WO2017076805A1 - Utilisation d'un inhibiteur de l'il18 pour le traitement d'une lésion rénale aiguë - Google Patents

Utilisation d'un inhibiteur de l'il18 pour le traitement d'une lésion rénale aiguë Download PDF

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Publication number
WO2017076805A1
WO2017076805A1 PCT/EP2016/076228 EP2016076228W WO2017076805A1 WO 2017076805 A1 WO2017076805 A1 WO 2017076805A1 EP 2016076228 W EP2016076228 W EP 2016076228W WO 2017076805 A1 WO2017076805 A1 WO 2017076805A1
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antibody
seq
light chain
cdrs
interleukin
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PCT/EP2016/076228
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Luke Richard DEVEY
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • 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

Definitions

  • This invention relates to a new pharmaceutical use of an inhibitor of interleukin - 18. More specifically this invention relates to the use of an inhibitor of interleukin -18 in the treatment and/or prevention of one or more of acute kidney injury (including Delayed Graft Function), and graft rejection.
  • Human interleukin-18 is a cytokine that is synthesized as a biologically inactive 193 amino acid precursor protein (Ushio et al., J. Immunol. 156:4274, 1996). Cleavage of the precursor protein, for example by caspase-1 liberates the 156 amino acid mature protein (Gu et al., Science 275:206, 1997; Ghayur et al., Nature 386:619, 1997), which exhibits biological activities that include the costimulation of T cell proliferation, the enhancement of NK cell cytotoxicity, the induction of IFN- ⁇ production by T cells and NK cells, and the potentiation of T helper type 1 (Thl) differentiation (Okamura et al., Nature 378:88, 1995; Ushio et al., J.
  • T helper type 1 Thl
  • IL-18 is an efficacious inducer of human monocyte proinflammatory mediators, including IL-8, tumor necrosis factor-a (TNF-a), and prostaglandin E 2 (PGE 2 ) (Ushio, S. et al., J. Immunol. 156:4274- 4279, 1996; Puren, A. J. et al., J. Clin. Invest. 10:711-721, 1997.
  • Ischemic renal injury is the consequence of processes that result directly from cellular hypoxia and from immune amplification of injury.
  • IL-18 is an inflammatory cytokine secreted in response to cellular injury or inflammatory stimulus [Gu Science. 1997 275(5297):206-9.].
  • Transcriptional control of IL-18 is uniquely regulated such that stores are available at rest for immediate release in response to injury, and is dependent on cleavage from pro-IL-18 by caspase-1 [Puren PNAS 1999; 96; 2256-2261, Tone J. Immunol. 1997. 159 6156-63].
  • IL-18 release signals proximally in the pro-inflammatory cascade, inducing synthesis of IFN, TNFa, IL-6, IL-8, and IL-1 amongst other cytokines [Puren PNAS 1999; 96; 2256-2261, Fortin FASEB J. 2009 (1): 194-203].
  • IL-18 has been shown in vitro to be directly cytotoxic to renal tubular epithelial cells [Zhang Am J Physiol Renal Physiol. 2011;301(l):F171-8].
  • IL-18 has been implicated in acute kidney injury.
  • early rises in urinary IL-18 levels in the first few hours after renal insults correlate closely with the subsequent development of AKI both in native [Parikh J Am Soc Nephrol 2011; 22: 1748-1757] and transplanted [Hall J Am Soc Nephrol 21: 189-197, 2010] kidneys, and predict long term dysfunction [Hall Clin J Am Soc Nephrol 7: 1224-1233, 2012. Coca J Am Soc Nephrol 25: 1063-1071, 2014].
  • These findings have been replicated in a large literature, rendering IL-18 a well validated biomarker.
  • emerging data has correlated IL-18 levels measured in organ preservation fluids with post-operative graft dysfunction.
