8CHE

TLT-1 binding Fab of the bispecific antibody HMB-001 in complex with the TLT-1 stalk peptide

Summary for 8CHE

• Entry DOI: 10.2210/pdb8che/pdb
• Descriptor: Fab heavy chain, Fab light chain, Trem-like transcript 1 protein, ... (4 entities in total)
• Functional Keywords: tlt-1, fab, bispecific antibody, hmb-001, blood clotting
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 102035.60

Authors

Johansson, E.,Schluckebier, G. (deposition date: 2023-02-07, release date: 2023-12-27, Last modification date: 2024-09-11)

Primary citation

Gandhi, P.S.,Zivkovic, M.,Ostergaard, H.,Bonde, A.C.,Elm, T.,Lovgreen, M.N.,Schluckebier, G.,Johansson, E.,Olsen, O.H.,Olsen, E.H.N.,de Bus, I.A.,Bloem, K.,Alskar, O.,Rea, C.J.,Bjorn, S.E.,Schutgens, R.E.,Sorensen, B.,Urbanus, R.T.,Faber, J.H.
A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders.
Nat Cardiovasc Res, 3:166-185, 2024

PubMed Abstract: 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.

PubMed: 39196196
DOI: 10.1038/s44161-023-00418-4

Experimental method

X-RAY DIFFRACTION (1.49 Å)