WO2000027417A1 - Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating gvhd and hvgd - Google Patents
Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating gvhd and hvgd Download PDFInfo
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- WO2000027417A1 WO2000027417A1 PCT/US1999/027107 US9927107W WO0027417A1 WO 2000027417 A1 WO2000027417 A1 WO 2000027417A1 US 9927107 W US9927107 W US 9927107W WO 0027417 A1 WO0027417 A1 WO 0027417A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
Definitions
- the present invention provides compositions and methods for prevention and treatment of graft rejection in transplantation of tissues and organs from HLA matched and unmatched allogeneic human donors, as well as xenografts from donors of other species.
- Transplanted organs include hearts, lungs, kidneys, livers, skin and other organs or tissues transplanted from donor to recipient.
- the present invention also relates to compositions and methods for preventing or treating graft-versus-host disease in bone marrow transplantation.
- GVHD graft-versus-host disease
- GVHD GVHD-induced GVHD
- Acute GVHD develops within the first 3 months after bone marrow transplantation and features disorders of skin, liver and gastrointestinal tract.
- Chronic GVHD is a multiorgan autoimmune-like disease, emerging from 3 months up to 3 years post-transplantation and shares features common to naturally occurring autoimmune disorders, like systemic lupus erythematosus (SLE) and scleroderma.
- SLE systemic lupus erythematosus
- EAE experimental allergic encephalomyelitis
- MS multiple sclerosis
- Copolymer 1 or Cop 1 were shown to be highly effective in protecting and suppressing EAE in several animal species (Teitelbaum et al., 1971, 1974a, 1974b) .
- D-Copolymer 1 or D-Cop 1 in which the four amino acids have the D-configuration, namely a random copolymer containing the D-Ala, D-Glu, D-Lys and D-Tyr residues, has also been described (Webb et al., 1976).
- Copolymer 1 in the form of the acetate salts of synthetic polypeptides containing L-Glu, L- Ala, L-Tyr and L-Lys with an average molar fraction of 0.141, 0.427, 0.095 and 0.338, is the active ingredient of
- COPAXONE® a medicament for the treatment of multiple sclerosis.
- Cop 1 The mechanism underlying the therapeutic activity of Cop 1 in MS has been extensively studied.
- Cop 1 was found to be immunologically cross-reactive with myelin basic protein (MBP) , the main autoantigen in EAE and MS. Its suppressive effect results from several mechanisms, such as inhibition of the autoreactive pathogenic T-cells on one hand (Teitelbau et al., 1988), and stimulation of suppressor cells on the other hand (Aharoni et al . , 1993).
- MBP myelin basic protein
- the first step essential for the activation of these specific processes is the binding of Cop 1 to the histocompatibility molecules.
- Cop 1 in two different batches of molecular weight 5,550 and 8,600, and relative molar ratio of L-Ala (4.1-5.8 residues), L-Glu (1.4-1.8 residues), L-Lys (3.2-4.2 residues) and L-Tyr (1 residue), binds very efficiently to a variety of MHC class II molecules of mouse and human origin, and furthermore competes with MBP and its major epitope p84-102 for MHC binding and can even displace such antigens that had already been bound to the MHC molecule (Fridkis-Hareli et al . , 1994).
- Cop 1 Mixed lymphocyte reaction (MLR) which is used clinically to assess immune rejection between donors and recipients was inhibited by Cop 1 (Schlegel et al . , 1996).
- Cop 1 prevents GVHD in a murine model of lethal GVHD, which mimics MHC matched bone marrow transplantation in human (Schlegel et al . , 1996).
- post transplantation administration of Cop 1 over a limited time after transplantation significantly reduced the incidence onset and severity of disease, resulting in improved long-term survival.
- Studies on the effect of Cop 1 on various processes involved in the pathological course of immune rejection showed that Cop 1 inhibited T cell proliferation in response to host cell (Aharoni et al . , 1997).
- Cop 1 is a candidate drug for the prevention of GVHD in humans. See WO 96/32119 and U.S. Patent No. 5,858,964.
- Cop 1 may be used to prevent or to treat HVGD, nor that there are other copolymers useful for preventing or treating GVHD or HVGD.
- the nomenclature GLAT copolymer or YEAR copolymer has also been used for Cop 1.
- Copolymer 1, Cop 1, L-GLAT and L-YEAK will be used interchangeably for the L form of Cop 1
- D-Copolymer 1, D-Cop 1, D-GLAT and D-YEAK will be used interchangeably for the D form of Cop 1.
- the present invention is based on the surprising discovery that not only is Copolymer 1 useful for the treatment of GVHD, but it is also useful for the treatment of HVGD. Furthermore, heteropolymers other than the specific composition of Copolymer 1 can be used both for the GVHD indication and for the HVGD indication.
- the present invention provides a pharmaceutical composition for use in the prevention and treatment of graft-versus-host disease and host-versus-graft disease comprising random heteropolymers of amino acids.
- the polymers comprise random copolymers comprising a suitable quantity of an amino acid of positive electrical charge, such as lysine or arginine, in combination with an amino acid with a negative electrical charge (preferably in a lesser quantity) , such as glutamic acid or aspartic acid, optionally in combination with an electrically neutral amino acid such as alanine or glycine, serving as a filler, and optionally with an amino acid adapted to confer on the copolymer immunogenic properties, such as an aromatic amino acid like tyrosine or tryptophan.
- an amino acid of positive electrical charge such as lysine or arginine
- an amino acid with a negative electrical charge preferably in a lesser quantity
- an electrically neutral amino acid such as alanine or glycine
- the pharmaceutical composition for use in preventing and treating graft-versus-host disease (GVHD) and host-versus-graft disease (HVGD) comprises at least one copolymer selected from the group consisting of random copolymers comprising one amino acid selected from each of at least three of the following groups:
- the copolymer contains four different amino acids each from one of the groups (a) to (d) .
- a preferred copolymer according to this embodiment of the present invention comprises in combination alanine, glutamic acid, lysine, and tyrosine, of net overall positive electrical charge and of a molecular weight of about 2,000 to about 40,000 daltons, preferably of about 2,000 to about 13,000 daltons.
