Statut:
ppublish
Résumé
We describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 antibody in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively spliced EDB domain of fibronectin), retained the activity of the parental cytokine and was able to selectively localize to murine tumors in vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent antitumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with checkpoint blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case, cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents, Immunological
0
Fibronectins
0
Interleukin-12
187348-17-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2518-2530Informations de copyright
© 2019 UICC.
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