Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-L...

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Bibliographic Details
Published inbioRxiv
Main Authors Yu, Juntao, Li, Qian, Luo, Shenggen, Wang, Xiaona, Cheng, Qiang, Hu, Rongkuan
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 12.01.2024
Cold Spring Harbor Laboratory
Edition1.1
Subjects
Adaptive immunity
Antitumor agents
Bioengineering
Cancer therapies
Intellectual property
Interleukin 15
Metastases
mRNA
Nanoparticles
Toxicity
Tumors
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Summary:Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNPLocal) and to pulmonary (LNPLung). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNPLocal and LNPLung, respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNPLung in non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers.Competing Interest StatementThe authors have declared no competing interest.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
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Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2024.01.11.575299