Phosphatidylserine Containing Liposomes Reduce Immunogenicity of Recombinant Human Factor VIII (rFVIII) in a Murine Model of Hemophilia A**Karthik Ramani and Razvan D. Miclea contributed equally to the manuscript.

Ramani, Karthik; Miclea, Razvan D.; Purohit, Vivek S.; Mager, Donald E.; Straubinger, Robert M.; Balu‐Iyer, Sathy V.

doi:10.1002/jps.21102

Cited by 49 publications

(55 citation statements)

References 54 publications

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“…Therefore, it is important to investigate the role of macromolecular interactions on catabolism and immunogenicity of FVIII. Our previous results showed that FVIII-PS complex reduced inhibitor development (27,28), but molecular details of catabolism of FVIII in vivo could not be clearly understood due to rapid uptake of PS by reticuloendothelial system (RES) (29,30). Here, we have replaced PS with another anionic phospholipid, PI, which resists RES uptake (31), and investigated its effect on the immunogenicity and catabolism of FVIII.…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Peng

Straubinger

Balu‐Iyer

2010

AAPS J

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Abstract. Factor VIII (FVIII) is an important cofactor in blood coagulation cascade. It is a multidomain protein that consists of six domains, NH 2 -A1-A2-B-A3-C1-C2-COOH. The deficiency or dysfunction of FVIII causes hemophilia A, a life-threatening bleeding disorder. Replacement therapy using recombinant FVIII (rFVIII) is the first line of therapy, but a major clinical complication is the development of inhibitory antibodies that abrogate the pharmacological activity of the administered protein. FVIII binds to anionic phospholipids (PL), such as phosphatidylinositol (PI), via lipid binding region within the C2 domain of FVIII. This lipid binding site not only consists of immunodominant epitopes but is also involved in von Willebrand factor binding that protects FVIII from degradation in vivo. Thus, we hypothesize that FVIII-PL complex will influence immunogenicity and catabolism of FVIII. The biophysical studies showed that PI binding did not alter conformation of the protein but improved intrinsic stability as measured by thermal denaturation studies. ELISA studies confirmed the involvement of the C2 domain in binding to PI containing lipid particles. PI binding prolonged the in vivo circulation time and reduced catabolism of FVIII in hemophilia A mice. FVIII-PI complex reduced inhibitor development in hemophilia A mice following intravenous and subcutaneous administration. The data suggest that PI binding reduces catabolism and immunogenicity of FVIII and has potential to be a useful therapeutic approach for hemophilia A.

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Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Peng

Straubinger

Balu‐Iyer

2010

AAPS J

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“…administration, believed to result from rapid uptake by the reticuloendothelial system (RES) (25). Grafting liposomes with polyethylene glycol (PEG) has been shown to prolong liposome circulation in vivo (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Peng

Kosloski

Nakamura

et al. 2011

AAPS J

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Abstract. Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease. Previously, we used phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII-PI formulation resulting from the addition of polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated lipid into the FVIII-PI complex. PEGylated FVIII-PI (FVIII-PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in hemophilia A mice. Following intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII-PI, but exposure determined by area under the curve was reduced. The formation of inhibitory antibodies after subcutaneous immunization with FVIII-PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following intravenous administration. Passive transfer of PEG onto the FVIII-PI complex does not provide any therapeutic benefit.

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“…Our previous studies showed that FVIII complexed with phosphatidylserine (PS) significantly reduced the development of antibody response against FVIII in HA mice (2,3). The studies aimed at understanding the mechanism of this reduction showed that FVIII-PS down-regulated the expression of CD40 upon exposure to bone marrow-derived dendritic cells (DC) (4).…”

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Exposure to Factor VIII Protein in the Presence of Phosphatidylserine Induces Hypo-responsiveness toward Factor VIII Challenge in Hemophilia A Mice

Gaitonde¹,

Ramakrishnan²,

Chin³

et al. 2013

Journal of Biological Chemistry

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Background: Phosphatidylserine (PS) reduces immunogenicity of FVIII by possibly inducing tolerance. Results: FVIII-PS exposure leads to hypo-responsiveness in hemophilia A mice to FVIII challenge but responds normally to ovalbumin. Conclusion: Exposure of FVIII in the presence of PS leads to hypo-responsiveness/tolerance. Significance: An innovative reverse/inverse vaccination could desensitize the patients to antigen.

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Phosphatidylserine Containing Liposomes Reduce Immunogenicity of Recombinant Human Factor VIII (rFVIII) in a Murine Model of Hemophilia A**Karthik Ramani and Razvan D. Miclea contributed equally to the manuscript.

Cited by 49 publications

References 54 publications

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

Phosphatidylinositol Containing Lipidic Particles Reduces Immunogenicity and Catabolism of Factor VIII in Hemophilia A Mice

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Exposure to Factor VIII Protein in the Presence of Phosphatidylserine Induces Hypo-responsiveness toward Factor VIII Challenge in Hemophilia A Mice

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