Anti-human VISTA antibody and its use

Abstract

The present invention provides anti-VISTA antibody drug conjugates that can be used for the targeted delivery of anti-inflammatory agents, such as steroids, to immune cells, such as myeloid cells. The present invention also provides methods of using anti-VISTA antibody drug conjugates in the treatment of inflammatory and / or autoimmune conditions and / or to mitigate the toxicity of anti-inflammatory agents, such as steroids.

Claims

[Claim 1] An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment containing an antigen-binding region that specifically binds to the human V-domain Ig suppressor (human VISTA) for T cell activation, (i) The anti-human VISTA antibody or its antigen-binding fragment preferentially binds to VISTA-expressing cells at physiological pH (approximately 7.5), and (ii) The anti-human VISTA antibody or its antigen-binding fragment has a pK of up to 70 hours in human VISTA knock-in rodents, and further, (A) The anti-VISTA antibody or its antigen-binding fragment in the ADC (i) V of sequence numbers 200, 201 and 202 H CDR and V of Sequence IDs 203, 204 and 205 L Items including CD-Rs, (ii) V of sequence numbers 740, 741 and 742 H CDR and V of Sequence IDs 743, 744 and 745 L Items including CD-Rs, (iii) V of sequence numbers 400, 401 and 402 H CDR and V of Sequence IDs 403, 404 and 405 L Items including CD-Rs, (iv) V of sequence numbers 770, 771 and 772 H CDR and V of Sequence IDs 773, 774 and 775 L Items including CD-Rs, or (v) Vs with SEQ ID NO: 500, 501 and 502 H CDRs and Vs with SEQ ID NO: 503, 504 and 505 L those containing CDRs And, (B) The anti-inflammatory agent in the ADC includes dexamethasone, prednisolone, budesonide, or a functional derivative thereof. (C) ADC comprises at least two of the anti-inflammatory agents, (D) The anti-human VISTA antibody or its antigen-binding fragment in the ADC is directly or indirectly covalently bound to the anti-inflammatory agent via a cleavable peptide linker, and (E) Anti-inflammatory agents in ADCs induce anti-inflammatory activity upon internalization into VISTA-expressing immune cells. Antibody-drug conjugate (ADC). [Claim 2] Anti-VISTA antibodies or their antigen binding, (i) V of sequence number 206 H Polypeptide and V of SEQ ID NO: 208 L containing polypeptides, (ii) V of sequence number 746 H Polypeptides and V of SEQ ID NO: 748 L containing polypeptides, (iii) V of sequence number 406 H Polypeptide and V of SEQ ID NO: 408 L containing polypeptides, (iv) V of sequence number 776 H Polypeptides and V of SEQ ID NO: 778 L containing polypeptides, or (v) V of sequence number 506 H Polypeptides and the V of SEQ ID NO: 508 L containing polypeptides The ADC according to claim 1. [Claim 3] The ADC according to claim 1 or 2, wherein the PD of the ADC is at least 14 days in human VISTA knock-in rodents and / or humans or non-human primates, optionally cynomolgus monkeys. [Claim 4] The anti-human VISTA antibody in the ADC contains an Fc region with impaired FcR binding, optionally a human IgG1, IgG2, IgG3, or IgG4 Fc region with impaired FcR binding, or a human IgG1 Fc region with impaired FcR binding, or the ADC contains a human IgG2κ backbone with V234A / G237A / P238S / H268A / V309L / A330S / P331S silencing mutations in the Fc region, or the ADC contains an L234A / L235A silencing mutation in the Fc region, optionally complement (C1 Q The ADC according to any one of claims 1 to 3, comprising a human IgG1 / κ backbone having a mutation that impairs binding, or the ADC comprising a human IgG1 / κ backbone having the L234A / L235A silencing mutation and the E269R and E233A mutations in the Fc region. [Claim 5] The ADC according to any one of claims 1 to 3, wherein the ADC comprises a human IgG2 Fc region in which endogenous FcR binding is not impaired, and optionally a natural (unmodified) human IgG2 Fc region. [Claim 6] The ADC according to any one of claims 1 to 5, wherein the anti-VISTA antibody or antigen-binding fragment in the ADC has a KD of 0.02 to 0.64 nM as measured by surface plasmon resonance (SPR) at 24°C or 37°C. [Claim 7] The ADC according to any one of claims 1 to 6, wherein the ADC comprises a positively, negatively, or neutrally charged cleavable peptide linker, and optionally an esterase-cleavable linker. [Claim 8] The ADC according to any one of claims 1 to 7, wherein the anti-inflammatory agent-to-antibody ratio of the ADC is in the range of 2 to 8:1, 4 to 8:1, or 6 to 8:1, or the anti-inflammatory agent-to-antibody ratio of the drug antibody is 8:

1. [Claim 9] The ADC according to any one of claims 1 to 8, wherein the ADC is internalized in one or more of monocytes, myeloid cells, T cells, Tregs, macrophages, and neutrophils, and the ADC is not internalized in B cells to a degree that can be detected. [Claim 10] The ADC according to any one of claims 1 to 9, wherein the ADC comprises an esterase-sensitive linker and dexamethasone or a functional derivative as an anti-inflammatory agent. [Claim 11] The ADC according to any one of claims 1 to 10, wherein the anti-inflammatory agent is complexed with an anti-VISTA antibody or antigen-binding fragment via interchain disulfides. [Claim 12] A pharmaceutical composition comprising at least one therapeutically effective amount of antibody-drug conjugate (ADC) according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier, which is optionally administerable via an injection route, optionally intravenous, intramuscular, subarachnoid or subcutaneous injection route, or is subcutaneously administerable. [Claim 13] A device or kit comprising the pharmaceutical composition described in claim 12, which provides subcutaneous administration and optionally delivers a fixed dose of an anti-inflammatory agent to a patient, selected from the group consisting of a syringe, an injection device, an infusion pump, an injection pen, a needleless device, an autoinjector and a subcutaneous patch delivery system, further comprising instructions for informing the patient of a method of administering the ADC composition contained in the device and a drug regimen. [Claim 14] An antibody-drug conjugate (ADC) or composition according to any one of claims 1 to 12, wherein the composition may optionally be in the apparatus according to claim 13, and is used for the treatment and / or prevention of inflammation in a subject requiring treatment and / or prevention. [Claim 15] (i) Used in human subjects to treat allergies, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis, or to treat or prevent inflammatory, autoimmune, or allergic side effects associated with any of the aforementioned conditions. (ii) Used to treat a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, childhood Crohn's disease, ulcerative colitis, psoriasis vulgaris, hidradenitis suppurativa, uveitis, Behçet's disease, spondyloarthropathy, or psoriasis. (iii) Those who will be treated: (a) Conditions that can be effectively treated primarily with high-dose steroids, optionally, polymyalgia rheumatica and / or giant cell arteritis (the patient has been or is being treated with high-dose steroids optionally), (b) Conditions with complications that limit the use of steroids, optionally: diabetes mellitus, non-alcoholic steatohepatitis (NASH), morbid obesity, avascular necrosis / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis. (c) Conditions for which safe long-term therapeutic agents are available but several months of induction with high-dose steroids are desirable, optional for AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, and gout patients for whom several months of induction with high-dose steroids is therapeutically justified. (d) Optional dermatological conditions requiring short / long-term treatment for which there is no effective alternative to treatment or duration and / or steroid administration; optional Stevens-Johnson syndrome, other severe rash conditions, conditions including widespread contact dermatitis, PG, LCV, other severe immune-related dermatological conditions, (e) Conditions treated with high-dose corticosteroids for erythema / recurrence, optional: COPD, asthma, lupus, gout, pseudogout, (f) Immune-related neurological disorders such as small fibrous neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis. (g) Optionally, hematological / oncological indications for which high doses of steroids are therapeutically justified or may be effective, (h) Ophthalmic conditions, optional, such as uveitis, iritis, scleritis, etc. (i) Conditions associated with persistent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally iatrogenic Addison's disease crisis, (j) Conditions that are often treated with long-term low-dose steroids, and optionally with lupus, RA, psA, vasculitis, etc., (k) Special classes of patients, e.g., pregnant / lactating women, pediatric patients, and optionally patients with growth disorders or cataracts. Includes one or more of the