anti-CD2 antibody

Abstract

The present invention provides pharmaceutical compositions for treating or preventing immune-related disorders or diseases. [Solution] A pharmaceutical composition for treating or preventing an immune-related disorder or disease in a subject requiring it, comprising an anti-CD2 antibody or its antigen-binding fragment, wherein the subject is administered a CTLA-4 costimulatory blocker before, simultaneously with, or after administration of the pharmaceutical composition to the subject.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 182,095, filed Apr. 30, 2021, U.S. Provisional Application No. 63 / 135,381, filed Jan. 8, 2021, and U.S. Provisional Application No. 63 / 042,844, filed Jun. 23, 2020, and the entire contents of each of them are incorporated herein by reference.

[0002] Reference to electronically submitted sequence listing In this application, the sequence listing submitted together with this application is incorporated by reference as a text file named "Sequence_Listing_1 4526 - 005 - 228.TXT" created on Jun. 15, 2021 and having a size of 33,862 bytes.

[0003] 1. Technical Field This application relates to improved anti - CD2 antibodies and their use in the treatment and / or prevention of chronic or acute disorders of the immune system. Their use in the induction and maintenance of immune tolerance is also disclosed. Also disclosed herein are methods for treating or preventing immune - related disorders or diseases in a subject by administering an anti - CD2 antibody or an antigen - binding fragment thereof and a CT LA - 4 costimulation blocker. Compositions for use in these methods and kits are also disclosed.

[0004]

Background Art

[0004] 2. Background Art Patients with disorders of the immune system (such as chronic inflammatory disorders of the immune system) need to receive long - term treatment to manage their condition. Therefore, potential treatment regimens ​In this field, the goal is to treat the symptoms of the disease and maintain the patient's quality of life while minimizing organ damage and other adverse effects. Therefore, it is necessary to prioritize minimizing the use of immunosuppressants that cause this condition. There is a significant need for treatments that minimize the harmful side effects of standard immunosuppressive therapy. Furthermore, because the long-term outcomes of organ transplantation are still not satisfactory, Improved treatment for immune-related disorders such as immune diseases and organ transplant-associated immune disorders. Methods and compositions are needed. Chronic rejection of donor grafts and long-term immunity. Health problems associated with the use of inhibitors remain a serious complication of this treatment. It can be administered chronically to patients for several months or years without the harmful side effects of immunosuppressive therapy. What is most needed is a treatment method that can alleviate the signs and symptoms of the disorder. This reduces the likelihood of recurrence of the disability and prevents organ or tissue transplant rejection. In subjects who are and / or who are likely to develop an immune disorder, the occurrence of an immune disorder Methods and compositions that can treat acute symptoms of immune-related diseases by preventing them are also needed. Yes, they are.

[0005] Ciprizumab is a humanized IgG1κ monoclonal antibody against human CD2 glycoprotein. It is a receptor that is expressed in virtually all mature human T cells and the majority of thymocytes. (Bierer BE, Burakoff SJ., Immunol Rev.1989 ;111:267-294). CD2 interacts with ligand LFA-3 (CD58). This promotes the adhesion of T cells to antigen-presenting cells (van der Merwe P A, Barclay AN, Mason DW, et al.Biochemistry .1994;33(33):10149-10160). CD2 binds to LFA-3. This also brings about a cascade of intracellular signals necessary for T cell activation, and this molecule It provides important co-stimulatory functions (Bockenstedt LK. et al., J Immunol.1988;141(6):1904-1911).

[0006] Ciprizumab is used to induce tolerance in hematopoietic stem cell transplantation and compound renal bone marrow transplantation (CKBMT). It is used in the conditioning regimen. Ciprizumab is used in the T cells throughout the body. It depletes the cell line while simultaneously enhancing regulatory T cells (Tregs) in the early post-transplant period. (Malignant tumor) Recipients of hematopoietic stem cell transplantation to treat (Shaffer J. et al., E xp Hematol.2007;35(7):1140-1152) and CKBMTre Scipient (Andreola G. et al., Am J Transplant.) In 2011;11(6):1236-1247), the expression of regulatory T cells (Tregs) Remarkable early potentiation was observed during the T cell rearrangement stage.

