Browsing by Subject "immunogenicity"
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Item Open Access Stealth Polymer Conjugates of Biologics(2021) Ozer, ImranBiologics are potent, highly specific, and well-tolerated and have become an important class of drugs. Despite their promise, most of them have a short half-life due to rapid renal elimination and in vivo degradation. Their short in vivo half-life hence necessitates frequent injections, resulting in a peak-and-valley profile in drug concentration that is pharmacologically suboptimal and incurs a high treatment cost and suboptimal patient compliance because of the need for frequent drug administration and the side-effects associate with a peak-and-valley drug concentration profile.One of the most common approaches to overcome these challenges is the covalent attachment of biologics to polyethylene glycol (PEG), a technology that is colloquially termed PEGylation. PEGylated drug conjugates have a much longer plasma half-life than the native drug due to their larger size leading to slower renal clearance, reduced opsonization that reduces clearance by the reticuloendothelial system (RES) organs, and improved solubility. Unfortunately, PEGylation has several significant limitations, some of which have come to the forefront recently. First, PEG was initially believed to be non-immunogenic. However, it is now well accepted that PEGylated therapeutics induce PEG antibodies upon treatment. Pre-existing PEG antibodies have also been reported in up to 70% of the population who are naïve to PEGylated therapeutics, possibly due to chronic exposure to PEG in consumer products and because PEG is used as an excipient in many drug formulations. Both induced and pre-existing PEG antibodies have caused a severe allergic reaction and accelerated clearance in some patients, reducing the drugs’ clinical efficacy. These issues have collectively led to the early termination of several clinical trials of PEGylated drug candidates and the withdrawal of several PEGylated therapeutics from the market. Second, attempts to improve the pharmacokinetics (PK) of PEG have focused on synthesizing branched and star-shaped PEGs. However, these architectures have a modest effect on PK and have antigenic and immunogenic profiles similar to linear PEG. Third, PEG forms vacuoles in major organs due to its non-biodegradable structure and clearance by the RES. Clearly, optimization of PEG is now at an asymptote, and new architectures that radically depart from linear PEG are needed to address these limitations. Motivated by these needs, we have developed a “next-gen” PEG-like polymer, poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). POEGMA is an amphiphilic, hyperbranched polymer that breaks up the long ethylene glycol sequences in PEG and presents them as much shorter oligomeric ethylene glycol (OEG) side-chains along a hydrophobic backbone. It has been previously shown that POEGMA with three EG unit long side chains improves the PK of exendin, a peptide drug used in the clinic to treat type 2 diabetes (T2D). The POEGMA conjugate of exendin (Ex-POEGMA) also showed no in vitro binding to human-derived PEG antibodies, presumably because the short OEG side-chains in POEGMA lack the anti-PEG epitope. Although these results were encouraging, the soluble Ex-POEGMA conjugate reported previously only showed a modest improvement in the PK of the drug. This study also did not report how POEGMA conjugates compare with PEG in the PK and efficacy and the intrinsic immunogenicity of POEGMA that could occur upon repeated administration of POEGMA-drug conjugates, which are critical for its clinical translation. This doctoral dissertation had three goals. The first goal was to devise a strategy to further enhance the half-life of exendin beyond the four days of therapeutic action of a soluble POEGMA conjugate in mice and do so without compromising its lack of reactivity to pre-existing PEG antibodies. Improving the PK of POEGMA beyond the duration exhibited by soluble POEGMA conjugates is important because recent long-acting delivery technologies such as Fc fusions have been shown to work for 4-6 day in mice and 7 days in humans so that a next-generation PEGylation technology must match—at a minimum— the performance of Fc conjugates. To address this goal, we report on the design and optimization of a gel-like injectable depot of an Ex-POEGMA conjugate that achieves sustained-release from the depot into the bloodstream while retaining its lack of reactivity towards PEG antibodies. We identify an optimal Ex-POEGMA depot that maximizes blood glucose control in diabetic mice, followed by investigating its PK and efficacy benefits. The second goal was to investigate the intrinsic immunogenicity and toxicity of a POEGMA-drug conjugate and compare it to PEG. We report the somewhat remarkable result that Ex-POEGMA conjugates have very little if any humoral immunogenicity in mice, as seen by the lack of an IgM and IgG response to repeated doses of Ex-POEGMA. Furthermore, this lack of immunogenicity is highly robust, as confirmed by the lack of Immunoglobulin (Ig) G and IgM against POEGMA observed with a POEGMA conjugate of the highly immunogenic ovalbumin (OVA) protein, even with co-administered Freund’s adjuvant. While POEGMA was non-immunoreactive, PEG induced a persistent anti-PEG immune response, leading to its subsequent doses' early clearance and loss of efficacy. Fortuitously, POEGMA did not induce vacuolization. The third goal was to apply the POEGMA technology to solve the limitations of two PEGylated drugs that failed at the late-stage clinical trials (Pegnivacogin) or was withdrawn from the market (Pegloticase) due to the life-threatening infusion reactions deriving from the reactivity to pre-existing PEG antibodies and induction of a strong anti-PEG immune response, respectively. Remarkably, the POEGMA formulated drugs showed no in vitro reactivity to pre-existing PEG antibodies and did not induce an anti-POEGMA immune response while showing efficacy at least comparable to the PEG conjugates. Overall, solving immunogenicity problems of PEG and improving upon its half-life benefits by creating injectable POEGMA conjugates that form a drug depot under the skin and provide sustained efficacy breathe new life into an established and valuable drug delivery technology that is facing an impasse.
Item Open Access Systematic review of safety and efficacy of COVID-19 vaccines in patients with kidney disease.(Kidney international reports, 2021-02-09) Glenn, Dorey A; Hegde, Anisha; Kotzen, Elizabeth; Walter, Emmanuel B; Kshirsagar, Abhijit V; Falk, Ronald; Mottl, Amy