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WO1991008773A1 - Conjugues immunoglobuline-proteine tolerogene - Google Patents

Conjugues immunoglobuline-proteine tolerogene Download PDF

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Publication number
WO1991008773A1
WO1991008773A1 PCT/US1989/005539 US8905539W WO9108773A1 WO 1991008773 A1 WO1991008773 A1 WO 1991008773A1 US 8905539 W US8905539 W US 8905539W WO 9108773 A1 WO9108773 A1 WO 9108773A1
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Prior art keywords
protein
conjugate
mice
igg
antibody
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PCT/US1989/005539
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English (en)
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Halina Borel
Yves Borel
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The Center For Blood Research
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Application filed by The Center For Blood Research filed Critical The Center For Blood Research
Priority to EP19900902970 priority Critical patent/EP0504136A4/en
Priority to JP90503225A priority patent/JPH05502854A/ja
Priority to PCT/US1989/005539 priority patent/WO1991008773A1/fr
Publication of WO1991008773A1 publication Critical patent/WO1991008773A1/fr

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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

Definitions

  • This invention relates to the inhibition of unwanted immune responses, to proteins which are either foreign (i.e., heterologous) or native (i.e., isologous).
  • the immune system reacts to a natural body protein as if it were a foreign antigen, that causes what are known as the autoimmune diseases.
  • autoimmune diseases are Systemic Lupus Erythromatosus (SLE) and Myas henia Gravis (MG).
  • SLE is a disease in which the patient produces auto-antibody to a wide variety of antigens, including, probably most significantly, antibody to the patient's own DNA.
  • SLE has been treated J L vitro using a tolerogenic conjugate of an oligonucleotide covalently linked c an isologous IgG carrier.
  • the conjugate was shown to inhibit the production of anti-DNA antibodies by cultured lymphoid cells from SLE patients. Because of this ability a conjugate having the ability to inhibit the immune response of a mammal, particularly a human, to an immunogen, the conjugate can be said to be tolerogenic. (Borel et al . , U.S. Patent No. 4,650,675, hereby incorporated by reference) .
  • Non-immunoge ic carrier molecules other than immunoglobulin that have been used to induce tolerance are D-GL (D-aminoglutamic acid L)(Katz et al. , 1971, J. Exper. Med. 134:201), carboxmethyl cellulose (Diner et al. , 1979, J. Immunol. 122:1986), and polyethylene glycol (Wilkinson et al., 1987, J. Immunol. 139:326).
  • the invention features a tolerogenic conjugate for inhibiting a mammal's immune response to a protein
  • the conjugate is composed of the protein, or a fragment of peptide thereof (preferably an immunogenic fragment or peptide, encompassing an immunodominant portion of the protein) covalently linked to a soluble isologous (i.e., human) immunoglobulin (preferably IgG) carrier molecule.
  • the protein can be a foreign protein, e.g., a therapeutic monoclonal antibody, or an isologous protein which acts as a causative agent in an autoimmune disease such as SLE.
  • causal protein means the protein which causes ⁇ ymptom(s) of the unwanted immune response and to which the destructive antibodies are made;
  • protein fragment means a proteolytic portion of a protein; and
  • peptide thereof means a synthetic portion of the protein.
  • the conjugates of the invention when administered to a patient, is capable of inducing tolerance in a patient suffering from an unwanted immune response.
  • the conjugate is administered to the patient y conventional methods, e.g., intraveneously admixed with a pharmaceutically acceptable carrier such as saline.
  • a pharmaceutically acceptable carrier such as saline.
  • the immunoglobulin portion functions not only as a carrier molecule for the protein, peptide or fragment, but also, it is believed, helps to induce tolerance in some circumstances.
  • the causative protein, protein fragment, or peptide can correspond to the entire protein molecule, or to an immunodominant portion of the protein; an example of immunodominant region of a causative protein is amino acids 172-204 of the a subunit of the acetylcholine receptor for the autoimmune disease Myasthenia Gravis.
  • Other causative proteins which can be used to make tolerogenic conjugates of the invention include ? protein, associated with SLE, Factor VIII Light chain, associated with an autoimmune response to the blood coagulation Factor VIII, and insulin, associated with insulin-dependent diabetes.
