EP0397798A1 - Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes - Google Patents

Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes

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Publication number
EP0397798A1
EP0397798A1 EP89902872A EP89902872A EP0397798A1 EP 0397798 A1 EP0397798 A1 EP 0397798A1 EP 89902872 A EP89902872 A EP 89902872A EP 89902872 A EP89902872 A EP 89902872A EP 0397798 A1 EP0397798 A1 EP 0397798A1
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EP
European Patent Office
Prior art keywords
cell
immunotoxin
disease
rta
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89902872A
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German (de)
English (en)
Other versions
EP0397798A4 (en
Inventor
Patrick J. Scannon
Richard C. Harmon
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Xoma Corp
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Xoma Corp
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Publication date
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Publication of EP0397798A1 publication Critical patent/EP0397798A1/fr
Publication of EP0397798A4 publication Critical patent/EP0397798A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to the treatment of autoimmune disease.
  • this invention relates to the use of anti-T cell immunotoxins comprising a I ⁇ . cytotoxic agent conjugated to an anti-T cell immunoglobulin for treating autoimmune disease.
  • Autoimmunity The development of immunologic responsiveness of self is called autoimmunity and reflects the impairment of self-tolerance.
  • Autoimmune diseases are pathological 15 conditions characterized by host production of autoreactive T lymphocytes and antibodies reactive with host tissues (autoantibodies) . Autoantibodies are found in some normal persons without evidence of autoimmune disease. Autoimmune diseases can occur as either organ specific or multisystem 2Q- immunopathologies.
  • autoimmune diseases include: systemic lupus erythematosus, scleroder a diseases (including lichen sclerosus, morphea and lichen planus), rheumatoid arthritis, chronic thyroiditis, pemphigus vulgaris, diabetes mellitus type 1, progressive systemic 25 sclerosis, aplastic anemia, myasthenia gravis, myositis,
  • Autoimmunity may be a disorder of abnormal immun ⁇ logic regulation resulting in excessive B cell
  • NZB/NZW F j hybrids develop a disease analogous to systemic lupus erythematosus (SLE).
  • CD system ⁇ s the standardized nomenclature accepted for molecular markers of leukocyte cell differentiation molecules by the International Workshop on Human Leukocyte
  • the CD5 cluster antigen is one of
  • CD5 positive B cells are greatly expanded in NZB 5 mice which develop autoimmune hemolytic anemia. These same mice contribute genes to (NZB x NZW) F 1 mice, which develop a lupus-like disease.
  • B cells having a CD5 antigen produce a wide variety of the antibodies responsible for pathogenesis in at 5 Least some autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. See, for example, P. Y ⁇ uinou et al., "CD5 Positive B cells in patients with Rheumatoid arthritis," Ann Rheum Dis 46: 17-22 (1987); R.R. Hardy, et al., "Rheumatoid Factor Secretion from Human Leu- X3) 1 + B Cells, Science 236:81-83 (1987); and Casali et al.,
  • T cell antigens other than CD5 are also present on subp ⁇ pulations of B lymphocytes.
  • Small et al., J “ . I mu ⁇ Q. (1987) 138:2864-68 describe the expression of the CDlc portion of the CDl molecule on a subpopulation of B " lymphocytes.
  • the CDlc antigen comprises a 33 kD backbone and ' isr expressed on 14 to 46% of normal B cells derived from tonsil, peripheral blood, and spleen cells.
  • Monoclonal antibodies directed against the CD5 antigen have been developed for use in treatment of ' non-autoimmune diseases such as graft versus host disease
  • GVHD cytotoxic ricin A chain
  • Patent Application Serial No. 822,898 which is incorporated by reference herein.
  • the MoAb targets to mature T lymphocytes and a subpopulation of B cells and causes their destruction by allowing internalization of the RTA-MoAb 3 im u ⁇ otoxin.
  • Chronic GVHD patients frequently present con ⁇ ditions and symptoms similar to certain autoimmune diseases. Chief among these are scleroderma and primary biliary s ⁇ iearosis. Human patients having chronic graft versus host D disease (cGVHD) provide an excellent model for the study of a number of autoimmune diseases.
  • Monoclonal antibodies have been used to treat autoimmune disease.
  • Wofsy, D. and Seaman, W.E., J. Exptl. Med.. 161, 378 (1985) treated urine models 5 for: systemic lupus erythematosus (SLE) with weekly injec ⁇ tions of a monoclonal antibody (MoAb) to L3T4 (CD4) .
  • SLE systemic lupus erythematosus
  • MoAb monoclonal antibody
  • CD4 L3T4
  • U.S. Patent 4,550,086 describes monoclonal antibodies capable of binding to a surface recognition structure of a predetermined mature human T cell clone. 0 "* They propose that the recognition structure renders the clone capable of acting as a causative agent in a particular autoimmune disease. MoAbs to that recognition structure neutralized the clone in vitro.
  • the immunotoxin included an anti-pancreatic tumor antibody conjugated to pokeweed antiviral protein.
  • An object of the present invention is. to provide a ⁇ 2 therapeutic composition for the treatment of autoimmune disease.
  • autoimmune diseases include: systemic lupus erythematosus, scleroderma diseases (including lichen sclerosus, morphea and lichen planus), rheumatoid arthritis, chronic thyroiditis, pemphigus S ⁇ vulgaris, diabetes mellitus type 1, progressive systemic sclerosis, apalastic anemia, myasthenia gravis, myositis, S ⁇ ogrens disease, Crohn's disease, ulcerative colitis, and primary biliary cirrhosis.
  • Another object of this invention is to provide a method of treatment of such autoimmune XE disorders.
  • the present invention is based on the novel and unexpected observation that an anti-T cell immunotoxin can 25 be administered safely and effectively in the treatment of autoimmune disease.
  • the invention is directed to administration of a pharmaceutical composition comprising an anti-T cell immunotoxin to patients having an autoimmune disease. It has been observed for the first time that the therapeutic benefit, to a patient having an autoimmune disease, of administration of an anti-T cell 5 immunotoxin is sustained well beyond the time of administration.
  • the invention is directed to a method of treatment of autoimmune disease. More specifically the anti-T cell immunotoxin comprises a cytotoxic molecule such as a lectin A chain conjugated to an ICP immunoglobulin reactive with a T cell.
  • Fig. 1 shows the depletion of the lymphocyte pop ⁇ ulation with the CD5 marker in two patients with cGVHD 15 resulting from a 14 day course of injections of XMMLY-H65- RTA.
  • Fig. 2 shows the depletion of the lymphocyte population with the CD3 marker in three patients with cGVHD resulting from a 14 day course of injections of XMMLY-H65- 2X7 RTA.
  • Fig. 3 summarizes the results of lymphocyte cell depletion in a patient who was administered the subject immunotoxins of Figs. 1 and 2.
  • anti-T Cell Immunotoxin refers to an immunotoxin capable of therapeutically improving the medical condition of a patient with autoimmune disease.
  • the anti-T cell immunotoxin comprises a cytotoxic molecule and a
  • the cytotoxic molecule is typically fatal to a cell.
  • the T cell reactive component binds to a T-lymphocyte and is capable of delivering the cytotoxic molecule to that T-lymphocyte. While the immunoglobulin portion of the immunotoxin is referred to as
  • the T-lymphocyte reactive component of the immunotoxin is an immunoglobulin which can be obtained from a number of sources and which is reactive with a T cell specific antigen.
  • the term "immunoglobulin(s)" includes polyclonal antibodies, monoclonal antibodies, reactive- fragments thereof, such as Fv, Fab, F(ab) 2 , synthetic immunoglobulins and recombinant immunoglobulins including chtmeric immunoglobulins or their derivatives.
  • the- immunoglobulins are MoAbs of the IgM or IgG isotype of 0 murine,.
  • the MoAbs are reactive with one or more of several T cell markers including CD2, CD3, CD5 and CD7. : : Most preferably the MoAb is reactive with the CD5 antigen found on both T and B cells. It would be understood that MoAbs of other animal species could be prepared using analogous non-human mammalian markers.
  • an immunoglobulin is "reactive" with an antigen when the immunoglobulin interacts with the antigen.
  • This interaction is analogous to a chemical reaction in which two reactants come together to form a product.
  • the product of the interaction is an antigen- immunoglobulin complex.
  • the preferred antigen is generally aauniques surface protein, including various types of receptors * produced by or displayed by T cells or a subset of T and: other lymphoid cells.
  • the T cell specific antigens useful in the present invention are antigens or markers typically found on most T cells present in a human patient. Preferred markers are the CD2, CD3, CD5 and CD7 antigens. Other antigen clusters such as CD6 could also serve as sources for T cell specific anti ⁇ gens. A most preferred marker is the CD5 antigen cluster.
  • anti-T cell immunoglobulins which may be utilized in the present 5 invention, cross react with a small number of other lymphoid cells, such as B cells.
  • Anti-CD5 immunoglobulins for instance, react with T cells and with a small sub-population of B cells.
  • the immunotoxin preparation may be composed of two or more immunoglobulins, each reactive with 10. a* different marker or the same marker or different cell populations to ensure a broad spectrum of T cell neutral ⁇ ization.
  • immunoglobulins may be produced by methods well-known to those skilled in the art; e.g., chromatographic purification of polyclonal sera to produce 01 substantially monospecific antibody populations.
  • the most preferred monoclonal antibody for use in this invention is that produced by hybridoma cell line XMMLY-H65 deposited with the A.T.C.C. and given the Accession No. HB9285.
  • the antibody portion of the preferred immunotoxin is prepared as 5- described in the U.S. Patent Application Serial No. 974,824, page 14, lines 25-36.
  • the antibody is preferably activated for coupling to the preferred cytotoxin, RTA, with SPDP (as described in U.S. 4,590,071, column 4, line 55 to column 5, Line 5, except that the buffer contains 5% dextrose instead XX, of azide) .
  • cytotoxic molecules are suitable for use in immunotoxins.
  • the cytotoxic molecules contemplated by this invention can include radionuclides, such as Iodine- 131, Yttrium-90, Rhenium-188, and Bismuth-212; a number of 5? chemotherapeutic drugs, such as vindesine, methotrexate, adriamycin, and cisplatinum; and cytotoxic proteins such as ribosomal inhibiting proteins including, pokeweed antiviral protein, abrin and ricin (or their A-chains).
  • Functionally equivalent are the ADP ribosylatine toxins such as diph ⁇ theria toxin and Pseudomonas exotoxin A, etc. or their recombinant derivatives. See generally, “Chimeric Toxins", 5 Ol ⁇ nes and Pihl, Pharmac. Ther. , 25:355-381 (1982), and
  • the B chain is essentially a delivery vehicle for the A chain.
  • the B chain recognizes polysaccharide units at the surface of cells and creates a high affinity interaction with such units. Once the B chain binds with polysaccharide units at
  • the A chain is incorporated into the cell, blocking ribosomal protein synthesis and ultimately leading to cell death.
  • the use of ricin A chain is preferred in this invention.
  • ribosomal inac ⁇ tivating protein is the toxin with only one subunit halti g functional characteristics analogous to ricin A chain. This type of RIP Lacks cytotoxicity to the intact
  • 3J cell because of the inherent absence of a binding fragment analogous to ricin B chain.
  • RIP's of this latter type include gelonin and pokeweed antiviral protein.
  • any toxic lectin which may be split into A and B polypeptide chains, specifically
  • abrin, modeccin and mistletoe toxin may be used in the same way ricin is used in the preferred embodiment.
  • any RIP or equivalent ADP ribosylating toxin specifically gelonin, pokeweed antiviral protein may be used in the same way as ricin A chain.
  • Such materials are equivalent to the toxic lectin A chain for purposes of this invention.
  • the most preferred ricin toxin A chain for use in this invention is one wherein substantially pure RTA-30 is used.
  • RTA-30 refers to a species of ricin toxin A chain having a molecular weight of approximately 30 kD, such as described in detail by Fulton et al. J. Biol. Chem. , 281:5314-5319 (1986) and Vidal et al. Int. J. Cancer, 36:705-711 (1985).
