Factor viia complex using an immunoglobulin fragment
AssigneeHanmi Science Co., Ltd.
InventorsDae Hae Song, Sung In Lim, Chang Hwan Kim, Sung Kap Hong, Dae Seong Im, Se Chang Kwon
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Abstract
Disclosed are a blood coagulation factor complex in which FacVIIa, a non-peptidyl polymer and an immunoglobulin Fc region are bonded by covalent bonds, and the uses thereof. The FacVIIa complex guarantees the in vivo activity of FacVIIa and significantly enhances the serum half life of FacVIIa, so that it is useful for developing long-acting FacVIIa formulations which can improve the compliance of role behavior of patients whose blood does not coagulate.
Claims32
A FacVIIa complex, comprising FacVIIa linked to an immunoglobulin Fc region via a non-peptidyl polymer, said non-peptidyl polymer being selected from the group consisting of polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, biodegradable polymers, lipid polymers, chitins, hyaluronic acid, and a combination thereof.
A method for preparing the FacVIIa complex, comprising:
- (1) linking a non-peptidyl polymer having an aldehyde, maleimide or succinimide derivative as a functional group at a terminal to an amine or thiol group of an immunoglobulin Fc region via a covalent bond to give a conjugate;
- (2) isolating the non-peptidyl polymer-immunoglobulin Fc region conjugate from the reaction mixture of step (1);
- (3) covalently linking FacVII to another end of the non-peptidyl polymer of the isolated conjugate to afford a FacVII complex in which the non-peptidyl polymer is linked at one end to the immunoglobulin Fc region and at another end to FacVII;
- and
- (4) activating the FacVII complex of step (3) into a FacVIIa complex in which FacVIIa is linked to the immunoglobulin Fc region via the non-peptidyl polymer.
A method for preparing the FacVIIa complex, comprising:
- (1) linking a non-peptidyl polymer having an aldehyde group at each terminus to the N-terminus of an immunoglobulin Fc via a covalent bond at a pH of 5.0 to 7.0 to give an immunoglobulin-non-peptidyl polymer conjugate;
- (2) isolating the conjugate from the reaction mixture of step (1);
- (3) covalently linking FacVII to another end of the non-peptidyl polymer of the conjugate to form a FacVII complex in which the non-peptidyl polymer is linked at one end to the immunoglobulin Fc region and at another end to FacVII;
- and
- (4) activating the FacVII complex of step (3) into a FacVIIa complex in which FacVIIa is linked to the immunoglobulin Fc region via the non-peptidyl polymer.
Dependencies are inferred from the claim text.