following: (iv) The patient being treated has been further treated with another active drug, (v) The patient being treated has been further treated with an immunomodulatory antibody or fusion protein selected from an immunosuppressive antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, or VISTA, and / or an agonist antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS, (vi) Use is for the treatment or prevention of acute or chronic inflammation and associated autoimmune and inflammatory conditions, and the condition is, optionally, acquired aplastic anemia+, acquired hemophilia+, acute disseminated encephalomyelitis (ADEM)+, acute hemorrhagic leukoencephalitis (AHLE) / Hearst disease+, primary agammaglobulinemia+, alopecia areata+, ankylosing spondylitis (AS), anti-NMDA receptor encephalitis+, antiphospholipid syndrome (APS)+, arteriosclerosis, autism spectrum disorder (ASD), autoimmune Addison's disease (AAD)+, autoimmune Autoimmune autonomic dysfunction / autoimmune autonomic ganglion disorder (AAG), autoimmune encephalitis+, autoimmune gastritis, autoimmune hemolytic anemia (AIHA)+, autoimmune hepatitis (AIH)+, autoimmune hyperlipidemia, autoimmune hypophysitis / lymphocytic hypophysitis+, autoimmune inner ear disease (AIED)+, autoimmune lymphoproliferative syndrome (ALPS)+, autoimmune myocarditis, autoimmune oophoritis+, autoimmune orchitis+, autoimmune pancreatitis (AIP) / immunoglobulin G4-related disease (IgG4-RD)+, autoimmune polyglandular syndrome type I, type II, and Type III+, autoimmune progesterone dermatitis+, autoimmune sudden sensorineural hearing loss (SNHL) achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axon and Neuropathy (AMAN), Balo's disease, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), scarring pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, type 1 diabetes, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica). Disc Lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrous alveolitis, giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or bullous pemphigoid (PG), hidradenitis suppurativa (HS) (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis, immunodiarrhea Lepopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes mellitus), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus (including nephritis and cutaneous infections), chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mohren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin oligodilation Ndrocytic glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, ocular clonus-myoclonus ataxia (OMS), relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), hemifacial atrophy, ciliary body squamous cellulitis (peripheral uveitis), personality-Turner syndrome, pemphigus, peripheral neuropathy, perivenosis encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, type I, type II, type III polyglandular syndromes, Polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm / testicular autoimmunity, generalized rigidus syndrome (SPS), subacute bacterial endocarditis (SBE), Suzac syndrome,This includes sympathetic ophthalmitis (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, or Vogt-Koyanagi-Harada syndrome. (vii) Use is for the treatment or prevention of acute or chronic inflammation and associated autoimmune and inflammatory conditions, the conditions of which include, optionally, severe asthma, giant cell arteritis, ANKA vasculitis and IBD (colitis and Crohn's disease), (viii) Use is for the treatment or prevention of a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, childhood Crohn's disease, ulcerative colitis, psoriasis vulgaris, hidradenitis suppurativa, uveitis, Behçet's disease, spondyloarthropathy, or psoriasis, or (ix) Any combination of (i) to (viii), The antibody-drug conjugate (ADC) or composition according to claim 14 for use. [Claim 16] An in vitro method for internalizing a steroid into one or more of T cells, CD4 T cells, CD8 T cells, Treg cells, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, and macrophages by contacting the ADC described in any one of claims 1 to 11 with the cells ex vivo. [Claim 17] An ADC or composition according to claims 1 to 12 for use in treating an inflammatory or autoimmune condition involving one or more of the following: T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, and macrophages.

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