WO2004072116A2 - ANTIBODY MOLECULES HAVING SPECIFICITY FOR HUMAN IL-1β - Google Patents
ANTIBODY MOLECULES HAVING SPECIFICITY FOR HUMAN IL-1β Download PDFInfo
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- WO2004072116A2 WO2004072116A2 PCT/GB2004/000463 GB2004000463W WO2004072116A2 WO 2004072116 A2 WO2004072116 A2 WO 2004072116A2 GB 2004000463 W GB2004000463 W GB 2004000463W WO 2004072116 A2 WO2004072116 A2 WO 2004072116A2
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- 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
- C07K16/244—Interleukins [IL]
- C07K16/245—IL-1
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- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P19/00—Drugs for skeletal disorders
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Definitions
- Antibody molecules having specificity for human IL-l ⁇ having specificity for human IL-l ⁇
- the present invention relates to an antibody molecule having specificity for antigenic ' determinants of IL-l ⁇ .
- the present invention also relates to the therapeutic uses of the antibody molecule and methods for producing the antibody molecule.
- IL-l ⁇ The pro-inflammatory cytokine interleukin-l ⁇ (IL-l ⁇ ) is a member of the IL-1 gene family, which also includes IL-l ⁇ and the IL-1 receptor antagonist (IL-1RA) (reviewed by Dinarello, 1996, Blood, 87, 6, 2095-2147).
- IL-l ⁇ is primarily involved in inflammation and has direct effects on endothelial cells and macrophages as well as on both T and B cells. It stimulates bone marrow stromal cells to produce IL-6 as well as a number of colony- stimulating factors and also induces the production of TNF ⁇ .
- IL-l ⁇ is implicated in many pathological conditions that are associated with inflammation. These include infections (viral, bacterial, fungal and parasitic), endotoxic shock, arthtitis, rheumatoid arthritis, pelvic inflammatory disease, multiple sclerosis, asthma, osteoarthritis, psoriasis, Alzheimer's Disease, Crohn's disease, Peyronies's disease, heart disease (such as atherosclerosis), colon cancer, coeliac disease, gallbladder disease, Pilonidal disease, peritonitis, meningoencephalitis, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus host disease and transplant rejection.
- infections viral, bacterial, fungal and parasitic
- endotoxic shock arthtitis
- rheumatoid arthritis pelvic inflammatory disease
- multiple sclerosis asthma
- osteoarthritis psoriasis
- Alzheimer's Disease Crohn's disease
- Peyronies's disease heart
- IL-l ⁇ is also implicated in cancer, osteoporosis and pain signalling.
- the involvement of IL-1 ⁇ in inflammation, pain and other pathological conditions suggests that IL-l ⁇ is a good target for drugs and other molecules for the prophylaxis and/or treatment of these conditions.
- IL-l ⁇ The mature 17 kDa form of IL-l ⁇ exerts its biological effects by binding to the IL-1 receptor IL-IR.
- IL-IRII on the other hand, has been termed a 'decoy' receptor, as binding of IL-l ⁇ does not transduce a signal.
- the antibody is a neutralising antibody as defined in alternative (ii), above.
- the present invention provides a neutralising antibody having specificity for human IL-l ⁇ , comprising a heavy chain, wherein the variable domain of the heavy chain comprises at least one of a CDR (complementarity determining region) having the sequence given in SEQ ID NO: 5 for CDR-H1, a CDR having the sequence given in SEQ ID NO:6 for CDR-H2 and a CDR having the sequence given in SEQ ID NO:7 for CDR-H3.
- a CDR complementarity determining region
- the Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues.
- the actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether f amework or CDR, of the basic variable domain structure.
- the correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a "standard" Kabat numbered sequence.
- the CDRs of the heavy chain variable domain are located at residues 31-35 (CDR-
- CDR-H1 residues 50-65
- CDR-H3 residues 95-102
- Chothia Chothia, C. and Lesk, A.M. J. Mol. Biol., 196, 901-917 (1987)
- the loop equivalent to CDR-H1 extends from residue 26 to residue 32.
- 'CDR-H1' comprises residues 26 to 35, as described by a combination of the Kabat numbering system and Chothia' s topological loop definition.
- the CDRs of the light chain variable domain are located at residues 24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3) according to the Kabat numbering system.
- the term 'neutralising antibody' describes an antibody that is capable of neutralising the biological signalling activity of IL- 1 ⁇ , in particular by blocking binding of IL-l ⁇ to the IL-IRI.
- an antibody of the first aspect of the present invention comprises a heavy chain wherein at least two of CDR-H1, CDR-H2 and CDR-H3 of the variable domain of the heavy chain are selected from the following: the sequence given in SEQ ID NO: 5 for CDR- Hl, the sequence given in SEQ ID NO:6 for CDR-H2 and the sequence given in SEQ ID NO:7 for CDR-H3.
- the antibody may comprise a heavy chain wherein CDR-H1 has the sequence given in SEQ ID NO:5 and CDR-H2 has the sequence given in SEQ ID NO: 6.
- the antibody may comprise a heavy chain wherein CDR-H1 has the sequence given in SEQ ID NO:5 and CDR-H3 has the sequence given in SEQ ID NO:7, or the antibody may comprise a heavy chain wherein CDR-H2 has the sequence given in SEQ ID NO: 6 and CDR-H3 has the sequence given in SEQ ID NO: 7.
- CDR-H1 has the sequence given in SEQ ID NO:5
- CDR-H3 has the sequence given in SEQ ID NO:7
- the antibody may comprise a heavy chain wherein CDR-H2 has the sequence given in SEQ ID NO: 6 and CDR-H3 has the sequence given in SEQ ID NO: 7.
- the antibody of the first aspect of the present invention comprises a heavy chain, wherein the variable domain comprises the sequence given in SEQ ID NO:5 for CDR-H1, the sequence given in SEQ ID NO: 6 for CDR-H2 and the sequence given in SEQ ID NO:7 for CDR-H3.
- the antibody of the first aspect of the present invention comprises a heavy chain, wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO: 3.
- the antibody of the first aspect of the present invention comprises a heavy chain, wherein the variable domain of the heavy chain comprises a sequence having at least 60% identity or similarity to the sequence given in SEQ ID NO:3.
- Identity indicates that at any particular position in the aligned sequences, the amino acid residue is identical between the sequences.
- similarity indicates that, at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences.
- leucine may be substituted for isoleucine or valine.
- Other amino acids which can often be substituted for one another include but are not limited to:
- amino acids having basic side chains amino acids having basic side chains
- amino acids having glutamate amino acids having acidic side chains
- the antibody of the first aspect of the present invention comprises a heavy chain, wherein the variable domain of the heavy chain comprises a sequence having at least 90%, 95% or 98% identity or similarity to the sequence given in SEQ ID NO:3.
- the present invention provides a neutralising antibody having specificity for human IL-l ⁇ , comprising a light chain, wherein the variable domain of the light chain comprises at least one of a CDR (complementarity determining region) having the sequence given in SEQ ID NO:8 for CDR-Ll, a CDR having the sequence given in SEQ ID NO:9 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 10 for CDR-L3.
- a CDR complementarity determining region
- the antibody of the second aspect of the present invention comprises a light chain, wherein at least two of CDR-Ll, CDR-L2 and CDR-L3 of the variable domain of the light chain are selected from the following: the sequence given in SEQ ID NO:8 for CDR-Ll, the sequence given in SEQ ID NO: 9 for CDR-L2 and the sequence given in SEQ ID NO: 10 for CDR-L3.
- the antibody may comprise a light chain wherein CDR-Ll has the sequence given in SEQ ID NO:8 and CDR-L2 has the sequence given in SEQ ID NO:9.