- the most preferred example is Copolymer 1 of average molecular weight of about 4,700 to about 13,000 daltons. It is clear that this is given by way of example only, and that the composition can be varied both with respect to the constituents and relative proportions of the constituents if the above general criteria are adhered to.
- the copolymer contains three different amino acids each from one of three groups of the groups (a) to (d) .
- These copolymers are herein referred to as terpolymers.
- compositions which include a therapeutically effective amount of a random terpolymer consisting essentially of amino acids tyrosine (or tryptophan) , alanine (or glycine) and lysine (or arginine) , preferably tyrosine, alanine and lysine, in the molar ratio of from about 0.005 to about 0.25 tyrosine, from about 0.3 to about 0.6 alanine, and from about 0.1 to about 0.5 lysine, along with a pharmaceutically acceptable carrier.
- This terpolymer hereinafter designated YAK, is preferably substantially free of glutamic acid.
- the present invention further provides a pharmaceutical composition which includes a therapeutically effective amount of a random terpolymer consisting essentially of glutamic acid (or aspartic acid) , tyrosine (or tryptophan) , and lysine (or arginine) , preferably glutamic acid, tyrosine, and lysine, in the molar ratio of from about 0.005 to about 0.300 glutamic acid, from about 0.005 to about 0.250 tyrosine, and from about 0.3 to about 0.7 lysine, and a pharmaceutically acceptable carrier.
- This terpolymer hereinafter designated YEK, is preferably substantially free of alanine.
- the present invention is also directed to pharmaceutical compositions which include a therapeutically effective amount of a random terpolymer consisting essentially of the amino acids tyrosine (or tryptophan) , glutamic acid (or aspartic acid) and alanine (or glycine) , preferably tyrosine, glutamic acid and alanine, in the molar ratio of from about 0.005 to about 0.25 tyrosine, from about 0.005 to about 0.3 glutamic acid, and from about 0.005 to about 0.8 alanine, and a pharmaceutically acceptable carrier.
- This terpolymer hereinafter designated YEA, is preferably substantially free of lysine.
- the present invention also provides a pharmaceutical composition which includes a therapeutically effective amount of a random terpolymer consisting essentially of glutamic acid (or aspartic acid) , alanine (or glycine) and lysine (or arginine) , preferably glutamic acid, alanine and lysine, in the molar ratio of from about 0.005 to about 0.3 glutamic acid, from about 0.005 to about 0.6 alanine, and from about 0.2 to about 0.7 lysine, and a pharmaceutically acceptable carrier.
- This terpolymer, herein after designated KEA is preferably substantially free of tyrosine.
- the present invention further provides methods for treating and preventing GVHD or HVGD in a mammal by administering a therapeutically effective amount of a composition comprising at least one copolymer selected from the group consisting of random copolymers comprising one amino acid from at least three or four of the following groups :
- transplanted grafts include hearts, lungs, kidneys, livers, skin and other organs or tissues transplanted from donor to recipient.
- Therapeutically effective amounts of Copolymer 1, according to the present invention are about 1.0 mg to about 500.0 mg. Preferably, such therapeutically effective amounts of Copolymer 1 are about 20.0 mg to about 100.0 mg.
- the copolymers used in the present invention preferably have an average molecular weight of about 5,500- 10,000 Da, more preferably of 6,000-8,000 Da, and most preferably, of about 6,000 or of about 8,000.
- terpolymers comprised of these amino acids will also be referred to as copolymers.
- the amino acid residues of the groups (a) to (d) above may all have the L-configuration or the D configuration or some of the residues may have the L- and the others the D- configuration .
- preferred molar ratios of the amino acid residues include the relative molar ratios 1.7 Glu to 3.8 Lys to 4.9 Ala to 1.0 Tyr, and 1.9 Glu to 4.0 Lys to 6.0 Ala to 1 Tyr.
- the present invention encompasses the use of any synthetic random copolymer of at least three of Glu or Asp, Lys or Arg, Ala or Gly, and Tyr or Trp, having a relative molar ratio of the amino acid residues and an average molecular weight as defined herein, including those forms of Cop 1 described in the literature that fall within the definition of the present invention, but excluding Copolymer 1 and D-Copolymer 1 for the treatment of GVHD.
- the invention relates to the use of the random copolymers described above for the manufacture of a medicament for prevention and treatment of graft-versus- host disease or host-versus-graft disease, but excluding Copolymer 1 and D-Copolymer 1 for the treatment of graft- versus-host disease.
- the invention relates to a method of treatment of a patient for prevention and treatment of graft-versus-host disease and/or host-versus-graft disease in the course of bone marrow and organ transplantation, said method comprising administering to said patient effective amounts of said random copolymers, but excluding Copolymer 1 and D-Copolymer 1 for the treatment of Graft-versus-host disease.
- the random copolymer is used according to the invention for prevention of Graft- versus-host disease and/or Host-versus-graft disease in allogeneic bone marrow transplantation, optionally together with other immunosuppressive agents.
- the preferred copolymer according to the present invention for the treatment of HVGD is Copolymer 1.
- Figs. 1, 4 and 5 hereinbelow correspond to Figs. 1, 2 and 3, respectively, of US Patent No. 5,858,964 and Figs. 2 and 3 to Figs. 1 and 3, respectively, of Schlegel et al . , 1996, and are presented herein for the matter of illustration only.
- GLAT in Figs. 1- 5 is Copolymer 1/Cop 1.
- Figs. 1A-B show the inhibition of secondary mixed lymphocyte reaction (MLR) across minor as well as major histocompatibility barriers, caused by several peptides.
- the peptides L-GLAT, MBP Acl-11 [4A], MBP 35-47, a mixture of MBP Acl-11 [4A] + MBP 35-47, MBP 89-101 and KM-core (all described in Materials and Methods hereinafter) were tested (20 ⁇ g/well of each peptide) for their ability to inhibit the proliferation of B10.
- PL (H-2 U ) mice responder cells to stimulator cells of either the same haplotype (PL/J mice, Fig. 1A) or of a different H-2 haplotype (BALB/c mice, Fig. IB) .
