WO1989006967A1 - Immunosuppresion a l'aide de compositions d'immunotoxines de cellules t anti-pan - Google Patents

Immunosuppresion a l'aide de compositions d'immunotoxines de cellules t anti-pan Download PDF

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Publication number
WO1989006967A1
WO1989006967A1 PCT/US1989/000439 US8900439W WO8906967A1 WO 1989006967 A1 WO1989006967 A1 WO 1989006967A1 US 8900439 W US8900439 W US 8900439W WO 8906967 A1 WO8906967 A1 WO 8906967A1
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immunotoxin
immunosuppressive
cell
immunotoxins
patient
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PCT/US1989/000439
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English (en)
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Patrick J. Scannon
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Xoma Corporation
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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
    • A61K47/6819—Plant toxins
    • A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
    • A61K47/6827—Ricin A
    • 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 generally to methods for improving the effectiveness of immunogenic substances, such as proteins, in various human treatment applications and, more particularly, to the concurrent administration of T-cell specific immunotoxins as an immunosuppressive agent to permit extended treatment regimes with monoclonal antibodies, immunotoxins, recombinantly-produced proteins and the like in cancer and other therapies.
  • An immune response against an immunotoxin can cause premature removal of the immunotoxin from the patient's serum, significantly limiting the immunotoxin's effectiveness.
  • Multiple treatment regimes are extremely susceptible to this problem, and significantly increasing the immunotoxin dosage is generally undesirable, in part because the patient may suffer allergies and other harmful effects of immune reactions against the immunotoxin.
  • the advent of recombinant DNA technology has provided a vast arsenal of novel therapeutic proteinaceous agents (including new forms of immunotoxins) for treating a whole array of disease states. Unfortunately, many of these agents are highly antigenic, severely limiting their effectiveness.
  • the immune system comprises cellular and humoral components, both of which operate under positive and negative feedback systems. Any modification of an immune response against a therapeutic agent must be carefully controlled so as to not destroy the patient's immune competence as a whole.
  • the present invention provides novel methods for enhancing the effectiveness of biological response modifiers in therapy on human patients, which methods comprise concurrently administrating with the modifiers an immunosuppressive dose of an immunotoxin comprising an anti-pan T-cell monoclonal antibody, such as those reactive with the CD3, CD5 or CD7 antigen clusters.
  • This novel treatment has particular applicability in multiple dose treatment regimens using proteinaceous biological response modifiers, such as in chemotherapy when utilizing multiple injections of a primary immunotoxin comprising a cytotoxic agent conjugated to monoclonal antibodies specifically reactive with melanoma or other tumor associated antigens.
  • the immunosupprassive immunotoxin can be administered concomitantly with the response modifier, e.g..
  • the delivery component of the immunosuppressive immunotoxin may comprise one pan T-cell reactive immunoglobulin or a collection of immunoglobulins reactive with a plurality of T-cell markers, such as those associated with antigen clusters CD2, CD3, CD4, CD5, CD6, CD7, CD9, CD11 and CD45R.
  • the cytotoxic agent component of the immunotoxin is preferably a ribosomal inhibiting protein, such as ricin or ricin A-chain.
  • Various administration intervals and dosages that produce a substantially decreased immune response to the desired antigen may be utilized.
  • Novel methods are provided for improving immunogenic biological response modifier therapy in human patients, by inhibiting the patient's immune response against the modifier through the co-administration of at least one immunosuppressive dose of an immunosuppressive immunotoxin capable of neutralizing mature T-cell activity.
  • the immunotoxin treatment diminishes the patient's immune response against antigenic components of the modifier.
  • the patient's immune response would be reduced against both the delivery component and the toxic component of a primary immunotoxin, thus prolonging the efficacy of the primary immunotoxin and enhancing the prognosis for recovery.
  • use of an immunosuppressive immunotoxin avoids raising subsequent doses of the primary immunotoxin or other response modifier.
  • biological response modifier refers to those immunogenic agents capable of altering the natural host response to a disease state. This term is intended to encompass pharmaceutical substances, typically antigenic, produced by traditional purification and chemical modification procedures, as well as those produced through the use of recent developments in molecular biology, recombinant genetics, hybridoma technology and the like.
