EP0946195A1 - Produits pharmaceutiques contenant un inhibiteur de la kinase agissant sur la tyrosine de proteines et des anticorps anti-cd4 - Google Patents

Produits pharmaceutiques contenant un inhibiteur de la kinase agissant sur la tyrosine de proteines et des anticorps anti-cd4

Info

Publication number
EP0946195A1
EP0946195A1 EP97943980A EP97943980A EP0946195A1 EP 0946195 A1 EP0946195 A1 EP 0946195A1 EP 97943980 A EP97943980 A EP 97943980A EP 97943980 A EP97943980 A EP 97943980A EP 0946195 A1 EP0946195 A1 EP 0946195A1
Authority
EP
European Patent Office
Prior art keywords
antibody
cells
antibodies
tyrosine kinase
ref
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Withdrawn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
EP97943980A
Other languages
German (de)
English (en)
Inventor
Ulrike Charlotte Deutsches Rheuma Gimsa
Nicholas Avrion Deutsches Rheuma Mitchison
Rodger Anthony Allen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gimsa Ulrike Charlotte
Mitchison Nicholas Avrion
UCB Celltech Ltd
Original Assignee
Gimsa Ulrike Charlotte
Mitchison Nicholas Avrion
Celltech R&D Ltd
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
Priority claimed from GBGB9620465.6A external-priority patent/GB9620465D0/en
Priority claimed from GBGB9620834.3A external-priority patent/GB9620834D0/en
Priority claimed from GBGB9709941.0A external-priority patent/GB9709941D0/en
Application filed by Gimsa Ulrike Charlotte, Mitchison Nicholas Avrion, Celltech R&D Ltd filed Critical Gimsa Ulrike Charlotte
Publication of EP0946195A1 publication Critical patent/EP0946195A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum

Definitions

  • This invention relates to pharmaceutical products comprising a protein- tyrosine kinase inhibitor and an anti-CD4 antibody and to their use in medicine.
  • Th1 and Th2 cells both differentiate from ThO cells which produce either none or a mixed range of cytokines.
  • Th2 cells preferentially: salbutamol (ref. 6), monomethylfumarate (ref. 7), thalidomide (ref. 8, but see also ref. 9) and prostaglandin-E22 (ref. 10). Additional agents have been found able to prolong allograft survival in association with Th2 differentiation. Some of these agents have been identified as acting on antigen-presenting cells (APC), others appear to act within the responding T-cells themselves, while for the majority the target cell is uncertain. For those agents which do act within T-cells the underlying question remains open of whether they modify signal-strength from the TCR complex, or whether they act on the process of differentiation independently of this pathway.
  • API antigen-presenting cells
  • Costimulation of T cells through the CD4 and CD28 cell-surface receptors plays a significant role in determining the extent to which Th1 or Th2 cells are produced. While the effect of blocking the latter receptor is unclear (ref. 12, 13), several experiments indicate that blocking CD4 favours Th2 differentiation (ref. 14).
  • CD4-/-mice show a bias away from Th2 differentiation (ref. 17) presumably reflecting unexpected selective events in the immune system as it develops in these mice.
  • the Src-family protein-tyrosine kinase p56 ick (abbreviated hereinafter as "lck” except where otherwise indicated) is physically associated with the cytoplasmic tail of CD4 and is the only molecule known to transmit signals from CD4 (ref. 18). Lck also regulates tyrosine phosphorylation of the T- cell receptor (TCR) - ⁇ chain, CD3- ⁇ , and ZAP-70. Lck-/- mice have greatly reduced numbers of thymocytes and peripheral ⁇ + T-cells (ref. 19).
  • p59 f y n is another member of the same family that also phosphorylates proteins of the T-cell receptor complex, although it does not bind to the CD4 molecule.
  • the immune system of Fyn-/- mice is impaired, but to a much lesser extent than that of lck-/- mice (ref. 20).
  • a pharmaceutical product comprising a protein-tyrosine kinase p56 lck inhibitor and an anti- CD4 antibody for simultaneous combined, simultaneous separate or sequential use in therapy.
  • One such pharmaceutical product for use according to the invention may take the form of a pharmaceutical composition in which the lck inhibitor and the anti-CD4 antibody are formulated in admixture, optionally together with a pharmaceutically acceptable excipient, diluent, or carrier and the invention extends to such compositions.
  • the product for use according to the invention may take the form of a separately formulated lck inhibitor and a separately formulated anti-CD4 antibody optionally presented together for simultaneous or sequential use.
  • the lck inhibitor for use in any aspect of the invention may in general be any compound which inhibits the action of the protein-tyrosine kinase p56 lck .
  • the lck inhibitor will be a selective inhibitor of p56 lck .
  • a number of such inhibitors has been described in the art. Particular examples include quinolones (ref. 21 ) and analogues thereof; pyrazolopyrimidines (ref. 22) and analogues thereof; 1 ,2-diarylethanes and 1 ,2-diarylethenes (ref. 23) and analogues thereof; naphthalenes, quinolines and isoquinolines (ref.
  • Especially useful inhibitors include the pyrazolopyrimidines 4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1 ) and 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[4,5- djpyrimidine (PP2) (ref. 22).
  • a lck inhibitor for use in the invention may be obtained by conventional screening methods, for example by the use of in vitro enzyme assays (ref. 22).
  • the anti-CD4 antibody for use in the product according to the invention may be a whole antibody or an antigen binding fragment thereof, for example a Fab or F(ab')2 fragment.
  • the antibody may be of animal, for example mammalian origin and may be for example of murine, rat or human origin. It may be polyspecific, but is preferably monospecific for a CD4 protein, especially a human CD4 protein.
  • the antibody may preferably bind to an epitope in the 3rd extracellular and/or membrane-proximal 4th domain of human CD4 (ref. 26).
  • the antibody will in particular be a blocking, non-stimulatory antibody. It may be a polyclonal antibody or, preferably, a monoclonal antibody. Where desired, it may be a recombinant antibody or a labelled antibody, the label being for example a reporter or effector group.
  • the anti-CD4 antibody may be selected or derived from known anti-CD4 antibodies, for example the antibodies OKT4, RmCD4-2 (ref. 32) or YTA3.12 (ref. 33) or obtained using conventional immunisation and/or recombinant DNA techniques.
  • suitable antibodies may be selected by using an appropriate in vitro screen employing for example human CD4+ T cells and examining the ability of the antibody to enhance differentiation of Th2 cells in the presence of a lck inhibitor.
  • a simple screen may be for example based on the measurement of IL-4 and IFN- ⁇ production by human CD4+T cells in an analogous method to that described in the Example hereinafer using mouse splenocytes.
  • polyclonal antibodies may be obtained from the sera of animals immunised with a CD4 immunogen.
  • the immunogen may be the whole CD4 protein or preferably a fragment thereof, particularly the 3rd and/or 4th extracellular domains.
  • Well known methods may be used to obtain the immunogen either from readily available cell sources e.g. human thymocytes or CD4 gene and/or protein sequence data.
  • Any suitable host for example BALB/c mice where it is desired to obtain a mouse polyclonal antibody, may be injected with the immunogen, the serum collected and the antibody recovered therefrom.
  • Monoclonal antibodies may be obtained from hybridomas derived from the spleen cells of an animal immunised as just discussed and fused to an appropriate "immortal" B-tumour cell.
  • any selected antibody may be recovered from either the serum or the hybridoma by making use of standard identification and purification and/or concentration techniques, for example by chromatography, using for example Protein A or by other affinity chromatography.
  • Identification of the antibody may be by any conventional means, for example by use of one or more cell based binding assay systems utilising appropriate indicator cell lines, for example as described in International Patent Specification No. WO 91/09966.
  • a cell line for example a hybridoma, expressing an antibody suitable for use in the invention
  • other recombinant antibodies for use in to the invention may be obtained by preparing one or more replicable expression vectors containing at least the DNA sequence encoding the variable domain of the antibody heavy or light chain and optionally other DNA sequences encoding remaining portions of the heavy and/or light chains as desired, and transforming an appropriate cell line, e.g. a non-producing myeloma cell line, such as a mouse NSO line, in which production of the antibody will occur.
  • an appropriate cell line e.g. a non-producing myeloma cell line, such as a mouse NSO line
  • the DNA sequence in each vector should include appropriate regulatory sequences, particularly a promoter and leader sequence operably linked to the variable domain sequence.
  • appropriate regulatory sequences particularly a promoter and leader sequence operably linked to the variable domain sequence.
  • Particular methods for producing antibodies in this way are generally well known and routinely used. For example, basic molecular biology procedures are described by Maniatis et al [Molecular Cloning, Cold Spring Harbor Laboratory, New York, 1989]; DNA sequencing can be performed as described in Sanger et al [PNAS 74, 5463, (1977)] and the Amersham International pic sequencing handbook; and site directed mutagenesis can be carried out according to the method of Kramer et al [Nucl. Acids Res. 12, 9441 , (1984)] and the Cambridge Biotechnology Ltd handbook.
  • Formulation of the lck inhibitor and anti-CD4 antibody for use in a product according to the invention may be carried out using conventional procedures.
  • Each active ingredient may take any suitable form for administration to the host, for example a form for oral, parenteral or rectal administration.
