0:14 Today, we'll talk about the cutting-edge releasable PEG SUNBRIGHT BD series for peptide therapy.
0:25 We'll cover three topics: introducing our company, discussing challenges for peptide therapy, and presenting the cutting-edge releasable PEG SUNBRIGHT BD series for peptide conjugates and its effectiveness based on in vitro and in vivo studies.
0:56 NOF Corporation is a chemical company handling various chemical products, including functional chemicals, pharmaceuticals, and medical and health products. Our life science division offers biocompatible products, biochemical reagents, and ingredients for eye drops, as well as drug delivery products like activated PEGs, phospholipids, polysorbate 80, and novel excipients.
1:52 We provide polydisperse and monodisperse PEGs with functional groups for protein and peptide conjugates. Our polydisperse activated PEGs are produced with high purity due to our advanced techniques and high-quality starting material. We have over 13 years of experience manufacturing high-quality activated PEGs under cGMP systems with innovative analytical technologies. We carry out risk assessments and analytical validation studies for cGMP.
3:04 For ADC and linker applications, we offer monodisperse PEGs with hetero-functional groups in linear, branched, or pendant structures. The pendant structure is more phosphorylated than the linear and branched types. We can provide GMP-grade PEGs for hydrogel applications, including 4-arm and 8-arm PEGs. So we provide a variety of PEGs with GMP grade.
4:06 Next, let's discuss the challenges for peptide therapy. Peptide therapy has advantages and drawbacks compared to small molecules and biologics. Compared to small molecules, peptides have high specificity, good efficacy, and safety but suffer from low stability, short half-life, and low membrane permeability. Compared to biologics, peptides have low immunogenicity, membrane permeability, and cost advantages but still face stability and half-life challenges.
5:15 To improve peptide stability and half-life, we use three techniques: cyclization, manipulation of amino acid sequences, and polymer conjugation (PEGylation). PEGylation was the most effective technique: PEGylation is a well-known technique for enhancing stability and half-life but can sometimes decrease bioactivity. However, PEGylated peptides generally have higher therapeutic efficacy due to longer half-life.
7:00 The PEG chain makes it hard for the peptide to interact with the receptor. To address the drawbacks of PEGylation, we developed the cutting-edge releasable PEG SUNBRIGHT BD series. We determined that to retain half-life and improve bioactivity, the PEG chain should be released from the peptide gradually. These PEGs consist of a PEG chain for retaining half-life, a hydrolysable acetal linker for releasing the peptide, and a functional group to link the peptide. The acetal linker is crucial for achieving both functions: retaining half-life and improving therapeutic efficacy.
8:05 We found the appropriate linker structure to achieve these functions. The peptide conjugated with SUNBRIGHT BD series PEGs can release the native peptide gradually under physiological conditions while maintaining the advantages of PEGylation.
9:08 The acetal linker in releasable PEGs hydrolyses, releasing the peptide and a small molecule. This reaction is non-enzyme dependent, ensuring consistent release rates in both in vitro and in vivo studies. The hydrolysis rate can be controlled by modifying the aromatic structure of the acetal linker.
10:09 We demonstrated the release mechanism with insulin conjugated with releasable PEGs in PBS at 37°C. The native insulin was released gradually under physiological conditions. We also tested various aromatic structures to control the release rate.
12:00 In cell proliferation assays, releasable PEGylated IL-2 showed improved bioactivity compared to non-releasable PEGylated IL-2. The EC50 value of releasable PEGylated IL-2 was lower, indicating higher therapeutic efficacy.
15:20 In vivo studies with insulin conjugated with releasable PEGs showed improved PK profiles and therapeutic efficacy compared to non-releasable PEGylated insulin. The AAC value of releasable PEGylated insulin was higher, demonstrating better therapeutic outcomes.
17:19 We also checked the acute toxicity of PEGylated insulin and observed no signs of toxicity.
18:27 In summary, peptides conjugated with SUNBRIGHT BD series PEGs can be released gradually under physiological conditions. The release rate can be controlled by the aromatic moiety of the PEGs. Releasable PEGylated peptides achieved better in vitro and in vivo bioactivity compared to non-releasable PEGylated peptides, with no observed toxicity.