- the antibody may comprise a light chain wherein CDR-Ll has the sequence given in SEQ ID NO:8 and CDR-L3 has the sequence given in SEQ ID NO:10, or the antibody may comprise a light chain wherein CDR-L2 has the sequence given in SEQ ID NO: 9 and CDR-L3 has the sequence given in SEQ ID NO: 10.
- the antibody of the second aspect of the present invention comprises a light chain, wherein the variable domain comprises the sequence given in SEQ TD NO: 8 for CDR-Ll, the sequence given in SEQ ID NO:9 for CDR-L2 and the sequence given in SEQ ID NO:10 for CDR-L3.
- the antibody of the second aspect of the present invention comprises a light chain, wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4.
- the antibody of the second aspect of the present invention comprises a light chain, wherein the variable domain of the light chain comprises a sequence having at least 60% identity or similarity to the sequence given in SEQ ID NO:4.
- the antibody of the second aspect of the present invention comprises a light chain, wherein the variable domain of the light chain comprises a sequence having at least 90%, 95% or 98% identity or similarity to the sequence given in SEQ ID NO:4.
- the antibody molecules of the first and second aspects of the present invention preferably comprise a complementary light chain or a complementary heavy chain, respectively.
- the antibody according to either of the first and second aspects of the present invention comprises a heavy chain, wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:5 for CDR-H1, the sequence given in SEQ ID NO:6 for CDR-H2 and the sequence given in SEQ ID NO.7 for CDR-H3 and a light chain wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO: 8 for CDR-Ll, the sequence given in SEQ ID NO:9 for CDR-L2 and the sequence given in SEQ ID NO:10 for CDR-L3.
- the antibody comprises a heavy chain, wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:3 and a light chain, wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4.
- the monoclonal antibody comprises a heavy chain, wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:3 and a light chain, wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4.
- the monoclonal antibody is a murine monoclonal antibody, wherein the monoclonal antibody comprises a heavy chain and a light chain, wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:3, and wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4.
- This murine monoclonal antibody is referred to herein as 'IC8' or as the "donor” antibody or as the "murine monoclonal antibody”.
- the complete nucleotide and amino acid sequences of the variable domains of the heavy and light chains of mouse monoclonal antibody IC8 are shown in Figure 1 and are given in SEQ ID NOS: 1 to 4.
- the CDRs given in SEQ TD NOS: 5 to 10 are derived from murine monoclonal antibody IC8.
- a CDR-grafted antibody molecule wherein one or more of the CDRs have been obtained from the murine monoclonal antibody IC8.
- the term 'CDR-grafted antibody molecule' refers to an antibody molecule wherein the heavy and/or light chain contains one or more CDRs (including, if desired, one or more modified CDRs) from a donor antibody (e.g. a murine monoclonal antibody) grafted into a heavy and/or light chain variable region framework of an acceptor antibody (e.g. a human antibody).
- a donor antibody e.g. a murine monoclonal antibody
- acceptor antibody e.g. a human antibody
- any appropriate acceptor variable region framework sequence may be used having regard to the class/type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions.
- the CDR-grafted antibody of the fourth aspect of the present invention has a variable domain comprising human acceptor framework regions as well as one or more of the CDRs derived from the donor antibody as referred to above.
- a neutralising CDR-grafted antibody wherein the variable domain comprises human acceptor framework regions and non- human donor CDRs.
- human frameworks which can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al., supra).
- KOL and NEWM can be used for the heavy chain
- REI can be used for the light chain and EU
- LAY and POM can be used for both the heavy chain and the light chain.
- human germline sequences may be used.
- the acceptor heavy and light chains do not necessarily need to be derived from the same antibody and may, if desired, comprise composite chains having framework regions derived from different chains.
- the preferred framework region for the heavy chain of the CDR-grafted antibody of the present invention is derived from the human sub-group VH3 sequence 3-11 (DP-35) shown in Figure 3 (SEQ ID NO: 12) together with JH4. Accordingly, provided is a neutralising CDR-grafted antibody comprising at least one non-human donor CDR wherein the heavy chain framework region is derived from the human subgroup sequence 3-11 (DP- 35) together with JH4.
- the sequence of human JH4 is as follows:
- the YFDY motif is part of CDR-H3 and is not part of framework 4 (Ravetch, JV. et al, 1981, Cell, 27, 583-591).
- the donor sequence is the IC8 VH sequence (SEQ ID NO: 11) shown in Figure 3a.
- the preferred framework region for the light chain of the CDR-grafted antibody of the present invention is derived from the human germline sub-group VK1 sequence O12 (DPK9) shown in Figure 3 (SEQ ID NO: 17) together with JK1. Accordingly, provided is a neutralising CDR-grafted antibody comprising at least one non-human donor CDR wherein the light chain framework region is derived from the human subgroup sequence O12 (DPK9) together with JK1.
- the JK1 sequence is as follows: (WT)FGQGTKVEIK (SEQ ID NO.75).
- the WT motif is part of CDR-L3 and is not part of framework 4 (Hieter, PA., et al, 1982, J. Biol. Chem., 257, 1516-1522).
- the donor sequence is the IC8 NL sequence (SEQ ID NO: 16) shown in Figure 3b.
- the framework regions need not have exactly the same sequence as those of the acceptor antibody. For instance, unusual residues may be changed to more frequently-occurring residues for that acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to the residue found at the same position in the donor antibody (see Reichmann et al. Nature, 332, 323-324, 1988). Such changes should be kept to the minimum necessary to recover the affinity of the donor antibody.
- a protocol for selecting residues in the acceptor framework regions which may need to be changed is set forth in WO 91/09967.
- the acceptor heavy chain has the human DP-35+JH4 sequence
- the acceptor framework regions of the heavy chain comprise, in addition to one or more donor CDRs, a donor residue at position 44 (according to Kabat et al.,(supra).
- a donor residue at position 44 according to Kabat et al.,(supra).
- the acceptor heavy chain has the human DP-35+JH4 sequence
- the acceptor framework regions of the heavy chain preferably comprise, in addition to one or more donor CDRs, a donor residue at position 89 (according to Kabat et al., supra). Accordingly, provided is a CDR-grafted antibody, wherein at least the residue at position 44 and/or position 89 of the variable domain of the heavy chain is a donor residue.
- the acceptor framework regions of the light chain comprise donor residues at positions 45, 70 and 85 and may additionally comprise donor residues at positions 40 and 48 (according to Kabat et al., supra).
- the residues at positions 45, 70 and 85 are donor residues.
- Donor residues are residues from the donor antibody, i.e. the antibody from which the CDRs were originally derived, which in the case of the present invention is the murine monoclonal antibody IC8.
- the heavy chain preferably comprises the sequence of gHl (SEQ ID NO: 13), gH2 (SEQ ID NO:14) or gH3 (SEQ ID NO: 15). The sequences of the variable domains of these grafted heavy chains are shown in Figure 3 a.
- the light chain preferably comprises the sequence of gLl (SEQ ID NO: 18), gL2 (SEQ ID NO: 19) or gL3 (SEQ ID NO:20).
- the sequences of the variable domains of these grafted light chains are shown in Figure 3b.
- the heavy chain of the antibody molecule according to the alternative embodiment of the second or fourth aspects of the present invention comprises variable domain gH3 (SEQ ID NO : 15) and the light chain of the antibody molecule of the present invention comprises variable domain gL3 (SEQ ID NO:20).
- an antibody according to any one of the first to fourth aspects of the present invention which binds to the same epitope as IC8.
- a neutralising antibody having specificity for human IL-l ⁇ which binds to the same epitope as an antibody whose heavy chain comprises the sequence gH3 (SEQ ID NO: 15) and whose light chain comprises the sequence gL3 (SEQ ID NO:20).
- the antibody molecule of the present invention may comprise a complete antibody molecule having full length heavy and light chains or a fragment thereof, such as a Fab, modified Fab, Fab', F(ab')2, Fv or scFv fragment.