  • the covalent crosslinking reagent used to form the conjugate is preferably a homobifunctional reagent, e.g., disuccinimidyl suberate (DSS).
  • DSS disuccinimidyl suberate
  • Tolerogenic conjugates of the invention can be used to treat any autoimmune diseases in which a protein or peptide acts as a causative agent by generating an unwanted immune response.
  • autoimmune diseases in which a protein or peptide acts as a causative agent by generating an unwanted immune response.
  • Examples are the autoimmunity that develops from repeated treatment of hemophiliac patients with Factor VIII; the central nervous system manifestations of SLE, pemphigus vulgaris, or myasthenia gravis; and from diabetes.
  • Fig. 1 is a graph showing the antibody response to Factor VIII Light chain in two Balb/c mice preimmunized to Factor VIII light chain.
  • Fig. 2 is a graph showing the antibody response to Factor VIII Light chain in adult mice preimmunized to Factor VIII.
  • Fig. 3 is a graph showing a T cell proliferation assay to cytochrome C in BIO.A mice.
  • Fig. 4 is a graph showing the long-term antibody response to P protein in MRL/LPR mouse "v4".
  • Fig. 5 is a graph showing the long-term antibody response to P protein in MRL/LPR mouse "v2" .
  • Figs. 6 (a-d) are graphs showing the longitudinal antibody response to ribonucleoproteins P and Sm in 4 control (i.e., untreated) MRL/LPR mice.
  • Fig. 7 is graph showing results of an ELISA in which the detecting antibody is anti-beef insulin antibody.
  • the conjugates of the invention have the general structure recited in the Summary of the Invention above. Examples of preferred structures are those referred to as preferred embodiments herein.
  • Tolerogenic an igen/immunoglobulin conjugates of the invention can be made using disuccinimidyl suberate (DSS) , or any other suitable homobifunctional or heterobifunctional cross-linking reagent. Conjugation can be carried out so as to effect any of a range of protein: IgG molar ratios.
  • the IgG molecules can be of any suitable subclass, with IgG2a and IgGl subclasses being most preferred for murine IgG because both subclasses bind to Fc receptors on monccytes and lymphoid cells. ... ---, . .
  • a preferred cross linker of the invention is a non-cleavable amine-reactive, homobifunctional crosslinking reagent, available from Pierce, Rockford, Illinois. It has been used to link ricin to other proteins, as described in Montesano et al. (1982) Biochem, Biophys. Res. Comm. 109, 7.
  • crosslinking is carried cut under mild basic conditions at pK 8 - 8.5, for a time period of 30 - 120 minutes, in a small reaction volume (1-2 ml), and at a concentration of IgG of about 10 mg/ml . 3y varying the amounts of the crossiinker and reciprocal ratios of the proteins, the conditions necessary for forming a suitable conjugate from a given antigen can be determined.
  • the protein or fragment or peptide thereof that is conjugated to the carrier IgG can be either the entire protein or an immuno-dominant portion of the protein.
  • the immuno-dominant region can be determined, for example, using X-ray crystallography to reveal portions of the protein that are external and therefore more susceptible to antibody recognition, or by injecting fragments of the protein into an animal and measuring the resulting immune response.
  • Specific examples of DSS promoted crosslinking of P protein and Factor VIII Light chain are given below; however, the procedure described can be used to cross link any ether protein of interest to IgG with appropriate modification which should be apparent to anyone of ordinary skill in this field.
  • Factor VIII The undesirable formation of anti-Factor VIII antibody is a major problem in hemophiliac patients treated with Factor VIII replacement therapy; about 40-60% of these antibodies are directed to the light chain, whereas the remaining antibodies formed are specific for 91 08773 PCT. US8-- . 53-
  • a tolerogenic IgG/Factor VIII Light chain (F8L described in Kaufman et al. , WO 8704187, hereby incorporated by reference) conjugate was made using DSS as the crosslinking reagent.
  • the 76 kD domain light chain of Factor VIII was linked to affinity purified Balb/c myeloma IgG2a, as follows.
  • F8L and IgG2a were first mixed together in borate saline, pH 8.3.
