The Pharmacology of PEGylation: Balancing PD with PK to Generate Novel Therapeutics

Fishburn, C. Simone

doi:10.1002/jps.21278

Cited by 423 publications

(343 citation statements)

References 72 publications

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“…23). In the past, the primary function of PEG was to improve half-life using standard stable conjugation chemistry (24)(25)(26). In this report, PEG is used to bias receptor selectivity and alter pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

Charych

Hoch

Langowski

et al. 2016

Clinical Cancer Research

343

298

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Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.

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Section: Discussionmentioning

confidence: 99%

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

Charych

Hoch

Langowski

et al. 2016

Clinical Cancer Research

343

298

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“…We may also repeat some of the experiments using Fab9 and Fab9 2 fragments [modified via pegylation (Fishburn, 2008) or not] of some of the mAbs to understand better the underlying mechanisms.…”

mentioning

confidence: 99%

Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis

Féraudet-Tarisse

Andréoletti

Morel

et al. 2010

Journal of General Virology

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“…Surface modification of the nanoparticle with PEG has been reported to decrease surface interactions with opsonins through steric repulsion (15), thereby conferring long-circulating property to the nanoparticles (16). PEG has excellent biocompatibility and is already approved by the Food and Drug Administration for human use (17). To develop the ''stealth'' nanoparticles (i.e., to mask them from tissue macrophages or the reticuloendothelial system), we synthesized a PLGA-b-PEG block copolymer 10 by amide coupling of the carboxylic acid of PLGA with the amine group of 2 KDa amine ethylene glycol using the coupling reagent HBTU with diisopropylethyl amine (DIPEA) as base ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

Basu

Harfouche

Soni

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

119

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The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,Llactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.cancer ͉ signal transduction C ancer is the second leading cause of mortality in the United States, with an estimated 1,444,180 new cases and 565,650 deaths in 2008 (1). Standard chemotherapy nonspecifically targets all dividing cells, resulting in dose-limiting toxicities. Consequently, there is an urgent need to develop novel strategies that are more specifically targeted against the tumor. The MAPK pathway comprising of RAS, RAF, MEK, and ERK has been implicated in a majority of human tumors, often through gain of function mutations in the RAS and RAF families (2, 3). Indeed, RAS mutations occur in 30% of all cancer, and are particularly implicated in over 90% of pancreatic cancers (4) and 50% of colon cancers (5); RAF mutations are prevalent in over 60% of melanomas (6) and over 35% of ovarian cancers (7). As a result, the MAPK pathway has evolved as a focus of intense investigation for developing small molecule inhibitors as targeted therapeutics.Another emerging strategy for targeted chemotherapy is to harness nanovectors for preferential delivery of drugs into the tumor (8). A wide range of nanovectors, including liposomes, micelles, polymeric nanoparticles, silicon and gold nanoshells, polymeric dendrimers, and carbon-based nanostructures, have been used for drug delivery to the tumor (9). It is well established that nanoparticles preferentially localize at the tumors as a result of the enhanced permeation and retention effect (10, 11). Indeed, a nanoliposomal formulation of cisplatin was shown to attain 10-to 200-fold increased drug concentration in tumors during a Phase-I clinical trial (12). However, standard liposomal or protein carrier-based nanoplatforms have limited control over drug release. In contrast, controlled-release drug delivery systems have the potential to induce standardized and durable clinical responses.Interestingly, while extensive studies have been done on delivering cytotoxic agents to solid tumors using nanovectors, no report exists on combining targeted therapeutics with nanopa...

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The Pharmacology of PEGylation: Balancing PD with PK to Generate Novel Therapeutics

Cited by 423 publications

References 72 publications

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

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