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 Kd 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 g 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.
Radiation research