  • the active ingredient is for parenteral administration, for example for intravenous, intramuscular or subcutaneous injection or infusion, it may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. It may be formulated as a suspension, solution or emulsion in an oily or aqueous vehicle optionally containing formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively the active ingredient may be in a dry form, e.g. a powder for reconstitution before use with an appropriate sterile liquid, e.g. sterile pyrogen-free water.
  • an appropriate sterile liquid e.g. sterile pyrogen-free water.
  • the active ingredient may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • the active ingredient may be formulated with a binding and/or lubricating agent, for example with a polymeric glycol, a gelatin, cocoa-butter or other vegetable wax or fat.
  • the active ingredient(s) may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing each active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the anti-CD4 antibody is likely to be unsuitable for oral administration and it is preferably used in a formulation for parenteral administration using for example one of the approaches described above.
  • the product comprises a lck inhibitor and an anti-CD4 antibody in admixture and according to a further aspect of the invention we therefore provide the use of a lck inhibitor and an anti-CD4 antibody in the manufacture of a pharmaceutical product for simultaneous combined, simultaneous separate or sequential use in therapy.
  • the lck inhibitor and the anti-CD4 antibody may be mixed together and other ingredients, e.g. a pharmaceutically acceptable excipient, diluent or carrier, also mixed in as required, to yield for example a product formulated for oral, parenteral or rectal administration as described previously.
  • a particular therapeutic use to which the products according to the invention may be put is in the treatment or prophylaxis of autoimmune diseases.
  • autoimmune diseases include rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus.
  • the products according to the invention will thus contain active ingredients at a therapeutically effective dose and in a further aspect of the invention we provide a method of treatment or prophylaxis of a human or animal subject suffering or at risk of suffering from an autoimmune disease the method comprising administering to the subject a pharmaceutical product comprising an effective amount of a lck inhibitor and an effective amount of an anti-CD4 antibody.
  • the doses at which the lck inhibitor and anti-CD4 antibody will be administered will depend for example on variables such as the age and condition of the patient and the route of administration. In general the active ingredients will be used at doses generally recognised to be effective for the class of compound involved.
  • the anti-CD4 antibody may be used at a dose between 0.05 - 25mg/kg, preferably 0.1 - 10mg/kg body weight per single dose.
  • the lck inhibitor for example may be used at doses within the range 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral administration and from around 10ng/kg to 50mg/kg body weight for parenteral administration.
  • the lck inhibitor may be used at the lower ends of these dose ranges thus minimising any potential side effects of the compound.
  • the doses may be administered singly one or more times a day or continuously during a day up to a maximum effective or tolerated total dose.
  • Example illustrates the invention, in particular the ability of a lck inhibitor and an anti-CD4 antibody to synergistically promote the differentiation of Th2 cells.
  • the mouse line DO 10 expresses a transgenic ⁇ T-cell receptor (TCR) able to recognise the ovalbumin peptide 323-339 (ref. 29). Upon stimulation in vitro by the ovalbumin peptide these cells produce IFN- ⁇ and IL-4, the cytokines characteristic of Th1 and Th2 cells. This system has been widely used to investigate conditions which favour differentiation of one or other cell type (ref. 30, 31 ). Experimental Design Used Here
  • a lck inhibitor was added to cultures of spleen cells derived from the TCR- transgenic mice referred to above, while these cells were undergoing stimulation with ovalbumin peptide.
  • the purpose of this experiment was to determine whether the inhibitor would favour differentiation of Th2 cells, as judged by the production of IL-4 and inhibition of the production of interferon-gamma.
  • an anti-CD4 monoclonal antibody was added into some of the cultures, to determine whether this treatment would enhance the Th2-favouring effect of the inhibitor.
  • Spienocytes of DO 10 mice were isolated by Ficoll (Histopaque-1083, Sigma, Deisenhofen, Germany) gradient centrifugation and taken into culture at a concentration of 2 x 10 6 cells/ml in complete medium (RPMI 1640-Medium; Gibco, BRL, Life Technologies, Eggenstein, Germany; supplemented with 10% FCS, Sigma, Deisenhofen, Germany, 2 mM L-glutamine: Gibco, BRL, Life Technologies, Eggenstein, Germany; 50 ⁇ M mercaptoethanol and 100 U/ml antibiotic-antimycotic; Gibco, BRL, Life Technologies, Eggenstein, Germany) together with 0.3 ⁇ M ovalbumin peptide 323-339 (TIB Molbiol, Berlin, Germany).
  • Th2 differentiation recombinant mouse IL-4 As a control for Th2 differentiation recombinant mouse IL-4 (BioSource International, Camarillo, CA, USA) was added to one well to a concentration of 200 U/ml, and as a control for Th1 differentiation recombinant mouse IL-12 (Hoffmann-La Roche, Nutley, NJ, USA) was added to another well to a concentration of 1 ng/ml. Another well contained cells and ova-peptide alone as a further control.
  • tyrosine kinase inhibitors were added, and/or monoclonal anti-CD4 antibodies. These were tested alone or in combination in varying concentrations.
  • the inhibitors, dissolved in dimethylsulphoxide (DMSO) were added with or without antibodies so that the final DMSO concentration was 0.1 %
  • APC antigen-presenting cells
  • the level of IL-4 detected in the supernatant of cells treated only with ova-peptide was taken as the minimum produced.
  • the maximum was the mean level from cells treated with the IL-4-inducing drug at concentrations of 0.6-1 ⁇ M, i.e. at the plateau of the dose-response curve shown below in Figure 1. Data were then calculated as follows: observed level - minimum level
  • % maximum IL-4 production x 100 maximum level - minimum level
  • Rat-anti-mouse anti-CD4 antibodies were tested: RmCD4.2 (lgG2b) and RmCD4.4 (lgG2a) (ref. 34) from S. Thierfelder (GSF-Forschungstechnik furler und Pass GmbH, Kunststoff); YTA3.12 (lgG2b), YTS177.9 (lgG2a) and YTS191.1 (lgG2b) from H. Waldmann (Oxford University); and H129.19 (lgG2a) from M. Pierres (CNRS/INSERM, Marseille).
  • the mouse anti-CD4 antibody GK1.5 (lgG2b) from F. Fitch (Chicago) was also tested.
  • CD4 Binding Assays and FACS Analysis 0.5x 10 5 lymph node cells of BALB/c mice were incubated with blocking anti-CD4 antibodies at a concentration of 10 ⁇ g/ml in PBS/0.5% bovine serum albumin /0.01 % NaN ⁇ on ice for 30 min. Biotinylated (labelling kit from Boehringer Mannheim, Germany) anti-CD4 antibodies YTS191 .1 , YTA3.12 or RmCD4.2 (staining antibodies) were added and incubated for a further 30 min on ice. As controls, cells were incubated with blocking or staining antibodies alone.
  • the lck inhibitor PP2 significantly enhanced IL-4 production at concentrations of 400 nM and above (Figure 1 ). Above 1000nM the effect is more pronounced, but cell proliferation at 10 ⁇ M PP2 was reduced by up to 50% (data not shown). Over the one-week culture period cells proliferated at the same rate as untreated cells only at concentrations of PP2 below 1000nM (data not shown). As shown in Table 1 , individual mice varied markedly in the maximum level of IL-4 production that could be elicited with the inhibitor, unrelatedly to the level obtained by adding IL-4 itself at the beginning of the cultures. Nevertheless consistent values were obtained for the concentration of inhibitor needed to obtain a half- maximum effect, as shown in Table 1.
  • IFN- ⁇ production was reduced at PP2 concentrations above 400nM.
  • the anti CD4 antibody RmCD4.2 had a small suppressive effect on IL-4 and IFN- ⁇ production when applied alone, although when used at lower concentrations it had a slight enhancing effect on IL-4 production, in line with work in the rat cited above (ref. 14). In combination with PP2 significantly more IL-4 was produced than by PP2 alone while IFN- ⁇ production was reduced (Figure 2).