- it may comprise a light chain or heavy chain monomer or dimer or a single chain antibody, e.g. a single chain Fv in which the heavy and light chain variable domains are joined by a peptide linker.
- the heavy and light chain variable regions may be combined with other antibody domains as appropriate.
- the antibody molecule of the present invention may have an effector or a reporter molecule attached to it.
- it may have a macrocycle for chelating a heavy metal atom, or a toxin, such as ricin, attached to it by a covalent bridging structure.
- the antibody of the present invention may be modified to enable an effector or reporter molecule to be attached to it.
- the antibody molecule of the present invention is a modified Fab fragment as described below.
- procedures of recombinant DNA technology may be used to produce an antibody molecule in which the Fc fragment (CH2, CH3 and hinge domains), the CH2 and CH3 domains or the CH3 domain of a complete immunoglobulin molecule has (have) been replaced by, or has (have) attached thereto by peptide linkage, a functional non- immunoglobulin protein, such as an enzyme or toxin molecule.
- the antibody molecule of the present invention is a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector or reporter molecule.
- the additional amino acids form a modified hinge region containing one or two cysteine residues to which the effector or reporter molecule may be attached.
- a neutralising antibody molecule according to the present invention having an effector or a reporter molecule attached to it.
- Effector or reporter molecules include a molecule such as a cytotoxic agent, a radionuclide or drug moiety.
- a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin
- a protein such as tumour necrosis factor, ⁇ -interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor or tissue plasminogen activator, a thrombotic agent or an anti-angiogenic agent, e.g.
- angiostatin or endostatin or, a biological response modifier such as a lymphokine, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), nerve growth factor (NGF) or other growth factor.
- IL-1 interleukin-1
- IL-2 interleukin-2
- IL-6 interleukin-6
- GM-CSF granulocyte macrophage colony stimulating factor
- G-CSF granulocyte colony stimulating factor
- NGF nerve growth factor
- a preferred effector group is a polymer molecule, which may be attached to the modified Fab fragment to increase its half-life in vivo.
- the polymer molecule may, in general, be a synthetic or a naturally occurring polymer, for example an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, e.g. a homo- or hetero- polysaccharide.
- Particular optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.
- synthetic polymers include optionally substituted straight or branched chain poly(ethyleneglycol), poly(propyleneglycol) poly(vinylalcohol) or derivatives thereof, especially optionally substituted poly(ethyleneglycol) such as methoxypoly(efhyleneglycol) or derivatives thereof.
- Particular naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.
- Derivatives as used herein is intended to include reactive derivatives, for example thiol-selective reactive groups such as maleimides and the like.
- the reactive group may be linked directly or through a linker segment to the polymer. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.
- the size of the polymer may be varied as desired, but will generally be in an average molecular weight range from 500Da to 50000Da, preferably from 5000 to 40000Da and more preferably from 25000 to 40000Da.
- the polymer size may in particular be selected on the basis of the intended use of the product.
- a small molecular weight polymer for example with a molecular weight of around 5000Da.
- a higher molecular weight polymer for example having a molecular weight in the range from 25000Da to 40000Da.
- Particularly preferred polymers include a polyalkylene polymer, such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 25000Da to about 40000Da.
- a polyalkylene polymer such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 25000Da to about 40000Da.
- Each polymer molecule attached to the modified antibody fragment may be covalently linked to the sulphur atom of a cysteine residue located in the fragment.
- the covalent linkage will generally be a disulphide bond or, in particular, a sulphur-carbon bond.
- the antibody fragment may have one or more effector or reporter molecules attached to it.
- the effector or reporter molecules may be attached to the antibody fragment through any available amino acid side-chain or terminal amino acid functional group located in the fragment, for example any free amino, imino, hydroxyl or carboxyl group.
- An activated polymer may be used as the starting material in the preparation of polymer-modified antibody fragments as described above.
- the activated polymer may be any polymer containing a thiol reactive group such as an ⁇ -halocarboxylic acid or ester, e.g. iodoacetamide, an imide, e.g. maleimide, a vinyl sulphone or a disulphide.
- a thiol reactive group such as an ⁇ -halocarboxylic acid or ester, e.g. iodoacetamide, an imide, e.g. maleimide, a vinyl sulphone or a disulphide.
- Such starting materials may be obtained commercially (for example from Nektar, formerly Shearwater Polymers Inc., Huntsville, AL, USA) or may be prepared from commercially available starting materials using conventional chemical procedures.
- Particular PEG molecules include 20K methoxy-PEG-amine (obtainable from Nektar, formerly Shear
- an antibody fragment linked to an effector or reporter molecule this may be prepared by standard chemical or recombinant DNA procedures in which the antibody fragment is linked either directly or via a coupling agent to the effector or reporter molecule either before or after reaction with the activated polymer as appropriate.
- Particular chemical procedures include, for example, those described in WO 93/06231, WO 92/22583, WO 89/00195 and WO 89/01476.
- the linkage may be achieved using recombinant DNA procedures, for example as described in WO 86/01533 and EP0392745.
- the modified Fab fragment of the present invention is PEGylated (i.e. has
- the antibody molecule of the present invention is a PEGylated modified Fab fragment as shown in Figure 12.
- the modified Fab fragment preferably has a maleimide group covalently linked to a single thiol group in a modified hinge region.
- a lysine residue is preferably covalently linked to the maleimide group.
- To each of the amine groups on the lysine residue is preferably attached a methoxypoly(ethyleneglycol) polymer having a molecular weight of approximately 20,000 Da. The total molecular weight of the entire effector molecule is therefore approximately 40,000 Da.
- a neutralising antibody having attached to one of the cysteine residues at the C-terminal end of the heavy chain a lysyl-maleimide or lysyl bis-maleimide group wherein each amino group of the lysyl residue has covalently linked to it a methoxypoly(ethyleneglycol) residue having a molecular weight of about 20,000 Da.
- the molecular weight may be 15,000- 25,000Da, or preferably 18,000-22,000Da, and even more preferably 19,000-2 l.OOODa.
- the present invention provides a neutralising antibody molecule having specificity for human IL-1 ⁇ , which is a modified Fab fragment having a heavy chain comprising the sequence given in SEQ ID NO: 15 and a light chain comprising the sequence given in SEQ ID NO:20 and having at the C-terminal end of its heavy chain a modified hinge region containing one cysteine residue to which an effector or reporter molecule may be attached.
- a neutralising antibody molecule having specificity for human IL-1 ⁇ which is a modified Fab fragment having a heavy chain comprising the sequence given in SEQ ID NO: 15 and a light chain comprising the sequence given in SEQ ID NO:20 and having at the C-terminal end of its heavy chain a modified hinge region containing one cysteine residue to which an effector or reporter molecule may be attached.
- a neutralising antibody molecule having specificity for human IL-l ⁇ which is a modified Fab fragment having a heavy chain comprising the sequence given in SEQ ID NO: 15 and a light chain comprising the sequence given in SEQ ID NO:20 and having at the C-terminal end of its heavy chain a modified hinge region containing one cysteine residue to which an effector or reporter molecule is attached.
- a neutralising antibody molecule having specificity for human IL-l ⁇ which is a modified Fab fragment having a heavy chain comprising the sequence given in SEQ ID NO: 15 and a light chain comprising the sequence given in SEQ ID NO: 20 having attached to the cysteine residue at the C-terminal end of the heavy chain a lysyl-maleimide group, wherein each amino group of the lysyl residue has covalently linked to it a methoxypoly(ethyleneglycol) residue having a molecular weight of about 20,000 Da.
- a neutralising antibody molecule wherein its heavy chain comprises or consists of amino acid residue numbers 22 to 251 of the sequence given in SEQ ID NO-71, and wherein its light chain comprises or consists of amino acid residue numbers 22 to 235 of the sequence given in SEQ ID NO: 70.
