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Lecture 18

CHEM564 Lecture 18: Summmary-Romiplostim

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Christopher Cairo

Romiplostim (AMG 531, Nplate) Romiplostim is a recombinant engineered fusion protein that belongs to peptibodies or peptide-Fc class of antibodies which is an alternative therapeutic format of mAb. The “pepti-” part of peptibodies represent peptide and the “-body” is belong to antibody. Romiplostim is the first approved peptibody for the treatment of ITP (immune thrombocytopenic purpura) which is a low platelet count blood disorder disease that cannot properly clot blood or may be observed as bleeding under the skin or inside the organ because of both antibody-mediated destruction and platelet production imperfection. Romiplostim contains 269 amino acids monomer and is produce1 by recombinant DNA technology in E.coli. Romiplostim’s Design:Production of this drug as a peptibody requires the identification of a desired biologically active bindingpeptide to attach to Fc domain of antibody. Romiplostimis composed of two optimized peptide repeats,Ile-Glu-Gly-Pro-Thr -Leu-Arg-Gln-Trp-Leu-Ala-Ala-Arg-Ala (IEG PTL RQW LAA RA), which the first repeat is fused tofive-glycine linker from the C-term of LgG1’s heavy chainand the second repeat is bound to the first repeat through eight-glycine linker. In a vitro experiment, the data has shown that the best optimized length of polyglycine bridges that has connected to identical peptides is 8. This bridge has the best cellular activity for dipeptides. Glycine/Proline sequences are also a flexible interpeptide bridge. These repeats identified from random peptides in screening library. The 5-glycine linker has been chosen based on computer modeling to simplify peptide-receptor binding. According to the empirical tests, researchers found out that the best linker between the Fc and the peptide contains 5 Glycine residues. 1,2,The attachment of these peptides to Fc undergoes endothelial recirculation, so it preserves not only the features of antibody, but also remarkably increases Romiplostim’s plasma residency time .2,In other words, these peptides conjugate the drug to a partner molecule and extend its residency time in body. The more molar mass the Fc has, the more longevity the antibody wil
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