ArticleJournal of controlled release : official journal of the Controlled Release Society2021
Replacement of L-amino acid peptides with D-amino acid peptides mitigates anti-PEG antibody generation against polymer-peptide conjugates in mice.
Article in Journal of controlled release : official journal of the Controlled Release Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- From a membrane-lytic toxin to a programmable therapeutic module: exposure control and detoxified delivery strategies for translating melittin into antitumor therapy.Molecular biology reports · 2026Review
- Therapeutic Bioactivity Exerted by theMolecules (Basel, Switzerland) · 2025Article
- Introducing Sulfur Ylides as Charge-Neutral Termini for Mitigating Poly(ethylene glycol) Antigenicity in Nanomedicine.JACS Au · 2025Article
- Therapeutic peptides: chemical strategies fortify peptides for enhanced disease treatment efficacy.Amino acids · 2025Review
- The Art of PEGylation: From Simple Polymer to Sophisticated Drug Delivery System.International journal of molecular sciences · 2025Review
- Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines.Signal transduction and targeted therapy · 2025Review
- Article
- Striving for Uniformity: A Review on Advances and Challenges To Achieve Uniform Polyethylene Glycol.Organic process research & development · 2024Review
- Dimerization and lysine substitution of melittin have differing effects on bacteria.Frontiers in pharmacology · 2024Article
- Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies.Journal of nanobiotechnology · 2023Review
- Review
- Recent advances in the development of therapeutic peptides.Trends in pharmacological sciences · 2023Review
- A mannosylated polymer with endosomal release properties for peptide antigen delivery.Journal of controlled release : official journal of the Controlled Release Society · 2023Article
- Leveraging the therapeutic, biological, and self-assembling potential of peptides for the treatment of viral infections.Journal of controlled release : official journal of the Controlled Release Society · 2022Review
- In vivo fate and intracellular trafficking of vaccine delivery systems.Advanced drug delivery reviews · 2022Review
- Well-Defined Mannosylated Polymer for Peptide Vaccine Delivery with Enhanced Antitumor Immunity.Advanced healthcare materials · 2022Article
- Polyethylene Glycol-Like Brush Polymer Conjugate of a Protein Drug Does Not Induce an Antipolymer Immune Response and Has Enhanced Pharmacokinetics than Its Polyethylene Glycol Counterpart.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Development of D-melittin polymeric nanoparticles for anti-cancer treatment.Biomaterials · 2021Article
- Lytic polyplex vaccines enhance antigen-specific cytotoxic T cell response through induction of local cell death.Advanced therapeutics · 2021Article
- Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The generation of anti-PEG antibodies in response to PEGylated proteins, peptides, and carriers significantly limits their clinical applicability. IgM antibodies mediate the clearance of these therapeutics upon repeat injection, resulting in toxicity and hindered therapeutic efficacy. We observed this phenomenon in our polymer platform, virus-inspired polymer for endosomal release (VIPER), which employs pH-sensitive triggered display of a lytic peptide, melittin, to facilitate endosomal escape. While the polymer-peptide conjugate was well tolerated after a single injection, we observed unexpected mortality upon repeat injection. Thus, the goal of this work was to enhance the safety and tolerability of VIPER for frequent dosing. Based on previous reports on anti-PEG antibodies and the adjuvant activity of melittin, we characterized the antibody response to polymer, peptide, and polymer-peptide conjugates after repeat-dosing and measured high IgM titers that bound PEG. By substituting the L-amino acid peptide for its D-amino acid enantiomer, we significantly attenuated the anti-PEG antibody generation and toxicity, permitting repeat-injections. We attempted to rescue mice from L-melittin induced toxicity by prophylactic injection of platelet activating factor (PAF) antagonist CV-6209, but observed minimal effect, suggesting that PAF is not the primary mediator of the observed hypersensitivity response. Overall, we demonstrated that the D-amino acid polymer-peptide conjugates, unlike L-amino acid polymer-peptide conjugates, exhibit good tolerability in vivo, even upon repeat administration, and do not elicit the generation of anti-PEG antibodies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.