- Amino acid residue numbers 1 to 21 of the sequences given in SEQ ID NOS: 70 and 71 represent the E. Coli leader sequence which is most preferably cleaved to give a neutralising antibody molecule of the present invention.
- a neutralising antibody molecule wherein its heavy chain comprises or consists of amino acid residue numbers 22 to 251 of the sequence given in SEQ ID NO:71, and wherein its light chain comprises or consists of amino acid residue numbers 22 to 235 of the sequence given in SEQ ID NO:70 having attached to the cysteine residue at the C-terminal end of the heavy chain a lysyl-maleimide group, wherein each amino group of the lysyl residue has covalently linked to it a methoxypoly(ethyleneglycol) residue having a molecular weight of about 20,000 Da.
- a neutralising antibody molecule having specificity for human IL- 1 ⁇ , which binds to the same epitope as a neutralising antibody which comprises a light chain comprising the sequence given in SEQ ID NO:20.
- the constant region domains of the antibody molecule of the present invention may be selected having regard to the proposed function of the antibody molecule, and in particular the effector functions which may be required.
- the constant region domains may be human IgA, IgD, IgE, IgG or IgM domains, hi particular, human IgG constant region domains may be used, especially of the IgGl and IgG3 isotypes when the antibody molecule is intended for therapeutic uses and antibody effector functions are required.
- IgG2 and IgG4 isotypes may be used when the antibody molecule is intended for therapeutic purposes and antibody effector functions are not required, e.g. for simply blocking IL-l ⁇ activity.
- the antibody molecule of the present invention preferably has a binding affinity of at least 4.4 x 10 "10 M, more preferably at least 3.2 x 10 "10 M.
- the present invention also relates to variants of the antibody molecules of the present invention, which have an improved affinity for IL-l ⁇ .
- variants can be obtained by a number of affinity maturation protocols including mutating the CDRs (Yang et al, J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al, Bio/Technology, 10, 779-783, 1992), use of mutator strains of E. coli (Low et al, J. Mol. Biol., 250, 359-368, 1996), DNA shuffling (Patten et al, Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display (Thompson et al, J.
- the present invention also provides an isolated DNA sequence encoding the heavy and/or light chain(s) of the antibody molecule of the present invention.
- the DNA sequence encodes the heavy or the light chain of the antibody molecule of the present invention.
- the DNA sequence of the present invention may comprise synthetic DNA, for instance produced by chemical processing, cDNA, genomic DNA or any combination thereof.
- DNA sequences which encode the antibody molecule of the present invention can be obtained by methods well known to those skilled in the art. For example, DNA sequences coding for part or all of the antibody heavy and light chains may be synthesised as desired from the determined DNA sequences or on the basis of the corresponding amino acid sequences.
- DNA coding for acceptor framework sequences is widely available to those skilled in the art and can be readily synthesised on the basis of their known amino acid sequences.
- Standard techniques of molecular biology may be used to prepare DNA sequences coding for the antibody molecule of the present invention. Desired DNA sequences may be synthesised completely or in part using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate.
- PCR polymerase chain reaction
- the present invention also relates to a cloning or expression vector comprising one or more DNA sequences of the present invention. Accordingly, provided is a cloning or expression vector comprising one or more DNA sequences encoding an antibody of the present invention.
- the cloning or expression vector comprises two DNA sequences, encoding the light chain and the heavy chain of the antibody molecule of the present invention, respectively.
- a vector according to the present invention comprises the sequence given in SEQ ID NO: 69.
- a host cell comprising one or more cloning or expression vectors comprising one or more DNA sequences encoding an antibody of the present invention.
- Any suitable host cell/vector system may be used for expression of the DNA sequences encoding the antibody molecule of the present invention.
- Bacterial, for example E. coli, and other microbial systems may be used or eukaryotic, for example mammalian, host cell expression systems may also be used.
- Suitable mammalian host cells include CHO, myeloma or hybridoma cells.
- the present invention also provides a process for the production of an antibody molecule according to the present invention comprising culturing a host cell containing a vector of the present invention under conditions suitable for leading to expression of protein from DNA encoding the antibody molecule of the present invention, and isolating the antibody molecule.
- the antibody molecule may comprise only a heavy or light chain polypeptide, in which case only a heavy chain or light chain polypeptide coding sequence needs to be used to transfect the host cells.
- the cell line may be transfected with two vectors, a first vector encoding a light chain polypeptide and a second vector encoding a heavy chain polypeptide.
- a single vector may be used, the vector including sequences encoding light chain and heavy chain polypeptides.
- the present invention also provides a pharmaceutical or diagnostic composition comprising an antibody molecule of the present invention in combination with one or more of a pharmaceutically acceptable excipient, diluent or carrier. Accordingly, provided is the use of an antibody of the invention for the manufacture of a medicament.
- the composition will usually be supplied as part of a sterile, pharmaceutical composition that will normally include a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the present invention may additionally comprise a pharmaceutically- acceptable adjuvant.
- the present invention also provides a process for preparation of a pharmaceutical or diagnostic composition comprising adding and mixing the antibody molecule of the present invention together with one or more of a pharmaceutically acceptable excipient, diluent or carrier.
- the antibody molecule may be the sole active ingredient in the pharmaceutical or diagnostic composition or may be accompanied by other active ingredients including other antibody ingredients, for example anti-T cell, anti-IFN ⁇ or anti-LPS antibodies, or non- antibody ingredients such as xanthines.
- the pharmaceutical compositions preferably comprise a therapeutically effective amount of the antibody of the invention.
- therapeutically effective amount refers to an amount of a therapeutic agent needed to treat, ameliorate or prevent a targeted disease or condition, or to exhibit a detectable therapeutic or preventative effect.
- the therapeutically effective amount can be estimated initially either in cell culture assays or in animal models, usually in rodents, rabbits, dogs, pigs or primates. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
- the precise therapeutically effective amount for a human subject will depend upon the severity of the disease state, the general health of the subject, the age, weight and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician. Generally, a therapeutically effective amount will be from 0.01 mg/kg to 50 mg/kg, preferably 0.1 mg/kg to 20 mg/kg. Pharmaceutical compositions may be conveniently presented in unit dose forms containing a predetermined amount of an active agent of the invention per dose.
- compositions may be administered individually to a patient or may be administered in combination (e.g. simultaneously, sequentially or separately) with other agents, drugs or hormones.
- the dose at which the antibody molecule of the present invention is administered depends on the nature of the condition to be treated, the extent of the inflammation present and on whether the antibody molecule is being used prophylactically or to treat an existing condition.
- the frequency of dose will depend on the half-life of the antibody molecule and the duration of its effect. If the antibody molecule has a short half-life (e.g. 2 to 10 hours) it may be necessary to give one or more doses per day. Alternatively, if the antibody molecule has a long half life (e.g. 2 to 15 days) it may only be necessary to give a dosage once per day, once per week or even once every 1 or 2 months.
- a short half-life e.g. 2 to 10 hours
- a long half life e.g. 2 to 15 days
- the pharmaceutically acceptable carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.
- Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
- salts can be used, for example mineral acid salts, such as hydrochlorides, hydrobromides, phosphates and sulphates, or salts of organic acids, such as acetates, propionates, malonates and benzoates.
- mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulphates
- organic acids such as acetates, propionates, malonates and benzoates.
- Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents or pH buffering substances, may be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for ingestion by the patient.
- compositions of the invention can be administered directly to the subject.
- the subjects to be treated can be animals. However, it is preferred that the compositions are adapted for administration to human subjects.
- compositions of this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra- arterial, intramedullary, intrathecal, intraventricular, transdermal, transcutaneous (for example, see WO 98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the invention.
- the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
- Direct delivery of the compositions will generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue.
- the compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule.
- the active ingredient in the composition will be an antibody molecule. As such, it will be susceptible to degradation in the gastrointestinal tract. Thus, if the composition is to be administered by a route using the gastrointestinal tract, the composition will need to contain agents which protect the antibody from degradation but which release the antibody once it has been absorbed from the gastrointestinal tract.
- the antibody of the present invention will be administered by use of gene therapy.
- DNA sequences encoding the heavy and light chains of the antibody molecule under the control of appropriate DNA components are introduced into a patient such that the antibody chains are expressed from the DNA sequences and assembled in situ.
- the present invention also provides an antibody molecule for use in the control of inflammation.
- the antibody molecule can be used to reduce the inflammatory process or to prevent the inflammatory process.
- the present invention also provides the antibody molecule of the present invention for use in the treatment or prophylaxis of a pathological disorder that is mediated by IL-l ⁇ or associated with an increased level of IL-1 ⁇ .
- the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endo toxic shock associtated with infection, arthritis, rheumatoid arthritis, pelvic inflammatory disease, Alzheimer's Disease, Crohn's disease, Peyronie's Disease, coeliac disease, gallbladder disease, Pilonidal disease, peritonitis, meningoencephalitis, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, cancer (both solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myelogen
- the present invention further provides the use of an antibody molecule according to the present invention in the manufacture of a medicament for the treatment or prophylaxis of a pathological disorder that is mediated by IL-l ⁇ or associated with an increased level of IL- l ⁇ .
- the present invention further provides the use of an antibody molecule according to the present invention in the manufacture of a medicament for the treatment or prophylaxis of pain.
- An antibody molecule of the present invention may be utilised in any therapy where it is desired to reduce the effects of IL- 1 ⁇ in the human or animal body.
- IL- 1 ⁇ may be circulating in the body of may be present in an undesirably high level localised at a particular site in the body, for example a site of inflammation.
- the antibody molecule of the present invention is preferably used for the control of inflammation.
- the present invention also provides a method of treating human or animal subjects suffering from or at risk of a disorder mediated by IL-l ⁇ , the method comprising administering to the subject an effective amount of the antibody molecule of the present invention.
- the antibody molecule of the present invention may also be used in diagnosis, for example in the in vivo diagnosis and imaging of disease states involving IL-l ⁇ .
- Figure la shows the nucleotide and amino acid sequence (SEQ ID NOS:l and 3, respectively) of the variable domains of the heavy chain
- Figure lb shows the nucleotide and amino acid sequence (SEQ ID NOS:2 and 4, respectively) of the variable domains of the light chain of murine monoclonal antibody IC8.
- Figure 2 shows the vectors MRR14 and pMRRlO.
- Figure 3 shows the graft design for the IC8 heavy ( Figure 3a; SEQ ID NOS:ll-15) and light chain ( Figure 3b; SEQ ID NOS: 16-20) sequences.
- ) highlights differences between donor: acceptor: grafted framework sequences.
- CDR's are single underlined for the IC8 sequences. These are as defined by Kabat, except for CDR-H1 which encompasses both Kabat and Chothia definitions. Double-underlined sequences are donor residues retained in the grafts. Starred (*) residues are common in human sub-group VH3 germline sequences, but not present in this particular germline — these are not considered mouse residues even though they are present in the original donor sequence.
- Figure 4 shows the nucleotide and amino acid sequences of the designed genes gHl ( Figure 4a) and gLl ( Figure 4b).
- Figure 5 shows the oligonucleotides that were used for gene construction.
- Figure 6 shows the oligonucleotide cassettes that were used for further grafts. Shown are: the IC8gL2 sense strand sequence (SEQ ID NO:59), the reverse strand sequence (SEQ ID NO:72) and the corresponding amino acid sequence (SEQ ID NO:60); the IC8gL3 sense strand sequence (SEQ ID NO:61), the reverse strand sequence (SEQ ID NO:73) and the corresponding amino acid sequence (SEQ ID NO:62); the IC8gH2 sense strand sequence (SEQ ID NO:63), the reverse strand sequence (SEQ ID NO:64) and the corresponding amino acid sequence (SEQ ID NO:65), and the IC8gH3 sense strand sequence (SEQ ID NO:66), the reverse strand sequence (SEQ ID NO: 67) and the corresponding amino acid sequence (SEQ ID NO: 68). Underlined residues denote changed amino acids.
- Figure 7 shows the results from the IL-l ⁇ neutralisation assay with IC8 grafts.
- Figure 8 shows a map of the vector pTTOD(Fab').
- Figure 9 shows steps 1-4 in the cloning of IC8 N-region genes into the intermediate vector pTTOD(Fab').
- Figure 10 shows a map of vector pTTOD(gH3gL3 Fab' IGS-2).
- Figure 11 shows the coding and flanking sequence of pTTOD(gH3gL3 Fab' IGS-2); SEQ ID ⁇ O:69.
- Figure 12 shows the structure of a modified Fab fragment derived from an antibody to IL-l ⁇ covalently linked via a cysteine residue to a lysyl-maleimide linker wherein each amino group on the lysyl residue has covalently attached to it a methoxy PEG residue wherein n is about 420.
- E. coli strain INN ⁇ F' (Invitrogen) was used for transformation and routine culture growth. DNA restriction and modification enzymes were obtained from Roche Diagnostics Ltd. and New England Biolabs. Plasmid preparations were performed using Maxi Plasmid purification kits (QIAGEN, catalogue No. 12165). DNA sequencing reactions were performed using the ABI Prism Big Dye terminator sequencing kit (catalogue No. 4304149) and run on an ABI 3100 automated sequencer (Applied Biosystems). Data was analysed using the program AutoAssembler (Applied Biosystems). Oligonucleotides were obtained from OSWEL. The concentration of Fab' was determined using Fab' assembly ELISA.
- Example 1 Gene cloning and expression of the variable regions from murine monoclonal antibody IC8
- RNA was prepared from IC8 hybridoma cells using the QIAGEN RNeasy kit (QIAGEN Ltd, catalogue no. 74104). The RNA obtained was reverse transcribed to cDNA using the Clontech cDNA Advantage RT for PCR kit (catalogue no. K1402).
- the cDNA prepared from hybridoma cells was used as the template for PCR in a series of reactions designed to amplify the N-region sequences.
- the reactions used a set of 'forward' degenerate primers designed to anneal to DNA within the conserved signal sequence, and a reverse primer annealing to DNA encoding the framework 4/constant region junction.
- PCR was performed using Taq Plus Precision (Stratagene, catalogue No. 600211) and a 0.25 mM concentration of dNTP.
- the resultant PCR products were cloned into sequencing vectors (h Vitrogen Zero Blunt TOPO PCR cloning kit for sequencing, catalogue No. K2875) and the DNA sequence was determined.
- N-terminal protein sequencing of the purified IC8 antibody (from the hybridoma) was used to confirm that the translated sequences corresponded to the observed protein sequence.
- the N-region sequences are shown in Figure l and in SEQ ID ⁇ OS:l to 4.
- the murine N-region genes were then sub-cloned into the expression vectors pMRRlO and pMRR14 ( Figure 2). These are separate vectors for expression of the light and heavy chain respectively and contain genomic D ⁇ A encoding constant region genes for human kappa light chain and gamma-4 heavy chain respectively.
- the double chimeric IC8 antibody molecule cHcL was expressed by transient co- transfection of the heavy and light chain expression vectors described above (pMRRlO and pMRR14 containing IC8 NL and NH respectively) into CHO-L761 cells. Transfections were performed using the lipofectamine procedure according to manufacturer's instructions (InVitrogen, catalogue No. 18324).
- the CDRs from IC8 were CDR-grafted into human frameworks in order to reduce potential immunogenicity and to facilitate E. coli expression.
- Human germline acceptor frameworks were chosen from sub-groups NH3 and NK1.
- Figure 3 shows an alignment between the donor mouse sequence and the acceptor human frameworks.
- the heavy chain acceptor framework is the human germline sequence NH3-11 (DP-35), with framework 4 coming from this portion of the human JH-region germline JH4.
- the light chain acceptor framework is the human germline sequence O12 (DPK9), with framework 4 coming from this portion of the human JK-region germline JK1.
- the alignment in Figure 3 shows that there are 13 framework differences between the donor and acceptor heavy chains (excluding CDRs). At each of these positions an analysis was made of the potential of that residue to contribute to antigen binding, through direct contact with antigen, through a role in CDR packing, or through involvement at the NL/VH interface; if considered important, the murine donor residue was retained.
- the light chain alignment shows that there are 15 framework differences between the donor and acceptor sequences (excluding CDRs).
- the potential of the murine residue to contribute to antigen binding was again analysed. In this way, three NH grafts and three NL grafts were designed.
- oligonucleotides were used to construct the genes encoding gHl and gLl ( Figure 5; SEQ ID NOS:27-58).
- the oligonucleotides encoding the designed genes were annealed together by mixing at a concentration of 100 pmoles/ ⁇ l in buffer (12.5 mM TrisHCl pH 7.5, 2.5 mM MgCl 2 , 25 mM NaCl, 0.25 mM dithioerythritol) and heating to 95°C for 3 minutes in a PCR block programmed to cool down to 30°C at a rate of -0.01 °C every 10 seconds.
- T4 DNA ligase (5U) and its appropriate reaction buffer were added, and the oligonucleotides were ligated together by incubation at 25 °C for 1 hour.
- the ligated heavy and light chain genes were then amplified by PCR following addition of a 10-fold excess of 'end' primers TI (SEQ ID NO:25) and B 1 (SEQ ID NO:26).
- a proof-reading DNA polymerase was used for this amplification (Taq Plus Precision, Stratagene). Amplification products were run on a 1.5% agarose gel.
- the 400-450 band was isolated and gel purified then cloned into the intermediate vector pCR4 blunt TOPO according to the manufacturer's instructions (InNitrogen).
- FIG. 6 shows the design of the oligonucleotide cassettes.
- the vector pCR4(IC8gLl) was cut with the restriction enzymes Kpnl and ⁇ hel.
- the resulting large vector fragment was gel purified from agarose and was used in ligation with the oligonucleotide cassette.
- Oligonucleotide pairs were annealed together by mixing at a concentration of 0.5 pmoles/ ⁇ l in a volume of 200 ⁇ l buffer (12.5 mM TrisHCl pH 7.5, 2.5 mM MgCl 2 , 25 mM ⁇ aCl, 0.25 mM dithioerythritol), and heating to 95 °C for 3 minutes in a waterbath (volume 500 ml) then allowed to slow-cool to room temperature. The annealed oligonucleotide cassette was then diluted ten-fold in water before ligation into the appropriately cut vector. DNA sequencing was used to confirm the correct sequence, creating plasmids pCR4(IC8gL2) and pCR4(IC8gL3).
- the variant gH2 was constructed from pCR4(IC8gHl) using a PCR strategy.
- the reverse strand of the cassette shown in Figure 6 (SEQ ID NO:64) was used as a reverse primer in PCR using a vector specific 5 ' forward primer to generate a product representing the partial gH2 sequence.
- This was digested with restriction enzymes Hin ⁇ TII and BspEI then cloned into Hindlll-BspEI restricted pCR4(IC8gHl) to create pCR4(IC8gH2).
- the variant gH3 was constructed using a different PCR strategy.
- the two gH3 oligos shown in Figure 6 were used in separate PCR reactions: the sense strand (SEQ ID NO:66) as a forward primer using a vector-specific 3 'reverse primer, and the non-sense strand (SEQ ID NO:67) as a reverse primer using a vector-specific 5' forward primer.
- the template was pCR4(IC8gHl).
- the two resulting amplification products were isolated and purified, then added together with both 5' and 3' vector-specific primers and cycled through additional PCR amplifications to generate a full length gH3 product. This was digested with Hindlll and Apal and inserted into pCR4(IC8gHl) restricted with Hindlll-Apal, to create pCR4(IC8gH3). All variants were confirmed by DNA sequencing.
- Each of the heavy chain grafts was then sub-cloned into the expression vector pMRR14 as Hindlll-Apal fragments.
- Each of the 3 light chain grafts was sub-cloned into the light chain expression vector pMRRlO as SfuI-BsiWI fragments.
- the grafted antibodies were expressed by transient co-transfection of the grafted heavy and light chain expression vectors described above (pMRRlO and pMRR14 containing IC8 gLl, gL2 and gL3 and gHl, gH2 and gH3 respectively) into CHO-L761 cells. Transfections were performed usmg the lipofectamine procedure according to manufacturer's instructions (h Nitrogen, catalogue no. 18324).
- the assay format used anti-IL-l ⁇ antibody captured by anti-hFc with a titration of recombinant human IL-l ⁇ in the solution phase.
- Mouse anti-human IgG, Fc fragment-specific (Celltech) was immobilised on flowcell 2 of a CM5 Sensor Chip via amine coupling chemistry to a level of 12757RU.
- a blocked reference surface was prepared on flowcell 1 by activation with EDC/NHS and deactivation with ethanolamine using the same volumes as for flowcell 2.
- Anti-IL-l ⁇ antibody was passed over flowcells 1 and 2 and captured on the immobilised anti-hFc surface using a flowrate of 10 ⁇ l/min.
- IL-1 ⁇ from 400-0 nM was injected over the blocked and captured anti-IL-l ⁇ antibody surface using a flowrate of 30 ⁇ l/min for 3 min.
- the anti-hFc surface was regenerated with a 30 ⁇ l injection of 40 mM HCI.
- Kinetic parameters were calculated using BIAevaluation 3.1 software.
- gIC8 Fab' the assay format used anti-IL-l ⁇ antibody captured by anti-hF(ab') (where 'h' indicates that it is a human F(ab') 2 ) then IL-1 ⁇ titrated over.
- Affinipure goat anti- human IgG, F(ab') fragment-specific Jackson ImmunoResearch Code 109-005-097 was immobilised on flowcell 2 of a CM5 Sensor Chip via amine coupling chemistry to a level of 13025RU.
- a blocked reference surface was prepared on flowcell 1 by activation with EDC/NHS and deactivation with ethanolaomine using the same volumes as for flowcell 2.
- HBS-EP buffer (10 mM HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% Surfactant P20, Biacore AB) was used as the running buffer and assays were performed at 25°C.
- Anti-IL-l ⁇ antibody was passed over flowcells 1 and 2 and captured on the immobilised anti-hF(ab') 2 surface using a flowrate of 10 ⁇ l/min.
- IL-l ⁇ (Strathmann) from 400-0 nM was injected over the blocked and captured anti-IL-l ⁇ antibody surface using a flowrate of 30 ⁇ l/min for 3 min.
- the anti-hF(ab') surface was regenerated with a 30 ⁇ l injection of 40 mM HCI followed by a 15 ⁇ l injection of 5 mM NaOH.
- Kinetic parameters were calculated using BIAevalutation 3.1 software.
- Table 1 shows a summary of Biacore antigen affinity data. It is clear that the gHl graft, which has donor residues at positions 44 and 89, has a higher affinity than gH2, which only has a donor residue at position 89. The gH2 graft was, therefore, rejected. Surprisingly, high affinity was observed in the gH3 graft in which only position 44 is a donor framework residue.
- In vitro neutralisation assay Fibroblasts were grown to 80% confluence in 96 well plates. Antibodies were titrated in half log dilutions from 1 ⁇ g/ml and IL-l ⁇ was added to give 20 pg/ml final concentration. The plates were incubated at room temperature for 30 min. Culture medium was removed from fibroblast cultures and 100 ⁇ l antibody/IL-l ⁇ mix added to the appropriate wells and cultured overnight at 37°C. The amount of IL-6 produced in response to IL-l ⁇ was then estimated using the R&D Systems Human IL-6 Duoset Kit DY206.