  • DGF Delayed graft function after renal transplantation is a niche manifestation of acute kidney injury (AKI), defined as the failure of a transplanted kidney to function immediately (within 7 days of transplantation). Patients affected by DGF require dialysis pending the onset of renal function, and compared to those without DGF are at increased risk of graft failure at one year [Moers N Engl J Med 2009;360:7-19, Tapiawala JASN 2010; 21: 153-161]. Depending upon known risk factors (principally donor age, cold ischemic time, and whether a cadaveric organ donor has died from brain death (DBD) or circulatory death (DCD)), the risk of DGF is between 25 and 50% [Summers 2013]. Lancet 2013; 381: 727-34
  • IL-18 may contribute to acute rejection, which is also an important cause of allograft destruction.
  • routine biopsies did not demonstrate IL-18 on immunohistochemistry
  • graft biopsies from patients during rejection episodes stain positively for IL-18, with the number of IL18 positive renal tubules correlating with dysfunction [Striz Immunol Lett. 2005 Jun 15;99(l):30-5].
  • circulating IL-18 has been shown to correlate with renal allograft rejection [de Oliveira Nephron 2002;92:622-62, Striz Immunol Lett. 2005 Jun 15;99(l):30-5].
  • IL-18 was originally identified for its role in inducing IFNY [Gu . Science. 1997 275(5297):206-9. ], and is strongly implicated in Thl polarization. Acute cell-mediated rejection has been defined as a CD4+ Thl mediated process [Issa Expert Reviews in Immunology. 2010. 6: 155-9]. Elevated levels of the downstream Thl chemokine CXCL10 (IP-10) have been shown to portend impending rejection episodes when observed in serum [Field Transplant International 27 (2014) 362-370, Zhang Transplantation Proceedings, 46, 1420el425 (2014)] and urine [Rabant J Am Soc Nephrol 26. 2015 2015], while IP-10 inhibition was capable of prolonging graft survival in mismatched rodent transplantation models [Hancock J. Exp. Med. Volume 193, Number 8, April 16, 2001 975-980 2001].
  • Patent application WO2007/137984 discloses humanised anti-IL-18 antibodies and their use in autoimmunity.
  • an inhibitor of IL-18 for use in the treatment and/or prevention of one or more of acute kidney injury and graft rejection.
  • a pharmaceutical composition comprising the compound an inhibitor of IL-18 for use in the treatment and/or prevention of one or more of acute kidney injury and graft rejection.
  • a combination comprising an inhibitor of IL-18 and one or more other therapeutic agents which are suitable for the treatment and/or prevention of one or more of acute kidney injury and graft rejection.
  • a method for treatment and/or prevention of one or more of acute kidney injury and graft rejection in a subject in need thereof which comprises administering to said subject an inhibitor of IL-18.
  • an inhibitor of IL-18 in the manufacture of a medicament for use in the treatment and/or prevention of one or more of acute kidney injury and graft rejection.
  • the "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutic amount means any amount which as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • “Therapy” and “treatment” may include treatment and/or prophylaxis.
  • Acute kidney injury (AKI) previously called acute renal failure (ARF) is an abrupt loss of kidney function that develops within 7 days.
  • kidney ischemia damage to the kidney tissue caused by decreased kidney blood flow (kidney ischemia) from any cause (e.g., low blood pressure), exposure to substances harmful to the kidney, an inflammatory process in the kidney, or an obstruction of the urinary tract that impedes the flow of urine.
  • AKI is diagnosed on the basis of characteristic laboratory findings, such as elevated blood urea nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine.
  • Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue
  • DGF Delayed graft function
  • the term "inhibitor" can be any compound or treatment capable of inhibiting the expression and/or function of IL-18, i.e. any compound or treatment that inhibits transcription of the gene, RNA maturation, RNA translation, post-translational modification of the protein, binding of the protein to a target and the like.
  • inhibiting IL-18 includes inhibiting the expression and/or function of IL-18.
  • An antibody that "inhibits IL-18” includes but is not limited to an IL-18 neutralizing antibody.
  • the inhibitor may be of varied nature and origin including natural origin [e.g. plant, animal, eukaryotic, bacterial, viral] or synthetic [particularly an organic, inorganic, synthetic or semi-synthetic molecule].
  • natural origin e.g. plant, animal, eukaryotic, bacterial, viral
  • synthetic particularly an organic, inorganic, synthetic or semi-synthetic molecule.
