Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/36—Blood coagulation or fibrinolysis factors
  • A61K38/37—Factors VIII
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
  • A61K38/482—Serine endopeptidases (3.4.21)
  • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

• Factor VIII is a 265 kD single chain protein which circulates in a complex with von Willebrand factor (VWF).
• VWF von Willebrand factor
• Factor VIII is an important regulatory protein in the blood coagulation cascade. After activation by thrombin, it accelerates the rate of factor X activation by activated factor IX (factor IXa), eventually leading to the formation of the fibrin clot.
• the VWF molecule is an adhesive glycoprotein that plays a central role in platelet agglutination. It serves as a carrier for factor VIII in plasma and facilitates platelet- vessel wall interactions.
• VWF is made up of multiple, probably identical, subunits each of about 230 kD. VWF is synthesized in endothelial cells and megakaryocytes.
• CD80 and CD86 (B7-2) proteins expressed on APCs, are critical costimulatory molecules (Freeman et al. 1991. J. Exp. Med. 174:625; Freeman et al. 1989 J. Immunol. 143:2714; Azuma et al. 1993 Nature 366:76; Freeman et al. 1993. Science 262:909). B7-2 appears to be more significant during primary immune responses, while
• CTLA4 than for CD28 (Linsley, P.S., et al, 1991 J. Exp. Med. 174, 561-569) and B7-1 and B7-2 have been found to bind to distinct regions of the CTLA4 molecule and have different kinetics of binding to CTLA4 (Linsley et al. 1994. Immunity. 1 :793).
• the subject compositions further comprise a pharmaceutically acceptable carrier.
• the first agent is factor VIII. In another embodiment, the first agent is a B-domain deleted variant of factor VIII. In one embodiment, the first agent is factor IX. In another embodiment, the first agent is Von Willebrand factor.
• the second agent is a soluble form of a costimulatory molecule.
• the second agent is a soluble form of CTLA4.
• the second agent is a soluble form of B7-1, a soluble form of B7-2, or a combination of a soluble form of B7-1 and a soluble form of B7-2.
• the second agent is CTLA4Ig.
• the second agent is B7-lIg or B7-2Ig.
• the second agent is a soluble form of CD40 or CD40L.
• the second agent is an antibody which binds to a costimulatory molecule.
• the second agent is selected from the group consisting of an anti-B7-l antibody, anti-B7-2 antibody, and a combination of an anti-B7-l and an anti-B7-2 antibody.
• the antibody is a non- activating form of an anti-CD28 antibody.
• the subject has a significant titer of antibodies which bind to the first agent. In another embodiment, the subject does not have a significant titer of antibodies which bind to the first agent.
• the methods comprise administering a composition comprising an agent which inhibits a costimulatory signal in a T cell.
• the hemostatic disorder is selected from the group consisting of hemophilia A, hemophilia B, and von Willebrand's disease.
• the invention pertains to methods of treating a hemostatic disorder in a subject comprising administering to the subject a first agent which promotes hemostasis and a second agent which inhibits a costimulatory signal in a T cell, such that a hemostatic disorder is treated.
• the invention pertains to methods of treating a hemostatic disorder in a subject comprising administering to the subject a first agent which promotes hemostasis and a second agent which inhibits a costimulatory signal in a T cell, such that immunotolerance to the first agent occurs thereby treating a hemostatic disorder.
• the first agent is factor VIII.
• the first agent is a B-domain deleted variant of factor VIII.
• the first agent is factor IX.
• the first agent is Von Willebrand factor.
• the second agent is a soluble form of an agent which delivers a costimulatory signal to a T cell.
• the agent is a soluble form of CTLA4.
• the agent is CTLA4Ig.
• the agent is a soluble form of B7-1, a soluble form of B7-2 or a combination of both B7-1 and B7-2.
• the agent is B7-lIg, B7-2Ig, or a combination of both B7-lIg and B7-2Ig.
• the hemostatic disorder is selected from the group consisting of hemophilia A, hemophilia B, and von Willebrand's disease.
• the subject has a significant titer of antibodies which bind to the first agent.
• Figure 3 illustrates the experimental design used for Example 2 to test the inhibition of secondary antibody responses to factor VIII.
