PEG‐Like Brush Polymer Conjugate of RNA Aptamer That Shows Reversible Anticoagulant Activity and Minimal Immune Response

Ribonucleic acid (RNA) therapeutics are an emerging class of drugs. RNA aptamers are of significant therapeutic and clinical interest because their activity can be easily reversed in vivo—a useful feature that is difficult to achieve using other therapeutic modalities. Despite their therapeutic prom...

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Veröffentlicht in:Advanced materials (Weinheim) 2022-03, Vol.34 (10), p.e2107852-n/a
Hauptverfasser: Ozer, Imran, Pitoc, George A., Layzer, Juliana M., Moreno, Angelo, Olson, Lyra B., Layzer, Kyle D., Hucknall, Angus M., Sullenger, Bruce A., Chilkoti, Ashutosh
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container_issue 10
container_start_page e2107852
container_title Advanced materials (Weinheim)
container_volume 34
creator Ozer, Imran
Pitoc, George A.
Layzer, Juliana M.
Moreno, Angelo
Olson, Lyra B.
Layzer, Kyle D.
Hucknall, Angus M.
Sullenger, Bruce A.
Chilkoti, Ashutosh
description Ribonucleic acid (RNA) therapeutics are an emerging class of drugs. RNA aptamers are of significant therapeutic and clinical interest because their activity can be easily reversed in vivo—a useful feature that is difficult to achieve using other therapeutic modalities. Despite their therapeutic promise, RNA aptamers are limited by their poor blood circulation. The attachment of polyethylene glycol (PEG) to RNA aptamers addresses this limitation. However, an RNA aptamer‐PEG conjugate that is a reversible anticoagulant fails in a clinical trial due to the reactivity of the conjugate with pre‐existing PEG antibodies and has cast a pall over PEGylation of aptamers and other biologics, despite its long history of utility in drug delivery. Here, PEG antibody‐reactivity of this RNA aptamer is eliminated by conjugating it to a next‐generation PEG‐like brush polymer—poly[(oligoethylene glycol) methyl ether methacrylate)] (POEGMA). The conjugate retained the drug's therapeutic action and the ability to be easily reversed. Importantly, this conjugate does not bind pre‐existing PEG antibodies that are prevalent in humans and does not induce a humoral immune response against the polymer itself in mice. These findings suggest a path to rescuing the PEGylation of RNA therapeutics and vaccines from the deleterious side‐effects of PEG. Herein, a path is offered to rescuing RNA therapeutics from the deleterious immune side effects of PEG that induces life‐threatening hypersensitivity reactions upon reactivity toward PEG antibodies using a next‐generation PEG‐like stealth polymer conjugate technology. These results breathe new life into an established and valuable drug delivery technology facing an impasse.
doi_str_mv 10.1002/adma.202107852
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source Wiley Online Library - AutoHoldings Journals; MEDLINE
subjects Animals
Antibodies
Anticoagulants
Anticoagulants - pharmacology
antigenicity
Aptamers, Nucleotide
Blood circulation
Conjugates
Immune system
Immunity
immunogenicity
Mice
PEG
Polyethylene glycol
Polyethylene Glycols
Polymers
Ribonucleic acid
RNA
RNA aptamers
RNA therapeutics
title PEG‐Like Brush Polymer Conjugate of RNA Aptamer That Shows Reversible Anticoagulant Activity and Minimal Immune Response
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