  • it can be a nucleic acid, a polypeptide, a protein, a peptide or a chemical compound.
  • Neutralizing refers to an antibody that inhibits IL-18 activity by preventing the binding of human IL-18 to its specific receptor or by inhibiting the signalling of IL-18 through its receptor, should binding occur.
  • a mAb is neutralizing if it is 90% effective, 95% effective and 100% effective in inhibiting IL-18 activity as measured several binding assays known in the art.
  • the inhibitor is a chemical compound, of natural or synthetic origin, particularly an organic or inorganic molecule, capable of modulating the expression or the activity of IL-18.
  • the inhibitor is a small molecule.
  • the inhibitor compound is a polypeptide.
  • the polypeptide can also be an antibody against the IL-18, or a fragment or derivative of such an antibody, for example a Fab fragment, a CDR region, or, more preferably, a single chain antibody (e.g. ScFv).
  • the anti-interleukin-18 antibody comprises a heavy chain and light chain having the following complementarity determining regions (CDRs):
  • CDRL1 SEQ ID NO: 4
  • CDRL2 SEQ ID NO: 5
  • CDRL3 SEQ ID NO: 6
  • the anti-interleukin-18 antibody comprises a heavy chain and light chain having the following CDRs:
  • CDRL1 SEQ ID NO: 4
  • CDRL2 SEQ ID NO: 5
  • CDRL3 SEQ ID NO: 6
  • the antibody is a humanised antibody.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain and light chain having the following complementarity determining regions (CDRs):
  • CDRL1 SEQ ID NO: 4
  • CDRL2 SEQ ID NO: 5
  • CDRL3 SEQ ID NO: 6
  • the humanised anti-interleukin-18 antibody comprises a heavy chain and light chain having the following CDRs:
  • CDRL2 SEQ ID NO: 5
  • CDRL3 SEQ ID NO: 6
  • the humanised anti-interleukin-18 antibody comprises CDRs derived from a donor antibody grafted onto a human acceptor framework which anti-interleukin 18 antibody comprises CDRs having sequence set forth in SEQ ID NO: 1, 2, 3, 4, 5 and 6 wherein the residue at position 71 of the light chain of said anti-interleukin-18 antibody is identical to the residue found in the corresponding position in the donor antibody framework.
  • the humanised anti-interleukin-18 antibody comprises CDRs set forth in SEQ ID NO: 1, 2, 3, 4, 5 and 6 which antibody comprises a tyrosine at position 71 of the light chain.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain having CDRs set forth in SEQ ID NO: 1, 2 and 3 and a light chain having CDRs set forth in SEQ ID NO: 4, 5 and 6 wherein said light chain CDRs are derived from a donor antibody having a tyrosine at position 71 of the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises CDRs from a donor antibody and a tyrosine at position 71 of the light chain of said humanised antibody wherein the donor antibody is 2C10 or a framework variant thereof (i.e. the humanised antibody comprises the same CDRs but a different framework as 2C10, see US patent 6,706,487).
  • the humanised anti-interleukin-18 antibody comprises;
  • human light chain acceptor framework comprises framework regions derived from SEQ ID NO: 16 wherein position 71 of SEQ ID NO: 16 is a tyrosine.
  • the humanised anti-interleukin-18 antibody comprises;
  • the CDRs of the light chain are preferably located at positions within the acceptor framework which correspond to the respective positions of the sequences set forth in SEQ ID NO: 4, 5 and 6 within the sequence set forth in SEQ ID NO: 16.
  • the light chain and/or the heavy chain is preferably non-immunogenic in a human patient.
  • the humanised anti-interleukin-18 antibody comprises;
  • a light chain comprising CDRs having sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a human light chain acceptor framework
  • said light chain acceptor framework of said humanised anti-interleukin-18 antibody comprises framework regions derived from a variant of the sequence set forth in SEQ ID NO: 16 wherein said variant comprises a tyrosine at position 71 and wherein said variant comprises 75% or greater identity to the framework having the sequence set forth in SEQ ID NO: 16.
