Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood–brain barrier permeability for drug delivery to the brain in a non-human primate

Tachibana, Keisuke; Hashimoto, Yuichi; Shirakura, Keisuke; Okada, Yoshiaki; Hirayama, Renzo; Iwashita, Yumi; Nishino, Itsuki; Ago, Yukio; Takeda, Hiroyuki; Kuniyasu, Hiroki; Kondoh, Masuo

doi:10.1016/j.jconrel.2021.06.009

Cited by 17 publications

(11 citation statements)

References 25 publications

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“…To investigate the effect of acute functional defects of CLDN5 on vascular leakage in vivo, an antibody-mediated loss-of-function study was conducted. We previously reported a well-characterized antibody against CLDN5 that specifically binds to the extracellular domain of primate CLDN5 and inhibits its function in the monkey brain ( 16 , 17 ). To apply this efficient antibody to mice, we generated human CLDN5 knock-in mice (fig.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

et al. 2022

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In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells and then transfers to other organs the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin–mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2–induced respiratory endothelial barrier disruption. We concluded that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2–induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

et al. 2022

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“…IV administration of this MAb in primates at an injection dose (ID) of 3 mg/kg caused increased uptake of fluorescein in the CSF. However, the MAb has a narrow therapeutic index, as a dose of 6 mg/kg of the CLDN5 MAb induced convulsions in monkeys [243].…”

Section: Bbbd With Tight Junction Modulatorsmentioning

confidence: 99%

A Historical Review of Brain Drug Delivery

Pardridge

2022

Pharmaceutics

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The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.

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“…A more recent study has examined the efficacy and safety of R9 in cynomolgus monkeys 41 . Three of four monkeys treated with R9 at 3 mg/kg showed increased concentrations of a fluorescein tracer (376 Da) in the cerebrospinal fluid at 24 h after antibody administration; in contrast, none of the three monkeys administered rat IgG showed such an increase (Figure 3A), confirming that R9 enhances the permeation of solutes across the BBB into the CNS.…”

Section: Binders Of Cldn‐5 Eclsmentioning

confidence: 79%

“…Indeed, rat IgG2b, which is in the same subclass as R9, has been shown to induce these two cytotoxicities. This suggests that R9‐bound vascular endothelial cells can become targets for antibody‐dependent cellular cytotoxicity or complement‐dependent cytotoxicity immune responses 41 . Thus, if the toxicity of R9 is due to these antibody‐related reactions, other modalities, such as chemicals or peptides, may be potentially safer leads for the development of CLDN‐5 modulators.…”

Section: Binders Of Cldn‐5 Eclsmentioning

confidence: 99%

Modifying the blood–brain barrier by targeting claudin‐5: Safety and risks

Wakayama

Kuzu

Tachibana

et al. 2022

Annals of the New York Academy of Sciences

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The blood-brain barrier is a major obstacle to the delivery of drugs to the central nervous system. In the blood-brain barrier, the spaces between adjacent brain microvascular endothelial cells are sealed by multiprotein complexes known as tight junctions. Among the many components of the tight junction, claudin-5 has received the most attention as a target for loosening the tight-junction seal and allowing drugs to be delivered to the brain. In mice, transient knockdown of claudin-5 and the use of claudin-5 binders have been shown to enhance the permeation of small molecules from the blood into the brain without apparent adverse effects. However, sustained knockdown of claudin-5 in mice is lethal within 40 days, and administration of an anti-claudin-5 antibody induced convulsions in a nonhuman primate. Here, we review the safety concerns of claudin-5-targeted technologies with respect to their clinical application.

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Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood–brain barrier permeability for drug delivery to the brain in a non-human primate

Cited by 17 publications

References 25 publications

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

A Historical Review of Brain Drug Delivery

Modifying the blood–brain barrier by targeting claudin‐5: Safety and risks

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