dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis

Lim, Su-Ho; Kim, Won-Ju; Kim, Yeon Ho; Lee, Sohee; Koo, Ja Hyun; Lee, Jung Ah; Yoon, Hyung Joon; Kim, Do Hyun; Park, Hong Jai; Kim, Hye Mi; Lee, Hong-Gyun; Kim, Ji Yun; Lee, Jae-Ung; Shin, Jae Hun; Kim, Lark Kyun; Doh, Junsang; Kim, Hongtae; Lee, Sang Kyou; Bothwell, Alfred L.M.; Suh, Minah; Choi, Je-Min

doi:10.1038/ncomms9244

Cited by 96 publications

(78 citation statements)

References 71 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…dNP2 is an amphiphilic human-derived CNS-permeable peptide shuttle. To evaluate the abilities of cargo translocation across the BBB, Lim et al conjugated the peptide with the cytoplasmic domain of CTLA4 (ctCTLA-4) [120]. CTLA-4 is an immune regulatory receptor expressed on the surface of T cells and often associated with susceptibility to multiple sclerosis.…”

Section: The Role Of Bbb Peptide-shuttlesmentioning

confidence: 99%

“…The exact mechanism of BBB translocation and cell internalization were not determined. However, due to dNP2 properties, BBB crossing was considered to be AMT, and cellular uptake of the fusion protein through lipid-raft mediated endocytosis [120].…”

Section: The Role Of Bbb Peptide-shuttlesmentioning

confidence: 99%

“…In the peptide shuttles-based approaches mentioned, researchers used mainly antibody fragments of a full IgG as therapeutic agents [120,122]. However, antibodies are proteins also used as pharmacokinetic enhancers owing to their Fc region.…”

Section: The Role Of Bbb Peptide-shuttlesmentioning

confidence: 99%

See 2 more Smart Citations

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

View full text Add to dashboard Cite

The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

show abstract

Section: The Role Of Bbb Peptide-shuttlesmentioning

confidence: 99%

Section: The Role Of Bbb Peptide-shuttlesmentioning

confidence: 99%

See 1 more Smart Citation

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Angiopep-2 is a rationally designed peptide from aprotinin, a low-density lipoprotein receptor-related protein, that has been shown to cross the BBB 74,78 and used in clinical trials to shuttle different drugs such as small molecule paclitaxel 79 , neurotensin peptide 80 , and Her2 antibody 81 way ANOVA). However, while R9 has been used as a cell-penetrating peptide 21,77 , there are no reports of the ability of R9 to transcytose and exit the BBB. These results suggest that our CX7C…”

Section: P E P T I D E P R E S E N T I N G M 1 3 K E P H a G E S T R mentioning

confidence: 99%

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

Peng¹,

Liu²,

Liu³

et al. 2019

Preprint

View full text Add to dashboard Cite

Here, we describe a combinatorial approach to identify peptide shuttles that successfully traverse the multiple barriers to systemic drug delivery to the brain--1. the blood-brain barrier (BBB) and the 2. extracellular space (ECS) of the brain. Leveraging the excellent molecular diversity of M13 phage libraries, we identified peptides that actively transport across the BBB and diffuse through the extracellular matrix of the ECS in cell culture and in mice. These peptides demonstrate higher accumulation in the brain than gold standard peptides used in clinical trials. Importantly, these findings suggest that different sized therapeutics that were previous poorly permeable into the brain can accumulate at higher concentrations, thereby improving the therapeutic index and ultimate efficacy of drugs into the brain.

show abstract

“…In that study, a novel CPP, dNP2, was identified by homology search against the human proteome database based on earlier reported CPP sequences. 109 Using multi-photon confocal imaging, the fluorescent signal of a dNP2-conjugated fluorophore diffused out of the vasculature of the mouse brain following IP administration; a trend not observed following administration of the fluorophore alone. In whole brain cryo-sections, the fluorescent signal of the dNP2-conjugaed fluorophore, but not the fluorophore alone, was moreover co-localized with neuronal cell markers.…”

Section: Adsorptive-mediated Transcytosis: Cell-penetrating Peptidesmentioning

confidence: 99%

Routes for Drug Translocation Across the Blood-Brain Barrier: Exploiting Peptides as Delivery Vectors

Kristensen

Brodin

2017

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

A number of potent drugs for the treatment of brain diseases are available. However, in order for them to reach their target site of action, they must pass the blood-brain barrier (BBB). The capillary endothelium comprises the major barrier of the BBB and allows only passive permeation of some small lipophilic molecules. Brain delivery of the larger biopharmaceuticals, which today includes an increasing number of novel drug entities, is therefore restricted, both due to their molecular size and their hydrophilic nature. Thus, the development of novel drug entities intended for the treatment of brain diseases such as neurodegenerative diseases or brain cancers require a delivery strategy for overcoming the BBB before reaching its final target within the brain. Peptide-based delivery vector is an emerging tool as shuttles for drug delivery across the BBB and one may explore receptor-mediated transcytosis, adsorptive-mediated transcytosis, and the paracellular route. The latter, however, being controversial due to the risk of co-delivery of blood-borne potential harmful substances. On the other hand, a number of studies report on drug delivery across the BBB exploiting receptor-mediated transcytosis and adsorptive-mediated transcytosis, indicating that peptides and peptide vectors may be of use in a central nervous system delivery context.

show abstract

dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis

Cited by 96 publications

References 71 publications

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

Routes for Drug Translocation Across the Blood-Brain Barrier: Exploiting Peptides as Delivery Vectors

Contact Info

Product

Resources

About