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The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune checkpoint inhibitors


Puca, Emanuele; Probst, Philipp; Stringhini, Marco; Murer, Patrizia; Pellegrini, Giovanni; Cazzamalli, Samuele; Hutmacher, Cornelia; Gouyou, Baptiste; Wulhfard, Sarah; Matasci, Mattia; Villa, Alessandra; Neri, Dario (2020). The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune checkpoint inhibitors. International Journal of Cancer, 146(9):2518-2530.

Abstract

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+ T cells for the anticancer activity observed in both tumor models. Upon L19‐mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+ T cells in CT26 tumors were specific to the retroviral AH1 antigen

Abstract

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+ T cells for the anticancer activity observed in both tumor models. Upon L19‐mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+ T cells in CT26 tumors were specific to the retroviral AH1 antigen

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pathology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > Cancer Research
Uncontrolled Keywords:Cancer Research, Oncology
Language:English
Date:1 May 2020
Deposited On:12 Feb 2020 14:27
Last Modified:29 Jul 2020 14:12
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0020-7136
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/ijc.32603
Project Information:
  • : FunderH2020
  • : Grant ID670603
  • : Project TitleZAUBERKUGEL - Fulfilling Paul Ehrlichâ��s Dream: therapeutics with activity on demand

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