• Figure 5 shows the effect of mCTLA4-Ig on anti-factor VIII antibody formation.
• Figure 6 shows the effect of repeated administration of mCTLA4-Ig on anti-factor VIII antibody formation.
• Figure 7 shows the effect of simultaneous administration of mCTLA4-Ig and factor VIII.
• Figure 8 shows the effect of mCTLA4-Ig on the secondary immune response to factor VIII.
• agent which promotes hemostasis includes a protein or polypeptide which is deficient or deleted in a subject and which, when administered to the subject, ameliorates or treats a hemostatic disorder.
• agents which promote hemotstasis include coagulation factors such as Factor VIII, Factor IX, VWF and analogs thereof.
• B7 polypeptides are capable of providing costimulation to activated T cells to thereby induce T cell proliferation and/or cytokine secretion or of inhibiting costimulation of T cells, e.g., when present in soluble form.
• B7 family members include B7-1, B7-2 , and soluble fragments or derivatives thereof.
• B7 family members bind to CTLA4, CD28, ICOS, and/or other ligands on immune cells and have the ability to inhibit or induce costimulation of immune cells.
• An agent which inhibits a costimulatory signal can act either extracellularly to inhibit the interaction between costimulatory molecules, thus blocking the production of intracellular signals, or can act intracellularly to inhibit costimulatory signals in a signal transduction pathway.
• agents are described in further detail herein and include, for example, soluble forms of costimultory molecules and antibodies which bind to costimulatory molecules.
• the phrase "downmodulation of the immune response” includes reduction in an immune response (e.g., suppression, dampening, or inhibition) in a patient that does not have an existing immune response or reduction in the length and magnitude of an existing immune response.
• an agent which promotes hemostasis is a factor VIII protein in which at least one domain (e.g., a nonessential domain) of the protein has been deleted.
• a factor VIII protein is a modified factor VIII protein in which one or more amino acids have been deleted or substituted between the 90 Kd and 69 Kd cleavage sites with respect to native factor VIII, as described in greater detail in United States Patent 4,868,112, the contents of which are incorporated herein by reference.
• the agent which promotes hemostasis is a factor VIII analog containing a deletion(s) of one or more amino acids between the 50/40 cleavage site and the 73 kD cleavage site which may be produced by methods analogous to those disclosed in United States Patent 4,868,112, the contents of which are hereby incorporated by this reference.
• a factor VIII analog retains part or all of the acidic amino acid region between the 80 kD and the 73 kD cleavage sites. In other embodiments part or all of this region is replaced with the corresponding acidic region immediately adjacent to the 50/40 cleavage site.
• factor VIII proteins are analogs (with or without deletions as mentioned above) such as are disclosed in International Application PCT/US87/01299 (the contents of which are incorporated herein by reference), e.g. wherein one or more of the cleavage sites spanning arginine residues at positions 226, 336, 562, 740, 776, 1313, 1648 or 1721 have been rendered resistant to proteolytic cleavage, e.g., by replacement of one or more amino acids with different amino acids by mutagenesis of the cDNA using techniques known in the art, e.g., standard site directed mutagenesis.
• factor IX also includes non-naturally occurring forms, e.g., mutant forms of factor IX which retain the therapeutic, e.g., hemostasis promoting properties of factor IX.
• non-naturally occurring forms e.g., mutant forms of factor IX which retain the therapeutic, e.g., hemostasis promoting properties of factor IX.
• DNA sequences capable of hybridizing to DNA encoding human factor IX under conditions that avoid hybridization to non-factor IX genes e.g., under conditions equivalent to
• Factor VIII or factor IX proteins can also be purchased commercially.
• concentrated forms of factor VIII are available, e.g., Immunate® (Immuno), Beriate® (Behring); monoclonal antibody purified forms of factor VIII are available e.g., Octanativ-M® (Pharmacia), Hemofil M® (Baxter), and Monoclate-P® (Armour); and recombinant forms of factor VIII are also available, e.g., Recombinate® (Baxter) and Kogenate® (Bayer).
