Certolizumab Pegol

Goel, Niti; Stephens, Sue

doi:10.4161/mabs.2.2.11271

Cited by 161 publications

(117 citation statements)

References 32 publications

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“…Since the Fab is shorter than the full-length antibody, it can be expressed and purified with good yield. 44 The marketed products ranibizumab (Lucentis®) 45 and certolizumab pegol (Cimzia®) 46 are Fabs made using E. coli .…”

Section: Discussionmentioning

confidence: 99%

Platform development for expression and purification of stable isotope labeled monoclonal antibodies inEscherichia coli

Reddy

Brinson

Hoopes

et al. 2018

mAbs

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The widespread use of monoclonal antibodies (mAbs) as a platform for therapeutic drug development in the pharmaceutical industry has led to an increased interest in robust experimental approaches for assessment of mAb structure, stability and dynamics. The ability to enrich proteins with stable isotopes is a prerequisite for the in-depth application of many structural and biophysical methods, including nuclear magnetic resonance (NMR), small angle neutron scattering, neutron reflectometry, and quantitative mass spectrometry. While mAbs can typically be produced with very high yields using mammalian cell expression, stable isotope labeling using cell culture is expensive and often impractical. The most common and cost-efficient approach to label proteins is to express proteins in Escherichia coli grown in minimal media; however, such methods for mAbs have not been reported to date. Here we present, for the first time, the expression and purification of a stable isotope labeled mAb from a genetically engineered E. coli strain capable of forming disulfide bonds in its cytoplasm. It is shown using two-dimensional NMR spectral fingerprinting that the unlabeled mAb and the mAb singly or triply labeled with 13C, 15N, 2H are well folded, with only minor structural differences relative to the mammalian cell-produced mAb that are attributed to the lack of glycosylation in the Fc domain. This advancement of an E. coli-based mAb expression platform will facilitate the production of mAbs for in-depth structural characterization, including the high resolution investigation of mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Platform development for expression and purification of stable isotope labeled monoclonal antibodies inEscherichia coli

Reddy

Brinson

Hoopes

et al. 2018

mAbs

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“…Таким образом, ЦЗП может являться перспективным препара-том в терапии молодых пациенток (а они составляют большинство пациентов с артериитом Такаясу), позволяя не прерывать лечение ни при планировании, ни при ве-дении беременности вплоть до родоразрешения, а также при лактации. К отличиям ЦЗП от других ингибиторов ФНОα относится отсутствие таких обусловленных нали-чием Fc-фрагмента свойств, как комплемент-зависимая или антитело-зависимая клеточно-опосредованная ци-тотоксичность и способность индуцировать апоптоз лимфоцитов [30,31]. Также важным преимуществом ЦЗП представляется его усиленное проникновение в очаги воспаления и высокая концентрация в них.…”

Section: Discussionunclassified

“…Кроме того, ЦЗП дольше задер-живался в очаге, чем другие два препарата. Данные свой-ства, наиболее вероятно, обусловлены пэгилированной структурой молекулы и отсутствием Fc-фрагмента [30,32] и могут являться преимуществами при лечении рев-матических заболеваний с очагами хронического воспа-ления, в частности, артериита Такаясу. В настоящее время ЦЗП (симзия) зарегистрирован для лечения ревматоидного артрита, псориатического арт-рита, анкилозирующего спондилита, а также болезни Кро-на.…”

Section: Discussionunclassified

“…Среди неблагоприятных реакций при назначении ЦЗП наиболее часто, как и при использовании других ин-гибиторов ФНОα, встречаются инфекционные осложне-ния, в том числе инфекции мочевыводящих путей, верхних дыхательных путей, туберкулез, пневмонии и рожа [30,35]. В нашем исследовании у одной пациентки терапия ЦЗП в сочетании с МТ осложнилась развитием внебольничной пневмонии.…”

Section: Discussionunclassified

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Certolizumab Pegol in the Treatment of Takayasu Arteritis: The First Experience and Prospects

