Role of Engineered Proteins as Therapeutic Formulations
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Several of the protein therapeutics have already been developed using different protein scaffolds and are under clinical trials. Some of them include: Affibodies® from the synthetic Z domain of staphylococcal protein, Adnectins® from type III fibronectin domains, Avimers® from LDLR-A modules, Anticalins® from lipocalins, engineered Kunitz Domains, and DARPins® from ankyrin repeat proteins. One of the synthetic scaffolds, namely ecallantide (Kalbitor®), is a 60-amino-acid-long protein based on kunitz domain and has been approved as a therapeutic that inhibits plasma kallikrein. It was selected by phage display technology and was grown in Pichia pastoris strain of yeast (Zuraw et al., 2010). Some of these scaffolds are described in detail in the following sections.
Urticaria and Angioedema
Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial in Textbook of Allergy for the Clinician, 2021
Acute attacks of HAE are most effectively treated with supplemental C1 inhibitor, a bradykinin B2 receptor antagonist (e.g., icatabant), or a kallikrein inhibitor (e.g., ecallantide) (Cicardi et al. 2010, Parikh and Riedl 2011, Zuraw et al. 2010, Antoniu 2011). The choice of medication is often based on availability. When these medications are not available, symptomatic care and airway monitoring for laryngeal edema should be provided. Administration of fresh frozen plasma, which contains C1 inhibitor, can also be considered; however there is significant concern that FFP may worsen ongoing AE in some patients (Dreskin 2012). The patient’s airway should be monitored, and if there is concern for laryngeal edema and stridor or respiratory distress is evident, the patient should undergo endotracheal intubation. If intubation is unsuccessful due to angioedema, emergent cricothyroidotomy may need to be performed. Other supportive care measures may include intravenous fluids and antiemetics for gastrointestinal symptoms, as well as analgesics for pain.
Lanadelumab for the treatment of hereditary angioedema
Published in Expert Opinion on Biological Therapy, 2019
The approved dose is 30 mg, given as three separate subcutaneous injections of 10 mg in the abdomen, upper arm or thigh on demand [23–27]. The efficacy of Ecallantide was tested in two controlled trials, EDEMA3 and EDEMA4 [26] and the drug was approved by the Food and Drug Administration (FDA) for the treatment of acute angioedema attacks in December 2009. Due to safety concerns (reported acute hypersensitivity reactions) [27], the European Medicines Agency (EMA) did not approve the release to the market of Ecallantide for Europe [Withdrawal of the marketing authorization application for Kalbitor (ecallantide) EMA/888,548/2011]. Until the development of lanadelumab, Ecallantide was the only anti kallikrein drug available for the treatment of C1-INH-HAE, with the specific indication as on-demand therapy.
Safety of medications for hereditary angioedema during pregnancy and lactation
Published in Expert Opinion on Drug Safety, 2023
Andrew Yeich, Ahmed Elhatw, Zaynab Ashoor, Kristen Park, Timothy Craig
Attacks of HAE during pregnancy should be treated with rescue therapy regardless of the site or the severity, to reduce anxiety, stress, morbidity, and rare, but possible mortality. As evident in Table 1, pdC1-INH is the drug of first choice [63]. Most of the reported thrombotic events associated with pdC1-INH are now thought to have occurred in the context of IV port catheters, but there have been cases likely related to the medication itself [70]. The use of rcC1-INH, similarly to pdC1INH, is not approved by the FDA, or other agencies, for use during pregnancy or lactation, but it is an alternative to pdC1-INH. Like pdC1-INH, rcC1-INH also contains a warning of thrombosis in the package insert. An alternative therapy is FFP, but the use is not as consistent secondary to the variable amounts of C1-INH found in different units of FFP and higher rates of adverse effects [71]. Case reports and small case series have been reported with icatibant, but further data are needed before suggesting icatibant during pregnancy and lactation for on demand therapy [72,73]. Both ecallantide and tranexamic acid should be avoided; the first because of anaphylaxis and the latter because of poor efficacy [53,63].
A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema
Published in Expert Review of Clinical Immunology, 2020
Maria Fernanda Villavicencio, Timothy Craig
The treatment of HAE can be divided into management of attacks (called on-demand treatment) and prophylactic therapies. For attacks, first-line treatments include human plasma-derived C1-INH (Berinert) or recombinant C1-INH (Ruconest), administered by a peripheral intravenous line. Icatibant, a synthetic bradykinin B2-receptor antagonist, is administered as a subcutaneous injection. Ecallantide, a plasma kallikrein inhibitor, is administered at three separate sites subcutaneously, and because of a low risk of anaphylaxis cannot be self-administered [2]. Second-line therapies are detergent-treated plasma or fresh frozen plasma [2].
Related Knowledge Centers
- Kallikrein
- Peptide
- Phage Display
- Amino Acid
- Medication
- Hereditary Angioedema
- Cardiothoracic Surgery
- Kunitz Domain
- Antibody Mimetic
- Subcutaneous Administration