  • said variant comprises 80% or greater e.g. 81%, 82%,83%,84%, more preferably 85% or greater e.g. 86%,87%,88%,89%, even more preferably 90% or greater e.g. 91%,92%,93%,94%, most preferably 95% or greater e.g. 96%, 97%, 98%, 99% identity to the framework set forth in SEQ ID NO: 16.
  • the humanised anti-interleukin-18 antibody which antibody comprises;
  • CDRs set forth in SEQ ID NO: 1, 2, 3, 4, 5 and 6 derived from a donor antibody which donor antibody comprises a tyrosine at position 71 of the donor antibody light chain;
  • the anti-interleukin 18 antibody comprises a tyrosine at position 71 of the light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • the anti-interleukin-18 antibody comprises a light chain having at position 71 an aromatic amino acid derived from the antibody of part (a).
  • the humanised anti-interleukin-18 antibody which antibody displays a equilibrium constant (KD) of 300pM or less with respect to binding of human IL-18 when measured by surface plasmon resonance (e.g. BiacoreTM, preferably using a BiacoreTM 3000 instrument and conditions as set out in WO2007/137984) at 37°C.
  • KD equilibrium constant
  • the humanised anti-interleukin-18 antibody which antibody comprises CDRs as set forth in SEQ ID NO:l, 2, 3, 4, 5 and 6 and displays a equilibrium constant (KD) of 300pM or less with respect to binding of human IL- 18 when measured by surface plasmon resonance (preferably using a BiacoreTM 3000 instrument and conditions as set out in WO2007/1437984) at 37°C.
  • KD equilibrium constant
  • the equilibrium constant (KD) of the antibody with respect to binding of human IL-18 when measured by surface plasmon resonance (preferably using a BiacoreTM T100 instrument and conditions as set out in WO2007/137984) at 37°C is less than 90pM. More preferably, the equilibrium constant is 70pM or less and still more preferably, 65pM, 60pM, 55pM, or 50pM or less.
  • the humanised anti-interleukin-18 antibody which antibody displays a dissociation constant or off-rate (kd) of 0.0002 1/s or more with respect to binding of human IL-18 when measured by surface plasmon resonance (e.g. BiacoreTM, preferably using a BiacoreTM T100 instrument and conditions as set out in WO2007/137984) at 37°C.
  • kd dissociation constant or off-rate
  • the humanised anti-interleukin-18 antibody which antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody, which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein one or more residue/s of position/s
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein position 71 and optionally one or more (e.g. all) residue/s of position/s 45, 83, 84, 85 of the light chain is identical to the corresponding residue in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27,
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residue at position 71 of the light chain of said anti-interleukin-18 antibody is identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27, 28, 29, 39, 40, 93 of the heavy chain are identical to the corresponding residues in the donor antibody heavy chain;
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residue at position 71 of the light chain is identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27, 28, 29, 36, 39, 40, 71, 89, 91, 93 of the heavy chain are identical to the corresponding residues in the donor antibody heavy chain;
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residue at position 71 of the light chain is identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27, 28, 29, 93 of the heavy chain are identical to the corresponding residues in the donor antibody heavy chain;
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residues at positions 71, 45, 83, 84, 85 of the light chain are identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27, 28, 29, 93, 39, 40 of the heavy chain are identical to the corresponding residues in the donor antibody heavy chain;
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residues at positions 71, 45, 83, 84, 85 of the light chain is identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises;
  • a heavy chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 1, 2 and 3 grafted onto a human heavy chain acceptor framework which heavy chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 15 wherein residues at positions 27, 28, 29, 93, 39, 40, 36, 71, 89, 91 of the heavy chain are identical to the corresponding residues in the donor antibody heavy chain;
  • a light chain comprising CDRs derived from a donor antibody which CDRs have sequences set forth in SEQ ID NO: 4, 5 and 6 grafted onto a light chain acceptor framework which light chain acceptor framework comprises framework regions derived from the sequence set forth in SEQ ID NO: 16 wherein residues at positions 71, 45, 83, 84, 85 of the light chain are identical to the corresponding residues in the donor antibody light chain.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain and a light chain, wherein a ratio between off-rate (kd) of said antibody from binding to human IL-18 at 25°C to off-rate (kd) of said antibody from binding to human IL-18 at 37°C is 1:5 or less, and wherein said antibody comprises CDRs derived from a donor antibody and a human acceptor framework, and wherein a residue at position 71 of the light chain of the human acceptor framework is substituted by the corresponding residue from the donor antibody.
