Certolizumab Pegol Overview

Introduction of Certolizumab Pegol

Certolizumab pegol (CDP870, tradename Cimzia) is a recombinant, humanized, pegylated monoclonal antibody (mAb) formed with a humanized Fab fragment of 50 kDa, from an IgG 1 isotype, fused to a 40 kDa polyethylene glycol moiety replacing the Fc antibody region. It was developed and manufactured by UCB Pharma. Targeting the tumor necrosis factor-alpha (TNFα), it has been approved by the U.S. Food and Drug Administration (FDA) to treat adults with Crohn’s disease (CD), rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), and plaque psoriasis (PsO).

Mechanism of Action of Certolizumab Pegol

Certolizumab pegol is a novel Fc-free, PEGylated, anti-TNFα monoclonal antibody. The parent antibody was selected from a screen of hybridomas for human TNFα binding. The complementarity determining regions (CDRs) from the murine antibody were then inserted into a human Fab’ IgG framework, along with several other framework residues of the variable domain that were essential for maintenance of affinity. The certolizumab Fab’ was subsequently PEGylated via the site-specific attachment of a 40 kDa polyethylene glycol (PEG) moiety. Certolizumab pegol binds and neutralizes both soluble and transmembrane TNFα and inhibits signaling through both the p55 and p75 TNFα receptors in vitro. Certolizumab pegol differs from the other TNFα-inhibitors in its lack of an Fc region, which minimizes potential Fc-mediated effects such as complement-dependent cytotoxicity (CDC) or antibody dependent cell-mediated cytotoxicity (ADCC). In vitro studies have shown that certolizumab pegol does not induce CDC and ADCC. In vitro studies have also demonstrated that certolizumab pegol, unlike other TNFα-inhibitors, does not cause activated peripheral blood lymphocytes to undergo apoptosis and that it inhibits lipopolysaccharide-induced cytokine production to a greater extent than other TNFα-inhibitors. The lack of an Fc region may also be a factor in the prevention of active transfer of certolizumab pegol across the placenta during pregnancy. Certolizumab pegol also differs from the other TNFα-inhibitors as it is PEGylated. PEGylation is widely used to improve drug pharmacokinetics and bioavailability. It has been demonstrated that PEGylation significantly increases the circulating half-life of Fab’ molecules, permitting a minimum dosing interval of 2 weeks for certolizumab pegol. Biofluorescence imaging in arthritic mice has shown that certolizumab pegol preferentially penetrates inflamed tissue compared to non-inflamed tissue, and does so to a greater extent than adalimumab or infliximab. Furthermore, the persistence of drug in the inflamed tissue was more prolonged for certolizumab pegol compared to either adalimumab or infliximab. These phenomena are most likely due to the PEGylation of the molecule, although the persistence in the tissue could also be due to the lack of Fc receptor-mediated recycling of the Fab’. These features of certolizumab pegol may be relevant to its action in RA. In animal models, the 40 kDa PEG moiety is cleaved from the Fab’ and is excreted intact via the renal route. It was found that PEG is rapidly excreted once cleaved from the Fab’ portion of the molecule. The majority of PEG is estimated to be removed by the kidneys.

Mechanism of Action of Certolizumab Pegol Fig.1 Mechanism of Action of Certolizumab Pegol

Table 1. Clinical Projects of Certolizumab Pegol *

NCT ID Status Conditions Lead Sponsor Update Time
NCT04053881 Recruiting Plaque Psoriasis UCB Biopharma S.P.R.L. August 13, 2019
NCT03215277 Active, not recruiting Ankylosing Spondylitis UCB Biopharma S.P.R.L. July 12, 2017
NCT01550003 Active, not recruiting Polyarticular-course Juvenile Idiopathic Arthritis (JIA) UCB BIOSCIENCES GmbH March 9, 2012
NCT00844285 Active, not recruiting Crohn's Disease UCB Pharma February 16, 2009
NCT02552212 Active, not recruiting Axial Spondyloarthritis, Nonradiographic Axial Spondyloarthritis, Nr-axSpA UCB BIOSCIENCES GmbH September 17, 2015
NCT01095393 Enrolling by invitation Rheumatoid Arthritis UCB Pharma March 30, 2010
NCT01090154 Active, not recruiting Ulcerative Colitis University of Washington March 19, 2010
NCT02120807 Active, not recruiting Stage IV Lung Adenocarcinoma Memorial Sloan Kettering Cancer Center April 23, 2014
NCT03152058 Recruiting High Risk Pregnancy, Pregnancy Complications, Antiphospholipid Syndrome in Pregnancy, Lupus Anticoagulant Disorder Ware Branch May 12, 2017
NCT01764321 Active, not recruiting Rheumatoid Arthritis UCB Pharma SA January 9, 2013
NCT01797224 Recruiting Crohn's Disease, Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis, Psoriasis University of California, San Diego February 22, 2013

Table 2. Approved Drugs of Certolizumab Pegol**

INN (trade name) Therapeutic area Dose Strength Route Company Marketing start Market
Cimzia Crohn’s Disease, Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Non-radiographic Axial Spondyloarthritis, Plaque Psoriasis Solution 200 mg / mL Subcutaneous UCB Inc. April 22, 2008
Cimzia Arthritis, Rheumatoid Solution 200 mg / mL Subcutaneous UCB Pharma SA October 1, 2009
Cimzia Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Non-radiographic Axial Spondyloarthritis, Plaque Psoriasis Solution 200 mg / mL Subcutaneous UCB Japan Co. Ltd. December 25, 2012
Cimzia Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Non-radiographic Axial Spondyloarthritis, Plaque Psoriasis Solution 200 mg / mL Subcutaneous UCB Australia Pty Ltd T/A UCB Pharma Division of UCB Australia January 20, 2010
Cimzia Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Non-radiographic Axial Spondyloarthritis, Plaque Psoriasis Solution 3.5 mg / mL Subcutaneous UCB Canada Inc. August 31, 2009

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References
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Certolizumab%20Pegol
** Information presented in the table were collected from the following website:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125160
https://www.ema.europa.eu/en/medicines/human/EPAR/cimzia-0
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=81737
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=154726
https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/3999437


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