OC 07.2 - Macrophage Galactose Lectin (MGL) is a clearance receptor determining Factor VIII half-life in haemophilia A patients

Saturday, July 9, 2022

1:15 PM – 1:30 PM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: In-Person

Co-Author(s)

SW

Soracha E. Ward, PhD

Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland
TG

Thomas Guest*

PhD Student
Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland
JO

Jamie M. O'Sullivan

Research Lecturer
Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland
AC

Alain Chion, PhD

Postdoctoral Fellow
Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland
JF

Judicael Fazavana

Postdoctoral Fellow
Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland
PF

Padraic G. Fallon

Professor
Trinity College Dublin
Dublin, Dublin, Ireland
RP

Roger Preston

Senior Lecturer
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI)
Dublin, Dublin, Ireland
Jill M. Johnsen, MD

Associate Professor, Division of Hematology
University of Washington, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
Seattle, Washington, United States
Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States
Peter L. Turecek, PhD, PharmD

Professor
Baxalta Innovations GmbH, a Takeda company
Vienna, Wien, Austria

Presenting Author(s)

JO

James S. O'Donnell, MD, PhD

Professor
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland (RCSI)
Dublin, Dublin, Ireland

Background: Although most plasma FVIII circulates in complex with VWF, a minority (3-5%) circulates as free-FVIII which is rapidly cleared. Modelling suggests that 20% of total FVIII is cleared as free-FVIII. Critically, the mechanisms of free-FVIII clearance remain poorly understood. Recent studies have implicated the Macrophage Galactose Lectin (MGL) in modulating VWF clearance.

Aims: Since VWF and FVIII share similar glycosylation, we investigated the role of MGL in FVIII clearance

Methods: FVIII binding to MGL was assessed in immunosorbent and cell-based assays. In vivo FVIII clearance was assessed in MGL-deficient murine models. Finally, VWF-/-/FVIII-/- mice were generated and used to specifically study free-FVIII clearance in the presence or absence of clodronate-induced macrophage depletion or MGL inhibition

Results: In vitro binding studies demonstrated dose-dependent binding of human FVIII to MGL. Sequential exoglycosidase digestions defined a critical role for FVIII O-glycans in regulating MGL interaction. Plasma FVIII levels were significantly higher in MGL1-/- mice compared to wild-type controls (FVIII:C 88.5±10.6 versus 124.0±15.7%; p< 0.05). Combined inhibition of both MGL1 and MGL2 receptors in mice was associated with a further increase in endogenous FVIII (FVIII:C 169.4±15.3%, p< 0.05). To investigate whether MGL contributes to free-FVIII clearance, PK studies were performed in VWF-/-/FVIII-/- mice. Clodronate-induced macrophage depletion inhibited free-FVIII clearance in VWF-/-/FVIII-/- mice (MRT 21.8±2.5 versus 29.7±3.1mins). Interestingly, specific anti-MGL 1/2 blocking also attenuated free-FVIII clearance (MRT 94.8±4.6 mins versus 49.4±3.6; p< 0.001).

Conclusion(s): Cumulatively, these findings demonstrate that MGL plays an important role in regulating macrophage-mediated clearance of both VWF-bound FVIII and free-FVIII in vivo. We propose that this novel FVIII clearance pathway may be of particular clinical importance in patients with type 2N or type 3 VWD. Further studies will be required to determine whether MGL inhibition may afford a novel therapeutic target to extend FVIII half-life