[0007] As monoclonal antibodies become essential in the treatment of various types of diseases, The manipulation of therapeutic antibodies involves designing and producing antibodies optimized for specific purposes. , they are becoming more sophisticated (Kellner et al., Transfus Me d Hemother. 2017 Sep;44(5):327-336). Modification of Fc Examples of such operations include Fc such as antibody-dependent cell-mediated cytotoxicity (ADCC). While mediated effector functions are an important element in some treatment regimens, in other regimens... This is an obstacle. Modifications that silence Fc signaling are further compounded by ADCC. It may be beneficial for patients who are likely to develop the disease. For patients who require long-term immunosuppression. Therefore, antibodies that have been engineered to exhibit immunomodulatory activity without possessing ADCC activity are beneficial. .

[0008] This disclosure also relates to anti-C for the treatment or prevention of immune-related diseases or disorders in the subject. This document also describes combination therapy with two antibodies or their antigen fragments and CTLA-4 costimulatory blockers. CLTA4 inhibits the immune response in two main ways, namely, CLTA4 inhibits B7 It competes with CD28 for ligands, thereby blocking co-stimulation and also activating T cells. Negative signaling is performed to inhibit sexualization (Krummel and Alliso) n,1995,J Exp Med 182:459-465;Walunas et al. al., 1994, Immunity 1:405-413). Extracellular CTLA-4 It is a fusion protein mainly composed of the Fc region of fused immunoglobulin IgG1. Abatacept binds to CD80 and CD86 molecules, and is expected to activate T cells. It prevents infection. Beratacept is a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4. It is a fusion protein composed of the Fc fragment of robulin, and two amino acids are abatasep It is different from Abatacept. Like Abatacept, Beratacept targets CD80 antigen and CD86 antigen. It is specific and acts as a negative regulator of peripheral T cell function. This disclosure relates to combination therapy (anti A C2 antibody or its antigen fragment and a CTLA-4 costimulatory blocker may be an anti-C2 antibody or The antigen fragment, or the CTLA-4 costimulatory blocker, is administered to only one of them, not both. It is provided in such a way that it exhibits a synergistic effect compared to the case where it is provided. [Overview of the project]

[0009] 3. Outline of the Invention Whenever “anti-CD2 antibody” is discussed herein, the same disclosure is “CD2-bound.” It is also related to molecules, and vice versa. Provided herein are recombinant anti-CD cells. Two antibodies are present, and here the antibodies are IgG antibodies, and the immunomodulatory activity of the antibodies is maintained. On the other hand, the ability of antibodies to mediate antibody-dependent cell-mediated cytotoxicity is reduced compared to ciprizumab. or is excluded. Also provided herein are recombinant anti-CD2 antibodies, Here, the antibody is an IgG antibody, and at least one consensus Ng of the constant region of the heavy chain The lycosylation site is not glycosylated. In one embodiment, at least one of the antibodies One consensus sequence has been mutated to prevent further glycosylation. Provided herein is a recombinant anti-CD2 antibody, where the Fc region is defined as the antibody being F It has been mutated to lack the ability to bind to the c receptor and C1q.

[0010] The “anti-CD2 antibody” or “CD2-binding molecule” disclosed herein may also be an additional component. This may include an extended anti-CD2 variant that is added to the Fc region. These components include While not limited to these, examples include the scFv, CH2 domain, and CH3 domain. can.

[0011] Furthermore, this specification provides a recombinant anti-CD2 antibody, where the antibody is Ig It is a G antibody, and at least one consensus N-linked glycosylation site in the constant region of the heavy chain The position holds one of the following oligosaccharides: [ka] The symbols are as follows: White triangle: Fucose; White square: N-acetylglucosamine; Gray Colored circles: mannose; white circles: galactose.

[0012] Furthermore, this specification provides a recombinant anti-CD2 antibody, where the antibody is a milk antibody. These are IgG antibodies expressed in animal cells, and the antibodies are treated with endoglycosidase. In one embodiment, mammalian cells are NS0 mouse myeloma cells, PER.C6( (Registered trademark) Human cells, or Chinese hamster ovary (CHO) cells. In the application form, the endoglycosidase is EndoS2. In one embodiment, human C The amino acid residues N18, K55, and T59 of D2 determine the parent of antibodies against human CD2. The harmonious nature is determined.