• a recombinant B-domain-deleted form of factor VIII, r-VIII SQ® (Pharmacia and Upjohn, Sweden) is also available.
• factor VWF also includes non-naturally occurring forms, e.g., mutant forms of factor VWF which retain the therapeutic properties, e.g., hemostasis promoting properties of factor VWF.
• DNA sequences which retain sequence identity over regions of the nucleic acid molecule which encode protein domains which are important in factor VWF function can be used to produce factor VWF proteins within the scope of the invention.
• the agents which promote hemostasis are mammalian in origin. In a preferred embodiment, the agents which promote hemostasis are porcine in origin. In yet another more preferred embodiment, the agents for which promote hemostasis are human in origin. In another embodiment the agent which promotes hemostasis are hybrid molecules.
• DNA sequences which retain sequence identity over regions of the nucleic acid molecule which encode protein domains which are important in costimulatory molecule function, e.g., binding to other costimultory molecules, can be used to produce costimulatory proteins which can be used as agents which inhibit a costimulatory signal in a T cell.
• nonnaturally occurring costimulatory molecules have significant (e.g., greater than 70%, preferably greater than 80%, and more preferably greater than 90-95%) amino acid identity with a naturally occurring amino acid sequence of a costimulatory molecule extracellular domain.
• a soluble CTLA4 protein comprises the extracellular domain of a CTLA4 protein.
• a soluble, recombinant form of the extracellular domain of CTLA4 has been expressed in yeast (Gerstmayer et al. 1997. FEBS Lett. 407:63).
• the soluble CTLA4 proteins comprise at least a portion of the extracellular domain of CTLA4 protein which retains the ability to bind to B7-1 and/or B7-2.
• the soluble CTLA4 protein or portion thereof is a fusion protein comprising at least a portion of CTLA4 which binds to B7-1 and/or B7-2 and at least a portion of a second non-CTLA4 protein.
• a mammal e.g., a mouse, hamster, or rabbit
• an immunogenic form of the costimulatory protein or peptide which elicits an antibody response in the mammal.
• the immunogen can be, for example, a recombinant costimulatory molecule protein, or fragment thereof, a synthetic peptide fragment or a cell that expresses a costimulatory molecule on its surface.
• the cell can be, for example, an antigen presenting cell, or a T cell, or a cell transfected with a nucleic acid encoding a costimulatory molecule such that the costimulatory molecule is expressed on the cell surface.
• Vector DNA can be introduced into mammalian cells via conventional techniques such as calcium phosphate or calcium chloride co -precipitation, DEAE-dextran-mediated transfection, lipofectin, or electroporation. Suitable methods for transforming host cells can be found in Sambrook et a (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory press (1989)), and other laboratory textbooks.
• the expression vector's control functions are often provided by viral material. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and most frequently, Simian Virus 40.
• Antibodies may either be polyclonal or monoclonal antibodies, or antigen binding fragments of such antibodies.
• antibodies that inhibit binding of a costimulatory molecule with its natural ligand(s) on the surface of immune cells, thereby inhibiting costimulation of the immune cell.
• Preferred anti-costimulatory molecule antibodies are those capable of inhibiting or downregulating T cell mediated immune responses by binding B7-2 or B7- 1 on the surface of B lymphocytes and preventing interaction with CTLA4 and/or CD28.
• costimulatory molecule for immunization
• synthetic peptides can alternatively be employed towards which antibodies can be raised for use this invention.
• Both soluble and membrane bound costimulatory molecule or peptide fragments are suitable for use as an immunogen and can also be isolated by immunoaffmity purification as well.
• a purified form of a costimulatory molecule protein such as may be isolated as described above or as known in the art, can itself be directly used as an immunogen, or alternatively, can be linked to a suitable carrier protein by conventional techniques, including by chemical coupling means as well as by genetic engineering using a cloned gene of the a costimulatory molecule.
• the purified costimulatory molecule protein can also be covalently or noncovalently modified with non-proteinaceous materials such as lipids or carbohydrates to enhance immunogenecity or solubility.
• a purified costimulatory molecule protein can be coupled with or incorporated into a viral particle, a replicating virus, or other microorganism in order to enhance immunogenicity.