  • the off-rate is preferably measured using a BiacoreTM T100 instrument and conditions as set out in WO2007/137984.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain selected from the group consisting of; SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 12; and a light chain selected from the group consisting of; SEQ ID NO: 9, SEQ ID NO: 13.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain of SEQ ID NO: 7 and a light chain of SEQ ID NO: 9 or a heavy chain of SEQ ID NO: 7 and a light chain of SEQ ID NO: 13.
  • the humanised anti-interleukin- 18 antibody comprises a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 9 or a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 13.
  • humanised anti-interleukin-18 antibody comprises a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 9 or a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.
  • the humanised anti-interleukin-18 antibody comprises a heavy chain of SEQ ID NO: 7 and a light chain of SEQ ID NO: 9, referred to as H1L2 in WO2007/137984.
  • the antibodies detailed above may be prepared as described in WO2007/137984.
  • non-human antibodies in the treatment of human diseases or disorders carries with it the now well established problems of potential immunogenicity, especially upon repeated administration of the antibody. That is, the immune system of the patient may recognise the non-human intact antibody as non-self and mount a neutralising response.
  • various techniques have been developed over the years to overcome these problems and generally involve reducing the composition of non-human amino acid sequences in the intact therapeutic antibody whilst retaining the relative ease in obtaining non-human antibodies from an immunised animal e.g. mouse, rat or rabbit. Broadly two approaches have been used to achieve this. The first are chimaeric antibodies, which generally comprise a non-human (e.g.
  • Chimaeric antibodies are typically produced using recombinant DNA methods.
  • DNA encoding the antibodies e.g. cDNA
  • oligonucleotide probes that are capable of binding specifically to genes encoding the H and L chains of the antibody of the invention, e.g.
  • Hybridoma cells serve as a typical source of such DNA.
  • isolated cDNAs encoding the entire mature variable regions of the light and heavy chains are inserted in-frame into suitable expression vectors which contain, inter alia, appropriate immunoglobulin constant regions, usually of human origin, together with signal sequences, stop codons, promoters, terminators and other elements as needed to obtain expression of the antibody.
  • suitable expression vectors which contain, inter alia, appropriate immunoglobulin constant regions, usually of human origin, together with signal sequences, stop codons, promoters, terminators and other elements as needed to obtain expression of the antibody.
  • Such vectors are then transfected into host cells such as E.Coli, COS cells, CHO cells or myeloma cells that do not otherwise produce immunoglobulin protein to obtain synthesis of the antibody.
  • the DNA may be modified by substituting the coding sequence for human L and H chains for the corresponding non-human (e.g. murine) H and L constant regions see e.g. Morrison; P
  • the second approach involves the generation of humanised antibodies wherein the non-human content of the antibody is reduced by humanizing the variable regions.
  • Two techniques for humanisation have gained popularity.
  • the first is humanisation by CDR grafting.
  • CDRs build loops close to the antibody's N-terminus where they form a surface mounted in a scaffold provided by the framework regions.
  • Antigen-binding specificity of the antibody is mainly defined by the topography and by the chemical characteristics of its CDR surface. These features are in turn determined by the conformation of the individual CDRs, by the relative disposition of the CDRs, and by the nature and disposition of the side chains of the residues comprising the CDRs.
  • a large decrease in immunogenicity can be achieved by grafting only the CDRs of a non-human (e.g.
  • human V regions showing the greatest sequence homology (typically 60% or greater) to the non-human donor antibody maybe chosen from a database in order to provide the human framework (FR).
  • the selection of human FRs can be made either from human consensus or individual human antibodies. Where necessary key residues from the donor antibody are substituted into the human acceptor framework to preserve CDR conformations. Computer modelling of the antibody maybe used to help identify such structurally important residues, see W099/48523.
  • humanisation maybe achieved by a process of "veneering".
  • a statistical analysis of unique human and murine immunoglobulin heavy and light chain variable regions revealed that the precise patterns of exposed residues are different in human and murine antibodies, and most individual surface positions have a strong preference for a small number of different residues (see Padlan E.A. et al; (1991) Mol.Immunol.28, 489-498 and Pedersen J.T. et al (1994) J.Mol.Biol. 235; 959-973). Therefore it is possible to reduce the immunogenicity of a non-human Fv by replacing exposed residues in its framework regions that differ from those usually found in human antibodies.
  • Such humanised antibodies preferably comprise a human constant region of an IgG isotype, such as IgGl or IgG4.
  • the humanised variable regions above may be fused with a non-human constant region ("reverse chimera”) such as non-human primate, rat, murine or rabbit.
  • reverse chimera such as non-human primate, rat, murine or rabbit.
  • acceptor frameworks set forth in SEQ ID NO: 15 and 16 constitute immunoglobulin amino acids encoded by a VH and Vkappa gene respectively. As such they comprise both the framework regions and the CDRs of the acceptor antibody. It is well within the capacity of the skilled person to substitute the acceptor antibody CDRs with the donor CDRs set forth in SEQ ID NO: 1, 2, 3, 4, 5 and 6 and to associate the resulting sequences with suitable framework 4 sequences such as those set forth in SEQ ID NO: 17 and SEQ ID NO: 18, so as to produce a complete immunoglobulin variable region such as set forth in SEQ ID NO: 8 and SEQ ID NO: 10.
  • FcyR Fc receptors
  • ADCC antibody-dependent cellular cytotoxicity
  • phagocytosis phagocytosis
  • half- life/clearance of the antibody Various modifications to the Fc region of antibodies of the invention may be carried out depending on the desired effector property. For example, specific mutations in the Fc region to render an otherwise lytic antibody, non-lytic is detailed in EP 0 629 240 Bl and EP 0 307 434 B2 or one may incorporate a salvage receptor binding epitope into the antibody to increase serum half-life, see US 5,739,277.
  • FcyR There are five currently recognised human Fey receptors, FcyR (I), FcyRIIa, FcyRIIb, FcyRIIIa and neonatal FcRn. Shields et al, (2001) J.Biol.Chem 276, 6591-6604 demonstrated that a common set of IgGl residues is involved in binding all FcyRs, while FcyRII and FcyRIII utilize distinct sites outside of this common set.
  • One group of IgGl residues reduced binding to all FcyRs when altered to alanine: Pro-238, Asp-265, Asp-270, Asn-297 and Pro- 239. All are in the IgG CH2 domain and clustered near the hinge joining CHI and CH2.
  • FcyRI utilizes only the common set of IgGl residues for binding
  • FcyRII and FcyRIII interact with distinct residues in addition to the common set.
  • Alteration of some residues reduced binding only to FcyRII (e.g. Arg-292) or FcyRIII (e.g. Glu-293).
  • Some variants showed improved binding to FcyRII or FcyRIII but did not affect binding to the other receptor (e.g. Ser-267Ala improved binding to FcyRII but binding to FcyRIII was unaffected).
  • Other variants exhibited improved binding to FcyRII or FcyRIII with reduction in binding to the other receptor (e.g.
  • glycosylation variants of the antibodies for use in the invention include glycosylation variants of the antibodies for use in the invention. Glycosylation of antibodies at conserved positions in their constant regions is known to have a profound effect on antibody function, particularly effector functioning such as those described above, see for example, Boyd et al (1996), Mol. Immunol. 32, 1311-1318. Glycosylation variants of the therapeutic antibodies or antigen binding fragments thereof of the present invention wherein one or more carbohydrate moiety is added, substituted, deleted or modified are contemplated. Introduction of an asparagine- X-serine or asparagine-X-threonine motif creates a potential site for enzymatic attachment of carbohydrate moieties and may therefore be used to manipulate the glycosylation of an antibody.