  • the DSS reagent was dissolved in DMSO (dimethyl sulfoxide) at a concentration of 20 mg/ml and a desired amount of the F8L/IgG2a/DMSO was then mixed with the antigen/Ig mixture by gentle inversion.
  • the pH was then readjusted to 8.3 with 0. IN or IN NaOH, and monitored and re-adjusted every 20 min. until it stabilized after approximately 90 - 120 min.
  • the reaction was then quenched with 100 times molar excess of glycine, adjusted to pH 8.3, and the reaction allowed to proceed for an additional 2 hours.
  • the mixture was then centrifuged and the conjugate purified by gel filtration chromatography using Ultragel AcA 44 or Sephacryl S300.
  • the gel chromatography of the F8L-mou ⁇ e IgG conjugate yielded three different but overlapping fractions with the following molar ratios: Al, 5 IgG/1 F8L; A2, 3 IgG/1 F8L; and A3, 1 IgG/1 F8L.
  • a 25 mg dose of tolerogen conjugate was administered intraperitoneally within 30 hr. parturition to 3 sets of 5 - 8 Balb/c newborn mice (Jackson Laboratory, Bar Harbor, ME). On days 17 and 24, 2 mice from each group were challenged with F8L in RIBI adjuvant. Serum samples were collected by retroorbital plexus puncture on days 14, 21, and 28. These sera were assessed by ELISA for antibodies directed against the antigen KLH, intact Factor VIII, and F8L. It was found that specific non-responsiveness to F8L was induced in >80% of the animals, and remained demonstrable throughout the 28 day experimental period, regardless of the IgG/F8L molar ratio of the tolerogenic conjugate injected. Each of fractions Al - A3 was capable of inducing neonatal tolerance against the tolerogen, but none rendered the mice tolerant to intact Factor VIII.
  • FIG. 2 shows titers of anti-F8L antibody for each of the six mice tested; in 5 out of 6 mice, there was a significant reduction of anti-F8L antibody; in 2 out of the 5 tolerized mice, there was a total disappearance of F8L antibody titer, and in the 3 other mice, there was a transient reduction of F8L antibody.
  • Fig. 2 shows that none of the 4 control mice treated with either light chain alone (closed circles) or IgG alone (open circles) showed a significant reduction of anti-F8L antibody. In all mice tested, the antibody response to intact Factor VIII was unaffected.
  • Cytochrome is not associated with an immune disease, but does induce an immune response in mice in vivo, manifested by T cell proliferation.
  • This immune system thus provides a model for T cell non-responsiveness in vivo and also permits study of the parameters of crosslinking for the tolerogen conjugate; i.e., the cytochrome causative protein is well-characterized, and the molar ratio of cytochrome/IgG is easy to control.
  • the amounts of cytochrome and IgG in the reaction mixture are kept identical, e.g., 0.6 mg and 0.9 mg, respectively, while the amount of the bifunctional cross linking reagent is increased, e.g., in steps of 1.2 mg. This results in a higher substitution in the presumed monomer peak, and may also cause increase the degree of polymerization of molecules within the conjugate.
  • the following experiment was designed to prevent a T cell proliferation response in vitro rather than to suppress the ongoing response.
  • a tolerogenic conjugate of pidgeon cytochrome C (Sigma Chemical Co., St. Louis, MO) and mouse IgG2a (0.41 mole/1 mole) was made and purified as described above for Factor VIII Light chain, using DSS as the crosslinking reagent.
  • BIO.A mice Jackson Labs were immunized with 20 nmoles of pidgeon cytochrome C emulsified in Freunc's complete adjuvant containing Mycobacteri m tuberculosis, (strain H37Ra, Difco Laboratories, Detroit, MI). A total volume of 0.2 ml was distributed in the hind (0.05 ml) and front (0.03 ml) footpads and at the base of the tail (0.04 ml).
  • the conjugate or control substance or test substance was administered to B10.A mice (Jackson Lab); on day 4, the mice were immunized with pidgeon cytochrome C (20 nmoles); and on day 11, the draining lymph nodes (auxiliary, inguinal, and paraaortic) were removed and cultured in vitro.
  • EHAA Click's
  • fetal calf serum Gibco, Grand Island, NY
  • T cells T cells isolated by passage over nylon wool.