  • representative modifiers include endotoxin-type inhibitors, immune RNAs and other non-protein antigenic immunomodulating agents, but more typically include any of the various well-known proteinaceous therapeutic substances such as lymphokines, colony stimulating factors, interleukins, growth factors and hormones (EGF, FGF, etc.), thymosins, and, of course, immunoglobulins.
  • primary immunotoxin refers to the immunotoxin responsible for treating a specific disease.
  • an immunosuppressive immunotoxin is used to limit a patient's response against the primary immunotoxin in accordance with the teachings of the present invention.
  • Immunotoxins are characterized by two components.
  • One component is a cytotoxic agent which is usually fatal to a cell when attached or absorbed.
  • the second component known as the "delivery vehicle" provides a means for delivering the toxic agent to a particular cell type, such as cells comprising a carcinoma.
  • the two components are commonly chemically bonded together by any of a variety of well-known chemical procedures.
  • the linkage may be by way of heterobifunctional cross-linkers, e.g.. SPDP, carbodiimide, glutaraldehyde, or the like.
  • Cytotoxic agents are suitable for use in immunotoxins.
  • Cytotoxic agents can include radionuclides, such as Iodine-131, Yttrium-90, Rhenium-188, and Bismuth-212; a number of chemotherapeutic drugs, such as vindesine, methotrexate, adriamycin, and cisplatinum; and cytotoxic proteins such as ribosomal inhibiting proteins, pokeweed antiviral protein, abrin and ricin (or their A-chains, diphtheria toxin A-chains, Pseudomonas exotoxin A, etc.).
  • radionuclides such as Iodine-131, Yttrium-90, Rhenium-188, and Bismuth-212
  • chemotherapeutic drugs such as vindesine, methotrexate, adriamycin, and cisplatinum
  • cytotoxic proteins such as ribosomal inhibiting proteins, pokeweed anti
  • the delivery component of the immunotoxin is typically proteinaceous and can be obtained from a number of sources. Intact immunoglobulins or their fragments, such as Fv, Fab, F(ab ), etc., or other proteins (i.e., specific binding proteins, such as interleukin-2 (IL-2)) specifically reactive with a selected cell marker (e.g., hormone receptors, such as the IL-2 receptor) are preferably used.
  • immunoglobulins will be monoclonal antibodies of the IgM or IgG isotype, of mouse, human or other mammalian origin.
  • a preferred source of monoclonal antibodies is immortalized murine or human cell lines that may be cloned and screened in accordance with conventional techniques.
  • immunoglobulins and methods of making them.
  • the utilization of recombinant DNA technology has produced functional, assembled immunoglobulins or hybrid chimeric immunoglobulins (e.g., the constant region from human monoclonal antibodies combined with mouse variable regions), suitable for use in immunotoxins.
  • functional, assembled immunoglobulins or hybrid chimeric immunoglobulins e.g., the constant region from human monoclonal antibodies combined with mouse variable regions
  • suitable for use in immunotoxins See, e.g., EPA 84302368.0, which is incorporated herein by reference.
  • the delivery component will be capable of binding to epitopes of markers on selected mature T-cell types, such as inducer T-cells.
  • the marker is generally a unique surface protein, but a variety of markers, such as other proteins, glycoproteins, lipoproteins, polysaccharides and the like, which are produced by the T-cells to be treated, can be utilized in accordance with the present invention.
  • the general immunization fusion, screening, and expansion methods of producing monoclonal antibodies against T-cell markers are well-known to those skilled in the art and can be found, for example, in Goding, Monoclonal Antibodies; Principles and Practice, Academic Press, 2nd Edition (1986), which is incorporated herein by reference.
  • T-cell markers most studied at the present time have been grouped into so-called "Clusters of Differentiation," as named by the First International Leukocyte Differentiation Workshop, Leukocyte Typing, Eds. Bernard, et al., Springer-Verlag, N.Y. (1984). This has recently been updated at the Second International Workshop, Leukocyte Typing II (Eds. Reinherz, et al., Springer-Verlag, N.Y. (1986), which is incorporated herein by reference), and Table I presents a list of the better characterized monoclonal antibodies (many of which are available publicly or commercially) reactive with various epitopes on these markers. Additional antibodies discovered to be reactive with these and other T-cell antigens may be utilized for immunotoxins in accordance with the present invention. TABLE I
  • An immunosuppressive immunotoxin composition will typically comprise immunoglobulins (complexed with toxins) that are capable of binding to and removing one or more T-cell subpopulations, preferably mature T-cells. Ideally, the immunoglobulins will only minimally, if at all, cross-react with other leukocyte subsets, particularly pluripotent stem cells.