  • the invention concerns a plurality of therapeutic (typically monoclonal) antibodies (which maybe of the IgG isotype, e.g. IgGl) as described herein comprising a defined number (e.g. 7 or less, for example 5 or less such as two or a single) glycoform(s) of said antibodies or antigen binding fragments thereof.
  • a defined number e.g. 7 or less, for example 5 or less such as two or a single
  • Further embodiments of the invention include therapeutic antibodies for use in the invention or antigen binding fragments thereof coupled to a non-proteinaeous polymer such as polyethylene glycol (PEG), polypropylene glycol or polyoxyalkylene.
  • PEG polyethylene glycol
  • PEG polypropylene glycol
  • polyoxyalkylene polyethylene glycol
  • Conjugation of proteins to PEG is an established technique for increasing half-life of proteins, as well as reducing antigenicity and immunogenicity of proteins.
  • the use of PEGylation with different molecular weights and styles has been investigated with intact antibodies as well as Fab' fragments, see Koumenis I.L. et al (2000) IntJ.Pharmaceut. 198:83-95.
  • An inhibitor of IL-18 may be prepared according to procedures described in patent application WO2007/137984.
  • the IL-18 inhibitor may be administered as the raw ingredient, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions comprising an inhibitor of IL-18 and one or more pharmaceutically acceptable carriers, diluents, or excipients for use in treating acute kidney injury and graft rejection.
  • the carrier(s), diluents(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered once or more than once a day.
  • Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions for use in the treatment of acute kidney injury may be incorporated into pharmaceutical compositions for use in the treatment of acute kidney injury.
  • compositions further comprise a pharmaceutically acceptable (i.e. inert) carrier as known and called for by acceptable pharmaceutical practice, see e.g. Remingtons Pharmaceutical Sciences, 16th ed, (1980), Mack Publishing Co.
  • pharmaceutically acceptable carriers include sterilised carrier such as saline, Ringers solution or dextrose solution, buffered with suitable buffers to a pH within a range of 5 to 8.
  • compositions comprise between lmg to lOOOmg of therapeutic antibodies of the invention in unit dosage form, optionally together with instructions for use.
  • Pharmaceutical compositions of the invention may be lyophilised (freeze dried) for reconstitution prior to administration according to methods well known or apparent to those skilled in the art.
  • a chelator of copper such as citrate (e.g. sodium citrate) or EDTA or histidine may be added to the pharmaceutical composition to reduce the degree of copper-mediated degradation of antibodies of this isotype, see EP 0 612 251.
  • Effective doses and treatment regimes for administering the antibody of the invention are generally determined empirically and are dependent on factors such as the age, weight and health status of the patient and disease or disorder to be treated. Such factors are within the purview of the attending physician. Guidance in selecting appropriate doses may be found in e.g. Smith et a/ (1977) Antibodies in human diagnosis and therapy, Raven Press, New York but will in general be between lmg and lOOOmg.
  • the agent may be administered in a daily dose. This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. A suggested dose is up to lOm/kg.
  • the agent may be employed alone or in combination with other therapeutic agents.
  • agent for use in the present invention may be used in combination with or include one or more other therapeutic agents and may be administered either sequentially or simultaneously by any convenient route in separate or combined pharmaceutical compositions.
  • the inhibitor of IL-18 may be employed alone or in combination with other therapeutic agents in the treatment and/or prevention of and/or prevention on one or more of acute kidney injury and graft rejection.
  • the present invention provides a combination comprising an inhibitor of IL-18 and one or more therapeutic agents which are suitable for the treatment and/or prevention on one or more of acute kidney injury and graft rejection.
  • the inhibitor of IL-18 is combined with the standard of care, for example the standard immunosuppressant regimen mayl comprise of basiliximab, mycophenolate mofetil (MMF) or azathioprine, tacrolimus and corticosteroids. This immunosuppressant regimen may be revised based on the clinical judgment of the investigator including titration of tacrolimus levels.
  • agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order by any convenient route in separate or combined pharmaceutical compositions.