[0013] In one embodiment, the immunomodulatory activity of the antibody is maintained, while antibody-dependent cell injury is mediated. The ability of the antibodies involved is reduced or eliminated. In a further embodiment, immunomodulatory activity Sexual activity may include induction of CD4+ / CD25+ T cells. In further embodiments, immunomodulation may occur. The activity may include increased FoxP3 expression. In further embodiments, the immunomodulatory activity is C This may include suppression of D69+ NK cells. In one embodiment, the antibody is IgG1, IgG2, Or IgG4. In further embodiments, the antibody is humanized. Yet another In this embodiment, the antibody is fully human.

[0014] In one embodiment, the antibody has a heavy chain variable region CDR1 of SEQ ID NO: 3 and a heavy chain variable region of SEQ ID NO: 4. Variable region CDR2, heavy chain variable region CDR3 of SEQ ID NO: 5, light chain variable region CDR of SEQ ID NO: 6 1. Includes light chain variable region CDR2 of SEQ ID NO: 7 and light chain variable region CDR3 of SEQ ID NO: 8 In further embodiments, the antibody Fc region has a point mutation that results in Fc silencing. It has. In a further embodiment, the antibody is IgG1. In a further embodiment, the antibody In a further embodiment, the antibody is IgG2. In a further embodiment, the antibody is IgG4. Further embodiment In this state, the antibody has a native constant region that is different from cyprizumab. Morphologically, the antibody has a native constant region different from cyprizumab, and Fc silensin It has a point mutation within the Fc region that causes the malformation.

[0015] In one embodiment, the heavy chain variable region of the antibody is the amino acid sequence of SEQ ID NO: 1, or sequence number The amino acid sequence of No. 1 and at least 80%, 85%, 90%, 95%, 98%, or 99% Contains % identical amino acid sequences; the light chain variable region is the amino acid sequence of SEQ ID NO: 2, or The amino acid sequence of SEQ ID NO: 2 is at least 80%, 85%, 90%, 95%, 98%, and also It contains amino acid sequences that are 99% identical.

[0016] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The sequence of the heavy chain constant region of the antigen-binding fragment is sequence number 09, 10, 11, 12, or 1 3 and 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 They are identical by %, 98%, 99%, or 100%. In some embodiments, C as described herein The sequence of the light chain constant region of a D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is , with sequence numbers 14 or 15 and 80%, 85%, 90%, 91%, 92%, 93%, 94% They are 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0017] In yet another embodiment, the heavy chain of the antibody is the DNA sequence of SEQ ID NO: 16, or SEQ ID NO: 16 DNA sequences and at least 80%, 85%, 90%, 95%, 98%, or 99% The light chain contains the same DNA sequence as sequence number 17, or sequence number 17. The DNA sequence is at least 80%, 85%, 90%, 95%, 98%, or 99% identical to that of [the specified DNA sequence]. It contains the following DNA sequence.

[0018] Provided herein is a pharmaceutical product comprising the antibody described in any one of the prior claims. It is a pharmaceutical formulation. In one embodiment, the pharmaceutical formulation is suitable for long-term administration. Also, in patients Methods for treating chronic disorders of the immune system are also provided herein, and these methods are described herein. This includes administering antibodies to the patient for at least one month. months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months , or 12 months, or at least 1, 2, 3, 4, 5, 6, 7, 8 years Year, Year 9, Year 10, Year 11, Year 12, Year 13, Year 14, Year 15, Year 16, Year 17, Year 18 They have been receiving treatment for 19 years, or at least 20 years.