  • an immunosuppressive immunotoxin composition will comprise at least one pan T-cell immunoglobulin reactive agent, e.g., reactive with the CD3, CD5 or CD7 antigen clusters.
  • the immunotoxin composition will be composed of two or more immunoglobulins, each reactive with a different marker of the same or different cell populations to ensure a broad spectrum of T-cell neutralization. Typical combinations will include immunoglobulins recognizing CD4 and CD8; TAC and CD4; or CD7, CD11 and CD5.
  • a preferred method of measuring the immune response to an immunotoxin is based on the common ELISA assay. Briefly, microtiter plates are coated with the immunotoxin components, i.e., the immunoglobulin and the cytotoxic agent. After standard blocking and washing procedures, appropriate dilutions of patient's serum are added to the plate and any antibodies in the serum binding to the antigens are detected using an alkaline phosphatase conjugated goat anti-human antibody with specificity for IgM or IgG heavy chains. The antibody response is typically reported as a ratio. For each patient, the maximum measurable binding activity following therapy is determined by extrapolating the titration curve to the X axis.
  • the response ratio is defined as a ratio of the titration end point value of the maximum response to the end point value of the patient's pre-treatment (baseline) serum.
  • Other protocols may be substituted to assess the patient's immune response according to means well known by those skilled in the art.
  • positive responses to both the immunoglobulin and the cytotoxic agent components of the immunotoxin can be identified.
  • the humoral aspect of the immune response is analyzed and a wide range of responses to each and/or both of the immunotoxin components is seen.
  • an abrogation or prevention of the development of an immune response is indicated by a ratio less than about 2.0.
  • An acceptable inhibition of a human immune response to either or both components of an immunotoxin would be preferably less than about 5.0 to 10 for both components, most preferably less than about 2.0 to 3.0.
  • a variety of dosage protocols may be followed, again, depending, e.g., upon the particular primary immunotoxin utilized and the condition of the patient.
  • the protocol for administration of the immunosuppressive immunotoxin must be tailored to the primary protocol.
  • the amount of immunosuppressive immunotoxin administered per injection may range from about 0.01 up to about 4.0 mg/kg or more. Larger amounts per injection may be tolerated if the administration schedule calls for a single or a few injections. Lower amounts per injection may be administered over longer time periods of up to two weeks or more. Patient's disease status could influence dose tolerated.
  • XMMLY-H65-RTA is administered in 14 injections over a period of about 14 days.
  • the initial injections are preferably administered preceding or given concurrently with treatment with the primary immunotoxin, and the remaining injections administered at regular intervals thereafter.
  • An immunosuppressive dose would be an amount of immunosuppressive immunotoxin sufficient to limit the patient's immune response to a significantly reduced level of interference with the functional activity of the biological response modifier (e.g., to a level where a subsequent modifier, such as a primary immunotoxin, dose regimen retains substantial efficacy).
  • This corresponds to the inhibiting the T-cell immune response in comparison to a normal response, ideally by about 85% to 95% or more, but inhibition levels of about 50% to 60% may be acceptable in some patients, and at least about 75% inhibition is preferred. Diminishment of various components of the T-cell immune response may be obtained, but reduction in antibody formation is a preferred result.
  • the period of co-administration of biological response modifiers and immunosuppressive immunotoxin raay coincide.
  • the IgG or IgM response to either the RTA or immunoglobulin portion of an immunotoxin commonly can be detected about 7 to 8 days after exposure to the primary immunotoxin, and peaks at about 15 to 20 days or more thereafter.
  • the immunosuppressive immunotoxin is preferably administered between 3 days before and 3 days after each exposure to the primary immunotoxin. Subsequent doses of the immunosuppressive immunotoxin may be administered to further abrogate this or other aspects of the immune response.
  • neoplasms particularly those showing retarded growth or total remission when subjected to primary immunotoxin treatment.
  • treatable neoplasms can include melanomas, gastrointestinal carcinomas, various leukemias, and T-cell and B-cell lymphomas.
