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WO1988007869A2 - ANTICORPS ANTI-INTERFERON gamma ET LEUR APPLICATION THERAPEUTIQUE - Google Patents

ANTICORPS ANTI-INTERFERON gamma ET LEUR APPLICATION THERAPEUTIQUE Download PDF

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Publication number
WO1988007869A2
WO1988007869A2 PCT/BE1988/000011 BE8800011W WO8807869A2 WO 1988007869 A2 WO1988007869 A2 WO 1988007869A2 BE 8800011 W BE8800011 W BE 8800011W WO 8807869 A2 WO8807869 A2 WO 8807869A2
Authority
WO
WIPO (PCT)
Prior art keywords
interferon
immunoglobulin
antibody
mice
man
Prior art date
Application number
PCT/BE1988/000011
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English (en)
Other versions
WO1988007869A3 (fr
Inventor
Alfons Josef Denis Alida Billiau
Original Assignee
Stichting Rega Vzw
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Stichting Rega Vzw filed Critical Stichting Rega Vzw
Publication of WO1988007869A2 publication Critical patent/WO1988007869A2/fr
Publication of WO1988007869A3 publication Critical patent/WO1988007869A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Inflammatory responses are a component of many diseases of vertebrates including man.
  • the term "inflammation” denotes local as well generalized responses.
  • Local inflammation is characterized by vasodilatation, fluid transsudation from the vessels, infiltration of the tissues by leukocytes and, in some severe cases, intravascular thrombosis, damage to the blood vessels and extravasation of blood.
  • the generalized inflammatory response also denoted as acute phase response, is characterized by various reactions including increased body temperature, changes in the levels of various blood components (cellular as well as dissolved elements) and changes in blood pressure. In severe cases shock and death may occur.
  • Local and/or general inflammatory response occur as part of many diseases with endogenous or exogenous etiologies, in particular in (1) infections (local or generalized) with bacteria, viruses, fungi, parasites; (2) allergic reactions to common substances from the environment, drugs, erroneous blood transfusions; (3) as part of auto-immune diseases where the body's defense mechanism erroneously attacks its own tissues (e.g. rheumatoid arthritis, lupus erythematosus, demyelinating diseases, etc.); (4) rejection of tissue transplants. In many cases local inflammation is self-limiting.
  • mediators which trigger or regulate the changes seen in the tissues or in the physiological parameters of patients suffering from the inflammatory diseases.
  • mediators belong to several categories: (1) small molecules such as histamine and prostaglandins; (2) serum proteins such as the complement factors; (3) certain hormones such as the corticoids; and (4) cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and interferons.
  • IL-1 interleukin-1
  • TNF tumor necrosis factor
  • interferons interleukin-1
  • the present invention is constituted by the observation that the administration to vertebrate experimental animals of antibodies which bind and neutralize interferon-- ⁇ can block local as well as generalized inflammatory responses, particularly in lethal cerebral malaria.
  • the antibodies are proteins belonging to the class of immunoglobulins. They must be prepared such that they possess binding and neutralizing potential for the interferon- ⁇ molecules of the specific animal species in which the inflammation is to be suppressed. In the examples described the experimental animal used was the mouse, and hence the antibodies were directed against mouse interferon- ⁇ .
  • the antibodies in order for the antibodies to be suitable as anti-in flammatory agents in vivo, they must have a chemical composition (or: an epitope recognition pattern) such that they not only bind to interferon-gamma, but also that they neutralize its biological effects on cells cultured in vitro, such as its antiviral effect and, in particular, its effects on macrophages. Incubation of cultured fibroblasts with homologous interferon-gamma renders them resistant against infection with viruses.
  • a chemical composition or: an epitope recognition pattern
  • interferon-gamma Incubation of cultured macrophages with interferon-gamma renders them more reactive to chemoluminescence induction by a suitable inducer substance, such as bacterial lipopolysaccharide. Characterization of an anti-interferon-gamma antibody as an anti-inflammatory agent depends on its neutralizing ability on these in vitro biological effects. Addition of antibodies should remove the antiviral activity of interferon-gamma, but should also anihilate other biological activities.