  • 4 x 10 nylon-adherent cells were cultured in flat bottom 96 well culture plates (Costar #3596, Cambridge, MA) along with 1 x 10 irradiated (3,300R) B10.A spleen cells as a source of antigen-presenting cells, and various concentrations of antigen in a total volume of 0.2 mi of EHAA medium.
  • T cell proliferation was found to be proportionate to incorporation of radioactive thymidine into cellular DNA.
  • Fig. 3 shows that administration of the pidgeon cytochrome C/IgG2a tolerogenic conjugate (PC-RPC5, 0.41 mole/mole, open circles) resulted in almost complete suppresion of T cell proliferation.
  • the untreated control closed circles showed a maximal T cell proliferation response of 60,000 cpm.
  • This figure also shows the results of the proliferative response after administration of IgG2a alone (RPC5, a Balb/c myeloma protein, open squares), a horse cytochrome C/IgG2a conjugate (HC-RPC5, substituted 0.41 mole/mole, open triangles), an unconjugated mixture of pidgeon cytochrome C and IgG2a (PC + RPC5, 0.41 mole/mole, upside down open triangles), pidgeon cytochrome C alone (PC, closed squares), and pidgeon cytochrome C conjugated with splenocytes (PC.501, Jenkins et al. , 1987, J. Expt. Med. 165:302).
  • P protein is a ribonucleopr ⁇ tein of 2500 molecular weight (obtained from Cornell Univ. and Hoffman LaRoche). Patients with the central nervous system manifestation of SLE are known to make antibodies to P protein.
  • a useful model system for treatment is MRL mice, which at 4 - 5 months of age spontaneously form antibodies to ? protein.
  • FIGs. 4 and 5 are graphs representing the antibody response to ? protein in two mice following intravenous administration of three small doses (18.5 mg, 37 mg, and 55.5 mg) of the tolerogenic conjugate.
  • the long-term an i-P protein antibody response was suppressed after treatment with the tolerogenic conjugate.
  • the short-term anti-P response varied; mouse "v2" showed a slight increase in anti-P antibody, followed by a precipitous decrease after approximately 6 weeks, whereas mouse "v4" showed a gradual increase in anti-P antibody immediately following administration of the conjugate, followed by a gradual decrease after approximately 8 weeks.
  • Fig. 4 and 5 are graphs representing the antibody response to ? protein in two mice following intravenous administration of three small doses (18.5 mg, 37 mg, and 55.5 mg) of the tolerogenic conjugate.
  • the long-term an i-P protein antibody response was suppressed after treatment with the tolerogenic conjugate.
  • the short-term anti-P response varied; mouse “v2" showed a slight
  • Myasthenia gravis is an autoimmune disease O91/08773 w __, r _ _,
  • acetyl choline receptor ACR
  • Symptoms of the disease are tissue damage, muscle weakness, and, in certain cases, death.
  • ACR is a heterodimeric protein composed of a and ⁇ subunits.
  • the a chain has several immunodominant regions; one region in particular, amino acids 107-204, may be especially effective when used as a tolerogenic conjugate in the mouse model system.
  • a tolerogenic conjugate consisting of the aARC peptide, corresponding to amino acids 172-204 of the a chain, linked to Balb/c myeloma IgG2a (RPC5) can be administered to mice, causing the mice to become tolerant to aACR.
  • Pemphigus Vulgaris Pemphigus Vulgaris
  • PV Pemphigus Vulgaris
  • ICS intercellular cement sustance
  • the protein which is believed to be the causative protein of PV has been biochemically characterized, although the results have been conflicting because of differences in substrates and techniques of extraction.
  • PV peripheral blood leukocytes
  • the PV protein can be isolated from tumor cells derived from patients with squamous ceil carcinoma, according to conventional methods. Serum antibodies from 15 PV patients have been known to recognize a 110 kD protein on the surface of such cells, which can be cultured to provide a source for the causative 110 kD protein. The protein will be isolated using high titer PV sera mouse monoclonal antibody to PV antigen.
  • An autoimmune disease in which the immune system recognizes insulin as a foreign antigen may be treated by tolerizing the immune system to a conjugate containing the insulin protein or a fragment of insulin.