- Figs . 2A-E are graphs showing dose-dependent inhibition of the MLC across major histocompatibility barriers (Figs. 2A-2D, H-2 d anti H-2 u ' k ' b,s , E, H-2 b anti H-2 d ) .
- Responder spleen cells (2.5 x 10 5 ) were incubated with 2.5 x 10 5 irradiated (30 Gy, Cs source) spleen stimulator cells as described in Materials and Methods in a final volume of 200 ⁇ l .
- GLAT or HEL were added at the indicated concentrations
- Fig. 3A shows onset of GVHD in individual mice of the experimental groups. The median disease onset is indicated by lines (day 73 for GLAT , day 21 for PBS, and day 22 for HEL) . Statistical analysis by ⁇ 2 distribution.
- FIG. 3B shows maximum disease severity in individual mice of the experimental groups. The median disease severity is indicated by lines (2.0 for GLAT, 5.5 for PBS, 6.5 for HEL).
- Fig. 3C shows actuarial survival from lethal GVHD. The median survival times (days) for the experimental groups are as follows: > 140 days for GLAT, 47 for PBS, and 41 for HEL.
- Fig. 3D shows mean body weight curves after transplant. Data given in Figs. 3A-D are pooled from three similar experiments.
- Figs. 4A-B show the effect on survival of BALB/c mice transplanted with bone marrow and spleen cells form B10.D2 mice after treatment with L-GLAT (Batch I), HEL or PSB (Fig. 4A) or with L-GLAT (Batch II), HEL, PBS or TGA polymer (Fig. 4B) .
- Fig. 5 shows the effect on survival of BALB/c mice transplanted with bone marrow and spleen cells from B10.D2 mice after treatment with D-GLAT or PBS.
- Fig. 6 depicts the effect of Cop 1 treatment on skin graft rejection in BALB/c mice receiving skin grafts from B10D2 donor mice.
- the percent survival of the B10D2 skin was used as a measure of skin graft rejection or acceptance.
- Cop 1 treatment was compared to treatment with PBS, and treatment with two known immunosuppressive agents, cyclosporin A (CyA) and FK 506.
- the BALB/c recipient mice were treated daily with: (1) PBS injected ip (squares) from the seventh day prior to skin grafting; (2) Cop 1 injected daily ip and subcutaneously (sc) from the seventh day prior to skin grafting at a dosage of 300 ⁇ g/day (small circles) and 600 ⁇ g/day (large circles) ; (3) CyA injected ip (white triangles) at a dosage of 1 ⁇ g/day from the seventh day prior to skin grafting and (4) FK 506 injected seven times ip (black triangles) at a dosage of 300 ⁇ g/day from the second day prior to transplantation. Skin grafts were inspected daily. Rejection was considered positive when no viable donor epidermis remained.
- Figs. 7A-D show the effect of Cop 1 treatment on thyroid function in different mice strains (Figs. 7A, 7B - BALB/c mice receiving grafts from B10.D2 donor mice; Fig. 7C - C3HSH mice receiving grafts from C57BL donor mice; and Fig. 7D - PLJ mice receiving grafts from B10. PL donor mice) .
- Thyroid glands from donor mice were transplanted in the kidney capsules of recipient mice. After one week the transplanted mice were injected with 125 I, and the radioactivity of each kidney was measured 20 hours later.
- Fig. 8 shows the effect of Cop 1 treatment on grafted thyroid function in BALB/c mice in which thyroid glands from B10D2 donor mice were transplanted into the kidney capsules.
- Cop 1 treatment 600 ⁇ g/day Cop 1 injected ip daily from seventh day prior to transplantation
- PBS injected ip daily from seventh day prior to transplantation
- cyclosporin A 1 ⁇ g/day CyA injected ip daily from seventh day prior to transplantation
- FK 506 300 ⁇ g/day injected ip seven times from second day prior to transplantation
- the random copolymers used in the present invention represent a novel therapeutic approach to treat human host- versus-graft disease for effective organ transplantation. Furthermore, a broader class of random copolymers than the previously disclosed Copolymer 1 is presented for the treatment of Graft-versus-host disease, particularly with regard to bone marrow transplantation.
- the copolymers for use in the present invention can be composed of L- or D-amino acids or mixtures thereof.
- L-amino acids occur in most natural proteins.
- D-amino acids are commercially available and can be substituted for some or all of the amino acids used to make the terpolymers and other copolymers of the present invention.
- the present invention contemplates copolymers containing both D- and L-amino acids, as well as copolymers consisting essentially of either L- or D-amino acids.
- the average molecular weight and the average molar fraction of the amino acids in the copolymers can vary. However, a molecular weight range of about 2,000 to 40,000 daltons is contemplated. A preferred molecular weight range is from about 2,000 to about 12,000 daltons.
- the copolymers can be from about 15 to about 100, preferably from about 40 to about 80, amino acids in length. Preferred molecular weight ranges and processes for making a preferred form of Copolymer 1 is described in U.S. Patent No. 5,800,808, the entire contents of which being hereby incorporated in the entirety.
- the terpolymers for use in the present invention contain tyrosine, alanine, and lysine, hereinafter designated YAK.
- the average molar fraction of the amino aids in these terpolymers can vary.
- tyrosine can be present in a mole fraction of about 0.005 to about 0.250; alanine can be present in a mole fraction of about 0.3 to about 0.6; and lysine can be present in a mole fraction of about 0.1 to about 0.5.
- the average molecular weight is between 2,000 to about 40,000 daltons, and preferably between about 3,000 to about 35,000 daltons. In a more preferred embodiment, the average molecular weight is about 5,000 to about 25,000 daltons. It is possible to substitute arginine for lysine, glycine for alanine, and tryptophan for tyrosine.
- the terpolymers for use in the present invention contain tyrosine, glutamic acid, and lysine, hereinafter designated YEK.
- the average molar fraction of the amino acids in these terpolymers can vary: glutamic acid can be present in a mole fraction of about 0.005 to about 0.300, tyrosine can be present in a mole fraction of about 0.005 to about 0.250, and lysine can be present in a mole fraction of about 0.3 to about 0.7.