- mice Intraperitoneal gH3gL3Fab '-PEG(40K) / intraperitoneal hIL-l ⁇ in mice
- mice Male Balb/c mice (18-25g) were injected intraperitoneally (i.p.) with gH3gL3Fab'- PEG(40K) (lOO ⁇ l, in PBS vehicle) or control Fab'-PEG(40K) (lOO ⁇ l, in PBS vehicle) 5 minutes prior to i.p. injection with hIL-l ⁇ (150 ng/kg) or vehicle (lOO ⁇ l PBS). After 120 minutes, mice were killed by cervical dislocation and peritoneal lavage performed (3ml HBSS (Hanks' Balanced Salts) + 0.25% BSA, 12mM HEPES). A total leukocyte count was performed using a Coulter Counter.
- GP-1 mAb anti-Ly6G/Ly6C
- Leukocytes were washed once in HBSS (0.25% BSA, 12mM HEPES), resuspended in 300 ⁇ l HBSS (0.25% BSA, 12mM HEPES) and analysed by flow cytometry. Neutrophils were identified as CD45 + GR-1 HIGH .
- Murine monocyte chemoattractant protein- 1 (mMCP-1) concentration in the peritoneal lavage samples was measured by sandwich ELISA according to the manufacturer's instructions (BD Biosciences OPT-EIA mMCP-1).
- mice Intravenous gH3gL3 Fab '-PEG(40K) / intravenous hIL-l ⁇ in mice
- mice Male Balb/c mice (18-25g) were anaesthetised with halothane and injected intravenously (i.v.) with gH3gL3Fab'-PEG(40K) (lOO ⁇ l, in PBS vehicle) or control Fab-PEG (lOO ⁇ l, in PBS vehicle) 15 minutes prior to i.v. injection with hIL-l ⁇ (37.5 or 50 ⁇ g/kg) or vehicle (lOO ⁇ l PBS). After 90 minutes, a blood sample was taken by cardiac puncture into heparin (20 ⁇ l, lOOU/ml), and plasma was prepared by centrifugation (14,000 x g, 2 min, RT). Plasma samples were stored at -20°C. Plasma samples were assayed for murine interleukin-6 (mIL-6) by sandwich ELISA according to the manufacturer's instructions (BD Biosciences OPT-EIA mIL-6).
- mIL-6 murine interleukin-6
- mice with i.p. gH3gL3Fab'- PEG(40K) were effective in reducing i.p. hIL-l ⁇ -induced neutrophil accumulation (Table 2) and mMCP-1 generation (Table 3).
- the pre-treatment of mice with i.v. gH3gL3Fab'-PEG (40K) was also effective in reducing i.v. hlL-l ⁇ -induced mIL-6 generation.
- Table 4 Data from 3 separate experiments are summarised in Table 4.
- the antibody gH3gL3Fab' can, therefore, be expected to be useful in the treatment of inflammation and other IL-l ⁇ mediated diseases.
- the expression vector containing an irrelevant Fab' termed pTTOD(Fab'), is shown in Figure 8.
- the DNA encoding both the light chain and heavy chain is preceded by DNA encoding the ⁇ . coli OmpA signal sequence (Mowa NR, Nakamura K and Inouye M. Amino acid sequence of the signal peptide of ompA protein, a major outer membrane protein of Escherichia coli. J Biol Chem. 1980; 255(1): 27-9).
- the V-regions of IC8 were cloned into this vector so that this signal sequence is maintained, directing the translocation of both chains to the E. coli periplasm.
- the signal peptide is cleaved on translocation, so that it does not form part of the product Fab' sequence, (note; the sequence of the OmpA signal peptide is amino acid residues 1 to 21 of the sequence given in SEQ ID NO:70.
- Plasmid pTTOD(Fab') was digested with resriction enzymes EcoRN and BsiWI (BsiWI and Spll are isoschizomers) to remove the irrelevant NL sequence and the IC8 gL3 N-region was inserted, following its isolation from pMRR10(IC8gL3). This created the cloning intermediate pTTOD(IC8gL3).
- pTTOD(IC8gL3) was then cleaved with BsiWI and Apal and 2 fragments were inserted in a 3-way ligation; a c-kappa/IGS-fragment (either IGS-2 or IGS-3) and the IC8gH3 fragment (see schematic representation in Figure 9).
- a c-kappa/IGS-fragment either IGS-2 or IGS-3
- the IC8gH3 fragment see schematic representation in Figure 9.
- the 2 vector variants pTTOD(IC8gL3gH3 IGS-2) and pTTOD(IC8gL3gH3 IGS-3) were constructed.
- IGS-2 confers very tight translational coupling between the 2 genes giving a rapid rate of heavy chain translation
- IGS-3 confers a slower rate of heavy chain translation (see UK patent application No. 0129105).
- the eluted product stream was concentrated, diafiltered into tris buffer using ultrafiltration and subjected to anion-exchange chromatography (Q sepharose FF resin) where the Fab' was contained in the unbound fraction.
- the purified Fab' was concentrated & diafiltered into reduction buffer (by ultrafiltration) followed by reduction using 2-mercaptoethylamine to activate the hinge thiol.
- the reductant is then removed by ultrafiltration buffer-exchange.
- N-terminal sequencing confirmed the correct amino acid sequence and cleavage of the OmpA leader. Expression of Fab' by these two plasmids was compared.
- Table 5 shows a comparison of fermenter Fab' yields for the IGS-2 and the IGS-3 variants.
- the IGS-2 construct clearly out-performs IGS-3 for Fab' productivity. Therefore the IGS-2 variant was selected.
- the plasmid map is shown in Figure 10.
- Figure 11 shows the Fab' coding and flanking sequence of pTTOD(gH3gL3 Fab' IGS-2).
- the purified modified Fab is site-specifically conjugated with a branched molecule of PEG. This is achieved by activation of a single cysteine residue in a truncated hinge region of the modified Fab, followed by reaction with (PEG)-lysyl maleimide as previously described (A. P. Chapman et al, Nature Biotechnology 17, 780-783, 1999).
- a PEGylated molecule of the invention is represented in Figure 12.
- the PEG used was 20K methoxy-PEG-amine (obtainable from Nektar, formerly Shearwater).
- the resulting Fab'-PEG was purified by cation-exchange chromatography (SP sepharose HP) using a linear NaCl gradient elution.