• the costimulatory molecule protein may be, for example, chemically attached to the viral particle or microorganism or an immunogenic portion thereof.
• cross-linking agents are heterobifunctional cross-linkers, which can be used to link proteins in a stepwise manner.
• heterobifunctional cross-linkers include succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC), m-Maleimidobenzoyl-N- hydroxysuccinimide ester (MBS); N-succinimidyl (4- iodoacetyl) aminobenzoate (SIAB), succinimidyl 4-(p-maleimidophenyl) butyrate (SMPB), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC); 4- succinimidyloxycarbonyl- a-methyl-a-(2-pyridyldithio)-tolune (SMPT), N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), succinimidyl 6-[3-(2-pyridyldithi
• Polycolonal antibodies to a purified costimulatory molecule protein or peptide having a costimulatory molecule activity can generally be raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of a costimulatory molecule immunogen, such as the extracellular domain of a costimulatory molecule protein, and an adjuvant.
• a costimulatory molecule immunogen such as the extracellular domain of a costimulatory molecule protein
• an adjuvant for example, as described above, it may be useful to conjugate a costimulatory molecule (including fragments containing particular eptitope(s) of interest) to a protein that is immunogenic in the species to be immunized, e.g., keyhole limpet hemocyanin, serum albumin.
• animals are typically immunized against the immunogenic costimulatory molecule conjugates or derivatives by combining about l ⁇ g to lmg of conjugate with Freund's complete adjuvant and injecting the solution intradermally at multiple sites.
• the animals are boosted with 1/5 to 1/10 the original amount of conjugate in Freund's complete adjuvant (or other suitable adjuvant) by subcutaneous injection at multiple sites.
• the animals are bled and the serum is assayed for anti- costimulatory molecule titer. Animals are boosted until the titer plateaus.
• Such mammal-produced populations of antibody molecules are referred to as "polyclonal" because the population comprises antibodies with differing immunospecificities and affinities for a costimulatory molecule.
• the antibody molecules are then collected from the mammal and isolated by well known techniques such as, for example, by using DEAE Sephadex to obtain the IgG fraction.
• the antibodies may be purified by immunoaffinity chromatography using solid phase-affixed immunogen.
• the antibody is contacted with the solid phase-affixed immunogen for a period of time sufficient for the immunogen to immunoreact with the antibody molecules to form a solid phase-affixed immunocomplex.
• the bound antibodies are separated from the complex by standard techniques.
• a suspension of antibody-producing cells removed from each immunized mammal secreting the desired antibody is then prepared. After a sufficient time, the mouse is sacrificed and somatic antibody-producing lymphocytes are obtained.
• Antibody-producing cells may be derived from the lymph nodes, spleens and peripheral blood of primed animals. Spleen cells are preferred, and can be mechanically separated into individual cells in a physiologically tolerable medium using methods well known in the art.
• Mouse lymphocytes give a higher percentage of stable fusions with the mouse myelomas described below. Rat, rabbit and frog somatic cells can also be used.
• variable region PCR primers the variable regions of both heavy and light chains are amplified, each alone or in combinantion, and ligated into appropriate vectors for further manipulation in generating the display packages.
• Oligonucleotide primers useful in amplification protocols may be unique or degenerate or incorporate inosine at degenerate positions. Restriction endonuclease recognition sequences may also be incorporated into the primers to allow for the cloning of the amplified fragment into a vector in a predetermined reading frame for expression.
• Hybridomas and Methods of Preparation are those characterized as having the capacity to produce a monoclonal antibody which will specifically immunoreact with a costimulatory molecule.
• the hybridoma cell producing anti-costimulatory molecule antibody can be directly implanted into the recipient animal in order to provide a constant source of antibody.
• the use of immuno-isolatory devices to encapsulate the hybridoma culture can prevent immunogenic response against the implanted cells, as well as prevent unchecked proliferation of the hybridoma cell in an immunocompromised host.
• a preferred hybridoma of the present invention is characterized as producing antibody molecules that specifically immunoreact with a costimulatory molecule expressed on the cell surfaces of activated human B cells.
• antibody as used herein is intended to include fragments thereof which are also specifically reactive with a costimulatory molecule as described herein.