  • RTA preparations containing concentrations of about 75% or more ; of RTA-30 are considered substantially pure. Preparation of substantially pure RTA-30 for use in conjunction with a MoAb is described in U.S. Patent Application Serial Number 074,824 which is incorporated herein by reference.
  • the two components are complexed or chemically bonded together by any of a variety of well-known chemical procedures.
  • the linkage may be by way of carbodiimide, glu ar ldehyde, heterobifunctional cross-linkers, e.g., N-succinimidyl 3-(2- pyridyldithio) propionate (SPDP) and derivatives, 2- imminothiolane and derivatives, homobifunctional cross- 5 linkers, e.g., bis-maleimide, cross-linking of proteins without exogenous cross-linkers by means of groups reactive to the individual protein such as carbohydrate, disulfide, carboxyl or amino groups via oxidation or reduction of the native protein, or treatment with an enzyme or the like.
  • groups reactive to the individual protein such as carbohydrate, disulfide, carboxyl or amino groups via oxidation or reduction of the native protein, or treatment with an enzyme or the like.
  • RTA solution and the antibody solution are preferably combined as described in U.S. Serial No. 974,824, page 15, lines 1-9 and the immunotoxin elutes as fractions (as described in U.S. 4,590,071, column 5, lines 15-24).
  • TWEEN 80 may be added up to 0.1% in the final solution.
  • RTA produced by Xoma Corporation, Berkeley, California may alternatively be used as the immunotoxin embodying a preferred immunotoxin preparation of this invention.
  • This preparation is a conjugate of RTA and a MoAb reactive with
  • the immunotoxin may be administered to a patient either singly or in a cocktail containing two or more immunotoxins, other therapeutic agents, compositions, or the like, including, but not limited to, immunosuppressive
  • Immunosuppressive agents useful in suppressing allergic reactions of a host.
  • Immunosuppressive agents of interest include prednisone, DECADRON (Merck, Sharp & Doh e, West Point, PA), cyclophosphamide,
  • Potentiators ⁇ f interest include monensin, ammonium chloride and chloroquin. All of these agents are. administered in generally accepted efficacious dose ranges such as those disclosed in the Physician Desk Reference, 41st Ed. (1987), Publisher Edward R. Barnhart, New Jersey. A commonly 5 assigned U.S. Application Serial No. 07/151,741 discloses administration of an immunotoxin as an immunosuppressive agent and is incorporated by reference herein.
  • anti-T cell immunotoxins may be formulated into either an injectable or
  • HE topical preparation HE topical preparation.
  • Parenteral formulations are known and are suitable for use in the invention, preferably for i.m. or i.v. administration.
  • the formulations containing therapeutically effective amounts of anti-T cell immuno ⁇ toxins are either sterile liquid solutions, liquid
  • Lyophilized compositions are reconstituted with suitable diluents, e.g., water for injection, saline, 0.3% glycine and the like, at a level of about from .01 mg/kg of host body weight to 10 mg/kg where Jd the biological activity is less than or equal to 20 ng/ml when measured in a reticulocyte lysate assay.
  • suitable diluents e.g., water for injection, saline, 0.3% glycine and the like
  • the pharmaceutical compositions containing anti-T cell immunotoxins will be administered in a therapeutically effective dose in a range of from about .01 mg/kg to about 5 5 mg/kg of the treated animal.
  • a preferred therapeutically effective dose of the pharmaceutical composition containing anti-T cell immunotoxin will be in a range of from about 0.01 mg/kg to about 0.5 mg/kg body weight of the treated animal administered over several days to two weeks by daily 3 ⁇ intravenous infusion, each given over a one hour period, in a sequential patent dose-escalation regimen.
  • Anti-T cell immunotoxin is formulated into topical preparations for local therapy by including a therapeu ⁇ tically effective concentration of anti-T cell immunotoxin S in a dermatological vehicle.
  • the amount of anti-T cell immunotoxin to be administered, and the anti-T cell immunotoxin concentration in the topical formulations, will depend upon the vehicle selected, the clinical condition of the patient, the systemic toxicity and the stability of the anti-T cell immunotoxin in the formulation. Thus, the physician will necessarily employ the appropriate 5 preparation containing the appropriate concentration of anti-T cell immunotoxin in the formulation, as well as the amount of formulation administered depending upon clinical experience with the patient in question or with similar patients.