Abstract
Description
Claims
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US10/544,911 US7608694B2 (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human IL-1β |
EP04708808A EP1597282B1 (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human il-1 beta |
AU2004210776A AU2004210776B2 (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human IL-1beta |
MXPA05007392A MXPA05007392A (en) | 2003-02-13 | 2004-02-06 | ANTIBODY MOLECULES HAVING SPECIFICITY FOR HUMAN IL-1beta. |
DK04708808.3T DK1597282T3 (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human IL-1 beta |
CA2515474A CA2515474C (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human il-1.beta. |
AT04708808T ATE525397T1 (en) | 2003-02-13 | 2004-02-06 | ANTIBODY MOLECULES WITH SPECIFICITY FOR HUMAN IL-1 BETA |
ES04708808T ES2373953T3 (en) | 2003-02-13 | 2004-02-06 | ANTIBODY MOLECULES WITH SPECIFICITY FOR IL-1 BETA HUMANA. |
JP2006502246A JP4668896B2 (en) | 2003-02-13 | 2004-02-06 | Antibody molecule having specificity for human IL-1β |
BR0407233-2A BRPI0407233A (en) | 2003-02-13 | 2004-02-06 | Neutralizing antibody, antibody molecule, cdr-grafted antibody, isolated dna sequence, cloning or expression vector, host cell, process for producing the antibody molecule, and, pharmaceutical composition |
SI200431797T SI1597282T1 (en) | 2003-02-13 | 2004-02-06 | Antibody molecules having specificity for human il-1 beta |
EA200501286A EA200501286A1 (en) | 2003-02-13 | 2004-02-06 | MOLECULES OF ANTIBODIES WITH SPECIFICITY TO HUMAN IL-1β |
IS8013A IS8013A (en) | 2003-02-13 | 2005-09-07 | Antibodies with specificity to IL-1β in humans |
NO20054223A NO20054223L (en) | 2003-02-13 | 2005-09-12 | Antibody molecules having specificity for human IL-1 beta |
US12/569,700 US8465744B2 (en) | 2003-02-13 | 2009-09-29 | Method of treating inflammation by administering human IL-1B antibodies |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001997A1 (en) * | 1993-07-09 | 1995-01-19 | Smithkline Beecham Corporation | RECOMBINANT AND HUMANIZED IL-1β ANTIBODIES FOR TREATMENT OF IL-1 MEDIATED INFLAMMATORY DISORDERS IN MAN |
WO1999015549A2 (en) * | 1997-09-19 | 1999-04-01 | Celltech Therapeutics Limited | Peptide sequences as hinge regions in proteins like immunoglobulin fragments and their use in medicine |
US20030026806A1 (en) * | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
WO2003010282A2 (en) * | 2001-07-26 | 2003-02-06 | Eli Lilly And Company | Interleukin-1 beta antibodies |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB129105A (en) | 1918-07-02 | 1919-07-02 | Alfred George Hubble | Improvements in and connected with Closing Means for Milk Churns, Containers and Vessels. |
EP0569687B1 (en) | 1984-05-18 | 2002-08-21 | New England Medical Center Hospitals, Inc. | Human IL-1 cDNA sequences encoding biologically-active human IL-1 proteins |
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
DK336987D0 (en) | 1987-07-01 | 1987-07-01 | Novo Industri As | immobilization |
US4935343A (en) | 1986-08-08 | 1990-06-19 | Syntex (U.S.A.) Inc. | Monoclonal antibodies for interleukin-1β |
US5474899A (en) * | 1987-05-13 | 1995-12-12 | Cistron Biotechnology, Inc. | Selective immunoassay for IL-1 β |
GB8719042D0 (en) | 1987-08-12 | 1987-09-16 | Parker D | Conjugate compounds |
GB8907617D0 (en) | 1989-04-05 | 1989-05-17 | Celltech Ltd | Drug delivery system |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
GB9112536D0 (en) | 1991-06-11 | 1991-07-31 | Celltech Ltd | Chemical compounds |
GB9120467D0 (en) | 1991-09-26 | 1991-11-06 | Celltech Ltd | Anti-hmfg antibodies and process for their production |
DE69622157T2 (en) | 1995-01-23 | 2003-03-13 | Xenotech Inc | COMPOSITION TO PREVENT OSTEOLYSIS AND METASTASES |
JPH09183799A (en) * | 1995-11-06 | 1997-07-15 | Merck Patent Gmbh | Hominized monoclonal antibody |
US5980898A (en) | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
GB9625640D0 (en) | 1996-12-10 | 1997-01-29 | Celltech Therapeutics Ltd | Biological products |
GB0001448D0 (en) | 2000-01-21 | 2000-03-08 | Novartis Ag | Organic compounds |
GB0013810D0 (en) * | 2000-06-06 | 2000-07-26 | Celltech Chiroscience Ltd | Biological products |
GB0020685D0 (en) | 2000-08-22 | 2000-10-11 | Novartis Ag | Organic compounds |
GB0303337D0 (en) | 2003-02-13 | 2003-03-19 | Celltech R&D Ltd | Biological products |
-
2003
- 2003-02-13 GB GBGB0303337.0A patent/GB0303337D0/en not_active Ceased
-
2004
- 2004-02-06 PT PT04708808T patent/PT1597282E/en unknown
- 2004-02-06 DK DK04708808.3T patent/DK1597282T3/en active
- 2004-02-06 WO PCT/GB2004/000463 patent/WO2004072116A2/en active Application Filing
- 2004-02-06 AU AU2004210776A patent/AU2004210776B2/en not_active Ceased
- 2004-02-06 BR BR0407233-2A patent/BRPI0407233A/en not_active Application Discontinuation
- 2004-02-06 JP JP2006502246A patent/JP4668896B2/en not_active Expired - Fee Related
- 2004-02-06 PL PL378412A patent/PL378412A1/en unknown
- 2004-02-06 ES ES04708808T patent/ES2373953T3/en not_active Expired - Lifetime
- 2004-02-06 SI SI200431797T patent/SI1597282T1/en unknown
- 2004-02-06 MX MXPA05007392A patent/MXPA05007392A/en not_active Application Discontinuation
- 2004-02-06 EP EP10182246A patent/EP2287193A1/en not_active Withdrawn
- 2004-02-06 EP EP04708808A patent/EP1597282B1/en not_active Expired - Lifetime
- 2004-02-06 KR KR1020057013813A patent/KR20050099509A/en not_active Application Discontinuation
- 2004-02-06 CA CA2515474A patent/CA2515474C/en not_active Expired - Fee Related
- 2004-02-06 US US10/544,911 patent/US7608694B2/en not_active Expired - Fee Related
- 2004-02-06 EA EA200501286A patent/EA200501286A1/en unknown
- 2004-02-06 CN CNA2004800033654A patent/CN1745103A/en active Pending
- 2004-02-06 AT AT04708808T patent/ATE525397T1/en active
- 2004-02-09 PE PE2004000142A patent/PE20040947A1/en not_active Application Discontinuation
- 2004-02-12 TW TW093103340A patent/TW200505942A/en unknown
- 2004-02-12 CL CL200400259A patent/CL2004000259A1/en unknown
- 2004-02-12 AR ARP040100431A patent/AR043159A1/en unknown
-
2005
- 2005-09-07 IS IS8013A patent/IS8013A/en unknown
- 2005-09-12 NO NO20054223A patent/NO20054223L/en unknown
- 2005-09-13 EC EC2005006014A patent/ECSP056014A/en unknown
-
2009
- 2009-09-29 US US12/569,700 patent/US8465744B2/en not_active Expired - Fee Related
-
2010
- 2010-06-04 JP JP2010128372A patent/JP2010246553A/en active Pending
-
2011
- 2011-12-21 CY CY20111101274T patent/CY1112507T1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001997A1 (en) * | 1993-07-09 | 1995-01-19 | Smithkline Beecham Corporation | RECOMBINANT AND HUMANIZED IL-1β ANTIBODIES FOR TREATMENT OF IL-1 MEDIATED INFLAMMATORY DISORDERS IN MAN |
WO1999015549A2 (en) * | 1997-09-19 | 1999-04-01 | Celltech Therapeutics Limited | Peptide sequences as hinge regions in proteins like immunoglobulin fragments and their use in medicine |
US20030026806A1 (en) * | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
WO2003010282A2 (en) * | 2001-07-26 | 2003-02-06 | Eli Lilly And Company | Interleukin-1 beta antibodies |
Non-Patent Citations (2)
Title |
---|
CHAPMAN ANDREW P: "PEGylated antibodies and antibody fragments for improved therapy: a review." ADVANCED DRUG DELIVERY REVIEWS. 17 JUN 2002, vol. 54, no. 4, 17 June 2002 (2002-06-17), pages 531-545, XP001199533 ISSN: 0169-409X * |
DAVIES J ET AL: "Affinity improvement of single antibody VH domains: residues in all three hypervariable regions affect antigen binding" 1 September 1996 (1996-09-01), IMMUNOTECHNOLOGY, ELSEVIER SCIENCE PUBLISHERS BV, NL, PAGE(S) 169-179 , XP004070292 ISSN: 1380-2933 the whole document * |
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