title: A TPO receptor agonist, ALXN4100TPO, mitigates radiation-induced lethality and stimulates hematopoiesis in CD2F1 mice.
abstract: Thrombopoietin (TPO) receptor agonists lacking sequence homology to TPO were designed by grafting a known peptide sequence into the hinge and/or kappa constant regions of a human anti-anthrax antibody. Some of these proteins were equipotent to TPO in stimulating cMpl-r activity in vitro and in increasing platelet levels in vivo. ALXN4100TPO (4100TPO), the best agonist in this series with a K(d) of 30 nM for cMpl-r, exhibited potent activity as a radiation countermeasure in CD2F1 mice exposed to lethal total-body radiation from a cobalt-60 γ-ray source. 4100TPO (2 mg/kg, s.c.) administered once either 24 h before or 6 h after TBI showed superior protection to five daily doses given before or after TBI. Prophylactic administration (69 to 94% survival) was superior to therapeutic schedules (60% survival). 4100TPO conferred a significant survival benefit (P < 0.01) when administered 4 days before or even 12 h after exposure and across a dose range of 0.1 to 8 mg/kg. The dose reduction factors (DRFs) with a single dose of 1 mg/kg 4100TPO 24 h before or 12 h after TBI were 1.32 and 1.11, respectively (P < 0.0001). Furthermore, 4100TPO increased bone marrow cellularity and megakaryocytic development and accelerated multi-lineage hematopoietic recovery in irradiated mice, demonstrating the potential of 4100TPO as both a protector and a mitigator in the event of a radiological incident.
authors.affiliation: Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, Maryland 20889 USA. satyamitra@afrri.usuhs.mil
authors.forename: Merriline
authors.initials: M
authors.lastname: Satyamitra
authors.forename: Eric
authors.initials: E
authors.lastname: Lombardini
authors.forename: John
authors.initials: J
authors.lastname: Graves
authors.forename: Conor
authors.initials: C
authors.lastname: Mullaney
authors.forename: Patrick
authors.initials: P
authors.lastname: Ney
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hunter
authors.forename: Krista
authors.initials: K
authors.lastname: Johnson
authors.forename: Paul
authors.initials: P
authors.lastname: Tamburini
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Springhorn
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Srinivasan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D034061:Thrombopoiesis / Q000187:drug effects; D013926:Thrombopoietin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C559765:ALXN4100TPO; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011837:Radiation-Protective Agents; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin