Abstract: The present invention provides von Willebrand Factor-polymer conjugates and Factor VIII-polymer conjugates, each having a releasable linkage. Methods of making conjugates, methods for administering conjugates, are also provided.

Abstract: The present invention relates to a proteinaceous construct (also designated as polymer-VWF-conjugate) comprising plasmatic and/or recombinant von Willebrand factor (VWF), said VWF being bound to at least one physiologically acceptable polymer molecule, as well as to a complex between said proteinaceous construct and at least one factor VIII (FVIII) protein. The physiologically acceptable polymer molecule can be, for instance, polyethylene glycol (PEG) or polysialic acid (PSA). Further the present invention relates to methods for prolonging the in vivo-half-life of VWF or FVIII in the blood of a mammal having a bleeding disorder associated with functional defects of or deficiencies of at least one of FVIII or VWF.

Abstract: The present invention provides albumin-binding probes capable of reversibly linking to short-lived amino-containing drugs and non-covalently associating with albumin in-vivo, thereby converting said drugs into inactive reactivable prodrugs having prolonged lifetime in-vivo. The invention further provides conjugates of said probes with amino-containing drugs, as well as pharmaceutical compositions and uses thereof.

Abstract: The present invention is related to peptides that can be used to reduce the immune response against FVIII or to induce tolerance to human FVIII in patients with, e.g., hemophilia A. Furthermore, the peptides can be used for immunodiagnostic purposes to detect FVIII-specific CD4+ T cells to monitor patients with hemophilia A during replacement therapy and during immune tolerance induction therapy.

Abstract: A method is disclosed for filtering a protein in a liquid mixture in a manner that does not substantially damage or otherwise limit the recovery of the protein in the filtration filtrate. The method generally includes passing a liquid mixture containing a protein (e.g., an aqueous vWF mixture) through a filter while applying a counter pressure to the liquid mixture filtrate to accurately reduce and control the pressure differential across the filter. The disclosed method has the advantage that relatively high filtration flow rates can be achieved at relatively low pressure differentials, in contrast to high pressure differentials, which actually reduce the filtration flow rate of protein liquid mixtures. Further, the method can recover substantially all of the protein that is initially present in the liquid mixture.

Abstract: The present invention provides novel purified and isolated nucleic acid sequences encoding procoagulant-active FVIII proteins. The nucleic acid sequences of the present invention encode amino acid sequences corresponding to known human FVIII sequences, wherein residue Phe309 is mutated. The nucleic acid sequences of the present invention also encode amino acid sequences corresponding to known human FVIII sequences, wherein the APC cleavage sites, Arg336 and Ile562, are mutated. The nucleic acid sequences of the present invention further encode amino acid sequences corresponding to known human FVIII sequences, wherein the B-domain is deleted, the von Willebrand factor binding site is deleted, a thrombin cleavage site is mutated, an amino acid sequence spacer is inserted between the A2- and A3-domains.

Abstract: The present invention relates to a recombinant factor VIII that is characterized by one or more mutations within a region surrounding an activated protein C cleavage site, which one or more mutations result in a reduced rate of inactivation by activated protein C. Isolated nucleic acid molecules, recombinant expression vectors, and host cells suitable for expression of the recombinant factor VIII are also disclosed. The recombinant factor VIII can be used for the treatment of clotting disorders, such as hemophilia A.

Abstract: The invention is directed to a procoagulant conjugate having an endopeptidase-activatable procoagulant protein moiety and one or more bioprotective moieties, which are conjugated to one another by a linker that is cleaved by an endopeptidase in situ to release the bioprotective moiety. The invention is also directed to therapeutic uses of the procoagulant conjugate and methods of making the conjugate.

Abstract: The present invention provides novel methods of increasing the survival of a coagulation protein by inhibiting the interaction with a clearance receptor. The invention also provides methods of preparing compositions that inhibit coagulation protein clearance receptors. Conjugated coagulation proteins, including compositions and formulations thereof, are also provided by the present invention.

Abstract: A Tat-based tolerogen composition comprising at least one immunogenic antigen coupled to at least one human immunodeficiency virus (HIV) trans-activator of transcription (Tat) molecule wherein the immunogenic antigen can be a foreign or endogenous antigen or fragments thereof. Additionally methods of suppressing organ transplant rejection and methods of treating autoimmune diseases are provided.

Abstract: The invention described herein relates to novel molecules and polypeptides comprising at least one amino acid sequence having significant identity with (homology to) human Factor VIII or biologically active portion(s) thereof, related molecules (such as nucleic acids encoding such polypeptides), compositions (such as pharmaceutical formulations) comprising such polypeptides, and methods of making and using such polypeptides.

Abstract: The present invention relates to a proteinaceous construct comprising a blood coagulation factor, e.g., Factor VIII (FVIII), being bound to at least one water soluble polymer, including a poly(alkylene oxide) such as polyethylene glycol (PEG). Further the present invention relates to methods of preparing PEGylated blood coagulation factor, e.g., FVIII, in the presence of bound antibodies. The invention also relates to methods for prolonging the in vivo-half-life of blood coagulation factor, e.g., FVIII, in the blood of a mammal having a bleeding disorder associated with functional defects or deficiencies of blood coagulation factor, e.g., FVIII.

Abstract: Conjugates of a Factor VIII moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.

Abstract: The invention relates to a recombinant factor VIII that includes one or more mutations at an interface of A1 and C2 domains of recombinant factor VIII. The one or more mutations include substitution of one or more amino acid residues with either a cysteine or an amino acid residue having a higher hydrophobicity. This results in enhanced stability of factor VIII. Methods for making the recombinant factor VIII, pharmaceutical compositions containing the recombinant factor VIII, and use of the recombinant factor VIII for treating hemophilia A are also disclosed.

Abstract: The present invention provides von Willebrand Factor-polymer conjugates and Factor VIII-polymer conjugates, each having a releasable linkage. Methods of making conjugates, methods for administering conjugates, are also provided.

Abstract: Conjugates of a Factor VIII moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.

Abstract: The invention relates to stabilized preparations of serine endopeptidases which are suitable for use as a test reagent in a diagnostic procedure or for a therapeutic use. As a result of the addition of various additives, the preparations have improved stability and shelf life.

Abstract: It is an object of the present invention to provide novel binding molecules for factor VIII and factor VIII-like proteins. Preferred binding molecules of the present invention exhibit not only distinct characteristics for binding of the target factor VIII polypeptides but also specific and desirable characteristics for release (elution) of the target polypeptides. Especially preferred binding molecules according to the invention are short polypeptide sequences, characterized by a stable loop structure.

Abstract: The present invention relates, in general, to methods for detecting and quantitating plasma-derived protein and recombinant protein in a sample based on the difference in protein glycosylation, when the plasma protein and the recombinant protein are essentially the same protein.

Abstract: The invention relates to materials and methods of conjugating a water soluble polymer to an oxidized carbohydrate moiety of a therapeutic protein comprising contacting the oxidized carbohydrate moiety with an activated water soluble polymer under conditions that allow conjugation. More specifically, the present invention relates to the aforementioned materials and methods wherein the water soluble polymer contains an active aminooxy group and wherein an oxime or hydrazone linkage is formed between the oxidized carbohydrate moiety and the active aminooxy group on the water soluble polymer, and wherein the conjugation is carried out in the presence of a nucleophilic catalyst.

Abstract: Provided herein are methods and compositions for producing Factor VIII proteins. Such methods include introducing into a cell a nucleic acid molecule encoding a Factor VIII protein operably linked to a promoter, wherein the promoter is characterized by the ability to produce commercially viable Factor VIII protein; and incubating the cell under conditions for producing commercially viable Factor VIII protein. Also provided are nucleic acid molecules which encode a Factor VIII protein operably linked to a Chinese hamster elongation factor 1-? (CHEF1) promoter, which may be used in the methods provided herein.

