Hamostaseologie 2024; 44(S 01): S79-S80
DOI: 10.1055/s-0044-1779182
Abstracts
Topics
T-12. Gene and cell therapy

Immunoadsorption plasmapheresis for the removal of plasma immunoglobulins to enable repeat dose administration with an AAV5 gene therapy vector

B. Long
1   BioMarin Pharmaceutical Inc., Novato, USA
,
B. Hock
1   BioMarin Pharmaceutical Inc., Novato, USA
,
C. O'Neill
1   BioMarin Pharmaceutical Inc., Novato, USA
,
J. Arens
1   BioMarin Pharmaceutical Inc., Novato, USA
,
T. Seitel
1   BioMarin Pharmaceutical Inc., Novato, USA
,
L. Crockett
1   BioMarin Pharmaceutical Inc., Novato, USA
,
F. Relouzat
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
C.-M. Fovet
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
N. Dereuddre-Bosquet
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
P. Maisonnasse
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
H. Letscher
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
R. Le Grand
2   Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob, Fontenay-aux-Roses, France
,
C. Vettermann
1   BioMarin Pharmaceutical Inc., Novato, USA
,
S. Gupta
1   BioMarin Pharmaceutical Inc., Novato, USA
› Author Affiliations
 
 

    Introduction The investigation of adeno associated virus (AAV) vectored gene therapies has increased exponentially over the past decade for the treatment of monogenic disorders. However, the presence of pre-existing anti-AAV neutralizing antibodies (AAV NAb) may limit the efficacy of gene therapy. Moreover, a first administration of an AAV vector induces high titers of treatment emergent AAV NAb, which may compromise repeat dose administration with the same vector. Depletion of AAV NAb by immunoadsorption plasmapheresis (IAP) is a strategy that could allow successful vector administration in recipients with either pre-existing or treatment-emergent antibodies. The objective of this study was to evaluate the effectiveness of IAP to remove AAV serotype 5 (AAV5) NAb from animals sensitized by an initial gene therapy dose.

    Method Five cynomolgus macaques (Macaca fascicularis) were included in this study; four were sensitized by administration of an AAV5 capsid encoding for the beta subunit of cyno chorionic gonadotropin (AAV5-βCG) at a dose of 6E13vg/kg, and one control animal was naïve. All were subjected to IAP for a minimum of 1 day of 4 runs (plasma volume exchanges) to a maximum of 3 days of 3 runs. All 5 animals were challenged with the exact same AAV5 capsid encoding a different protein, human factor IX (AAV5-hFIX) at a dose of 6E13 vg/kg, administered within 10 minutes of the last run IAP. Efficacy of the IAP procedure was functionally evaluated by laboratory measures of plasma IgG and AAV5 total binding antibody (AAV5 TAb) titer, hFIX plasma protein concentration, and quantitation of vector genomes and transcripts in liver tissue.

    Results Maximal depletion of AAV5 TAb titer (>99%) was achieved in two animals resulting in a nadir titer of 61 and 59. These two animals achieved approximately 25% and 50% of hFIX plasma protein levels, respectively, compared to the naïve animal (0.8 IU/mL), and a proportional percentage of vector genome copies measured in liver tissue compared to the naïve animal (1.6 x 107 cp/mg tissue). Following a variable number of IAP sessions (plasma volume exchanges over consecutive days) and administration of the AAV5-hFIX challenge dose, there was significant perturbation of hematological and biochemical blood parameters; however, all parameters returned to baseline levels within hours or days of the procedure.

    Conclusion These results demonstrate the viability of IAP as an immune modulation procedure to deplete AAV5 capsid-specific antibody titers sufficient to allow repeat dose administration. As such, IAP may enable AAV-based vector gene therapy in patients currently excluded from gene therapy clinical trials or commercial product use due to pre-existing antibodies. Furthermore, additional evaluation of the efficacy of this procedure may be worthwhile in subjects with pre-existing antibody titers resulting from natural exposure to AAV infections, which result in lower antibody titers than the treatment-emergent titers observed here.


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    Conflict of Interest

    Brian R. Long, Benjamin M. Hock, Charles A. O’Neill, Jeremy Arens, Theresa Seitel, Lucy Crockett, Christian Vettermann and Soumi Gupta are employees and shareholders of BioMarin Pharmaceutical Inc. Francis Relouzat, Claire-Maëlle Fovet, Nathalie Dereuddre-Bosquet, Pauline Maisonnasse, Helene Letscher, Roger Le Grand are employees of Commissariat à l’Energie Atomique et aux Energies Alternatives, IMVA-IDMIT Center DRF/Institut de Biologie François Jacob.

    Publication History

    Article published online:
    26 February 2024

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