- the average molecular weight is between 2,000 and about 40,000 daltons, and preferably between about 3,000 and about 35,000 daltons. In a more preferred embodiment, the average molecular weight is about 5,000 to about 25,000 daltons. It is possible to substitute aspartic acid for glutamic acid, arginine for lysine, and tryptophan for tyrosine.
- the terpolymers for use in the present invention contain lysine, glutamic acid, and alanine, hereinafter designated KEA.
- the average molar fraction of the amino acids in these polypeptides can also vary.
- glutamic acid can be present in a mole fraction of about 0.005 to about 0.300
- alanine can be present in a mole fraction of about 0.005 to about 0.600
- lysine can be present in a mole fraction of about 0.2 to about 0.7.
- the average molecular weight is between 2,000 and 40,000 daltons, and preferably between about 3,000 and 35,000 daltons. In a more preferred embodiment, the average molecular weight is about 5,000 to about 25,000 daltons. It is possible to substitute aspartic acid for glutamic acid, glycine for alanine, and arginine for lysine.
- the terpolymers for use in the present invention contain tyrosine, glutamic acid, and alanine, hereinafter designated YEA.
- the average molar fraction of the amino acids in these polypeptides can vary.
- tyrosine can be present in a mole fraction of about 0.005 to about 0.250
- glutamic acid can be present in a mole fraction of about 0.005 to about 0.300
- alanine can be present in a mole fraction of about 0.005 to about 0.800.
- the average molecular weight is between 2,000 and about
- the average molecular weight is about 5,000 to about 25,000 daltons. It is possible to substitute tryptophan for tyrosine, aspartic acid for glutamic acid, and glycine for alanine.
- the mole fraction of amino acids of the terpolymers is about what is preferred for Copolymer 1.
- the mole fraction of amino acids in Copolymer 1 is glutamic acid about 0.14, alanine about 0.43, tyrosine about 0.10, and lysine about 0.34.
- the most preferred average molecular weight for Copolymer 1 is between about 5,000 and about 9,000 daltons.
- the activity of Copolymer 1 both in the treatment of GVHD and HVGD is expected to remain if one or more of the following substitutions is made: aspartic acid for glutamic acid, glycine for alanine, arginine for lysine, and tryptophan for tyrosine.
- the molar ratios of the monomers of the more preferred terpolymer of glutamic acid, alanine, and tyrosine, or YEA is about 0.21 to about 0.65 to about 0.14.
- the molar ratios of the monomers of the more preferred terpolymer of glutamic acid, alanine and lysine, or KEA is about 0.15 to about 0.48 to about 0.36.
- the molar ratios of the monomers of the more preferred terpolymer of glutamic acid, tyrosine, and lysine, or YEK is about 0.26 to about 0.16 to about 0.58.
- the molar ratios of the monomers of the more preferred terpolymer of tyrosine, alanine and lysine, or YAK, is about 0.10 to about 0.54 to about 0.35.
- the random copolymers described herein specifically exclude Copolymer 1 when the indication is GVHD. If necessary, the random copolymers may exclude any random mixture of heteropolymers containing all of glutamic acid, lysine, alanine and tyrosine.
- the preferred active principle is Copolymer 1.
- the present invention is directed to a pharmaceutical composition for the prevention and treatment of graft rejection, which includes a therapeutically effective amount of Copolymer 1 and a pharmaceutically acceptable carrier.
- the present invention in a further preferred embodiment is directed to methods for preventing and treating graft rejection which includes administering a therapeutically effective amount of Cop 1.
- Copolymer 1 has been approved in several countries for the treatment of Multiple Sclerosis (MS) under the trade name, COPAXONE®, Glatiramer acetate.
- MS Multiple Sclerosis
- COPAXONE® Glatiramer acetate
- Copolymer 1 binds promiscuously and with high affinity to various class II MHC molecules from mouse and human origin, and can even displace antigens from the MHC groove (Fridkis-Hareli et al . , 1994).
- Mixed lymphocyte reaction which is used clinically to assess immune rejection between donors and recipients, is also inhibited by Copolymer 1 (Schlegel et al., 1996).
- tissue from donor mice is transplanted to recipient mice, immune rejection generally occurs. This is manifested either by GVHD in bone marrow transplantation or graft rejection in organ transplantation.
- Copolymer 1 and D-Copolymer 1 were shown to prevent GVHD in a murine model of lethal GVHD which mimics matched bone marrow transplantation in humans (see U.S. Patent No. 5,858,964 and Figs. 3-5 herein in the present application). According to the present invention, random copolymers other than Copolymer 1 and D-Copolymer 1 are envisaged for use in the prevention and treatment of GVHD.
- Copolymer 1, D- Copolymer 1 and other random copolymers are envisaged to prevent or significantly delay graft rejection.
- Copolymer 1 is effective in suppressing in mice the rejection of grafts received from another mouse strain of the same MHC haplotype.
- graft rejection could be suppressed in BALB/c mice receiving grafts from B10.D2 donor mice, in C3HSH mice receiving grafts from C57BL donor mice, and in PJL mice receiving grafts from B10PL donor mice (see Figs. 6-8 and Tables 4 and 5 herein) .
- These transplantation mouse models are similar to the MHC matched organ transplantation in humans.
- Copolymer 1 is also effective in suppressing in mice rejection of grafts from strains of different MHC haplotypes, for example, suppressing in BALB/c mice rejection of grafts received from C57BL donor mice (see Tables 4 and 5 herein) , a model which is similar to the MHC unmatched organ transplantation in humans.
- pre- and post-transplantation administration of Copolymer 1 over a limited time after transplantation can significantly reduce the incidence, onset and severity of immunorejection, resulting in improved long-term survival.
- Copolymer 1 inhibits T cell proliferation in response to host cells.
- Copolymer 1 treatment completely abolished cytotoxic activity towards host cells, preventing the secretion of cytokines like interleukin 2 (IL-2) and interferon ⁇ (IFN- ⁇ ), and induced a beneficial anti-inflammatory response. Similar effects can occur in graft rejection disease.
