A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity

Abstract

The delivery of therapeutic peptides and proteins is often challenged by a short half-life, and thus the need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin) — a therapeutic peptide that is clinically used to treat type 2 diabetes — and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of 9 side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (PEG) antibodies than two FDA-approved PEGylated drugs, and that reducing the side-chain length to 3 EG repeats completely eliminates PEG antigenicity without compromising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients.

Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin

“…These nanomolar dissociation constants indicate that ABD–Dox has a high affinity for both HSA and MSA. Given the high concentration of albumin in plasma (≈0.6 × 10 −3 m ), it suggests that the ABD–Dox conjugates will largely exist as an albumin‐bound complex in murine or human circulation.…”

Architectural Modification of Conformal PEG‐Bottlebrush Coatings Minimizes Anti‐PEG Antigenicity While Preserving Stealth Properties

“…This is because POEGMA's 3D hyperbranched structure presents a high density of oligoethylene glycol (EG) moieties . In a recent study, we discovered that drug‐POEGMA conjugates having an average polymer sidechain length of nine EG units (“EG9”) demonstrated significantly reduced anti‐PEG antigenicity in patient plasma compared to two FDA‐approved PEGylated protein drugs (Krystexxa and Adagen) . In the same study, we also observed that shortening the POEGMA side‐chain length from EG9 to EG3 virtually eliminated the reactivity of the drug‐POEGMA conjugates to APAs in patient plasma samples and did so without substantially compromising in vivo pharmacokinetics in animal models.…”

“…Our work with poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) might offer an alternative, and less disruptive, solution. Specifically, over the past decade, we and others have explored POEGMA as an alternative to linear PEG for biomedical applications . POEGMA is a derivative of PEG with a “bottlebrush” architecture.…”

Improved Efficacy of Antibody Cancer Immunotherapeutics through Local and Sustained Delivery

“…For example, encapsulation of uricase in polycarboxybetaine (pCB) hydrogels increases protein stability and reduces immunogenicity . Conjugation of polymers such as PEG, poly(oligoethylene glycol)methacrylate (PEGMA), or poly‐zwitterions to proteins also increases their stability while reducing immunogenicity …”

“…[42] Conjugationo fp olymers such as PEG, poly(oligoethylene glycol)methacrylate( PEGMA), or poly-zwitterions to proteins also increases their stabilityw hiler educingi mmunogenicity. [43][44][45]…”