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Administration of fVIII Protein through Human Placental Cells Reduces the Risk of an Antibody Response in Juvenile Sheep

1Fetal Research and Therapy Program, Wake Forest Institute for Regenerative Medicine, Winston Salem, United States, 2Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Dpt. of Pediatrics, Emory University, Atlanta, United States, 3Special Hematology Laboratory, Wake Forest School of Medicine, Winston Salem, United States, 4HLA/Immunogenetics and Immunodiagnostics Laboratories, Wake Forest School of Medicine, Winston Salem, United States

Abstract Number: PB0675

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia

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, 2023.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/administration-of-fviii-protein-through-human-placental-cells-reduces-the-risk-of-an-antibody-response-in-juvenile-sheep/