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On décrit un produit pharmaceutique comprenant un inhibiteur de la kinase agissant sur la tyrosine de protéines (kinase 'p56lck') et un anticorps anti-CD4 pour une utilisation simultanée et combinée, simultanée et séparée ou séquentielle dans des traitements thérapeutiques et l'utilisation de ces produits en médecine, par exemple pour favoriser la différenciation des cellules Th2.
EP97943980A 1996-10-01 1997-10-01 Produits pharmaceutiques contenant un inhibiteur de la kinase agissant sur la tyrosine de proteines et des anticorps anti-cd4 Withdrawn EP0946195A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GBGB9620465.6A GB9620465D0 (en) 1996-10-01 1996-10-01 Pharmaceutical products
GB9620465 1996-10-01
GB9620834 1996-10-04
GBGB9620834.3A GB9620834D0 (en) 1996-10-04 1996-10-04 Pharmaceutical products
GB9709941 1997-05-16
GBGB9709941.0A GB9709941D0 (en) 1997-05-16 1997-05-16 Pharmaceutical products
PCT/GB1997/002695 WO1998014211A1 (fr) 1996-10-01 1997-10-01 Produits pharmaceutiques contenant un inhibiteur de la kinase agissant sur la tyrosine de proteines et des anticorps anti-cd4