  • Aggressive grades of cancers may be particularly suited for treatment with primary immunotoxins.
  • immunotoxins are particularly suited for use as surgical adjuvant.
  • suitable modifiers can be used to treat autoimmune diseases, graft rejection and graft versus host disease in allogeneic bone marrow transplantation, graft rejection in other organ transplants, and infectious disease states such as septic shock.
  • the immunosuppressive immunotoxin may be used alone or with other immunosuppressive agents.
  • These "cocktails" can be designed to universally and safely suppress immune responses in a wide variety of treatment regimens. Any of a variety of immunosuppressant agents known to the skilled artisan can be combined in the cocktail.
  • a preferred agent is cyclophosphamide at doses ranging from about 50 to 1500 mg/m 2 , preferably about 500 mg/m 2 /day or about 100 mg/m 2 /day for 14 days.
  • the use of cyclophosphamide in conjunction with immunotoxins is disclosed in the commonly assigned application U.S.S.N. 018,324, filed February 24, 1987, and incorporated herein by reference.
  • prednisone may be utilized at concentrations ranging from about 50 to 250 mg/m 2 , preferably about 100 mg/m 2 .
  • dexamethasone may be used in conjunction with the cyclophosphamide at doses of about 5 to 30 mg, preferably about 15 mg.
  • cyclophosphamide and the additional immunosuppressive agents will be given coincidentally, such as both at day one, or both on five daily injections, or the like, but alternating administrations may also be utilized.
  • alternating administrations may also be utilized.
  • Actual methods for preparing and administering oral and parenteral compositions will be known or apparent to those skilled in the art and are described in detail, e.g., in Remington's Pharmaceutical Science, 16th Ed., Mack Publishing Co., Pennsylvania (1982), which is incorporated herein by reference.
  • 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 was diafiltered against Tris buffer (10mM Tris, 10mM NaCl), and the resulting filtrate was passed through a QAE Sepharose Fast Flow column (Pharmacia Fine Chemicals) equilibrated to the same buffer.
  • the RTA obtained above was adjusted in NaCl concentration to 0.9 wt. %, and purified to remove toxin B-chain impurities by applying to a Sepharose column previously coupled to goat anti-RTB antibodies.
  • the murine monoclonal antibody XMMLY-H65 is directed against the CD5 antigen, one of the "pan T" antigens, present on 85-100% of human mature T lymphocytes, and on a small population of. B lymphocytes.
  • This antigen is not present on hematopoietic progenitor cells nor on any normal adult or fetal human tissue except lymphocytes; and extensive studies by flow cytometry, immunoperoxidase staining, and red cell lysis have not demonstrated binding to such tissues. It is of the IgG1 subclass, and does not fix human or rabbit complement.
  • the cell line XMMLY-H65 was deposited with the A.T.C.C. and designated Accession No. HB9286.
  • Immunotoxins utilizing that monoclonal antibody were prepared as follows:
  • a concentrated RTA-30 solution and the antibody solution were placed together in a formulation buffer consisting of 10mM P04, pH 7.0, 0.15 M NaCl, and 5% dextrose.
  • This solution was applied to a Sephacryl S-200 HR column (Pharmacia Fine Chemicals), which had been pre-equilibrated with PBS containing 5% dextrose, and the immunotoxin eluted as fractions (as described in U.S. 4,590,071, column 5, lines 15-24)
  • Tween 80 was added up to 0.1% in the final solution.
  • mice Human IgM and IgG antibody titers to ricin A chain and murine monoclonal antibody XMMLY-H65 were measured by enzyme linked immunosorbant assay (ELISA).
  • Mictrotiter plates (Falcon 3915 Pro-Bind, Becton Dickinson, Oxnard, CA) used to detect antibodies to ricin A chain were prepared by adsorbing ricin A chain (XOMA Corp., Berkeley, CA) diluted in phosphate buffered saline (PBS) [Gibco, Grand Island, NY] at 4oC overnight. After thorough washing in PBS containing 0 .05% Tween 20 (PBST) [Sigma, St. Louis, MO] the walls were blocked with 1% glycine (BioRad, Richmond, CA) in PBS at room temperature for 1 hour.
