Polysialic Acid and Polysialylation to Modulate Antibody Pharmacokinetics

Constantinou, Antony; Chen, Chen; Deonarain, Mahendra P.

doi:10.1002/9783527644827.ch6

Cited by 6 publications

(8 citation statements)

References 112 publications

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“…[70] Zusätzlich kann die Ladungsabstoßung an der glomerulären Membran die Eliminierung von PSA vermindern und die Zirkulationszeit erhöhen. [71] Bei physiologischem pH weist PSA eine ausreichende Stabilität auf, aber ihre Anlagerung in Organen kann durch Abbau von zellulären Neuraminidasen verhindert werden. [72] Auf Liposomen aufgepfropft, verhindert PSA nachweislich die Bildung von IgM-Antikörpern und mildert somit die beschleunigte Clearance aus dem Blut, ein Problem, das häufig bei PEGylierten Liposomen beobachtet wird.…”

Section: Polysialinsäure (Psa)unclassified

Chemische Ansätze für synthetische Wirkstofftransportsysteme für systemische Anwendungen

et al. 2022

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Schlechte Wasserlöslichkeit und geringe Bioverfügbarkeit von pharmazeutischen Wirkstoffen (APIs) sind die Hauptursache für Verzögerungen in der pharmazeutischen Industrie und stellen eine große Hürde für die Entwicklung neuer Arzneimittel dar. Der Transport von Arzneimitteln ist nach wie vor die größte Herausforderung für die Anwendung niedermolekularer Medikamente und Biopharmazeutika. Die drei Herausforderungen für synthetische Transportsysteme sind: (i) Kontrolle über die Wirkstoffverteilung und Clearance im Blut, (ii) Solubilisierung schlecht wasserlöslicher Wirkstoffe und (iii) selektive Akkumulation in bestimmten Geweben. Obwohl viele Polymer-basierte Systeme die ersten beiden Anforderungen erfüllen und in die klinische Praxis umgesetzt wurden, hat bisher noch kein zielgerichtetes, synthetisches Abgabesystem den Markt erreicht. Dieser Aufsatz soll einen Überblick über die Herausforderungen und Anforderungen zur Entwicklung und Umsetzung neuer Polymer-basierter Darreichungssysteme geben. Hauptaugenmerk liegt hierbei auf den chemischen Ansätzen für die Darreichung von Wirkstoffen für systemische Anwendungen.

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Section: Polysialinsäure (Psa)unclassified

Chemische Ansätze für synthetische Wirkstofftransportsysteme für systemische Anwendungen

et al. 2022

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“…An added potential benefit upon chemical conjugation or protein fusion is the enhanced protein stability due to steric hindrance and/or changes in surface properties. Conjugation moieties include PEG, glycans, and other hydrophilic substances . PEGs are arguably the most widely used conjugation agents and have been found to stabilize proteins against different stresses, such as thermal stability, pH‐induced or protease‐induced degradation, and oligomerization .…”

Section: Chemical Conjugation/protein Fusionmentioning

confidence: 99%

Advanced protein formulations

Wang

2015

Protein Science

100

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It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms-semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution.

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“…On pathogenic bacteria, PSA (columinic acid) is a capsular virulence factor and is involved in protecting against phagocytosis and immune clearance . PSA has similar properties to PEG, including the ability to associate with 5–10 times its mass of water increasing its hydrodynamic volume, hiding immunogenic epitopes, and increasing overall conjugate solubility and stability. − These properties have led to commercialized use of chemically linked PSA, and early clinical data have shown that polysialylated erythropoietin is well-tolerated in patients …”

Section: Introductionmentioning

confidence: 99%

“…We have recently examined the chemical conjugation of PSA onto antibody fragments, showing that their systemic half-life and bioavailabilty can be significantly increased while maintaining better tumor/blood ratios than whole immunoglobulins. − However, limitations such as loss of antibody binding, long processing times, and poor conjugate yields were observed.…”

Section: Introductionmentioning

confidence: 99%

“…12−14 These properties have led to commercialized use of chemically linked PSA, 15 and early clinical data have shown that polysialylated erythropoietin is well-tolerated in patients. 12 We have recently examined the chemical conjugation of PSA onto antibody fragments, showing that their systemic half-life and bioavailabilty can be significantly increased while maintaining better tumor/blood ratios than whole immunoglobulins. 12−14 However, limitations such as loss of antibody binding, long processing times, and poor conjugate yields were observed.…”

Section: ■ Introductionmentioning

confidence: 99%

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Glycoengineering Approach to Half-Life Extension of Recombinant Biotherapeutics

et al. 2012

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The potential for protein-engineered biotherapeutics is enormous, but pharmacokinetic modulation is a major challenge. Manipulating pharmacokinetics, biodistribution, and bioavailability of small peptide/protein units such as antibody fragments is a major pharmaceutical ambition, illustrated by the many chemical conjugation and recombinant fusion approaches being developed. We describe a recombinant approach that leads to successful incorporation of polysialic acid, PSA for the first time, onto a therapeutically valuable protein. This was achieved by protein engineering of the PSA carrier domain of NCAM onto single-chain Fv antibody fragments (one directed against noninternalizing carcinoembryonic antigen-CEA and one against internalizing human epidermal growth factor receptor-2-HER2). This created novel polysialylated antibody fragments with desired pharmacokinetics. Production was achieved in human embryonic kidney cells engineered to express human polysialyltransferase, and the recombinant, glycosylated product was successfully fractionated by ion-exchange chromatography. Polysialylation was verified by glycosidase digestion and mass spectrometry, which showed the correct glycan structures and PSA chain length similar to that of native NCAM. Binding was demonstrated by ELISA and surface plasmon resonance and on live cells by flow cytometry and confocal immunofluorescence. Unexpectedly, polysialylation inhibited receptor-mediated endocytosis of the anti-HER2 scFv. Recombinant polysialylation led to an estimated 3-fold increase in hydrodynamic radius, comparable to PEGylation, leading to an almost 30-fold increase in blood half-life and a similar increase in blood exposure. This increase in bioavailability led to a 12-fold increase in tumor uptake by 24 h. In summary, recombinant polysialylation of antibody fragments in our system is a novel and feasible approach applicable for pharmacokinetic modulation, and may have wider applications.

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Polysialic Acid and Polysialylation to Modulate Antibody Pharmacokinetics

Cited by 6 publications

References 112 publications

Chemische Ansätze für synthetische Wirkstofftransportsysteme für systemische Anwendungen

Chemische Ansätze für synthetische Wirkstofftransportsysteme für systemische Anwendungen

Advanced protein formulations

Glycoengineering Approach to Half-Life Extension of Recombinant Biotherapeutics

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