- IL-2 interleukin 2
- IFN- ⁇ interferon ⁇
- the present invention is also directed to the use of terpolymers as defined herein for the prevention and treatment of GVHD and HVGD.
- the terpolymers can be made by any procedure available to one of skill in the art.
- the terpolymers can be made under condensation conditions using the desired molar ratio of amino acids in solution, or by solid phase synthetic procedures.
- Condensation conditions include the proper temperature, pH, and solvent conditions for condensing the carboxyl group of one amino acid with the amino group of another amino acid to form a peptide bond.
- Condensing agents for example dicyclohexyl-carbodiimide, can be used to facilitate the formation of the peptide bond.
- Blocking groups can be used to protect functional groups, such as the side chain moieties and some of the amino or carboxyl groups against undesired side reactions. For example, the process disclosed in U.S. Patent
- N-carboxyanhydrides of tyrosine, alanine, ⁇ -benzyl glutamate and N ⁇ -trifluoroacetyl- lysine are polymerized at ambient temperatures in anhydrous dioxane with diethylamine as an initiator.
- the ⁇ -carboxyl group of the glutamic acid can be deblocked by hydrogen bromide in glacial acetic acid.
- the trifluoroacetyl groups are removed from lysine by 1 molar piperidine.
- the process can be adjusted to make peptides and polypeptides containing the desired amino acids, that is, three of the four amino acids in Copolymer 1, by selectively eliminating the reactions that relate to any one of glutamic acid, alanine, tyrosine, or lysine.
- the terms "ambient temperature” and "room temperature” mean a temperature ranging from about 20 to about 26°C.
- the molecular weight of the terpolymers can be adjusted during polypeptide synthesis or after the terpolymers have been made. To adjust the molecular weight during polypeptide synthesis, the synthetic conditions or the amounts of amino acids are adjusted so that synthesis stops when the polypeptide reaches the approximate length which is desired.
- polypeptides with the desired molecular weight can be obtained by any available size selection procedure, such as chromatography of the polypeptides on a molecular weight sizing column or gel, and collection of the molecular weight ranges desired.
- the present polypeptides can also be partially hydrolyzed to remove high molecular weight species, for example, by acid or enzymatic hydrolysis, and then purified to remove the acid or enzymes .
- the terpolymers with a desired molecular weight may be prepared by a process which includes reacting a protected polypeptide with hydrobromic acid to form a trifluoroacetyl-polypeptide having the desired molecular weight profile.
- the reaction is performed for a time and at a temperature which is predetermined by one or more test reactions. During the test reaction, the time and temperature are varied and the molecular weight range of a given batch of test polypeptides is determined. The test conditions which provide the optimal molecular weight range for that batch of polypeptides are used for the batch.
- a trifluoroacetyl-polypeptide having the desired molecular weight profile can be produced by a process which includes reacting the protected polypeptide with hydrobromic acid for a time and at a temperature predetermined by test reaction. The trifluoroacetyl-polypeptide with the desired molecular weight profile is then further treated with an aqueous piperidine solution to form a low toxicity polypeptide having the desired molecular weight.
- a test sample of protected polypeptide from a given batch is reacted with hydrobromic acid for about 10-50 hours at a temperature of about 20-28 °C.
- the best conditions for that batch are determined by running several test reactions.
- the protected polypeptide is reacted with hydrobromic acid for about 17 hours at a temperature of about 26°C.
- the random copolymers used in the present invention can be formulated into pharmaceutical compositions containing a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners and the like.
- the pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition.
- the use of such media and agents with pharmaceutically active substances well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
- compositions are formulated into any form known in the art using procedures available to one of skill in the art.
- the invention will now be illustrated by the following non-limiting examples.
- Copolymer 1 and Controls were prepared by polymerization of the N-carboxyanhydrides of L-Ala, ⁇ -benzyl- L-Glu, N, ⁇ -trifluoroacetyl-L-Lys, and L-Tyr. The polymerization reaction was carried out at room temperature in anhydrous dioxane with diethylamine as initiator. Deblocking of the ⁇ -carboxyl groups of the glutamic acid was carried out with hydrogen bromide in glacial acetic acid for 24 hours at room temperature, followed by removal of the trifluoroacetyl groups from the lysine residue by 1M piperidine.
- the end product is a mixture of acetate salts of random polypeptides with amino acid composition of Ala (4.1- 5.8 residues), Glu (1.4-1.8 residues), Lys (3.2-4.2 residues) , Tyr (1 residue) .
- Two L-GLAT batches were used in the experiments of GVHD: Batch I consisting of a copolymer of molecular weight of about 6,000, with the amino acids in the molar ratio of about 1.7 Glu to 3.8 Lys to 4.9 Ala to 1.0 Tyr, and Batch II, consisting of a copolymer of molecular weight of about 8,000, with the amino acids in the molar ratio of 1.8 Glu to 4.0 Lys to 6.0 Lys to 1.0 Tyr.
- D-GLAT was prepared by polymerization of the N-carboxyanhydrides of the D-amino acids D-Ala, ⁇ -benzyl- D-Glu, N, ⁇ -trifluoroacetyl-D-Lys, and D-Tyr in a residue molar ratio of 5.6 : 2.2 : 4.6 : 1.0 with an average molecular weight of approx. 29,000.
- TGA or YEA is a random basic polymer of L-Tyr, ⁇ -benzyl-L-Glu, and L-Ala in a residue molar ratio of 1.0 : 1.2 : 1.1. It was used as a negative control.
- Hen egg-white lysozyme (iv) Hen egg-white lysozyme (HEL) was obtained from Sigma Chemical Company (St. Louis, MO).
- MBP Acl-11 [4A] an acetylated N-terminal 1- 11 peptide of myelin basic protein (MBP) , with substitution of the original Lys residue at position 4 by Ala: ACASQARPSQRHG (SEQ ID NO:l);
- MBP 35-47 the epitope of MBP which is recognized in association with I-Eu: TGILDSIGRFFSG (SEQ ID NO : 2 )
- KM-core extension peptide based on the antigenic core sequence of ovalbumin 323-339: KMKMVHAAHAKMKM (SEQ ID NO: 3) ;
- Responder cells for MLR reactions across major histocompatibility barriers were harvested from spleen of non-immunized mice while responder cells for MLR across minor histocompatibility barriers were harvested from mice which were preimmunized with irradiated (30 Gy) 50 x 10 6 stimulator spleen cells 21 days before.