• Antibodies can be fragmented using conventional techniques and the fragments screened for utility in the same manner as described above for whole antibodies. For example, F(ab')2 fragments can be generated by treating antibody with pepsin. The resulting fragments thereof.
• the agent which inhibits a costimulatory signal in a T cell is an antibody which binds to B7-1.
• Such antibodies are known in the art or can be made as set forth above using a B7-1 molecule or a portion thereof as an immunogen and screened using the methods set forth above or other standard methods. Examples of B7-
• Wortmannii (Kyowa Hakko Kohyo Co. Ltd.) or from P. fumiculosum (Sigma).
• Wortmannin derivatives or analogues include compounds structurally related to wortmannin which retain the ability to inhibit PI3K and T cell responses. Examples of wortmannin derivatives and analogues are disclosed in Wiesinger, D. et al. (1974) Experientia 30:135-136; Closse, A. et al. (1981) J Med. Chem. 24:1465-1471; and Baggiolini, M. et al. (1987) Exp. Cell Res. 169:408-418.
• Signal 2 is delivered by antigen presenting cells bearing a B7 molecule.
• Potential blocking agents can be tested at a range of concentrations.
• potential blocking antibodies can be used as hybridoma supernatants or as purified antibody (e.g., at about lO ⁇ g/ml).
• Proliferation of T cells can be measured by ⁇ H- thymidine (l ⁇ Ci) incorporation for the last 12-18 hours of a 72 hour incubation.
• the delivery of a primary activation signal should result in some proliferation, but T cells receiving both the primary activation signal and costimulatory signal 2, signals should proliferate maximally. Blocking agents are identified by their ability to reduce the maximal, costimulatory signal induced proliferation.
• a first agent which promotes hemostasis and a second agent which inhibits or blocks a costimulatory signal in a T cell are used to treat a hemostatic disorder.
• compositions comprising a combination of a first agent which promotes hemostasis and a second agent which inhibits a costimulatory signal in a T cell can be used to treat a hemostatic disorder.
• staggered administration may be desirable to achieve optimal therapeutic effect of the agent which promotes hemostasis, while optimally inhibiting the immune response, preferably an antibody response, to the agent.
• an agent which inhibits a costimulatory signal can be administered alone prior to administration of an agent which promotes hemostasis, or can be administered alone for several days after administering an agent that promotes hemostasis.
• Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, asorbic acid, thimerosal, and the like.
• isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
• Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
• mCTLA-4Ig A murine CTLA4-lg cDNA expression plasmid was prepared by ligation of the leader and extracellular domains of murine CTLA4 to the hinge, CH2 and CH3 domains of IgHg2a that had been mutated to remove effector functions as described in Streurer et al (Streurer, J Immunol 155:1165, 1995). The insert was cloned into the expression vector pED and stably transfected into CHO cells as previously described (Lollar P et al, J Clin Invest 93:2497, 1994).
• Concentrated conditioned media was loaded onto a rProtein A Sepharose Fast Flow chromatography column (Amersham Pharmacia Biotech, Piscataway, NJ). The column was washed with PBS pH 7.1 and the mCTLA4-lg eluted with 20 mM Citrate pH 3.0. The peak pool was neutralized with IM Tris pH 8.0 to a final pH of 7.5 and formulated into PBS pH 7.1 using an Amicon stirred cell with a YM3O membrane.
• the mCTLA4-Ig was depyrogenated using a Poros PI (Perceptive Biosystems) chromatography column and the product eluted from the column in a linear NaCl gradient from O to I M NaCl in 25 mM Tris pH 7.5.
• the mCTLA-4-Ig was then formulated into PBS pH 7.1 using an Amicon stirred cell using a YM30 membrane.
• T cell proliferative activity determined by 3H-thymidine incorporation showed a factor VIII dose dependent response for cells from the hemophilia/A B7-1 7" mice ( Figure 10).
• no T cell response was detected at any factor VIII level for spleen cells from hemophilia A/B7-2 " " mice.
• B7-2 has the major role in supporting an immune response to factor VIII injected intravenously, and anti-factor VIII formation is prevented if it is missing.

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