The safe and effective delivery of macromolecular drugs into target cells is notoriously difficult due to their large molecular weight. Moreover, such carriers as virus-derived vectors and lipid nanoparticles often have safety and stability issues, while cell-penetration peptides lack targeting ability. The Nano Intelligent Biomedical Engineering Corporation (NIBEC) has the solution. The company, which was spun-out of Seoul National University in 2004, has developed a target-selective tissue-delivery technology that enables antibody, protein, and RNA drugs to be selectively and safely delivered into a target tissue, maximizing therapeutic potential while minimizing side effects.
Peptide-based drug delivery platform
NIBEC’s technology is based on a unique peptide-delivery carrier, NIPEP-TPP (NIBEC PEPtide as Target Penetrating Peptide). This target-selective cell-penetrating carrier consists of three sections: a cell-penetrating peptide; a linker that can be joined to a cargo drug; and a targeting moiety peptide. Consequently, NIPEP-TPPs enable the creation of peptide–drug conjugates (PDCs) that, depending on the targeting moiety, can be selectively delivered to almost any specific cell or tissue with high efficiency and safety.
“PDCs not only target but also penetrate cells. After the targeting moiety has bound the specific surface marker, the cell-penetrating peptide makes a channel at the cell membrane, allowing the PDC to infiltrate the cells of the targeted tissue. Once internalized, the cell membrane re-closes, trapping the PDC and its cargo inside, resulting in high therapeutic effect and low side effects,” explained Yoon Jeong Park, chief technical officer of NIBEC. “We believe we are the only company with these targeted intracellular-delivery capabilities.”
Targeted cell penetration
The team at NIBEC’s biologic facility is able to identify targeting moieties via in vitro/in vivo phage display. It can then prepare moieties and cell-penetrating peptides in a one-stop peptide synthesis, and produce NIPEP-TPPs fused with therapeutic cargos that target specific cells and tissues, including those in the liver, lung, bone, brain, muscle, and immune system (Fig. 1).
Fig. 1 | How NIPEP-TPP works. The NIBEC PEPtide as Target Penetrating Peptide (NIPEP-TPP) consists of a targeting moiety, a cell-penetrating peptide sequence, and a linker sequence for conjugation with cargo molecules such as antibodies and nucleic acids. The cell-penetrating part functions as a cassette for adapting the target-homing peptide and as a crosslinker for cargo conjugation. NIPEP-TPP is internalized only in the presence of the target surface marker.
NIBEC is applying its PDC concept to oncology and beyond. For example, the company is developing an NIPEP-TPP anti-mutant KRAS antibody that binds the G12C mutant form of the human KRAS protein expressed in some lung cancers. “Normally, the large size of an anti-KRAS antibody prevents it from penetrating cells but joining it to an NIPEP-TPP enables the antibody to penetrate the target cell, where it can bind mutant KRAS to decrease cancer growth,” explained Park. In preclinical studies, NIBEC’s NIPEP-TPP anti-KRAS antibody decreased the size of orthotopic lung cancer and increased the survival rate.
Peptide-based brain delivery
By targeting blood–brain barrier (BBB) receptors, NIPEP-TPP technology can also be used to ferry therapeutics across the BBB, offering hope to patients with notoriously difficult-to-treat Alzheimer’s disease, glioma, and other central nervous system disorders.
NIBEC has three targets of BBB delivery: the transferrin receptor, which is largely expressed in the BBB endothelial layer and is ideal for glioma therapy; the glucose transporter (GLUT) insulin receptor, which is significantly expressed in the brain and is also good for targeting glioma therapy; and the low-density lipoprotein (LDL) receptor, which recognizes apolipoprotein B100 (ApoB100) and apolipoprotein E (ApoE) and is ideal for neurodegenerative disease. “Once the targeting peptide of our NIPEP-TPP-BBB interacts with one of these receptors, the CPP enables penetration, after which the cargo drug is moved to other regions by transcytosis,” explained Park.
Studies show that NIBEC’s NIPEP-TPP-BBB shuttle increases the brain-delivery efficiency of therapeutic antibodies to about 10%, compared to only 3–4% for most other alternative approaches, according to Park. Moreover, with RNA drugs, NIPEP-TPP-BBB forms a double-layer nanocomplex preventing enzymatic attack while circulating, resulting in a 60–70% loading efficiency and effective gene knock-down in various brain regions, including the cortex, midbrain, and cerebellum.
Oral drug delivery
In addition, NIPEP-TPP technology can be used to increase the oral-delivery efficacy of peptide therapeutics, such as parathyroid hormone (PTH) or glucagon-like peptide-1 (GLP-1) receptor agonists. Such drugs are normally unsuitable for oral delivery because of enzyme degradation in the gastrointestinal tract and a short half-life. By combining them with an enzyme inhibitor and encapsulating them in a polymer that dissolves in high-pH environments, NIPEP-TPP drugs can travel safely through the stomach for release in the colon where they can penetrate the intestinal wall and enter the blood stream. Indeed, in vitro studies show that significantly more of an anti-GLP1 obesity drug reaches the blood when NIPEP-TPP is used compared to when it is not. “Uniquely, our penetrable carrier can also deliver a payload to organs such as the liver, enabling targeted oral delivery,” said Park.
NIBEC is seeking partnerships with biopharmaceutical companies interested in licensing or co-developing peptide-based therapeutic candidates or adapting its peptide-based drug delivery platforms for their own assets. “Whether its therapeutic peptide drug screening or superior drug delivery through selective tissue penetration, our unique peptide-based tissue-delivery technology is key to developing more effective drugs for the benefit of patients in dire need,” said Park.