- Responder cells (5 x 10 5 spleen cells per well) were tested for their proliferative response by plating with different amounts (2.5 to 10 x 10 5 ) of irradiated stimulator cells, in presence or absence of various peptide inhibitors (10-100 ⁇ g per well). Cultures were set up in 200 ⁇ l media containing 10% FCS in flat-bottom microtiter plates. After 4 days of incubation, cultures were pulsed with 1 ⁇ Ci of [ 3 H] thymidine for an additional 16 hours. Results are represented as mean counts per minute (cpm) thymidine incorporation from triplicate cultures.
- the murine GVHD model of B10.D2/nSnJ ⁇ BALB/c mice (both H-2 d ) across minor histocompatibility barriers, was selected since it is similar to the MHC matched bone marrow transplantation in humans.
- 10 x 10 6 bone marrow and 100 x 10 6 spleen cells from B10.D2 mice were injected into lethally irradiated (8.0 Gy) BALB/c recipients. This regimen induces the most severe form of GVHD (Schlegel et al . , 1996) and was selected for all experiments of GVHD.
- Recipient mice were 12-13 weeks at the time of transplantation.
- Engraftment of donor bone marrow was documented by PCR amplification of a polymorphic microsatellite region within the murine IL-lb gene.
- Primer sequences are as follows: 5' -CCAAGCTTCCTTGTGCAAGTA-3' (SEQ ID NO: 5) and 5' -AAGCCCAAAGTCCATCAGTGG-3' (SEQ ID NO: 6) (Jacob et al . , 1993). These sequences are available from EMBL/Gen- Bank/DDBJ database (Bethesda, MD) under the accession numbers: X78456 and X78457.
- Oligonucleotides were synthesized on a 391 DNA synthesizer (Applied Biosystems, Foster City, CA) and were purified. DNA was prepared from peripheral blood mononuclear cells 80-120 days after transplantation according to standard protocols. PCR conditions and amplification were as described previously (Schlegel et al., 1994) . (f ) Treatment of GVHD
- Recipient BALB/c mice were treated with Copolymer 1, PBS, or with HEL. Based on previous studies with Cop 1 in EAE (Sela et al . , 1990; Teitelbaum et al., 1971; Teitelbaum et al . , 1973) and class II-binding competitor peptides in GVHD (Schlegel et al . , 1994), the dosage of 600 ⁇ g per injection was selected, half of which was administered intraperitoneally (ip) , whereas the other half was given subcutaneously (sc) . Treatment of BALB/c recipient mice was initiated on day -1, followed by daily injections for the first five weeks starting on day 0 after transplantation.
- B10.D2 spleen cells were harvested, depleted of red blood cells (RBC) and used as irradiated (10 Gy) antigen-presenting cells (APC) presenting BALB/c mH antigens.
- RBC red blood cells
- APC antigen-presenting cells
- APC antigen-presenting cells
- APC were plated at 2.5 x 10 5 cells per well in 96-well round-bottom plates and incubated with 2.5 x 10 5 nylon-wool- enriched responder T cells (> 88% CD3 + by FACS analysis) from naive B10.D2 mice in the presence or absence of increasing concentrations of Copolymer 1 (2.5-80 ⁇ g/well).
- irradiated APC were plated at 2.5 x 10 5 cells/well in 96-well round-bottom plates, preincubated for 24 hours at 37 °C with increasing concentrations of GLAT (2.5- 80 ⁇ g/well) or with medium alone, and thereafter washed three times before the addition of 2.5 x 10 5 nylon-wool-enriched responder T cells from naive B10.D2 mice.
- Culture medium was RPMI 1640, supplemented with 10% pre-screened fetal calf serum, 2 mM glutamine, 50 ⁇ M 2-mercaptoethanol, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
- Skin graft rejection is a vigorous process, more difficult to suppress than the rejection of other organs (Isakov et al . , 1979). This may be due to the high expression of MHC molecules in this tissue. The ability to postpone this rejection process is therefore significant.
- Recipient mice were dorsally transplanted with circular pieces of donor skin. Mice were inspected daily. Grafts were considered rejected when no viable donor epidermis remained. The results are expressed in mean survival time (MST) . P values were obtained by analysis of variance (ANOVA) .
- mice were treated daily with Copolymer 1 600 ⁇ g/day (300 ⁇ g ip + 300 ⁇ g sc) in PBS solution, starting 7 days before transplantation.
- the first Cop 1 treatment on day -7 was injected sc in ICFA as a depot dose.
- Control mice were treated daily with PBS alone and PBS with ICFA on day -7 before transplantation.
- EXAMPLE 1 Inhibition of Mixed Lymphocyte Reaction by Cop 1 This example demonstrates the inhibition of mixed lymphocyte reaction (MLR) by Copolymer 1 and is presented here for illustration only. MLR, the proliferative response of allogeneic lymphocytes when cultured together, is considered an in vi tro model for the recognition phase of the GVHD reaction, and is part of the routine screening for bone marrow donors .
- MLR mixed lymphocyte reaction
- Copolymer 1 (Batch I; 20 ⁇ g/well) significantly inhibited MLR across minor as well as major histocompatibility barriers. 63% and 77% inhibition could be obtained, respectively, when 1:1 ratio of responder to stimulator cells was used, while the MBP 89-101 and the KM-core peptides (at the same concentration, i.e. 20 ⁇ g/well), which are specific to the H-2 S haplotype, did not induce any significant effect.
- the inhibition obtained by Copolymer 1 was similar (in response to minor histocompatibility antigen) or even higher (in response to major histocompatibility antigen) than the inhibition obtained with the combination of the two synthetic peptides Ac 1-11 [4A] and MBP 35-47, which specifically bind to the class II molecules I-A u and the I-E u , respectively.