[0019] This specification provides a method for maintaining immune tolerance to transplantation in transplant recipients. This method involves administering the antibody described herein to a transplant recipient. In this embodiment, the antibody is used for at least 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months. 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 1 3 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, or at least 20 years It is administered to the transplant recipient for a specified period. In further embodiments, it is used to treat acute or chronic immune system reactions. Disorders include, but are not limited to, graft-versus-host disease (GVHD), rheumatoid arthritis, Ankylosing spondylitis, type 1 diabetes, psoriasis, ulcerative colitis, inflammatory bowel disease (Crohn's disease), ceria Brooks disease, Sjögren's disease, lupus, multiple sclerosis, focal segmental glomerulosclerosis, atopic dermatitis Dermatitis, amyotrophic lateral sclerosis, primary biliary cirrhosis, and primary sclerosing cholangitis, and severe Asthma can be cited as an example.

[0020] In this specification, (a) administering an anti-CD2 antibody or its antigen-binding fragment as the target; (b) By administering CTLA-4 costimulatory blockers to the target, immune-related effects in the target Methods for treating or preventing disorders or diseases are provided. In some embodiments, Anti-CD2 antibodies or their antigen-binding fragments are administered to CTLA-4 costimulatory blockers. It is administered before, simultaneously with, or after the administration. In some embodiments, the subject is immune Resistant to treatment of related disorders or diseases. In some embodiments, the subject is untreated. It is a target for treatment. In some embodiments, a CTLA-4 costimulator is administered to the subject. If this is not the case, the dose of anti-CD2 antibody or its antigen-binding fragment is not therapeutically effective. In some embodiments, if the anti-CD2 antibody or its antigen-binding fragment is not administered to the subject, The dosage of CTLA-4 costimulators is not therapeutically effective.

[0021] In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and CTLA-4 co-sting Administering a stimulant to the target may result in the use of anti-CD2 antibodies or their antigen-binding fragments or CTLA. -4 Compared to administering a costimulator to one of the factors rather than both, the synergistic effect is In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and CTLA-4 are used together. The number of cells in a biological sample obtained from a subject after both stimulant-blocking agents have been administered to the subject is, After administering anti-CD2 antibodies or their antigen-binding fragments to elephants, or after CTLA-4 co-stinging After the administration of a stimulant blocker (not both), the number of cells in the biological sample obtained from the subject and Compared to that, it's about 10% less, or at least about 10% less.

[0022] In some embodiments, the methods provided herein involve an anti-CD2 antibody or its anti- The subject is administered at least one of the proto-binding fragment and / or a CTLA-4 costimulatory blocker. Before that, the reduction in the number of cells in the biological sample obtained from the subject was compared with the anti-CD2 antibody. The antigen-binding fragment and the CTLA-4 costimulator were administered to the subjects after they had been given the antigen-binding fragment and the CTLA-4 costimulator. This results in a greater reduction in the number of cells in the biological sample. In some embodiments, the target The number of cells in the biological samples obtained from this source is approximately 10%, 15%, 20%, 25%, 30%, and 35%. %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85 %, 90%, 100%, or less than 100%, or at least about 10% 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% 65%, 70%, 75%, 80%, 85%, 90%, 100%, or more than 100% There are very few.

[0023] In some embodiments, the methods provided herein involve an anti-CD2 antibody or its anti- The subject is administered at least one of the proto-binding fragment and / or a CTLA-4 costimulatory blocker. Before that, the decrease in CD2 levels in the biological sample obtained from the subject was compared with the anti-CD2 antibody After both the body or its antigen-binding fragment and a CTLA-4 costimulatory blocker are administered, This results in a greater decrease in CD2 levels in biological samples obtained from several implementations. In this context, the method provided herein involves an anti-CD2 antibody or its antigen-binding fragment or C After TLA-4 costimulatory blockers are administered to subjects (not both), the life obtained from the subjects is... Compared to the decrease in CD2 levels in the body sample, anti-CD2 antibodies or their antigen-binding fragments and C After both TLA-4 costimulatory blockers were administered to the subjects, the biological samples obtained from the subjects were... This results in a greater decrease in CD2 levels. In some embodiments, the decrease is about 5%. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or 100 Larger than % or at least about 5%, 10%, 15%, 20%, 25%, 30% %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 It is greater than %, 85%, 90%, 100%, or 100%.