  • Monoclonal or polyclonal antibodies can be administered by general route.
  • the preparations are supplied in for instance a lyophilized and cooled form and may comprise an excipient, a preservative, an anti-oxidant, etc.
  • the preferential route of administration is by intraperitoneal injection.
  • other routes of administration can be more suitable, e.g. intramuscular or intravenous injection.
  • the preparation of anti-mouse interferon-gamma antibodies may take the form of gels, creams, ointments with the antibody as one of the active components.
  • Vertebrate animals that have been injected with monoclonal antibodies against homologous interferon-gamma show a decreased responsiveness to various exogenous inflammatory stimuli.
  • the degree and duration of this inhibition depends on the dose and epitope-specificity of the antibody used. For long duration of the inhibitory effect it is essential that the injected antibody is eliminated slowly. Such elimination depends on the degree of foreigness between the administered antibody and the animals own immunoglobulins.
  • the antibodies should be of homologous origin.
  • Examples II-VI illustrate the effect of anti-interferon-gamma on local (examples II, III, IV, V) and generalized (example VI) inflammatory reactions elicited by bacterial lipopolysaccharides (LPS).
  • LPS is a universal component of the cell wall of all Gram-negative bacteria.
  • the lipoid core of the molecule has an invariant structure.
  • infections of vertebrate animals with Gram-negative bacteria local as well as generalized inflammatory responses are largely due to the multiple biological effects of the lipoid core.
  • the usual local reactions are constituted by oedema and cellular infiltration.
  • the casual generalized reaction is constituted by fever and the appearance of so-called acute phase proteins in the serum.
  • the reactions to LPS are known as Shwartzman reactions, which may be local and/or generalized. They are characterized by intravascular trhombosis.
  • the generalized Shwartzman reaction is often lethal.
  • a Shwartzman-like reaction also occurs in infections of vertebrates with parasites.
  • an infection with Plasmodium falciparum sometimes develop a lethal complication due to a thrombotic inflammatory lesion of the cerebral blood vessels.
  • Example VII demonstrates that monoclonal antibodies against mouse interferon-gamma, when administered to mice, makes them resistant against this lethal complication of cerebral malaria.
  • Example VIII refers to an inflammatory response elicited as a result of a delayed type hypersensitivity (DTH) reaction.
  • DTH -reactions occur as a result of repeated or sustained exposure of the body to certain proteins (antigens)which are foreign to the body.
  • the pathogenesis is well-known: the foreign antigen stimulates multiplication and activity of T-DTH-cells which produce interferon-gamma. This interferon activates macrophages to become toxic for their environment. This resultsin inflammation.
  • DTH-reactions are extremely frequent. They occur under the form of inflammatory skin reactions (eczema) to a wide range of environmental agents.
  • Fused cells were seeded in 96 microtiter plates (50 ul/well; Costar 3596, Cambridge) in Eagle's minimal essential medium (EMEM), supplemented with 10% fetal calf serum (FBS), 2 mM glutamine, 2.2 g/1 of sodium bicarbonate and HT (hypoxanthine, 0.1 mM, thymidine, 16 ⁇ M). The following day wells received an additional equal volume of EMEM containing HAT-medium (aminopterine, 0,4 ⁇ M) . Cultures showing hybridoma cell growth were screened for the presence of anti-MuIFN- ⁇ antibodies using an enzyme-linked immunosorbent assay (ELISA) and for antiviral activity by the direct neutralization assay. Positive hybridomas were subcloned twice by limiting dilution in microtiter plates. Three stable hybridomas secreting IgG2a antibodies directed against Mu-IFN- ⁇ were selected, designated F 1 , F 2 , and F 3 .
  • Hybridoma cells (10 6 ) were injected into the peritoneal cavity of thymusless nude mice that had been retreated with 0.5 ml Pristan mineral oil (2, 6, 10, 14-tetramethyl pentadecane, 96%). Asciric fluid and serum was harvested 7 to 14 days after cell inoculation. Ascitic fluid and sera of mice inoculated with hybridoma cells were tested for interferon- ⁇ -binding activity using an enzyme-linked immunosorbent assay (ELISA). Microtiter plates (Nunc, Immuno olate I-96F, Denmar) were coated with 0.1 ug of pure mouse interferon- and incubated for at least 24 h at 4°C.