- the molar efficiency of Copolymer 1 of M.W. 6000 is even higher since the molecular weight of the synthetic peptides is 4-5 fold lower.
- EXAMPLE 2 Inhibition of MLR across Major Histocompatibility Barriers The effect of Copolymer 1 (Batch I) on mixed lymphocyte cultures across major histocompatibility barriers was tested. T cell proliferation was assessed in six different MHC-disparate strain combinations. Data given in Figs. 2A-E are representative of five separate experiments with similar results. In all experiments, addition of Copolymer 1 (10-100 ⁇ g/well) resulted in a dose-dependent inhibition of the MLC. HEL showed no or only minimal inhibitory effect at all concentrations tested (Figs. 2A-E) . 10-25 ⁇ g/well of Copolymer 1 was sufficient to achieve 50% inhibition of the proliferative responses. Maximum inhibition (100%) was obtained in all strain combinations tested.
- Secondary assay (right) Identical cultures were set up in parallel to the primary assay. After 72 hours of incubation, responder cells were rechallenged with IL-2 (5,000 U/well) for an additional 48 hours before pulsing with 1 ⁇ Ci [ 3 H] -thymidine for an additional 16 hours. Results are expressed as mean cpm from triplicate cultures. Standard deviations were less ⁇ 16% of the mean.
- B10.D2 mice were injected ip with irradiated (20 Gy) BALB/c spleen cells 72 hours prior to the assay.
- B10.D2 spleen cells were harvested, depleted of RBC and used as irradiated (10 Gy) APC presenting BALB/c mH antigens.
- APC were plated at 2.5 x 10 5 cells/well in 96-well round-bottom plates and incubated with 2.5 x 10 5 nylon-wool-enriched responder T cells (> 88% CD3 + by FACS analysis) from naive B10.D2 mice in the presence or absence of increasing concentrations of Copolymer 1 (Batch I) (2.5-80 ⁇ g/well).
- Copolymer 1 (Batch II) inhibited the proliferative responses to mH antigens in a dose- dependent fashion. Maximum inhibition was 100% at a concentration of 80 ⁇ g/well.
- Culture medium was RPMI 1640, supplemented with 10% pre-screened fetal calf serum, 2 mM glutamine, 50 ⁇ M 2- mercaptoethanol, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin. As shown in Table 2, right, preincubation with Copolymer 1 inhibited proliferative responses to minor H antigens, suggesting that Copolymer 1 inhibits presentation of minor antigens in vi tro . Table 2
- EXAMPLE 4 Bone Marrow Transplantation in Mice, Induction of GVHD and Treatment with Copolymer 1
- FIG. 3A depicts the onset of GVHD in individual mice of the different experimental groups. In 12/25 animals treated with Copolymer 1 the onset of GVDH was delayed with a range of 32-112 days after transplant (median of 73 days) as compared to control mice treated with either PBS (median onset of 21 days) or HEL (median onset 22 days) .
- EXAMPLE 5 Bone Marrow Transplantation in Mice, Induction of GVHD and Treatment with D-Copolymer 1 (i) Effect of D-Copolymer 1 Treatment on the
- mice were treated with 60 ⁇ g of D-Copolymer 1 or PBS daily for the first five weeks after transplant followed by a tapering schedule over an additional four weeks.
- the dosage of 60 ⁇ g/injection was selected based on the prolonged half-life of D-Copolymer 1 and was administered ip.
- Treatment was initiated on day -1 and after five weeks the frequency of injections was tapered to three times per week for the following two weeks and to two times per week for another two weeks. Once a week the D-Copolymer 1 was administered with incomplete Freund' s adjuvant (IFA) ip as a depot dose. Treatment was discontinued after 9 weeks.
- IFA incomplete Freund' s adjuvant
- MST median survival time (in days)
- Conditioning Regimen Patients are submitted to a conditioning regimen comprising fractionated total body irradiation by administering 120 cGy per fraction 2 to 3 times daily over 4 days (days -8 to -5) to a total dose of 1200 cGy, a multiple drug treatment including, e.g., etoposide (60 mg/kg) over 4 hours at day -4, cyclophosphamide (60 mg/kg) over 1 hour at day -2, antibacterial agents, and standard prophylaxis agents against GVHD, e.g., cyclosporine, FK506, methotrexate and prednisone.
- GVHD Prophylaxis e.g., cyclosporine, FK506, methotrexate and prednisone.
- Copolymer 1 is administered to the patient subcutaneously (sc) , intramuscularly (im) or intravenously (iv) at a dosage of 1- 500 mg twice daily.
- the treatment starts at day -2 before and is continued until day +60 after the allogeneic bone marrow transplantation (BMT) . This day is chosen since nearly all of the acute GVHD that may occur, will do so by day +40.
- Standard prophylaxis against GVHD with cyclosporine and prednisone is also continued.
- Cyclosporine is administered until the patient is able to sustain oral caloric intake and has no evidence of gastrointestinal toxicity (usually around the end of the first month, fourth week following BMT) , at a dose from 1.5 to 5 mg/kg iv twice daily, by infusion in the first 35 days and then orally (per os) until the end of the treatment (day +180) .
- Serum samples are obtained and, if necessary, the drug concentration is adjusted to prevent drug-related toxicities .
- the aim is for a level of cyclosporine between 200-500 ng/ml.
- Methylprednisolone is administered iv until patients can be switched to oral (p.o.) Prednisone. For example, it is administered iv at a dose of 0.25 mg/kg - 0.5 mg/kg from day +7 to +28 and p.o. at a dose of 0.4 mg/kg - 0.1 mg/kg until the end of the treatment (day +180) .
- the first phase of the treatment is to establish engraftment. If engraftment is established, the post-transplantation immunosuppression is then stepwise decreased. The first step is to stop the use of prednisone. If no GVHD occurs, then the use of cyclosporine is stopped (see statistical analysis) . At that time only the random copolymer is used as the immunosuppressive regimen.
- the binary endpoint of success by the twentieth day is monitored by sequential test, using 20 as the hypothesized median based on past experience, and using a boundary for inferiority fixed to provide a Type I risk of 5% (one sided) and a degree of conservatism midway between constant p level and the O'Brien-Fleming approach.