  • 1O ⁇ topical formulations is in the range of greater than from about 0.1 mg/ml to about 25 mg/ml.
  • the concen ⁇ tration of anti-T cell immunotoxin for topical formulations is- in the range of greater than from about 1 mg/ml to about 20 mg/ml.
  • hydrogel vehicles in the treatment of skin inflammation.
  • Suitable vehicles are oil-in-water or water-in-oil emulsions using mineral oils, petrolatum and the like.
  • Anti-T cell immunotoxin optionally is administered
  • transdermal therapeutic system B&rry, 1983, Dermatolo ical Formulations, p. 181 and literature cited therein. While such topical delivery systems have been designed largely for transdermal administration of low molecular weight drugs, by definition
  • Topical preparations of anti-T cell immunotoxin either for systemic or local delivery may be employed and may contain excipients as described above for parenteral administration and other excipients used in a topical preparation such as cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. Any pharmacologically acceptable buffer may 5 be used, e.g., tris or phosphate buffers.
  • the topical' formulations may also optionally include one or more agents variously termed enhancers, surfactants, accelerants, adsorption promoters or penetration enhancers, such as an agent for enhancing percutaneous penetration of the anti-T
  • HOC- cell immunotoxin or other agents should desirably possess some or all of the following features as would be known to the ordinarily skilled artisan: be pharmacologically inert, non-promotive of body fluid or electrolyte loss, compatible with anti-T cell immunotoxin
  • Anti-T cell immunotoxin may also be administered by aerosol to achieve localized delivery to the lungs. This is accomplished by preparing an aqueous aerosol, liposomal 0 preparation or solid particles containing or derivatives thereof. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of anti-T cell immunotoxin together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and 5> stabilizers will vary depending upon the requirements for the particular anti-T cell immunotoxin, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as 0* glycine, buffers, salts, sugars or sugar alcohols.
  • the formulations also can include mucolytic agents as well as bronchodilating agents.
  • the formulations will be sterile. Aerosols generally wilL be prepared from isotonic solutions.
  • the particles optionally include normal lung surfactants.
  • Aerosols may be formed of the particles in aqueous or nonaqueous (e.g., fluorocarbon propellant) suspension.
  • Such particles include, for example, intramolecular aggregates of anti-T cell immunotoxin or derivatives thereof or liposomal or microcapsular-entrapped anti-T cell immunotoxin or derivatives thereof.
  • the aerosols should be free of lung irritants, i.e., substances which cause acute 5 bronchoconstriction, coughing, pulmonary edema or tissue destruction. However, nonirritating absorption enhancing agents are suitable for use herein.
  • Sonic nebulizers preferably are used in preparing aerosols. Sonic nebulizers minimize exposing the anti-T cell immunotoxin or derivatives 0- thereof to shear, which can result in degradation of anti-T cell immunotoxin.
  • Anti-T cell immunotoxin may be administered systemically, rather than topically, by injection i. ., subcutaneously, intrathecally or intraperitoneally or into 5 vascular spaces, particularly into the joints, e.g., intraarticular injection at a dosage of greater than about 1 ⁇ g/cc joint fluid/day.
  • the dose will be dependent upon the properties of the anti-T cell immunotoxin employed, e.g., its activity and biological half-life, the concentration of S anti-T cell immunotoxin in the formulation, the site and rate of dosage, the clinical tolerance of the patient involved, the autoimmune disease afflicting the patient and the like as is welL within the skill of the physician.
  • the anti-T cell immunotoxin of the present 5 invention may be administered in solution.
  • the pH of the solution shouid be in the range of pH 5 to 9.5, preferably pH 6.5 to 7.5.
  • the anti-T cell immunotoxin or derivatives thereof should be in a solution having a suitable pharmaceutically acceptable buffer such as phosphate, tris d (hydroxymethyl) aminome hane-HC1 or citrate and the like.
  • Buffer concentrations should be in the range of 1 to 100 mM.