Abstract: The invention is directed to methods of purifying Fc-containing molecules using a soluble neonatal Fc receptor (sFcRn). Native FcRn binds Fc-containing proteins at or below about pH 6.5 and releases them at or above about pH 7 and provides a much milder approach for capturing and purifying Fc-containing proteins, in particular, therapeutic Fc-containing proteins. Other embodiments of the invention provide modifications to alter the pH for binding and elution to the sFcRn, to modulate Fc-containing protein binding affinity, to affect sFcRn linkage to a support surface, or to improve the stability of sFcRn to conditions utilized in the methods of the invention.

Abstract: The present invention provides a method of administering porcine B-domainless factor VIII (OBI-1) to a patient having factor VIII deficiency to provide more rapid and effective protection against bleeding episodes, compared to formerly available methods, or to provide more effective protection to such patients during non-bleeding periods. This invention is based on the discovery that the recombinant B-domainless porcine fVIII, termed OBI-1, has greater bioavailability compared to the natural porcine fVIII partially purified from porcine plasma, termed HYATE:C. Therefore, the inventive method employs lower unit doses of OBI-1, including, alternatively, omission of antibody-neutralizing dosage, or has longer intervals between the administration, compared to HYATE:C, to provide equivalent protection in patients having fVIII deficiency.

Abstract: The present invention provides polypeptides that include an O-linked glycosylation site that is not present in the wild-type peptide. The polypeptides of the invention include glycoconjugates in which a species such as a water-soluble polymer, a therapeutic agent of a biomolecule is covalently linked through an intact O-linked glycosyl residue to the polypeptide. Also provided are methods of making a glycoconjugate, methods of isolating a glycoconjugate from a reaction mixture, pharmaceutical compositions containing a glycoconjugate, and methods of treating, ameliorating or preventing diseased in mammals by administering an amount of a glycoconjugate sufficient to achieve the desired response.

Abstract: The present invention relates to a drug delivery system for use in the treatment of vascular and vessel-related pathologies, comprising a drug delivery platform that comprises at least one compound capable of exerting an effect on the formation and/or maintenance of a thrombus in the vessel to be treated. The platform is preferably formed by liposomes that are sterically stabilized by grafting of poly(ethylene glycol) onto the liposome surface. The liposomes may further comprise photosensitizers and targeting molecules. The liposomes may be thermosensitive. The compound is suitably tranexamic acid. The drug delivery system is preferably used for the treatment of port wine stains.

Abstract: A Factor VIII derivative of formula (I): wherein: B represents C2 to C10 alkylene; m represents 0 or an integer from 1 to 19, n represents an integer from 1 to 20, and the sum of m and n is from 1 to 20; P represents a mono or polyradical of Factor VIII obtained by removing m+n carbamoyl groups from the side chains of glutamine residues in Factor VIII; and M represents a moiety (M1) that increases the plasma half-life of the Factor VIII derivative or a reporter moiety (M2); or a pharmaceutically acceptable salt thereof.

Abstract: The present invention relates to a proteinaceous construct (also designated as polymer-VWF-conjugate) comprising plasmatic and/or recombinant von Willebrand factor (VWF), said VWF being bound to at least one physiologically acceptable polymer molecule, as well as to a complex between said proteinaceous construct and at least one factor VIII (FVIII) protein. The physiologically acceptable polymer molecule can be, for instance, polyethylene glycol (PEG) or polysialic acid (PSA). Further the present invention relates to methods for prolonging the in vivo-half-life of VWF or FVIII in the blood of a mammal having a bleeding disorder associated with functional defects of or deficiencies of at least one of FVIII or VWF.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention features compositions and methods for site-specific modification of proteins by incorporation of an aldehyde tag. Enzymatic modification at a sulfatase motif of the aldehyde tag through action of a formylglycine generating enzyme (FGE) generates a formylglycine (FGly) residue. The aldehyde moiety of FGly residue can be exploited as a chemical handle for site-specific attachment of a moiety of interest to a polypeptide.

Abstract: There is described a chromatographic purification process that allows highly purified von Willebrand factor (vWF) and Fibronectin (Fn) to be obtained, starting from a biological fraction enriched in vWF and Fn and easily scaled up to industrial level. Chromatographic purification was obtained by a strong anionic exchange resin. The concentrates obtained have a high specific activity and, given the low content of contaminant proteins, are particularly suitable for therapeutic use.