[0024] In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and CTLA-4 co-sting Administration of a stimulant blocker involves either an anti-CD2 antibody or a CTLA-4 costimulatory blocker, rather than both. Compared to the decrease in the alloimmune response after administration to the subjects, the alloimmune response was greater in the subjects. This results in a significant reduction. In some embodiments, the reduction is about 5%, 10%, 1%. 5%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 6 5%, 70%, 75%, 80%, 85%, 90%, 100%, or more than 100% Larger than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% , 90%, 100%, or greater than 100%. In some embodiments, homogeneous The immune response is measured using an in vitro human T cell proliferation assay or a mixed lymphocyte reaction (MLR). Determined using an assay.

[0025] In some embodiments, the anti-CD2 antibody or its antigen-binding fragment is an anti-Fc silent antibody. CD2 antibody, BTI-322, CB.219, LO-CD2b, cyprizumab, and / or or the antigen-binding fragment thereof. In some embodiments, an anti-CD2 antibody or its antigen-binding fragment The combined fragments are (a) heavy chain variable region CDR1 of SEQ ID NO: 3; (b) heavy chain variable region C of SEQ ID NO: 4. DR2; (c) Heavy chain variable region of SEQ ID NO: 5 CDR3; (d) Light chain variable region of SEQ ID NO: 6 C DR1; (e) Light chain variable region of sequence number 7 CDR2; (d) Light chain variable region C of sequence number 8 Includes DR3. In some embodiments, the antibody is a humanized antibody. Several embodiments In this case, the antibody is ciprizumab.

[0026] In some embodiments, the CTLA-4 costimulator is human IgG1 immunoglobulin. It is a fusion protein containing the Fc fragment and the extracellular domain of CTLA-4. In this embodiment, the CTLA-4 costimulator is approximately 80%, 85%, and 90% of the CTLA-4 costimulator. 95%, 98%, 99%, or 100%, or at least about 80%, 85%, 9 Includes sequences that are 0%, 95%, 98%, 99%, or 100% identical. In terms of application, the CTLA-4 costimulator contains the same sequence as SEQ ID NO: 22. In some embodiments, the CTLA-4 co-stimulus blocker is approximately 80%, 85%, of the CTLA-4 co-stimulus blocker, as indicated by SEQ ID NO: 23. 90%, 95%, 98%, 99%, or 100%, or at least about 80%, 85% Includes arrays that are %, 90%, 95%, 98%, 99%, or 100% identical. How many? In that embodiment, the CTLA-4 costimulator includes a sequence identical to that of SEQ ID NO: 23. In some embodiments, the CTLA-4 costimulator is abatacept. In that embodiment, the CTLA-4 costimulator is beratacept.

[0027] In some embodiments, the immune-related disorder or disease is systemic lupus erythematosus, joint Rheumatoid arthritis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis (JIA), osteoarthritis, juvenile Chronic arthritis, spondyloarthritis, systemic scleroderma, idiopathic inflammatory muscle disease, Sjögren's syndrome, Systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, pernicious anemia, autoimmune platelet anemia Hypothyroidism, thyroiditis, diabetes mellitus, immune-mediated renal disease, demyelinating diseases of the central or peripheral nervous system, Idiopathic demyelinating polyneuropathy, Guillain-Barré syndrome, Lyme disease, chronic inflammatory demyelinating polyneuropathy Inflammation, hepatobiliary disease, infectious or autoimmune chronic active hepatitis, primary biliary cirrhosis, Good's disease Pasture syndrome, granulomatous hepatitis, sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive bowel disease Whipple's disease, autoimmune or immune-mediated skin diseases, bullous skin diseases, erythema multiforme, contact Dermatitis, psoriasis, allergic diseases, asthma, allergic rhinitis, atopic dermatitis, food overdose Sensitivity, urticaria, multiple sclerosis, uveitis, pulmonary immune disorders, eosinophilic pneumonia, idiopathic pulmonary fibrillation Diseases, hypersensitivity pneumonitis, diseases associated with organ transplantation, diseases associated with tissue transplantation, graft rejection, graft pair Host disease, Devic's disease, acute disseminated encephalomyelitis, acute demyelinating optic neuritis, demyelinating transverse myelitis, Miller-Fischer syndrome, cerebrospinal radiculopathy, acute demyelinating polyneuropathy, tumor-like multiple sclerosis, Balo-type concentric sclerosis, alopecia areata, ankylosing spondylitis, Meniere's disease, antiphospholipid syndrome, mixed connective tissue disease, autoimmune Addison's disease, myasthenia gravis, autoimmune hepatitis, pemphigus vulgaris, Behçet's disease, bullous pemphigoid, polyarteritis nodosa, cardiomyopathy, polychondritis, celiac plue dermatitis, polyglandular syndrome, chronic fatigue syndrome (CFID), polymyalgia rheumatica, chronic inflammatory demyelinating polymyositis and dermatomyositis, primary agalactagogue These include immunoglobulinemia, Churg-Strauss syndrome, bullous pemphigoid, Crest syndrome, Raynaud's phenomenon, cold agglutinin disease, Reiter's syndrome, Crohn's disease, rheumatic fever, discoid rash, essential mixed cryoglobulinemia, fibromyalgia, scleroderma, Graves' disease, Sjögren's syndrome, Stiffman syndrome, Hashimoto's thyroiditis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, idiopathic thrombocytopenic purpura (ITP), ulcerative colitis, IgA nephropathy, insulin-dependent diabetes mellitus (Type 1), lichen planus, vitiligo, or any combination thereof. In some embodiments, the immune-related disorder or disease is rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis, or any combination thereof.

