Tumour Necrosis Factor Antagonists
Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer in Handbook of Systemic Drug Treatment in Dermatology, 2015
Recently, new TNF antagonists such as golimumab and certolimumabpegol have been approved for rheumatological diseases. Golimumab, like adalimumab, is a fully human IgG1 antibody licensed for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Certolizumab-pegol is a humanized anti-TNF Fab’ fragment conjugated to a polyethylene glycol to prolong serum half-life, which facilitates once-monthly dosing. It is approved for the treatment of rheumatoid arthritis. As these two Adalimumab and infliximab bind to both sTNF and tmTNF, whereas etanercept binds primarily to sTNF and TNF-β. All three biological agents act by: (i) blocking TNF receptor mediated mechanisms and (ii) inducing tmTNF (reverse-signalling) events. In addition, adalimumab and infliximab can fix complement, thereby leading to antibody dependent cytotoxicity and can trigger T-cell apoptosis, whereas etanercept lacks these actions. Thus, adalimumab and infliximab seem to have a greater propensity to cause lymphocyte apoptosis compared with etanercept.
Biologic therapies in the pipeline
M. Alan Menter, Caitriona Ryan in Psoriasis, 2017
Certolizumab pegol (UCB, Brussels, Belgium) is a monoclonal Fab fragment antibody conjugated to polyethylene glycol (PEG) targeting soluble and transmembrane TNF-α. It is currently approved for psoriatic arthritis but not plaque psoriasis. In phase II studies, a Psoriasis Area and Severity Index 75 (PASI 75) response was seen in 74.6% of patients receiving a 200 mg dose and 82.8% of patients receiving a 400 mg dose.4 Phase III trials evaluating the efficacy and safety of certolizumab pegol compared with placebo and with etanercept in plaque psoriasis are ongoing.5,6 Certolizumab does not have an Fc portion and so Fc receptor–mediated transcytosis does not occur. As a result, studies are also underway to examine the placental transfer of certolizumab in pregnant females and its excretion in breastmilk.7
Compatibility of commonly used drugs in lactation
Amy Brown, Wendy Jones in A Guide to Supporting Breastfeeding for the Medical Profession, 2019
Babies of mothers with IBD on monoclonal antibodies should avoid live vaccines, especially rotavirus due to shedding into faeces. The mother is at risk of contracting virus from these. If vaccination is given, mother should wear gloves and be careful with hand hygiene. Infliximab – molecular weight 149,100. Poor oral bioavailability, RID 0.32–3.01%.Adalimumab – molecular weight 148,000. Poor oral bioavailability, RID 0.12%.Golimumab – molecular weight 150,000. Poor oral bioavailability.Certolizumab pegol – molecular weight 149,100. Poor oral bioavailability. RID 0.04–0.3%. Licensed for use in breastfeeding.
Risk of infection associated with anti-TNF-α therapy
Published in Expert Review of Anti-infective Therapy, 2018
Mario Fernández-Ruiz, José María Aguado
Certolizumab pegol (Cimzia®, UCB Pharma) is a humanized Fab’ fragment in which the complementarity determining regions from the mouse-origin antibody have been inserted into a human IgG4 framework. The resulting construct is PEGylated via the site-specific attachment of a 40-kDa polyethylene glycol (PEG) moiety. PEGylation improves pharmacokinetics and enhances therapeutic efficacy by increasing the hydrophilicity and serum half-life of the conjugate [41]. In contrast with remaining anti-TNF-α antibodies, certolizumab pegol does not contain the Fc region and does not fix complement, being unable to induce in vitro CDC or ADCC [40]. Certolizumab pegol is administered by subcutaneous infection and is approved for RA, AS, PsA, and CD (by the FDA but not the European Medicine Agency [EMA]).
Biased anti-idiotype response in rabbits leads to high-affinity monoclonal antibodies to biologics
Published in mAbs, 2020
Christina Großerichter-Wagener, Dorien Kos, Astrid van Leeuwen, Lisanne Dijk, Jorn Jeremiasse, Floris C. Loeff, Theo Rispens
Immunizations were carried out as described previously.21 Briefly, F(ab’)2 fragments of the therapeutic antibodies were generated by pepsin digestion, except for belimumab, of which F(ab’)2 fragments were prepared via IdeS (Fabricator, Genovis) digestion. Certolizumab pegol is a PEGylated F(ab’) fragment and was used for immunizations without any modifications. Female New Zealand white rabbits were immunized with 100 μg/ml F(ab’)2 fragments/Montanide ISA-50 (Seppic, Paris, France) multiple times at 4-week intervals. Blood was drawn 9 d after the 2nd, 3rd, and 4th immunizations, and either collected as serum, or as EDTA blood. In the latter case, PBMCs were isolated by density centrifugation using Ficoll (GE Healthcare, Chalfont St. Giles, UK). PBMCs were stored in liquid nitrogen, and plasma was stored at −30 °C.
Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases
Published in Expert Review of Clinical Immunology, 2019
Konstantinos Papamichael, Erik H. Vogelzang, Jo Lambert, Gertjan Wolbink, Adam S. Cheifetz
Regarding certolizumab pegol, a prospective cohort study of 115 patients with RA showed that drug concentrations were associated with 12 months EULAR response. Also, patients with the highest certolizumab pegol concentrations had the highest proportion of EULAR good responders. The presence of ADA was associated with lower certolizumab pegol concentrations during 12 months of treatment but not with 12 months EULAR response rates [95*]. In a small study of golimumab treated patients with RA, median golimumab concentrations at week 52 were significantly higher in EULAR responders compared with non-responders [median (IQR) 1.36 (0.5-1.82) vs 0.43 (0.23–0.84) μg/ml, p = 0.023] [96]. In a small observational study, tocilizumab concentrations >1 μg/mL were sufficient to normalize CRP levels. Furthermore, there was a significant association between tocilizumab concentrations and ΔDAS28. In this small study, ADA were detected in only one patient [97].
Related Knowledge Centers
- Biopharmaceutical
- Crohn's Disease
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Ankylosing Spondylitis
- Monoclonal Antibody
- Tumor Necrosis Factor
- Pegylation
- Fragment Antigen-Binding
- Tnf Inhibitor