Abstract: A Factor VIII composition formulated without albumin, comprising the following formulation excipients in addition to Factor VIII: 4% to 10% of a bulking agent selected from the group consisting of mannitol, glycine and alanine; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8. Alternatively, the formulation can comprise 2% to 6% hydroxyethyl starch; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule having at least a portion of the B domain intact, which is conjugated to a water-soluble polymer such as polyethylene glycol having a molecular weight of greater than 10,000 Daltons. The construct has a biological activity of at least 80% of the biological activity of native Factor VIII, and the in vivo half-life of the construct is increased by at least 1.5 fold as compared to the in vivo half-life of native factor FVIII.

Abstract: The invention relates to conjugated proteins, in particular but not exclusively, blood coagulation factors, to processes for preparing said conjugates, to pharmaceutical compositions comprising said conjugates and to the use of the conjugates in therapy, in particular but not exclusively, for the treatment of diseases alleviated by blood coagulation factors such as the prophylactic treatment of hemophilia.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: Conjugates of hydroxyalkyl starch and a protein are provided herein. The conjugates are formed by a convalent linkage between the hydroxyalkyl starch or a derivative of the hydroxyalkyl starch and the protein. Methods of producing the conjugates and the use of the conjugates also are provided herein.

Abstract: The present invention provides conjugates having a releasable linkage. Methods of making conjugates, and methods for administering conjugates, are also provided.

Abstract: A complex comprising at least one target protein and at least one binding molecule having a binding affinity for said target protein, wherein said molecule having a binding affinity is covalently or non-covalently bound to at least one water-soluble polymer

Abstract: The present invention relates to modified nucleic acid sequences coding for coagulation factor VIII (FVIII) and for von Willebrand factor (VWF) as well as complexes thereof and their derivatives, recombinant expression vectors containing such nucleic acid sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives coded for by said nucleic acid sequences which recombinant polypeptides and derivatives do have biological activities together with prolonged in vivo half-life and/or improved in vivo recovery compared to the unmodified wild-type protein. The invention also relates to corresponding FVIII sequences that result in improved expression yield. The present invention further relates to processes for the manufacture of such recombinant proteins and their derivatives. The invention also relates to a transfer vector for use in human gene therapy, which comprises such modified nucleic acid sequences.

Abstract: The invention relates to a chimeric protein comprising at least one clotting factor and at least a portion of an immunoglobulin constant region. The invention relates to a method of treating a hemostatic disorder comprising administering a therapeutically effective amount of a chimeric protein wherein the chimeric protein comprises at least one clotting factor and at least a portion of an immunoglobulin constant region.

Abstract: The invention relates to a chimeric monomer-dimer hybrid protein wherein said protein comprises a first and a second polypeptide chain, said first polypeptide chain comprising at least a portion of an immunoglobulin constant region and a biologically active molecule, and said second polypeptide chain comprising at least a portion of an immunoglobulin constant region without the biologically active molecule of the first chain. The invention also relates to methods of using and methods of making the chimeric monomer-dimer hybrid protein of the invention.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.

Abstract: The present invention provides unstructured recombinant polymers (URPs) and proteins containing one or more of the URPs. The present invention also provides microproteins, toxins and other related proteinaceous entities, as well as genetic packages displaying these entities. The present invention also provides recombinant polypeptides including vectors encoding the subject proteinaceous entities, as well as host cells comprising the vectors. The subject compositions have a variety of utilities including a range of pharmaceutical applications.

Abstract: A process of purifying or enriching coagulation FVIII employing chromatography comprising the steps of providing a fraction containing FVIII in an aqueous solution having a high ionic strength; contacting the fraction containing FVIII with a multimodal resin; optionally washing the multimodal resin having FVIII adsorbed with an aqueous washing buffer; eluting FVIII containing fractions by an aqueous elution buffer comprising at least one amino acid which is positively charged at pH 6 to 8; and optionally collecting FVIII containing fractions in purified or enriched form.