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Romiplostim Amgen, BLA #125268

Romiplostim Amgen, BLA #125268. David Frucht, M.D. Product Quality Reviewer Division of Monoclonal Antibodies Office of Biotechnology Products. Cellular Target: TPO Receptor (Mpl). T P O. Thrombopoietin (TPO) :

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Romiplostim Amgen, BLA #125268

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  1. RomiplostimAmgen, BLA #125268 David Frucht, M.D. Product Quality Reviewer Division of Monoclonal Antibodies Office of Biotechnology Products

  2. Cellular Target: TPO Receptor (Mpl) T P O • Thrombopoietin (TPO): • Constitutively synthesized in the liver, released into circulation; degraded following uptake • Binds the TPO receptor (c-Mpl, murine myeloproliferative leukemia proto-oncogene) • Interacts with TPO receptor dimers, leading to activation of the JAK/STAT and MAPK pathways • Activation of STAT and MAPK pathways leads to cellular proliferation and differentiation, respectively • Promotes the viability and growth of megakaryocyte colony-forming cells, increasing platelet production TYK2 JAK2 S T A T 5 S T A T 5

  3. Product History: TPO Receptor Agonists • Two prior therapeutic protein products: • Recombinant human TPO, identical amino acid acid structure to full-length endogenous TPO • Pegylated human recombinant megakaryocyte growth and development factor (PEG-MDGDF), truncated TPO, contains the first 163 amino acid residues coupled to polyethylene glycol • Sustained thrombocytopenia, associated with immunogenic responses that cross-reacted with TPO, in some healthy subjects receiving PEG-MGDF • Development of both products was discontinued, despite evidence that this class of products promoted platelet production in humans • Ongoing effort to develop TPO receptor agonists that do not induce immunogenic responses that cross-react with endogenous TPO

  4. Romiplostim: A New TPO Agonist • A homodimer of 59kD single-chain subunits • Each subunit consists of a human IgG1 Fc domain, linked at its C-terminus to a peptide chain containing two thrombopoietin receptor binding domains; termed a “Peptibody” by Amgen • Receptor binding domain has no homology with TPO

  5. Romiplostim: Mechanism of Action romiplostim TPO Receptor (Mpl) JAK2 TYK2 S T A T 5 S T A T 5 Cell membrane • Romiplostim: • Higher binding affinity than human TPO • Displaces TPO on human platelets • Leads to TPO receptor, JAK2 , Stat5 phosphorylation • Increases megakaryocyte colony formation in vitro

  6. Romiplostim: Manufacturing • Produced in E. coli • Purified using standard bioprocessing technology

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