Abstract Number: PB0675
Meeting: ISTH 2021 Congress
Background: Current hemophilia A treatments consist of fVIII protein infusions, but up to 30% of patients develop inhibitors to fVIII, rendering subsequent treatments ineffective, and placing the patient at risk of life-threatening bleeding events.
Aims: To develop a cell/gene-therapy product using mesenchymal placental cells (PLC) to enable the delivery of a bioengineered fVIII protein (mcoET3) without eliciting antibody formation.
Methods: PLC were transduced with a lentiviral vector (PLC-mcoET3) to produce high levels of fVIII/mcoET3 (4.9-6 IU/106cells/24hr; VCN: 0.5). PLC-mcoET3 were administered to juvenile sheep: 1) intravenously (IV), weekly, for three weeks at a dose to provide 20IU/kg ET3 each 24 hr (n=3); or 2) a single intraperitoneal (IP) infusion of PLC-mcoET3/kg to provide 60IU/kg ET3 each 24 hr. As a control/reference group, we administered 5 weekly IV injections of 20 IU/kg recombinant ET3 (n=3) protein or hfVIII protein (n=3). FVIII activity was evaluated by aPTT throughout 15 weeks. Formation of ET3/fVIII specific IgG and IgM antibodies was evaluated by ELISA, HLA antibodies assessed with a Luminex assay, and Th1 response with ELISpot assays.
Results: All sheep receiving hfVIII and ET3 protein developed fVIII/ET3-specific IgG antibodies, with titers of 1:20-1:245 that persisted up to 15 weeks. Sheep receiving PLC-mcoET3 IV and IP had 34% and 31% increases in FVIII activity from baseline, respectively, at week 15, demonstrating that PLC-mcoET3 persisted in treated animals. Recipients receiving IV cells did not develop ET3-specific IgM or IgG antibodies. ET3-specific IgG antibodies (titers of 1:20-1:245) were detected in 66% of IP recipients. However, in contrast to those that received proteins, the antibodies declined/disappeared by week 5. ET3-reactive Th1 cells were not present in any of the treated animals. In addition, none of the animals developed anti-HLA antibodies to PLC-mcoET3.
Conclusions: These results show that PLC-mcoET3 can provide an increase in FVIII levels while minimizing immunogenicity.
To cite this abstract in AMA style:Trevisan B, Rodriguez M, George S, Shields J, Lankford S, Combs R, Gautreaux M, Owen J, Atala A, Doering CB, Spencer HT, Porada CD, Almeida-Porada M. Administration of fVIII Protein through Human Placental Cells Reduces the Risk of an Antibody Response in Juvenile Sheep [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/administration-of-fviii-protein-through-human-placental-cells-reduces-the-risk-of-an-antibody-response-in-juvenile-sheep/. Accessed November 29, 2021.
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