Building better drugs: developing and regulating engineered therapeutic proteins

Kimchi-Sarfaty, Chava; Schiller, Tal; Hamasaki-Katagiri, Nobuko; Khan, Mansoor A.; Yanover, Chen; Sauna, Zuben E.

doi:10.1016/j.tips.2013.08.005

Cited by 81 publications

(79 citation statements)

References 66 publications

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“…We therefore assessed the binding affinities of all overlapping peptides from the artificial linker to 30 common human MHC-II variants. We found that these neopeptides bind with high affinity to some MHC-II variants but not to others [34]. This computational analysis estimated that approximately 25% of the US population carries the MHC-II variants that bind to the linker peptides.…”

Section: Protein Engineering Neo-epitopes and Immunogenicity: The Rolementioning

confidence: 79%

“…Significant lessons have been learned from such engineered coagulation factors that have entered clinical practice or Phase III clinical trials. This experience clearly illustrates that engineering a protein can achieve desired outcomes there are also accompanying risks [34].…”

Section: Protein Engineering Neo-epitopes and Immunogenicity: The Rolementioning

confidence: 93%

“…The last few years have seen an unprecedented number of bio-engineered FVII, FVIII and FIX products enter the drug development pipeline [34]. This is because the native proteins do not make good drug products.…”

Section: Protein Engineering Neo-epitopes and Immunogenicity: The Rolementioning

confidence: 99%

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Personalized Approaches to the Treatment of Hemophilia A and B

et al. 2015

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The recognition that individuals respond differently to the same medication is not new and dates almost to the founding of western medicine. In the last century it came to be recognized that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and effectiveness. Nonetheless, it has been challenging to integrate pharmacogenetic approaches in the routine practice of medicine as the identification of biomarkers is difficult due to the inherent complexity of biological systems. Here, we present potential applications of pharmacogenetics in managing hemophilia A and B. We discuss how predicting and circumventing immunogenicity, an important impediment to treating hemophilia patients, particularly lends itself to a pharmacogenetic approach. In addition, we discuss new trends toward personalizing the management of hemophilia in clinical settings.

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Section: Protein Engineering Neo-epitopes and Immunogenicity: The Rolementioning

confidence: 79%

Section: Protein Engineering Neo-epitopes and Immunogenicity: The Rolementioning

confidence: 93%

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Personalized Approaches to the Treatment of Hemophilia A and B

et al. 2015

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“…30,31 Currently, FVIII replacement products are dispensed interchangeably with the premise that each is equally suitable for all recipients. Until recently, there has been little deliberation on the effects of engineered differences in the amino acid sequence of the FVIII product on inhibitor risk.…”

Section: Future Directionsmentioning

confidence: 99%

The intron-22–inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics

Sauna

Lozier

Kasper

et al. 2015

Blood

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Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive “intracellular (I)-FVIII-CRM” status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for any HLA class-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire.

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“…Upon human LFA-3/IgG1 fusion protein administration the LFa-3 binds to CD2 inhibiting T-cell activation and proliferation. The Fc portion extends the circulatory half-life to 11.25 days (Kimchi-Sarfaty et al 2013) in addition to interacting with the FcγRIII receptor on the surface of NK cells which results in NK induced apoptosis of T-lymphocytes (Majeau et al 1994). This overall effect suppresses the immune system and can be used in the treatment of psoriasis, a skin condition that causes skin redness and irritation.…”

Section: Fusion Protein Drugsmentioning

confidence: 99%

Biopharmaceutical Products from Animal Cell Culture

Kuystermans

Al‐Rubeai

2014

Cell Engineering

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Animal cell culture bioprocesses based on mammalian expression systems have given the pharmaceutical industry a means to produce complex glycosylated therapeutic proteins that is projected to be at least a US$500 billion dollar market by 2020. Medicinal products produced by mammalian cell cultures include hormones, enzymes, cytokines, bone morphogenic proteins, clotting factors, antibodies, and fusion protein therapeutics. Activase®, a recombinant thrombolytic enzyme, was the first approved mammalian cell culture drug to be produced from Chinese hamster ovary cell culture and marketed to the public. Over time, other mammalian derived products followed and have evolved from simple replicas of endogenous proteins to complex engineered bio-molecules. Among the existing mammalian expressed biological drugs discussed, that have been produced in the USA and EU till early 2014, monoclonal antibody therapeutics have become the top earning products being over 40 % of products produced. The development of chimeric, humanized and eventually fully human antibodies has also decreased immunogenic reactions in human patients to below 10 %

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Building better drugs: developing and regulating engineered therapeutic proteins

Cited by 81 publications

References 66 publications

Personalized Approaches to the Treatment of Hemophilia A and B

Personalized Approaches to the Treatment of Hemophilia A and B

The intron-22–inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics

Biopharmaceutical Products from Animal Cell Culture

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