  • the amounts of the IL-18 inhibitor and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of the present invention and further therapeutic agent(s) may be employed in combination by administration simultaneously in a unitary pharmaceutical composition including both compounds.
  • the combination may be administered separately in separate pharmaceutical compositions, each including one of the compounds in a sequential manner wherein, for example, the compound of the invention is administered first and the other second and visa versa.
  • Such sequential administration may be close in time (e.g. simultaneously) or remote in time.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally.
  • combination kit or “kit of parts” as used herein is meant the pharmaceutical composition or compositions that are used to administer the combination according to the invention.
  • the combination kit can contain both compounds in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain each compound in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages.
  • the combination kit can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.
  • such sequential administration may be close in time or remote in time.
  • administration of the other agent several minutes to several dozen minutes after the administration of the first agent, and administration of the other agent several hours to several days after the administration of the first agent are included, wherein the lapse of time is not limited.
  • one agent may be administered once a day, and the other agent may be administered 2 or 3 times a day, or one agent may be administered once a week, and the other agent may be administered once a day and the like.
  • the present invention also provides for a method for treatment and/or prevention on one or more of acute kidney injury and graft rejection.
  • a subject in need thereof which comprises administering a therapeutically effective amount of an IL-18 inhibitor.
  • the subject in need thereof is a mammal, particularly a human.
  • the acute kidney injury is Delayed Graft Function.
  • the human is experiencing is graft rejection, including delayed graft rejection.
  • IL-18 inhibitor antibodies may be prepared as described in WO2007/137984, in particular the antibody designated H1L2 which for the avoidance of doubt have the following sequences.
  • Patients will be first-time, single organ recipients of kidneys from donation after cardiac death (DCD) donors.
  • Primary endpoint will be frequency of DGF defined by a requirement for dialysis (except as needed for hyperkalaemia) within the first 7 days post transplantation.
  • Secondary clinical outcome measures will be area under the curve serum creatinine during the first seven days, and 30 day (final) creatinine. Close monitoring will be conducted for evidence of excess immunosuppression.
  • PK assay by MS is available to characterize the PK profile in plasma.
  • Levels may be measured in post-reperfusion renal biopsy samples (see below) to ensure therapeutic PK within the target organ.
  • IP-10 (CXCL10) will be used as the main PD readout as in previous T2DM studies.
  • NK CD3-, CD56+, CD69+, CDllb+
  • Helper T cells CD3+ CD4+
  • Cytotoxic T Cells CD3+CD8+CD69+
  • Kidney transport medium will be analysed for IL-18, with results to be compared with clinical outcome of transplantation, and response to the antibody therapy.

Abstract

La présente invention concerne l'utilisation d'un inhibiteur de l'IL-18 dans le traitement d'une lésion rénale aiguë.
PCT/EP2016/076228 2015-11-02 2016-10-31 Utilisation d'un inhibiteur de l'il18 pour le traitement d'une lésion rénale aiguë WO2017076805A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007137984A2 (fr) * 2006-05-25 2007-12-06 Glaxo Group Limited Immunoglobulines
WO2014037899A2 (fr) * 2012-09-07 2014-03-13 Novartis Ag Molécules de liaison à l'il-18

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007137984A2 (fr) * 2006-05-25 2007-12-06 Glaxo Group Limited Immunoglobulines
WO2014037899A2 (fr) * 2012-09-07 2014-03-13 Novartis Ag Molécules de liaison à l'il-18

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LESLIE ET AL: "The Role of Interleukin-18 in Renal Injury", JOURNAL OF SURGICAL RESEARCH, ACADEMIC PRESS INC., SAN DIEGO, CA, US, vol. 145, no. 1, 12 February 2008 (2008-02-12), pages 170 - 175, XP022478057, ISSN: 0022-4804, DOI: 10.1016/J.JSS.2007.03.037 *
Z. HE ET AL: "Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury", AJP: RENAL PHYSIOLOGY, vol. 295, no. 5, 20 August 2008 (2008-08-20), US, pages F1414 - F1421, XP055337145, ISSN: 0363-6127, DOI: 10.1152/ajprenal.90288.2008 *

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