  • PBS phosphate buffered saline
  • PBST 0 .05% Tween 20
  • Microtiter plates used to detect antibodies to XMMLY-H65 were prepared by adsorbing XMMLY-H65 (or other antibody) diluted in 0.1M carbonate buffer, pH 9.6, as described above. After thorough washing in PBST, the wells were blocked with 1% bovine serum albumin (BSA) [Sigma, St. Louis, MO] in carbonate buffer at room temperature for 1 hour. Plates were washed as described above and patient serum samples, appropriately diluted in PBST with 1% BSA (PBST-BSA), were added to triplicate wells. The samples were incubated at 37°C for 1 hour.
  • BSA bovine serum albumin
  • An Overall Clinical Assessment of the GVHD response was determined utilizing the following categories: complete response, indicated resolution of all signs and symptoms of GVHD; partial response, indicated reduction of at least 1 grade of GVHD severity in any organ system without progression in any other system; mixed response, indicated improvement in one or more organ system with worsening in another organ; non-response, indicated no improvement; and progression, indicated worsening of GVHD activity in any organ system.
  • complete response indicated resolution of all signs and symptoms of GVHD
  • partial response indicated reduction of at least 1 grade of GVHD severity in any organ system without progression in any other system
  • mixed response indicated improvement in one or more organ system with worsening in another organ
  • non-response indicated no improvement
  • progression indicated worsening of GVHD activity in any organ system.
  • Table II represents a tabulation of data on selected patient's immune response to the two immunotoxin components.
  • an animal protection study is performed in rabbits as follows.
  • a formulation of XMMLY-H65-RTA immunotoxin is prepared as described above for use as the immunosuppressive immunotoxin.
  • Full grown adult rabbits are divided into two groups of six rabbits each, and blood drawn from each to determine a baseline antibody titer. All rabbits in each group are then individually innoculated intravenously (iv) with XMMME-001-RTA at a dose of 0.1 mg/kg, daily, for fourteen days.
  • each rabbit in the second group is also individually innoculated iv with XMMLY-H65-RTA at a dose of 0.1 mg/kg, daily for fourteen days.
  • the control group no additional innoculations are made. All of the animals are then observed for ninety days, during which blood samples are drawn every six days. The blood samples are analyzed for the pattern and intensity of rabbit IgM and IgG antibodies produced against each of the XMMME-001-RTA immunotoxin components as described above (except that goat-anti-rabbit IgM or IgG are used in the ELISA assay).
  • the rabbit IgM and IgG response patterns against XMMME-001-RTA are analyzed as above by using a response ratio comparing the maximum end point titer to the pretreatment baseline titer of the antibodies.
  • the control group exibits on average substantially higher response ratios to XMMME-001 and RTA than the second group, which exhibits an average ratio between about 1 and 10 to each of the two components.

Abstract

On parvient à une immunosupression améliorée destinée à être utilisée dans des thérapies mettant en oeuvre des modificateurs de réaction biologique antigénique, par l'administration conjointe d'immunotoxines spécifiques de cellules T en tant qu'agent immunosuppressif. Cette immunotoxine immunosuppressive peut comprendre une immunoglobuline de cellule T anti-pan complexée avec un agent cytotoxique, tel qu'une protéine d'inhibition de ribosome. On a développé des compositions comprenant l'immunotoxine immunosuppressive avec d'autres agents immunosuppressifs, afin de permettre des régimes multi-doses ou des thérapies prolongées à l'aide des modificateurs.
PCT/US1989/000439 1988-02-03 1989-02-03 Immunosuppresion a l'aide de compositions d'immunotoxines de cellules t anti-pan WO1989006967A1 (fr)

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US15174188A 1988-02-03 1988-02-03

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Cited By (13)

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EP0397798A1 (fr) * 1988-02-03 1990-11-22 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
EP0463114A1 (fr) * 1989-03-06 1992-01-02 Univ California Analyse de detection et traitement de maladies auto-immunes.