  • ELISA enzyme-linked immunosorbent assay
  • the neutralizing activity of the monoclonal antibodies was determined by incubating 0.5 login dilutions of the ascitic fluid or serum with 30 units/ml of murine interferon-g. The mixtures were incubated for 4 hours at 37°C and then examined for their antiviral activity on mouse L929 cells, as well as for their macrophages activating effect in a macrophage chemoluminescence assay. These tests were performed using a macrophage cell line (LA5-9.8) which, on stimulation with lipopolysaccharide, produces reactive oxygen metabolites. This activity, termed the "respiratory burst", represents a mechanism whereby macrophages can cause inflammatory damage to tissues.
  • the spontaneous degeneration of the labile oxygen components can be visualized as amplified light emission (chemoluminescence) by added luminescent substrates, e.g. lucigenin. If the macrophage cultures are first exposed to homologous interferon-g, light emission is greatly enhanced. This enhancement can be taken to measure macrophage activation by interferon-g.
  • Table I The results of the binding and neutralisation assays with the monoclonal antibodies are shown in Table I. This table shows that the preparations F 1 , F 2 , F 3 possess equivalent binding activity for interferon-g. However, F 2 and F 3 had a greater neutralizing activity for both the antiviral and the macrophage activating effect of interferon-g.
  • Example II Inhibition by monoclonal anti-interferon- ⁇ - antibody of local inflammation
  • mice were injected into the right hind footpad with 5 ⁇ g of LPS (in 25 ⁇ l).
  • PBS Phosphate-buffered saline
  • Footpad swelling was measured daily with the aid of micrometer-calipers. Footpad swelling was calculated as % increase in footpad thickness, by comparing thickness of the LPS-injected footpad (L) with that of the contralateral injected footpad (C).
  • a Antibodies were given i.p. 24 h before LPS challenge at a dose of 0.1 ml containing 4.55 log 10 binding units/ml.
  • Example II the same technique for measuring local inflammation was used as in Example II.
  • the design of this experiment was similar to that of the previous one, except that the antibodies were given on days 56, 42, 28, 21, 10 and 5 before local LPS challenge. Footpad swellings were recorded on days 2 and 3 post challenge.
  • Table II indicate that the inhibitory action of the monoclonal antibodies on the initial phase of the swelling reaction persisted for as long as 6 weeks.
  • Example IV Inhibition of inflammation by monoclonal antibody to interferon- ⁇ : dose-response relationship
  • Example II For this experiment the same technique for measuring local inflammation was used as in Example II. The design of the experiment was also similar, except that the monoclonal antibody (F 3 ) was given in 3 different doses. Footpad responses were recorded on days 2 and 3. The results, as shown in Table IV, indicate that a minimal dose of antibod necessary to inhibit inflammation is 10 3 . 75 neutralizing units per mouse. Since the mice weighed 25 g average, the minimal dose can also be estimated at 10 5 . 35 neutralizing units per kg body weight.
  • F 3 monoclonal antibody
  • Antibody dose a % Inhibtion b of footpad swelling on log 10 neutralizing units/mouse day 2 day 3 post LPS post LPS
  • Polyclonal antibodies were prepared as serum from rabbits immunized by serial injections of mouse interferon- ⁇ .
  • the antiserum was found to contain 10 3 . 75 iFN- ⁇ neutralizing units per ml.
  • the ability of this serum to inhibit inflammation was tested with an experimental protocol that was similar to that described for Example II.
  • the results, as shown in Table V, indicate that mice given 4 intraperitoneal injections of 0.1 ml of the antiserum (see timing in footnote to Table V) showed a significantly decreased footpad response to LPS.
  • a generalized inflammatory reaction known as the generalized Shwartzman reaction, or Sanarelli reaction was elicited in mice.
  • the technique consists in giving to consecutive injections of the endotoxin of Gramnegative bacteria.
  • the reaction is characterized by generalized coagulopathy apparent from petechiae on the ear skin of the mice.
  • General shock is apparent from inactivity of the mice, and pilo-erection.
