OC 06.4 - Therapeutic efficacy of a novel humanized anti-ADAMTS13 antibody to treat left ventricular assist device-induced acquired von Willebrand syndrome

Saturday, June 24, 2023

13:45 – 14:00 ET

Room: 510

Session Available As: On-Demand

Presenting Author(s)

Shannen J. Deconinck, PhD

Dr.
Laboratory for Thrombosis Research, KU Leuven Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium

Co-Author(s)

CN

Christoph Nix

Eng.
Abiomed Europe GmbH, Aachen, Germany
Aachen, Nordrhein-Westfalen, Germany
EB

Eveline Bennek-Schöpping

Dr.
Abiomed Europe GmbH, Aachen, Germany
Aachen, Nordrhein-Westfalen, Germany
AS

An-Sofie Schelpe

Dr.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
IP

Inge Pareyn

BSc.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
Joshua Muia, PhD

Prof., Dr.
Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
Tulsa, Oklahoma, United States
BM

Bart Meyns

Prof., Dr., MD
Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
CT

Claudia Tersteeg

Prof., Dr.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
SD

Simon F. De Meyer

Prof., Dr., Eng.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
SJ

Steven Jacobs

Prof., Dr., MD
Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
Karen Vanhoorelbeke, PhD

Prof., Dr.
KU Leuven
Kortrijk, West-Vlaanderen, Belgium

Background: Bleeding is a frequent complication in left ventricular assist device (LVAD) patients and is linked to the occurrence of acquired von Willebrand syndrome (aVWS). LVADs cause an increased shear-induced proteolysis of von Willebrand factor (VWF) mediated by ADAMTS13, leading to aVWS. We developed a murine anti-ADAMTS13 monoclonal antibody (mAb) 17C7 as a novel therapeutic agent and showed that this mAb efficiently treated LVAD-induced aVWS in a preclinical LVAD calf model. Generation of humanized mAb 17C7 and testing its therapeutic efficacy is needed to advance our drug towards the clinic.

Aims: To generate humanized 17C7 and study its therapeutic efficacy in our validated LVAD-induced aVWS calf model.

Methods: Nine different variants (combination of 2 heavy and 5 light chain modifications) were generated by grafting the murine CDRs on a human acceptor framework. The binding affinity (Kd) of all variants was determined via ELISA and the inhibitory activity was analyzed using the FRETS-VWF73 assay. Next, the optimal variant was selected and tested in our preclinical LVAD calf model.

Results: All humanized variants could efficiently bind to human ADAMTS13 with comparable binding affinities as the murine mAb. Moreover, humanization did not impact the inhibitory potential of all variants. The most human-like variant with the highest binding affinity (Kd= 0.4 µg/mL, IC50= 0.6 µg/mL) was selected. Similar to our previous results with the murine mAb, the loss of HMW VWF multimers after pump implantation could be rescued upon injection of the humanized mAb 17C7. As expected, ADAMTS13 activity was completely blocked after injecting one dose (600 µg/kg) of the humanized mAb. Importantly, no severe thrombocytopenia nor hemolytic anemia was observed.

Conclusion(s): We confirmed that humanization did not impact the therapeutic efficacy of our drug. Hence, our humanized anti-ADAMTS13 mAb could become a promising therapy to treat aVWS-induced bleeding in LVAD patients.

Learning Objectives:

learn that ADAMTS13-mediated proteolysis plays a major role in the development of aVWS in LVAD patients
conclude that blocking ADAMTS13 can rescue aVWS in calves with a heart pump
recognize that humanization did not affect the therapeutic efficacy of the novel drug