Novikov¹,

Smitienko²,

Соколова³

et al. 2018

rsp

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Certolizumab pegol (CZP) is the only pegylated biological agent (BA) that does not contain an Fc fragment, which minimizes its transplacental transfer. Takayasu arteritis mostly occurs in reproductive-aged women.Objective: to evaluate the efficacy and safety of CZP used to treat standard immunosuppressive therapy-resistant Takayasu arteritis.Subjects and methods. The retrospective study enrolled 6 female patients aged 18 to 35 years with Takayasu arteritis who received CZP. The median disease duration before BA usage was 66 months (24 to 204 months). The median duration of immunosuppressive therapy prior to CZP treatment was 92 months (14 to 132 months). All the female patients had taken glucocorticoids and methotrexate before and during CZP therapy. Only four patients had received two to five immunosuppressive drugs at different times prior to BA administration. Three patients had previously used other BAs. The disease activity was determined by the National Institute of Health (NIH) criteria. The Indian Takayasu Clinical Activity Score (ITAS2010) was used. The disease activity was recorded in all the patients prior to CZP therapy.Results and discussion. The median duration of CZP treatment was 17 months (6 to 24 months). The median erythrocyte sedimentation rate after CZP usage decreased from 22.5 to 10.5 mm/h; the median C-reactive protein level dropped from 7.8 to 0.39 mg/dl (p<0.05), the median daily dose of prednisolone was reduced from 20 to 8.75 mg (p<0.05). All the patients achieved complete remission an average of 4 months after starting CZP therapy. Three patients were still in remission after 12–24 months. One relapse of the disease was recorded following 24 months. ITAS2010 reduced from 1–4 to 0 in five patients and to 2 in one patient with recurrence. There was a good tolerance in five female patients. The adverse events were herpes labialis in two cases, community-acquired pneumonia in one case, and postoperative abscess in one case too.Conclusion. CZP in Takayasu arteritis was shown to be an effective drug for remission induction and maintenance. The presented results of the first experience in treating this disease with CZP are indicative of its promising further investigation as a steroid-sparing drug in patients with refractory vasculitis. One of the important advantages of CZP is its supposed high safety throughout pregnancy.

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“…5 With advances in molecular cloning, recombinant expression of antibody fragments became a more attractive route to generate Fab molecules as exemplified by 2 other approved Fab therapeutics, anti-vascular endothelial growth factor (VEGF) ranibizumab (Lucentis Ò ) 6 and anti-dabigatran idarucizumab (Praxbind Ò ) 7 and the approved pegylated Fab 0 , anti-tumor necrosis factor certolizumab pegol (Cimzia Ò ). 8 Fab molecules are advantageous when transient systemic activity that doesn't persist past dosing is desired, lack of Fc-mediated effects is wanted, or when administration and activity are localized to a peripheral compartment such as the eye.…”

Section: Introductionmentioning

confidence: 99%

Evading pre-existing anti-hinge antibody binding by hinge engineering

Kim¹,

Kim²,

Zheng³

et al. 2016

mAbs

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Antigen-binding fragments (Fab) and F(ab 0 ) 2 antibodies serve as alternative formats to full-length antibodies in therapeutic and immune assays. They provide the advantage of small size, short serum half-life, and lack of effector function. Several proteases associated with invasive diseases are known to cleave antibodies in the hinge-region, and this results in anti-hinge antibodies (AHA) toward the neoepitopes. The AHA can act as surrogate Fc and reintroduce the properties of the Fc that are otherwise lacking in antibody fragments. While this response is desired during the natural process of fighting disease, it is commonly unwanted for therapeutic antibody fragments. In our study, we identify a truncation in the lower hinge region of the antibody that maintains efficient proteolytic cleavage by IdeS protease. The resulting neoepitope at the F(ab 0 ) 2 C-terminus does not have detectable binding of pre-existing AHA, providing a practical route to produce F(ab 0 ) 2 in vitro by proteolytic digestion when the binding of preexisting AHA is undesired. We extend our studies to the upper hinge region of the antibody and provide a detailed analysis of the contribution of C-terminal residues of the upper hinge of human IgG1, IgG2 and IgG4 to pre-existing AHA reactivity in human serum. While no pre-existing antibodies are observed toward the Fab of IgG2 and IgG4 isotype, a significant response is observed toward most residues of the upper hinge of human IgG1. We identify a T 225 L variant and the natural C-terminal D 221 as solutions with minimal serum reactivity. Our work now enables the production of Fab and F(ab 0 ) 2 for therapeutic and diagnostic immune assays that have minimal reactivity toward pre-existing AHA.

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Certolizumab Pegol

Cited by 161 publications

References 32 publications

Platform development for expression and purification of stable isotope labeled monoclonal antibodies inEscherichia coli

Platform development for expression and purification of stable isotope labeled monoclonal antibodies inEscherichia coli

Certolizumab Pegol in the Treatment of Takayasu Arteritis: The First Experience and Prospects

Evading pre-existing anti-hinge antibody binding by hinge engineering

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