- the data on relapse is also monitored, using the time to relapse as the endpoint and including all patients under treatment, whether engraftment is successful at the twentieth day or not.
- EXAMPLE 7 Effect of Copolymer 1 on Graft Rejection (HVGD) in the B10.D2 ⁇ BALB/c Model
- Copolymer 1 for the prevention of graft rejection was first tested on transplantation systems across minor histocompatibility barriers.
- recipient mice BALB/c
- B10.D2 another strain
- H-2 haplotype H-2 d
- This model closely resembles the clinical setting in the majority of human transplantations, in which donor and recipient are usually HLA matched.
- Copolymer 1 was compared to the effect of control PBS treatment in two transplantation systems:
- the mean function index (MFI) for each treatment was calculated by dividing the mean 125 I absorbance of (transplanted kidney - untransplanted kidney) in the tested treatment by the mean 125 I absorbance of (transplanted kidney - untransplanted kidney) in the PBS treatment, as follows: mean ⁇ cpm for the Cop 1 tested treatment mean ⁇ cpm for the PBS tested treatment.
- the results of thyroid transplantation are summarized in Figs. 7 and 8 and in Tables 5 and 7.
- the MFI of the Copolymer 1-treated mice 600 ⁇ g/day) was 3.2 folds in one experiment and 5.2 folds in another experiment over PBS- treated mice.
- Copolymer 1 treatment was significantly effective in preventing the functional deterioration of transplanted thyroid grafts in the B10D2 ⁇ BALB/c system.
- Copolymer 1 induced significant and prominent effect on graft survival and function in both skin graft and thyroid transplantation systems .
- mice were then conducted with mice in order to establish the ability of Cop 1 to inhibit graft rejection of graft by host, using the two transplantation model systems described above while addressing the following aspects: (i) the effect of Copolymer 1 on HVGD in different murine strain combinations; and (ii) the effect of Copolymer 1 on HVGD in comparison to the effect of other immunosuppressive drugs that are currently used for human transplantation, namely FK506 and cyclosporin A.
- the mean function index (MFI] for each treatment was calculated as follows:
- EXAMPLE 8 The Effect of Copolymer 1 on HVGD in Different Murine Strain Combinations
- mice transplanted with grafts from donors of another H-2 haplotype transplantation across major histocompatibility barriers
- Copolymer 1 inhibited graft rejection in all strain combinations as demonstrated by the prolongation of the skin graft survival (Table 6) as well as by the elevation in the thyroid iodine absorbance (Fig. 7, Table 7) in the Copolymer 1-treated mice in comparison to the PBS-treated mice.
- Copolymer 1 significantly inhibited even the rejection of grafts from donors of different H-2 haplotypes (Tables 4 and 6) which usually induce a more potent rejection course than the rejection of H-2 matched transplants.
- MFI mean function index
- Cop 1 The effect of Cop 1 in comparison to the effect of two other immunosuppressive drugs that are currently used to prevent graft rejection in human transplantation, FK506 and cyclosporin A (CyA), was tested in the two model systems.
- BALB/c recipient mice were transplanted with skin grafts originated in B10.D2 donors and treated daily with: PBS ip from day -7, Cop 1 (ip + sc) from day -7, CyA ip from day -7, and FK 506 ip 7 injections from day -2 before transplantation. Grafts were inspected daily. Rejection was considered positive when no viable donor epidermis remained. Thyroid glands from B10.D2 donors were transplanted in the kidney's capsules of BALB/c mice. The results are shown in Figs. 6 and 8, and in Tables 4 and 5. While CyA induced no significant beneficial effect in these systems, FK 506 significantly improved grafts survival/function in both the skin and the thyroid transplantation systems.
- Cop 1 also induced significant beneficial effect on graft survival/function similar to the effect of FK 506. While Cop 1 effect on skin graft survival was somewhat smaller than the effect of FK 506 (MST 20.6 for Cop 1 in comparison to 21.2 for FK 506 (Table 4 and Fig. 6), Cop 1 was as effective as FK 506, in preventing the functional deterioration of transplanted thyroid grafts (3.2 and 3.1 folds over the PBS control for Cop 1 and FK 506 respectively, Table 5 and Fig. 8) .
- Fridkis-Hareli et al. "Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen- presenting cells - specificity and promiscuity", Proc. Natl . Acad. Sci. USA 91:4872-76 (1994).
- Teitelbaum et al. "Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen", Eur. J. Immunol. 3:272 (1973). Teitelbaum et al., "Suppression of experimental allergic encephalomyelitis in rhesus monkeys by a synthetic basic copolymer", Clin. Immunol. Immunopathol . 3:256 (1974a).
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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AU17270/00A AU775073C (en) | 1998-11-12 | 1999-11-12 | Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating GVHD and HVGD |
US09/831,629 US7053043B1 (en) | 1999-07-23 | 1999-11-12 | Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating GVHD and HVGD |
EP99960378A EP1128839A4 (en) | 1998-11-12 | 1999-11-12 | Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating gvhd and hvgd |
CA002355400A CA2355400A1 (en) | 1998-11-12 | 1999-11-12 | Pharmaceutical compositions comprising synthetic peptide copolymers and methods for preventing and treating gvhd and hvgd |
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US10818498P | 1998-11-12 | 1998-11-12 | |
US60/108,184 | 1998-11-12 | ||
US14521999P | 1999-07-23 | 1999-07-23 | |
US60/145,219 | 1999-07-23 |
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EP (1) | EP1128839A4 (en) |
AU (1) | AU775073C (en) |
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US7022663B2 (en) | 2000-02-18 | 2006-04-04 | Yeda Research And Development Co., Ltd. | Oral, nasal and pulmonary dosage formulations of copolymer 1 |
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AU1727000A (en) | 2000-05-29 |
CA2355400A1 (en) | 2000-05-18 |
EP1128839A1 (en) | 2001-09-05 |
AU775073C (en) | 2007-05-03 |
EP1128839A4 (en) | 2002-10-09 |
AU775073B2 (en) | 2004-07-15 |
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