  • the shock reaction is lethal.
  • mice received a local injection of 5 ⁇ g in the footpad, followed, after 24 hr, by an intravenous dose of 100 ⁇ g. From the results it can be seen that occurrence of disease was completely prevented by treatment with monoclonal antibody against interferon- ⁇ .
  • a Shock was provoked by a combination of 2 injections of LPS: a preparation dose of 5 ug in the footpad followed, after 24 hr by an intravenous provocative dose of 100 ⁇ g.
  • bIntraperitoneal injectioin of 0.1 ml (4.55 login binding units/ml) respectively 24 hrs before the local injection and simultaneously with the intravenous provocative dose.
  • Example VIa Prevention of lethal celebral malaria in mice by monoclonal antibody against interferon-gamma
  • Cerebral malaria which develops in human patients infected with Plasmodium falciparum can experimentally be mimicked in mice (e.g. strain CBA/Ca mice), by inocul-ition with Plasmodium berghei.
  • mice e.g. strain CBA/Ca mice
  • the disease appears in ca. 80% of infected mice, 1 to 2 weeks post inoculation and is characterized by convulsions, paralysis and ensueing death.
  • the effectivenessof anti-interferon- gamma antibody in this model disease are illustrated by the results of Table VII.
  • mice CBA/Ca - ANKA strain
  • mice were given intraperitoneal injections of monoclonal antibody F3 (see Example I) at times indicated in Table VII.
  • the potency of the antibody was 10 5 . 5 neutralizing units/ml and the dose was 0.1 ml per injection.
  • the mice were infected by intraperitoneal inoculat ion of 10 5 plasmodium berghei-containing red blood cells. The results demonstrate that mice which had received a suitable schedule of injections of antibody F 3 were protected against occurrence of lethal cerebral malaria.
  • a Donor C57B1/6J mice; recipients Ba1b/C mice.
  • PCT/BE88/00011 81) Designated States: AT (European patent), BE (E pean patent), BJ (OAPI patent), CF (OAPI pate
  • Immunoglobulin with neutralizing antibody activity against interferon- ⁇ of man or of an animal species for use a therapeuthic agent, as an active substance for inhibiting inflammatory reactions, or preventing or inhibiting cerebral m aria, and medical or veterinary preparation comprising immunoglobulin acceptable excipient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Immunoglobuline ayant une activité d'anticorps neutralisant dressée contre l'interféron gamma se trouvant chez l'homme et l'animal, destinée à être utilisée à titre d'agent thérapeutique, de substance active pour inhiber des réactions inflammatoires, empêcher ou inhiber la malaria cérébrale, et comme préparation médicale ou vétérinaire comprenant un excipient acceptable d'immunoglobuline.
PCT/BE1988/000011 1987-04-16 1988-04-18 ANTICORPS ANTI-INTERFERON gamma ET LEUR APPLICATION THERAPEUTIQUE WO1988007869A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL8700927 1987-04-16
NL8700927A NL8700927A (nl) 1987-04-16 1987-04-16 Anti-interferon-gamma-antilichamen; en hun therapeutische toepassing.

