PB0719 - The novel bispecific antibody HMB-001 enhances the haemostatic response in models of Glanzmann Thrombasthenia by targeting FVIIa to activated platelets

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Minka Zivkovic, MSc

Ph.D. candidate
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands

Co-Author(s)

PG

Prafull S. Gandhi

Scientific Director
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
Henrik Ostergaard, PhD

Scientific Director
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
EO

Eva H. Olsen

Director
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
CR

Catherine J. Rea

Medical Director
Hemab Therapeutics
41 King George Square, Richmond, England, United Kingdom
BS

Benny Sorensen

CEO
Hemab Therapeutics
Cambridge, Massachusetts, United States
JF

Johan H. Faber

Co-founder & CTO
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
Roger E.G. Schutgens, MD, PhD, MSc

Internist-hematologist, Professor
Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands
SB

Soren E. Bjorn

Co-founder
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
RU

Rolf T. Urbanus

Associate professor
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands

Background: Glanzmann Thrombasthenia (GT) is a severe platelet disorder caused by lack of functional integrin αIIbβ3. Acute bleeds in GT can be managed with recombinant FVIIa (rFVIIa), which enhances thrombin generation in a platelet-dependent manner. HMB-001 is a bispecific antibody that accumulates endogenous FVIIa and recruits it to the surface of activated platelets by binding FVIIa with one arm and the platelet TREM-like transcript 1 (TLT-1) receptor with the other. It thereby aims to restore clot formation in GT and enable long-term bleed prevention.

Aims: To evaluate the potentiation of FVIIa activity by HMB-001 on platelets in GT.

Methods: Platelet TLT-1 expression and plasma FVIIa levels were evaluated in GT patients and healthy controls. Effects of HMB-001 were evaluated with light transmission aggregometry in αIIbβ3-inhibited (GT-like) washed platelets with purified coagulation factors and in GT-like whole blood in a microfluidic flow chamber. Results were confirmed in blood of GT patients. Ethical committee approval was obtained.

Results: TLT-1 expression on activated GT platelets was normal and plasma FVIIa levels in GT patients and healthy controls were similar. Aggregation of activated GT-like platelets was absent, but aggregation occurred when fibrin formation was initiated with rFVIIa. Aggregation onset shortened with increasing FVIIa concentrations. HMB-001 lowered FVIIa requirements for aggregation 10-fold but had no effect in absence of FVIIa. Similar results were obtained with GT platelets. Addition of excess soluble TLT-1 attenuated the effects of HMB-001, confirming that HMB-001 is TLT-1-dependent. Perfusion of recalcified GT-like whole blood over a collagen surface at a shear rate of 300 s-1 resulted in platelet adhesion, but not in fibrin formation. Addition of rFVIIa caused a dose-dependent increase in fibrin formation on adhered GT-like platelets. HMB-001 strongly potentiated FVIIa-dependent fibrin formation on adhered platelets in flowing blood.

Conclusion(s): HMB-001 potentiates FVIIa-dependent fibrin formation on platelets in GT.