Lipid nanoparticle-targeted mRNA formulation as a treatment for ornithine-transcarbamylase deficiency model mice

Yamazaki, Kazuto; Kubara, Kenji; Ishii, Satoko; Kondo, Kazunori; Suzuki, Yuta; Miyazaki, Takuro; Mitsuhashi, Kaoru; Ito, Masashi; Tsukahara, Kappei

doi:10.1016/j.omtn.2023.06.023

Cited by 16 publications

(7 citation statements)

References 59 publications

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“…In a recent publication that characterized BNT141, an RNA-LNP encoding antihuman CLDN18.2 IgG RiboMab comprising the same LNP as BNT142, we demonstrated using a Luc RNA-LNP that protein expression in mouse livers is detectable up to 7 days after intravenous delivery (8). Similar durations of RNA persistence and protein expression in mouse livers were found by tissue sampling and subsequent reverse transcription quantitative polymerase chain reaction (RT-qPCR) and IHC analyses (29). Moreover, our Western blot results confirmed the correct assembly of RiboMab02.1 in vivo (fig.…”

Section: Discussionsupporting

confidence: 82%

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6

Stadler,

Ellinghaus,

Fischer

et al. 2024

Sci. Transl. Med.

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We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell–specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).

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Section: Discussionsupporting

confidence: 82%

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6

Stadler,

Ellinghaus,

Fischer

et al. 2024

Sci. Transl. Med.

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“…This includes improving their delivery efficiency and specificity, overcoming immune-related side effects, exploring more effective targeting strategies, and reducing costs to improve production processes. Addressing these challenges requires interdisciplinary collaboration, the integration of technologies and resources, strengthening of basic research and clinical trials, and the continuous improvement of regulatory policies in order to drive continued innovation in the development of LNP carriers in the field of tumor immunotherapy [ 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 ].…”

Section: Future Prospects and Challengesmentioning

confidence: 99%

Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity

Wu,

Li,

Qian

et al. 2024

Vaccines

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In recent years, lipid nanoparticles (LNPs) have attracted extensive attention in tumor immunotherapy. Targeting immune cells in cancer therapy has become a strategy of great research interest. mRNA vaccines are a potential choice for tumor immunotherapy, due to their ability to directly encode antigen proteins and stimulate a strong immune response. However, the mode of delivery and lack of stability of mRNA are key issues limiting its application. LNPs are an excellent mRNA delivery carrier, and their structural stability and biocompatibility make them an effective means for delivering mRNA to specific targets. This study summarizes the research progress in LNP delivery carrier-assisted targeted controlled release mRNA vaccines in tumor immunity. The role of LNPs in improving mRNA stability, immunogenicity, and targeting is discussed. This review aims to systematically summarize the latest research progress in LNP delivery carrier-assisted targeted controlled release mRNA vaccines in tumor immunity to provide new ideas and strategies for tumor immunotherapy, as well as to provide more effective treatment plans for patients.

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“…35,36 The LNPs in these formulations are mainly distributed in the liver and taken up by hepatocytes after administration, blocking protein production by siRNA 37 or producing the protein encoded by mRNA. 38 In contrast to intramuscular vaccines, for which PK is not a prerequisite for approval, 39 the plasma PK profile of intravenous formulations is critical for predicting an efficacious dose and dosing regimen in humans. Below, we summarize the clinical trials of the three intravenously administrated LNPbased RNA therapeutics.…”

Section: Lipid Nanoparticles As Delivery Carriersmentioning

confidence: 99%

“…In these formulations, LNPs mainly distributed near lymph nodes elicit acquired immunity after being taken up by antigen-presenting cells . Intravenous LNP formulations have been used for gene regulation in the liver. , The LNPs in these formulations are mainly distributed in the liver and taken up by hepatocytes after administration, blocking protein production by siRNA or producing the protein encoded by mRNA . In contrast to intramuscular vaccines, for which PK is not a prerequisite for approval, the plasma PK profile of intravenous formulations is critical for predicting an efficacious dose and dosing regimen in humans.…”

Section: Lipid Nanoparticles As Delivery Carriersmentioning

confidence: 99%

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Suzuki,

Katsurada,

Hyodo

2023

Mol. Pharmaceutics

Self Cite

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Lipid nanoparticles (LNPs) are clinically validated drug-delivery carriers. However, clinical data on intravenously administered LNPs are limited compared with those on intramuscularly administered LNPs (mRNA vaccines against COVID-19). Here, we reviewed three clinically tested intravenously administered LNPs (patisiran, mRNA-1944, and NTLA-2001). We summarize the differences and similarities in their formulations, mechanisms of action, and pharmacokinetics profiles. In humans, patisiran and mRNA-1944 exhibited similar multiphasic pharmacokinetic profiles with a secondary peak in the RNA concentration. siRNA (patisiran) and mRNA (mRNA-1944) exhibited prolonged blood circulation and were detectable for more than 28 days after a single administration. We further summarize the basics of extracellular vesicles (EVs) and discuss the potential linkages between LNPs and EVs. This Review provides an understanding of the human clinical data of intravenous LNP formulations, which can be potentially explored to develop next-generation LNP-and EV-based drug delivery carriers.

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Lipid nanoparticle-targeted mRNA formulation as a treatment for ornithine-transcarbamylase deficiency model mice

Cited by 16 publications

References 59 publications

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6

Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

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