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WO1988007869A2 true WO1988007869A2 (fr) 1988-10-20
WO1988007869A3 WO1988007869A3 (fr) 1988-11-17

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387095A1 (fr) * 1989-03-09 1990-09-12 Margreet Jonker Produit pharmaceutique pour le traitement des désordres immunorégulateurs
WO1990012813A1 (fr) * 1989-04-20 1990-11-01 Vangedal-Nielsen, Erling Proteines regulatrices
WO1991002005A1 (fr) * 1989-08-11 1991-02-21 Adolfo Turano Anticorps a interferons anti-gamma humains naturels, detectes et purifies par des peptides synthetiques
WO1992011018A1 (fr) * 1990-12-19 1992-07-09 Protein Design Labs, Inc. Immunoglobulines humanisees ameliorees
WO1995005849A1 (fr) * 1993-08-26 1995-03-02 Mouritsen & Elsner A/S Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes
GB2304342A (en) * 1995-08-18 1997-03-19 Univ Manchester Pharmaceutical comprising either an inhibitor or a stimulator of interferon gamma
US7220413B2 (en) 1995-08-18 2007-05-22 Renovo Limited Pharmaceutical composition containing inhibitors of interferon-γ
US7335743B2 (en) 2002-10-16 2008-02-26 Amgen Inc. Human anti-IFN-γ neutralizing antibodies as selective IFN-γ pathway inhibitors
US9072725B2 (en) 1998-12-09 2015-07-07 Abbvie Biotherapeutics, Inc. Method for treating psoriasis

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA831094B (en) * 1982-02-22 1983-11-30 Biogen Nv Dna sequences,recombinant dna molecules and processes for producing human immune interferon-like polypeptides

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7022500B1 (en) 1988-12-28 2006-04-04 Protein Design Labs, Inc. Humanized immunoglobulins
EP0387095A1 (fr) * 1989-03-09 1990-09-12 Margreet Jonker Produit pharmaceutique pour le traitement des désordres immunorégulateurs
WO1990010707A1 (fr) * 1989-03-09 1990-09-20 Margreet Jonker Produit pharmaceutique de traitement de troubles immunoregulateurs
GB2247837A (en) * 1989-03-09 1992-03-18 Margreet Jonker Pharmaceutical product for the treatment of immunoregulatory disorders
GB2247837B (en) * 1989-03-09 1992-10-28 Margreet Jonker Pharmaceutical product for the treatment of immunoregulatory disorders
WO1990012813A1 (fr) * 1989-04-20 1990-11-01 Vangedal-Nielsen, Erling Proteines regulatrices
WO1991002005A1 (fr) * 1989-08-11 1991-02-21 Adolfo Turano Anticorps a interferons anti-gamma humains naturels, detectes et purifies par des peptides synthetiques
EP1386932A1 (fr) * 1990-12-19 2004-02-04 Protein Design Labs, Inc. Immunoglobulines humanisées améliorées
WO1992011018A1 (fr) * 1990-12-19 1992-07-09 Protein Design Labs, Inc. Immunoglobulines humanisees ameliorees
WO1995005849A1 (fr) * 1993-08-26 1995-03-02 Mouritsen & Elsner A/S Procede d'induction de reactions immunitaires contre les proteines endogenes a l'aide d'epitopes de lymphocytes t exogenes
GB2304342A (en) * 1995-08-18 1997-03-19 Univ Manchester Pharmaceutical comprising either an inhibitor or a stimulator of interferon gamma
WO1997007136A3 (fr) * 1995-08-18 1997-08-21 Univ Manchester Composition pharmaceutique contenant des inhibiteurs de l'inteferon gamma
US7220413B2 (en) 1995-08-18 2007-05-22 Renovo Limited Pharmaceutical composition containing inhibitors of interferon-γ
US9072725B2 (en) 1998-12-09 2015-07-07 Abbvie Biotherapeutics, Inc. Method for treating psoriasis
US9078876B2 (en) 1998-12-09 2015-07-14 Abbvie Biotherapeutics, Inc. Method for treating psoriasis
US7335743B2 (en) 2002-10-16 2008-02-26 Amgen Inc. Human anti-IFN-γ neutralizing antibodies as selective IFN-γ pathway inhibitors
US7790859B2 (en) 2002-10-16 2010-09-07 Amgen Inc. Human anti-IFN-γ neutralizing antibodies as selective IFN-γ pathway inhibitors
US8202976B2 (en) 2002-10-16 2012-06-19 Amgen Inc. Nucleic acid molecules that encode human anti-IFN-gamma neutralizing antibodies as selective IFN-gamma pathway inhibitors
US8529893B2 (en) 2002-10-16 2013-09-10 Amgen Inc. Methods for treating IFN-γ mediated diseases using human anti-IFN-γ neutralizing antibodies as selective IFN-gamma pathway inhibitors
US8906371B2 (en) 2002-10-16 2014-12-09 Amgen Inc. Human anti-IFN-γ neutralizing antibodies as selective IFN-γ pathway inhibitors

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Publication number Publication date
WO1988007869A3 (fr) 1988-11-17
NL8700927A (nl) 1988-11-16

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