Design of therapeutic proteins
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recombinant DNA technology has lead to considerable advances in the manufacture of proteins for therapeutic use
- joining of 2 or more genes can be used to generate FUSION PROTEINS, which can have novel functions
- an example of a naturally occurring fusion protein is the Bcr-Abl protein which results from the translocation of two chromosomes (see chronic myeloid leukemia treatment)
- an example of a synthetic fusion protein is DENILEUKIN DIFTITUX, a drug used to treat cutaneous T-cell lymphoma
- modifications of therapeutic proteins improve efficacy, and overcome the limitations of native peptides
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PEGylation: the addition of polyethylene glycol (PEG) moieties significantly increases half-life and "masks" the drug from the host's immune system, resulting in decreased immunogenicity and antigenicityApproved PEG'd Drugs
in related lecturesL-asparaginase PEG-liposome containing doxorubicin Interferon α Methoxy polyethylene
glycol epoetinPegfilgrastim - so far, 12 drugs have been approved; the ones that I'll lecture about are listed in the table
- Radiolabelled tags: added to increase the cell kill induced by antineoplastic antibodies, and to allow visualization of the extent of malignancies
- Peptibodies: the newest modification is to use the structure of antibodies as a scaffold to build proteins that interact with a receptor, without activating the immune system
- the first of these "peptibodies" --- ROMIPLOSTIM (a megakaryocyte growth factor) was approved for clinical use in 2008
- several others are in phase 3 clinical trials
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