  • the following experiments demonstrate that a conjugate of beef insulin fragments coupled to mouse IgG tolerizes mice to additional exposure to beef insulin.
  • the tolerogenic conjugate was made by linking beef insulin proteolytic fragments to mouse IgG2a using DSS, as described above. After fractionation by gel filtration on Sephacryl S300 Superfine, three fractions (Peaks I, II, and III) were obtained. The tolerogenicity of each fraction was tested in Balb/c mice which had been immunized with whole beef insulin. Both T and B cell responses to the insulin-IgG conjugates were tested.
  • the B cell response to the insulin-IgG conjugates was measured by the ability of insulin-immunized mice to produce antibodies specific for beef insulin.
  • mice were tolerized with 0.2 mg/ml of conjugates. Eight days later, mice were challenged with 25 ug beef insulin in complete Freund's adjuvant (CFA) and boosted with the same antigen in incomplete Freund's adjuvant (IFA). Mice were bled 10 days later and serum anti-beef insulin antibody measured by ELISA. The results, presented in Fig. 7, represent anti-beef insulin antibody binding minus the background binding of antibodies present in normal serum.
  • the T cell response to the insulin-IgG conjugate was measured using a T cell proliferation assay, as described above for the pidgeon Cytochrome C-IgG conjugate. On day 0, mice were injected with 0.2 mg each of insulin conjugated with mouse IgG (RPC-5).
  • mice were challenged with 25 ug of beef insulin/CFA.
  • lymph nodes were collected and 10 cells/well were incubated in triplicate in complete medium with antigen.
  • cells were pulsed with l uCi/well of H-Tdr; incorporation was measured 24 hours later.
  • Any autoimmune disease in which insulin is recognized as a foreign antigen e.g. insulin-dependent "juvenile” diabetes
  • insulin-dependent "juvenile” diabetes may be treated according to the invention, using tolerogenic conjugates of human insulin or fragments thereof coupled to human IgG.
  • conjugates of the invention can be administered using conventional techniques, e.g., intravenous administration. Amounts and frequency will vary with application; generally, administration will need to be repeated at intervals, e.g., weekly, and may need to be more frequent during periods of disease flare-up.
  • Dosages will generally be in the range of those used for oligonucleotide conjugates, Borel et al. , U.S.P. 4,650,675, supra, generally be in the range of about 1 to 250 mg/kg/day.
  • 3 cell tolerance is a positive event that requires protein synthesis.
  • the mechanism for tolerance in B cells, or B cell non-responsiveness to a given protein, may occur by a mechanism of receptor blockade.
  • the Fc receptor for the IgG may help focus the antigenic determinant which actively mediates a tolerogenic signal (Waldsmidt et al., J. Immunol. 131:2204 (1983)), and thus create a double binding on the same B cells.
  • the immunoglobulin receptor on B cells that produce an antibody specific for the acetylchoiine receptor may be cross-linked by the Fc portion of the IgG molecule of the conjugate and the acetylchoiine receptor (or fragment) portion of the conjugate.
  • This dual crosslink may prolong the time of contact between the conjugate and the B cell, enabling the conjugate to remain on the cell surface fcr the time which is necessary to signal the cell to stop producing antibodies that are specific for the acetylchoiine receptor.
  • the B cell After the tolerogen has been removed from the cell surface either by tissue culture in vitro or by pronase treatment, the B cell remains tolerant (see Aldo-Ben ⁇ on et al. , J. Immunol. 114:141 (1975); Aido-Benson et al . , Cell. Immunol. 71:99 (1982)).
  • suppression may occur at a critical pcint in the cell cycle (e.g., before or during DNA synthesis), or prior to T cell factor influence.
  • thymectc y Natural tolerance originates in the thymus.
  • thymectc y is known to result in autoimmune phenomena (Yunis, ⁇ .J., J. Exp. Med. 125:947 (1967); Wick et al., J. Immunol. 104:54 (1970)).
  • Tolerance in T cells, cr T cell non-respcnsiveness to a given protein may occur by cional deletion, immunoregulation by suppressor T cells, or direct inactivation of T cells by the protein.
  • Cional deletion has been demonstrated for self MHC (Kappler et al. , Cell 49:273 (1987)) and extended to non MHC antigen (Kappler et al.