WO1992014491A1 (fr) * 1991-02-26 1992-09-03 Italfarmaco S.P.A. Immunotoxine tiree d'anticorps monoclonaux anti-cd5
EP0571613A1 (fr) * 1991-12-13 1993-12-01 Xoma Corporation Procedes et matieres de preparation de domaines variables d'anticorps modifies et leurs utilisations therapeutiques
WO1994004191A1 (fr) * 1992-08-13 1994-03-03 Antisoma Limited Traitement medical
US5397702A (en) * 1989-03-06 1995-03-14 The Regents Of The University Of California Assay for and treatment of autoimmune diseases
WO1995021251A1 (fr) 1994-02-04 1995-08-10 Cantab Pharmaceuticals Research Limited Antigenes des cellules t et leur emploi dans le diagnostic et le traitement d'affections dues aux cellules t
US5621083A (en) * 1991-11-04 1997-04-15 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5827655A (en) * 1990-07-27 1998-10-27 The Regents Of The University Of California Assay, methods and products based on n K+ channel expression
US5837491A (en) * 1991-11-04 1998-11-17 Xoma Corporation Polynucleotides encoding gelonin sequences
EP0945139A1 (fr) * 1998-03-23 1999-09-29 Katholieke Universiteit Nijmegen Méthode et moyens de traitement de maladies immunologiques telle que la maladie des greffes vis-à-vis de l'hÔte
US6146850A (en) * 1991-11-04 2000-11-14 Xoma Corporation Proteins encoding gelonin sequences
US6312700B1 (en) 1998-02-24 2001-11-06 Andrew D. Weinberg Method for enhancing an antigen specific immune response with OX-40L

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0397798A4 (en) * 1988-02-03 1991-10-30 Xoma Corporation Therapeutic use of anti-t cell immunotoxin for autoimmune diseases
EP0397798A1 (fr) * 1988-02-03 1990-11-22 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
US5397702A (en) * 1989-03-06 1995-03-14 The Regents Of The University Of California Assay for and treatment of autoimmune diseases
EP0463114A1 (fr) * 1989-03-06 1992-01-02 Univ California Analyse de detection et traitement de maladies auto-immunes.
EP0463114A4 (en) * 1989-03-06 1992-01-22 The Regents Of The University Of California Assay for and treatment of autoimmune diseases
US5827655A (en) * 1990-07-27 1998-10-27 The Regents Of The University Of California Assay, methods and products based on n K+ channel expression
WO1992014491A1 (fr) * 1991-02-26 1992-09-03 Italfarmaco S.P.A. Immunotoxine tiree d'anticorps monoclonaux anti-cd5
US6146850A (en) * 1991-11-04 2000-11-14 Xoma Corporation Proteins encoding gelonin sequences
US5621083A (en) * 1991-11-04 1997-04-15 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5744580A (en) * 1991-11-04 1998-04-28 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5756699A (en) * 1991-11-04 1998-05-26 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US6376217B1 (en) 1991-11-04 2002-04-23 Xoma Technology Ltd. Fusion proteins and polynucleotides encoding gelonin sequences
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EP0571613A1 (fr) * 1991-12-13 1993-12-01 Xoma Corporation Procedes et matieres de preparation de domaines variables d'anticorps modifies et leurs utilisations therapeutiques
EP0571613A4 (en) * 1991-12-13 1997-03-05 Xoma Corp Methods and materials for preparation of modified antibody variable domains and therapeutic uses thereof
EP1291360A1 (fr) * 1991-12-13 2003-03-12 Xoma Corporation Procedes et matieres de preparation de domaines variables d'anticorps modifies et leurs utilisations therapeutiques
WO1994004191A1 (fr) * 1992-08-13 1994-03-03 Antisoma Limited Traitement medical
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US6312700B1 (en) 1998-02-24 2001-11-06 Andrew D. Weinberg Method for enhancing an antigen specific immune response with OX-40L
US7504101B2 (en) 1998-02-24 2009-03-17 Sisters Of Providence In Oregon Methods for enhancing antigen-specific immune response using antibodies that bind OX-40
US7622444B2 (en) 1998-02-24 2009-11-24 Sisters Of Providence In Oregon Methods for using OX-40 ligand to enhance an antigen specific immune response
WO1999048534A1 (fr) * 1998-03-23 1999-09-30 Immunotoko B.V. Methodes et moyens de traitement de maladies d'origine immunologique
EP0945139A1 (fr) * 1998-03-23 1999-09-29 Katholieke Universiteit Nijmegen Méthode et moyens de traitement de maladies immunologiques telle que la maladie des greffes vis-à-vis de l'hÔte

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EP0407399A1 (fr) 1991-01-16
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