  • the solution of anti-T cell immunotoxin may also contain a salt, such as sodium chloride or potassium chloride in a concentration of 50 to 150 mM.
  • An effective amount of a 5- stabilizing agent such as an albumin, a globulin, a gelatin, a protamine or a salt of protamine may also be included and may be added to a solution containing anti-T cell immunotoxin or to the composition from which the solution is prepared.
  • Systemic administration of anti-T cell immunotoxin is made daily, generally by intramuscular injection, 5 although intravascular infusion is acceptable.
  • Administration may also be intranasal or by other nonparenteral routes.
  • Anti-T cell immunotoxin may also be administered via microspheres, liposomes or other microparticulate delivery systems placed in certain tissues lO' including blood.
  • Topical preparations are applied daily directly to the skin or mucosa and then preferably occluded, i.e., protected by overlaying a bandage, polyolefin film or other barrier impermeable to the topical preparation.
  • the diafiltrate was applied to a Sepharose 4B column (Pharmacia Fine Chemicals, Piscataway, NJ) and the nonbinding flow-through containing ricin was loaded onto an acid-treated Sepharose column in order to separate the ricin toxin A chain from the whole ricin (as described in U.S. 4,590,071, column 3, lines 26-52).
  • the eluant thus obtained 5 was diafiltered against Tris buffer (10 mM Tris, 10 mM
  • the murine monoclonal antibody XMMLY-H65 is
  • H65 was deposited with the A.T.C.C. and designated Accession No. HB9286.
  • Immunotoxins utilizing that monoclonal antibody were prepared as follows:
  • antibody passed through the column, and was diafiltered against PBS, pH 7.0, 5% dextrose.
  • the antibody was activated for coupling to the RTA with SPDP (as described in U.S. 4,590,071, coiumn 4, line 55, column 5, line 5, except that the buffer contained 5% dextrose instead of azide) .
  • 3X0 drug for the treatment of cGVHD patients The following summarizes the results of the therapy of several GVHD pa ⁇ tients with scleroderma and primary biliary sclerosis-like conditions. Scoring is based on a normal value of 0 pro ⁇ gressing to advanced disease at 4+. 5 a. Patient FC.
  • Patient FC was a 35 year old male with aplastic anemia. He received a bone marrow transplant (BMT) from an HLA identical sister. He developed acute GVHD within one month after transplant and progressed to chronic GVHD. At E time of immunotoxin therapy, he was on a high dose of methyl prednisolone and a moderate dose of Cyclosporin A. His chronic GVHD had been unresponsive, with 100% involvement of skin with open pustules, oral stomatitis, and a large ulcerated hard palate. On immunotoxin, the skin showed S> definite softening and oral stomatitis and the hard palate ulcers resolved. He was able to have Cyclosporine A and methyl prednisolone tapered to low levels. Chronic GVHD then flared up again in 6 months.
  • BMT bone marrow transplant
  • XMMLY-H65-RTA dose 0.05 mg/kg/day for 14 days.
  • Patient GH was a 47 year old female with chronic myelogenous leukemia (CML). She received BMT from an HLA identical brother. She developed acute GVHD 3 months post- 5 transplant and subsequently developed chronic GVHD. She was being treated with moderate methyl prednisolone and moderate Cyclosporine A. Her disease was refractory to treatment, with severe scaling, puritis, and increased pigmentation of the skin. Within 7 days of immunotoxin treatment, scaling
  • 25 XMMLY-H65-RTA dose 0.1 mg/kg/day for 14 days.
  • Lymphocyte population was decreased in patients 3BT with cGVHD by administration of immunotoxin therapy.
  • Patients FC and BM were each administered XMMLY- H65-RTA intravenously for a 14-day course in a sequential patient dose escalation regimen ranging from 0.05 mg/kg/day through 0.33 mg/kg/day for 14 days. Each dose was given 35 over a one-hour period. From the date of infusion and over the course of 20 days in the case of patient FC, and the course of 28 days in the case of patient BM, lymphocytes were isolated from whole blood and analyzed for the presence of CD5 markers using the immunofluorescence method to ⁇ E sialyze the cells by flow cytometry.
