A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders. / Gandhi, Prafull S.; Zivkovic, Minka; Østergaard, Henrik; Bonde, Amalie C.; Elm, Torben; Løvgreen, Monika N.; Schluckebier, Gerd; Johansson, Eva; Olsen, Ole H.; Olsen, Eva H.N.; de Bus, Ian Arris; Bloem, Karien; Alskär, Oskar; Rea, Catherine J.; Bjørn, Søren E.; Schutgens, Roger E.; Sørensen, Benny; Urbanus, Rolf T.; Faber, Johan H.
I: Nature Cardiovascular Research, Bind 3, Nr. 2, 2024, s. 166-185.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders
AU - Gandhi, Prafull S.
AU - Zivkovic, Minka
AU - Østergaard, Henrik
AU - Bonde, Amalie C.
AU - Elm, Torben
AU - Løvgreen, Monika N.
AU - Schluckebier, Gerd
AU - Johansson, Eva
AU - Olsen, Ole H.
AU - Olsen, Eva H.N.
AU - de Bus, Ian Arris
AU - Bloem, Karien
AU - Alskär, Oskar
AU - Rea, Catherine J.
AU - Bjørn, Søren E.
AU - Schutgens, Roger E.
AU - Sørensen, Benny
AU - Urbanus, Rolf T.
AU - Faber, Johan H.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
AB - Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
U2 - 10.1038/s44161-023-00418-4
DO - 10.1038/s44161-023-00418-4
M3 - Journal article
AN - SCOPUS:85184429737
VL - 3
SP - 166
EP - 185
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
SN - 2731-0590
IS - 2
ER -
ID: 383397919