  • Antigen presenting cells together with class II MHC may present the tolerogen to the T cell receptor, but whether both CD4 and CD8 T cells are rendered unresponsive is unkonwn.
  • Prostaglandin (PG2) favors tolerance induction (Geldings, J. Immunol. 136:817 (1986)), whereas interleukin 2 (IL2) favors immunogenicity and may prevent or reverse tolerance (Sadegh-Nasseri et al., Eur . J. Immunol. 18:417 (1988)).
  • T cells may occur through the production of ?G2-like iy pho ines .
  • the tolerogen in this case the conjugate, may stimulate the T helper cell to produce PG2, and thus prevent T helper cell function in B cell antibody production.
  • tolerogenic conjugates of the invention may be used to treat any disease in which an immune response to a protein causes unwanted symptoms.
  • conjugates of the invention may be used to treat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, or infertility resulting from autoantibodies , e.g., to human leutinizing hormone receptor in women.
  • Tolerogenic conjugates may also be used to treat congenital diseases resulting in unwanted immune responses; e.g., congenital lupus, in which the fetus experiences heartblock because of transplacental transfer of maternal antibodies specific for ribonucleoprotein La; cr coelic disease, in which a genetically determined intolerance to gliadin, a component of wheat results in the inability to digest wheat.
  • congenital diseases resulting in unwanted immune responses e.g., congenital lupus, in which the fetus experiences heartblock because of transplacental transfer of maternal antibodies specific for ribonucleoprotein La
  • cr coelic disease in which a genetically determined intolerance to gliadin, a component of wheat results in the inability to digest wheat.
  • allergies caused by an unwanted immune response to a foreign protein may be treated according to the invention; e.g., certain food or plant allergies.
  • Tolerogenic conjugates may also be used to suppress unwanted immune responses to therapeutic human natural or monoclonal antibodies; e.g., patients receiving the therapeutic monoclonal antibody OKT3, which is used to treat cancer and may require repeated doses of the antibody, sometimes is associated with an unwanted immune response; administration of a tolerogenic conjugate consisting of the OKT3 antibody crosslinked to an isologous human IgG carrier may prevent an immune response to antibodies used in diagnostic targeting, e.g., to image tumors or deliver drugs.
  • therapeutic monoclonal antibody OKT3 which is used to treat cancer and may require repeated doses of the antibody, sometimes is associated with an unwanted immune response
  • administration of a tolerogenic conjugate consisting of the OKT3 antibody crosslinked to an isologous human IgG carrier may prevent an immune response to antibodies used in diagnostic targeting, e.g., to image tumors or deliver drugs.
  • Tolerogens can be made using any soluble, isologous immunoglobulin, e.g., human IgG or IgA.
  • IgG is preferred because the Fc fragment participates in the immunological functioning of the conjugates.
  • the conjugates may be administered parentally, in the case of IgG, or enterally, in the case of IgA, which is more resistant to digestion than IgG.
  • Oral tolerance to food allergens, e.g., bovine ⁇ -lactoglobulin, or immunogens may be induced by linking these antigenic determinants to IgA.
  • proteins may be linked to the immunoglobulin carrier without aggregation of the conjugates and fetal autoimmune disease can be treated because of the ability of IgG to cross the placenta.

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Abstract

Conjugué tolérogène d'inhibition de réaction immunitaire à une protéine chez un mammifère, ce conjugué comprenant la protéine, ou un fragment ou un peptide de celle-ci, en liaison covalente avec une molécule porteuse d'immunoglobuline soluble isologue.
