Immunomodulation in Primary Immune Thrombocytopenia: A Possible Role of the Fc Fragment of Romiplostim?

Abstract

Fc fusion proteins and Fc fusion peptides or peptibodies are chimeric molecules composed of an active pharmacological protein or peptide and the Fc fragment of an immunoglobulin. The primary aim of this drug construct is to prolong the half-life of the active component. This molecular architecture is seen in drugs, such as etanercept, romiplostim, and the recombinant factor VIII (efmoroctocog alfa). A considerable number of Fc fusion proteins and peptibodies are currently in pre-clinical and clinical development. The isolated effect of the Fc fragment has been studied intensively during last years, but is still poorly understood in the clinical setting and in relation with the active drug and underlying disease. In this short review, we will propose new hypotheses of possible immunomodulatory functions of the Fc fragment of romiplostim in patients with primary immune thrombocytopenia.

Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia

“…The fact that the percentage of responders was similar in patients that received only a single type of TPO-RA indicates that factors other than platelet responses may be involved in the increased TFR observed in romiplostim treated individuals. Whether this is due to the recently proposed hypothesis of tolerogenic properties of romiplostim, attributed to the “carrying” Fc molecule 30 or to additional factors, is still an unanswered question to be unveiled.…”

Romiplostim in adults with newly diagnosed or persistent immune thrombocytopenia

“…Romiplostim is a peptibody that includes a carrier domain (IgG1 Fc portion) and a peptide-containing domain (four peptides, each comprising 14 amino acids, designed to activate the TPO receptor [c-mpl; TPO-R] but avoid production of antibodies that can bind to endogenous TPO) [44][45][46]. The peptides bind to the extracytoplasmic domain of the TPO-R and activate the receptor similarly to that of endogenous TPO, meaning that romiplostim and endogenous TPO compete for receptor binding [45,46].…”

“…Romiplostim is a peptibody that includes a carrier domain (IgG1 Fc portion) and a peptide-containing domain (four peptides, each comprising 14 amino acids, designed to activate the TPO receptor [c-mpl; TPO-R] but avoid production of antibodies that can bind to endogenous TPO) [44][45][46]. The peptides bind to the extracytoplasmic domain of the TPO-R and activate the receptor similarly to that of endogenous TPO, meaning that romiplostim and endogenous TPO compete for receptor binding [45,46]. Romiplostim differs from eltrombopag and avatrombopag in terms of both molecular structure (eltrombopag and avatrombopag are small molecules) and mechanism of action (eltrombopag and avatrombopag are noncompetitive agonists that bind to the transmembrane region of the TPO-R) [45][46][47].…”

“…The peptides bind to the extracytoplasmic domain of the TPO-R and activate the receptor similarly to that of endogenous TPO, meaning that romiplostim and endogenous TPO compete for receptor binding [45,46]. Romiplostim differs from eltrombopag and avatrombopag in terms of both molecular structure (eltrombopag and avatrombopag are small molecules) and mechanism of action (eltrombopag and avatrombopag are noncompetitive agonists that bind to the transmembrane region of the TPO-R) [45][46][47].…”

“…Although TFR may partially reflect spontaneous remissions that are known to occur in ITP patients [22], more specific mechanisms have been proposed. One possible mechanism relates to the antigen-specific tolerogenic responses that could be achieved through the increase in the platelet counts to restore immune homeostasis, an effect that can likely be achieved by any plateletincreasing agent [45]. A possible explanation was proposed by Schifferli et al, who suggested that as platelets have high concentrations of transforming growth factor-β (TGF), the elevation of platelet mass may increase the levels of TGF, inducing tolerance pathways [45].…”