  • Fig. 1 shows the marked depletion of lymphocytes with the CD5 marker in each patient resulting from the immunotoxin treatment.
  • Patients FC, MS and BM with cGVHD in a manner similar to that described in paragraph 3(a) above, were 5 administered XMMLY-H65-RTA.
  • the lymphocyte cell population with the CD3 marker was determined as above over the course of 20, 24 or 28 days (depending on the patient) from the date of initial infusion.
  • Fig. 2 shows the marked depletion o ⁇ lymphocytes with the CD3 marker in each patient resulting 0" from the immunotoxin treatment.
  • Fig. 3 shows the results in patient FC of the depletion of the lymphocytes with the CD3 marker, those with the CD5 marker and of all lymphocytes.
  • the depletion of CD5 and CD3 marker cells approaches zero, while the total depletion of lymphocytes, though 5 significantly decreased drops to about 200 cells/ml at day 15.
  • XomaZyme®-H65 prepared as described above was administered at doses of 0.05, 0.1, 0.2 and 0.33 mg/kg/day for a period of 5-9 days. Four patients were treated at each dose. Patients were monitored using several indicia including joint selling and tenderness scores. Patients responded at each of the dosage levels. One patient who received XomaZyme®-H65 at .05 mg/kg/day has for 6 months 5 shown significant therapeutic benefit. Similar sustained effects with a single treatment regimen over 5-9 days at the G 1 mg/kg/day (two patients) and at 0.33 mg/kg/day (one patient)' was observed. It has been observed for the first time, that the therapeutic benefit, to a patient having an ID "5 autoimmune disease, of administration of an anti-T cell immunotoxin is sustained well beyond the time of administration.
  • Aplastic anemia is a life-threatening disorder characterized by pancytopenia and bone marrow hypocellularity. There is a large body of data supporting Z0 the view that severe acute apalastic anemia is an autoimmune disease.
  • Patients are selected for treatment who are diagnosed as having moderate or severe aplastic anemia. That diagnosis is established as follows: a bone marrow 25 biopsy showing hypoplasia (decrease of 10% cellularity) ; and granulocyte ( ⁇ 500/mm 3 ), platelets ( ⁇ 20,000/mm 3 ) or reticulocyte ( ⁇ 90,000/mm ) counts as indicated.
  • XomaZyme®-H65 is prepared as described above. Patients are administered 10 infusions of XomaZyme®-H65 over 3X ⁇ one hour on ten successive days. The anti-T cell immuno ⁇ toxin is administered at doses of 0.2, 0.33 and 0.5 mg/kg/day. Patients are monitored for response to therapy by improvement in granulocytes and platelet counts or transfusion requirements at 3 and 6 months post therapy. 35 EXAMPLE 5 Anti-T Cell Immunotoxin Treatment of Type I Diabetes
  • Type I diabetes There are two major types of diabetes. Type I has classically been associated with the requirement of exogenous insulin. Type I typically occurs before the age of 40 and is associated with an absence of insulin secretion. The pancreas of patients with long-term type I insulin dependent diabetes are devoid of pancreatic islet cells. There is a large body of evidence that the etiology of type I insulin dependent diabetes (IDDM) is autoimmune.
  • IDDM insulin dependent diabetes
  • Patients are diagnosed as having IDDM based on the criteria established by the American Diabetes Association.
  • XomaZyme®-H65 is prepared as described above. Patients are administered 5 infusions of XomaZyme®-H65 over one hour on five successive days.
  • the anti-T cell immunotoxin is administered at doses of 0.1 and 0.2 mg/kg/day. Patients are monitored for response to therapy by measuring insulin levels required to maintain normal or acceptable fasting glucose levels. ' Using diagnostic criteria predictive of the onset of Type 1 diabetes, patients are selected for prophylactic treatment. Patients are administered anti-T cell immunotoxin at doses about 0.1 and about 0.2 mg/kg/day.

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Abstract

Un procédé et une composition thérapeutique destinés au traitement de maladies auto-immunes, par l'administration d'une immunotoxine anti-cellules T comprenant un agent cytotoxique conjugué avec une immunoglobine anti-cellules T.