PCT/US1989/005539 1989-12-07 1989-12-07 Conjugues immunoglobuline-proteine tolerogene WO1991008773A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19900902970 EP0504136A4 (en) 1989-12-07 1989-12-07 Tolerogenic immunoglobulin-protein conjugates
JP90503225A JPH05502854A (ja) 1989-12-07 1989-12-07 寛容原性イムノグロブリン―蛋白質結合体
PCT/US1989/005539 WO1991008773A1 (fr) 1989-12-07 1989-12-07 Conjugues immunoglobuline-proteine tolerogene

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US6030613A (en) * 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
EP1118335A1 (fr) * 2000-01-11 2001-07-25 Aventis Behring GmbH Préparation de conjugués pour le traitement des allergies et maladies autoimmunitaires
EP1118334A1 (fr) * 2000-01-11 2001-07-25 Aventis Behring Gesellschaft mit beschränkter Haftung Préparation de conjugués pour le traitement des allergies et maladies autoimmunitaires
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
EP1323346A2 (fr) * 1995-01-17 2003-07-02 Brigham And Women's Hospital, Inc. Transport épithélial spécifique de récepteurs d'immunogènes
WO2004098645A1 (fr) * 2003-05-12 2004-11-18 Tolerogen, Ltd. Conjugues immunoglobuline d'autoantigenes et utilisation de ceux-ci dans la prevention de maladies
WO2011036467A1 (fr) * 2009-09-24 2011-03-31 Russell David Keenan Produits utiles dans le traitement de l'hémophilie

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EP0117114A2 (fr) * 1983-02-16 1984-08-29 Dana-Farber Cancer Institute, Inc. Anticorps monoclonal
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Basic and Clinical Immunology, 5th edition, 1984, Theofilopoulous Chapter 12, "Autoimmunity", see page 153. *
Journal of Immunology, Volume 136 No. 1 01 January 1986, (KAWAMURA et al.) "Enhancement of antigenic potency invitro and immunogenicity in vivo by coupling the antigen to anti-immunoglobulin", pp. 58-65 see Abstract. *
Nature, Vol. 261, 06 May 1976, (BOREL et al.), "Isologous IgG-induced tolerance to benzyl penicilloyl" see pp. 49-50. *
Nature, Vol. 327 07 May 1987, (CARAYANNIOTIS et al.), "Adjuvant-free IgG responses induced with antgen coupled to antibodies against class II MHC", pp. 59-61, see Abstract. *
See also references of EP0504136A4 *
The Journal of Immunology, Vol. 137, No. 4, 15 August 1986, (GUTSTEIN et al.), Induction of immune tolerance by administration of monoclonal antibody to L3T4", see pp. 1127 and 1131. *

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EP1658772A2 (fr) * 1995-01-17 2006-05-24 The Brigham And Women's Hospital, Inc. Transport épithélial spécifique de récepteurs d'immunogènes
US7547436B2 (en) 1995-01-17 2009-06-16 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6030613A (en) * 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US7067129B2 (en) 1995-01-17 2006-06-27 The Brigham And Woman's Hospital, Inc. Receptor specific transepithelial transport in therapeutics
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
EP1323346A2 (fr) * 1995-01-17 2003-07-02 Brigham And Women's Hospital, Inc. Transport épithélial spécifique de récepteurs d'immunogènes
US7060274B2 (en) 1995-01-17 2006-06-13 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
EP1323346A3 (fr) * 1995-01-17 2003-11-26 Brigham And Women's Hospital, Inc. Transport épithélial spécifique de récepteurs d'immunogènes
US6537519B2 (en) 2000-01-11 2003-03-25 Aventis Behring Gmbh Method for the production of conjugates and uses thereof for the prevention and treatment of allergic reactions and autoimmune diseases
EP1118334A1 (fr) * 2000-01-11 2001-07-25 Aventis Behring Gesellschaft mit beschränkter Haftung Préparation de conjugués pour le traitement des allergies et maladies autoimmunitaires
US7306782B2 (en) 2000-01-11 2007-12-11 Tolerogen Ltd Method for the production of conjugates and uses thereof for the prevention and treatment of allergic reactions and autoimmune diseases
EP1118335A1 (fr) * 2000-01-11 2001-07-25 Aventis Behring GmbH Préparation de conjugués pour le traitement des allergies et maladies autoimmunitaires
WO2004098645A1 (fr) * 2003-05-12 2004-11-18 Tolerogen, Ltd. Conjugues immunoglobuline d'autoantigenes et utilisation de ceux-ci dans la prevention de maladies
WO2011036467A1 (fr) * 2009-09-24 2011-03-31 Russell David Keenan Produits utiles dans le traitement de l'hémophilie

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EP0504136A1 (fr) 1992-09-23
JPH05502854A (ja) 1993-05-20

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