Publications (1)

Publication Number Publication Date
EP0946195A1 true EP0946195A1 (fr) 1999-10-06

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EP97943980A Withdrawn EP0946195A1 (fr) 1996-10-01 1997-10-01 Produits pharmaceutiques contenant un inhibiteur de la kinase agissant sur la tyrosine de proteines et des anticorps anti-cd4

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EP (1) EP0946195A1 (fr)
AU (1) AU4563197A (fr)
WO (1) WO1998014211A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1140938T3 (da) * 1999-01-11 2003-12-22 Univ Princeton Højaffinitetsinhibitorer for målvalidering og anvendelser heraf
EP1460088A1 (fr) 2003-03-21 2004-09-22 Biotest AG Anticorps humanisé contre CD4 avec des caractéristiques immunosuppressives
KR20100135257A (ko) 2008-03-13 2010-12-24 바이오테스트 아게 질병 치료제
CN102027016A (zh) 2008-03-13 2011-04-20 生物测试股份公司 一种治疗疾病的试剂
RU2540018C2 (ru) 2008-03-13 2015-01-27 Биотест Аг Средство для лечения заболевания
GB0920944D0 (en) 2009-11-30 2010-01-13 Biotest Ag Agents for treating disease

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
AU5006693A (en) * 1992-08-07 1994-03-03 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Polyhydroxylated naphthyl 2-carboxylate, and quinolyl and isoquinolyl 3-carboxylate derivatives as protein tyrosine kinase inhibitors
US5587459A (en) * 1994-08-19 1996-12-24 Regents Of The University Of Minnesota Immunoconjugates comprising tyrosine kinase inhibitors
GB9523675D0 (en) * 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9814211A1 *

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WO1998014211A1 (fr) 1998-04-09
AU4563197A (en) 1998-04-24

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