EP19890902872 1988-02-03 1989-02-03 Therapeutic use of anti-t cell immunotoxin for autoimmune diseases Withdrawn EP0397798A4 (en)

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US151744 1988-02-03

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EP0397798A4 EP0397798A4 (en) 1991-10-30

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WO1989000583A1 (fr) * 1987-07-17 1989-01-26 Xoma Corporation Therapies ameliorees a base d'immunotoxines utilisant des especes a chaine-a de ricine purifiee
US5645998A (en) 1988-12-13 1997-07-08 University Of Florida Research Foundation Methods and compositions for the early detection and treatment of insulin dependent diabetes mellitus
US6001360A (en) * 1988-12-13 1999-12-14 University Of Florida Method and compositions for early detection and treatment of insulin dependent diabetes mellitus
WO1990007117A1 (fr) * 1988-12-13 1990-06-28 University Of Florida Procedes et compositions servant a la detection precoce et au traitement du diabete sucre dependant de l'insuline
US5762937A (en) * 1988-12-13 1998-06-09 University Of Florida Research Foundation, Inc. Methods and compositions for the early detection and treatment of insulin dependent diabetes mellitus
US5397702A (en) * 1989-03-06 1995-03-14 The Regents Of The University Of California Assay for and treatment of autoimmune diseases
ATE138196T1 (de) * 1989-03-06 1996-06-15 Univ California Testverfahren für und behandlung von autoimmunkrankheiten
US6113903A (en) * 1989-03-21 2000-09-05 The Immune Response Corporation Peptides and methods against diabetes
IL98932A0 (en) * 1990-07-27 1992-07-15 Univ California Assay,kits and methods based on nk+channel expression
IT1249051B (it) * 1991-02-26 1995-02-11 Italfarmaco Spa Immunotossina da anticorpi monoclonali anti-cd5
US5837491A (en) * 1991-11-04 1998-11-17 Xoma Corporation Polynucleotides encoding gelonin sequences
US5621083A (en) * 1991-11-04 1997-04-15 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US6146850A (en) * 1991-11-04 2000-11-14 Xoma Corporation Proteins encoding gelonin sequences
CA2507749C (fr) * 1991-12-13 2010-08-24 Xoma Corporation Methodes et materiaux pour la preparation de domaines variables d'anticorps modifies et leurs utilisations therapeutiques
AUPN115095A0 (en) * 1995-02-15 1995-03-09 Butt, Henry Lawrence Analysis of and compositions and methods for the treatment of disease
US7288254B2 (en) 1995-10-30 2007-10-30 The United States Of America As Represented By The Secretary, Department Of Health And Human Services, Nih Use of immunotoxins to induce immune tolerance to pancreatic islet transplantation
US7696338B2 (en) 1995-10-30 2010-04-13 The United States Of America As Represented By The Department Of Health And Human Services Immunotoxin fusion proteins and means for expression thereof
US7517527B2 (en) 1995-10-30 2009-04-14 The United States Of America As Represented By The Department Of Health And Human Services Immunotoxin with in vivo T cell suppressant activity and methods of use
JP2002501484A (ja) 1997-03-05 2002-01-15 アメリカ合衆国 免疫毒素および免疫寛容を誘導する方法
AU3654499A (en) * 1998-04-22 1999-11-08 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Use of immunotoxins to induce immune tolerance to pancreatic islet transplantation
WO2006115509A2 (fr) 2004-06-24 2006-11-02 Novartis Vaccines And Diagnostics Inc. Immuno-potentialisateurs a petites molecules et analyses visant a detecter leur presence
GB0707208D0 (en) * 2007-04-13 2007-05-23 Istituto Superiore Di Sanito Novel disease treatments
AU2020286508A1 (en) * 2019-06-05 2022-01-06 Heidelberg Pharma Research Gmbh T-cell depleting therapies
WO2024040195A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo

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WO1989006968A1 (fr) 1989-08-10
JPH03503887A (ja) 1991-08-29
DK184890D0 (da) 1990-08-02
EP0397798A4 (en) 1991-10-30
AU3215789A (en) 1989-08-25
AU633251B2 (en) 1993-01-28
DK184890A (da) 1990-10-03

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