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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Blood clotting factors are being engineered to overcome the bleeding disorders such as hemophilia. Recombinant Factor VIII (rFVIII) was given first in March 1987 to the hemophilic patient and after five years it became available for clinical usage (White et al., 1989; Pipe, 2005). Recombinant Factor IX (rFIX) and recombinant factor VIIa (rVIIa) were later developed for the treatment of hemophilia A and B. Few of the clotting factors have been already approved, and some are under clinical trials (Pipe, 2005; Key and Negrier, 2007). Recombinant activated protein C (APC) has been developed and was reported to reduce the mortality in patients suffering from severe sepsis. This recombinant protein also showed high bleeding risk due to its high anticoagulant activity; hence, efforts were made to reduce its anticoagulant activity to overcome bleeding risk. Two variants of APC were designed by site directed mutagenesis. In one variant, the two arginine residues at 229th and 230th position were mutated to alanine and in other variant three adjacent lysines at positions 191, 192, and 193 were mutated to alanine. Both the variants held back their apoptotic activity and evidenced a decrease in anticoagulant activity. These two APC variants can serve as future engineered therapeutics (Mosnier et al., 2004).
Unwanted Immunogenicity: From Risk Assessment to Risk Management
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
The immune response to biologic products often involves B or T cells. The former produce antibodies that bind to proteins and thus reduce or eliminate their therapeutic effects. Potential complications can be life threatening. Thus, measuring the tendency to trigger antibody formation is an important part of determining the clinical safety and efficacy of protein-based drugs. T cells help activate B cells, especially for disease cases in which a patient’s natural protein is defective in some way. That patient’s T cells could treat protein therapeutics as if they were foreign invaders because they are different from the native protein. Such a response has been noted, for example, in some hemophilia patients, whose blood factor VIII is genetically defective. They may develop ADAs when infused with a correct factor VIII therapeutic protein (e.g., Bayer’s Kogenate or Baxter’s Advate products), presenting a significant impediment to such treatment. It is, in fact, considered to be “the most important problem in hemophilia A care today” [1]. Rheumatoid arthritis is another condition for which treatments are complicated by immunogenicity [2].
Ireland
Published in Braithwaite Jeffrey, Mannion Russell, Matsuyama Yukihiro, Shekelle Paul, Whittaker Stuart, Al-Adawi Samir, Health Systems Improvement Across the Globe: Success Stories from 60 Countries, 2017
Hemophilia is an inherited disease caused by the lack of a specific clotting factor in blood, which leads to significant and sometimes life-threatening bleeding. Intravenous infusion of the missing clotting factor is used to treat and prevent bleeds. Regular infusion of clotting factor to prevent bleeding is called “prophylaxis” and is usually self-administered at home by the patient or a family member. Prophylaxis from childhood is proven to prevent the development of severe joint disease and disability. Modern prophylaxis means that people with hemophilia can achieve their full potential, including taking part in sports, education, and the workforce. Effective prophylaxis is tailored to the bleed rate and activity level of each individual patient.
When sex matters: a complete model of X-linked diseases
Published in International Journal of General Systems, 2018
C. Del Vecchio, F. Verrilli, L. Glielmo
In what follows, we apply the continuous-time model (7)–(6) to the haemophilia A, a hereditary bleeding disorder caused by a lack of blood clotting factor VIII, a protein encoded by FVIII gene placed on the X chromosome. It is largely an inherited disorder, that is the spontaneous gene mutation rate of the diseases can be considered negligible (Becker et al. 1996), therefore we can set . Affected males show a reduced reproduction capacity related to the severity of the disease symptoms; carrier females do not usually show any sign of the disease (Bowen 2002). Due to the severity of the disease, one can assign fertility factors equal to zero () to affected individuals; according to clinical considerations, the fertility factors of the other classes have been fixed at the following values: and .