[0028] In some embodiments, immune-related disorders or diseases are diseases associated with organ transplantation, tissue These are diseases associated with transplantation, or combinations thereof. In some embodiments, anti-C D2 antibodies or their antigen-binding fragments are found in small amounts within two weeks after organ and / or tissue transplantation. At most, it is administered to the target once. In some embodiments, an anti-CD2 antibody or its antigenic antibody is used. The composite fragments are used on the day of organ and / or tissue transplantation, one day after organ and / or tissue transplantation, and / or It is administered to the subject 4 days after organ and / or tissue transplantation. Anti-CD2 antibody or its antigen. The conjugated fragment is administered intravenously or subcutaneously to the target.

[0029] In some embodiments, the therapeutic methods provided herein involve administering additional drugs to the target. This further includes the following. In some embodiments, the additional agent is an immunosuppressant. In some embodiments, additional agents include steroids, calcineurin inhibitors, and cyclosulfamethoxazole. Polin, cyclophosphamide, antimetabolite therapy, NSAIDs, for treating rheumatoid arthritis It is one or more of the drugs used and / or mTOR inhibitors. In terms of administration methods, additional drugs include basiliximab inducer, mycophenolate mofetil, and corticosteroids. Costeroids, or combinations thereof. [Brief explanation of the drawing]

[0030] 4. Brief explanation of the drawing The above and other purposes, features and advantages are illustrated in the attached drawings, as per the present invention. This will be apparent from the following description of a specific embodiment. The drawings are not necessarily to scale. The focus is on demonstrating the principles of various embodiments of the present invention.

[0031] [Figure 1]This study demonstrates the absence of FcγRIIIA signaling induced by CD2-binding molecule 1 (a deglycosylated CD2-binding molecule) compared to Fcγ receptor (FcγR)IIIA signaling with anti-CD2 Ab1 (e.g., cyprizumab (MEDI-507)). In vivo, cells expressing FcγRIIIA are major mediators of antibody-dependent cell-mediated cytotoxicity (ADCC). In the absence of FcγRIIIA binding and signaling, CD2-expressing cells bound to CD2-binding molecule 1 are not depleted via ADCC.

[0032] [Figure 2] A exhibits equivalent ability to inhibit the activation of CD4+ / CD25+ T cells, as demonstrated by CD2-binding molecule 1 (deglycosylated CD2-binding molecule) and anti-CD2 Ab1 (e.g., cyprizumab). B exhibits equivalent ability to inhibit the proliferation of CD4+ / CD25+ T cells, as demonstrated by CD2-binding molecule 1 (deglycosylated CD2-binding molecule) and anti-CD2 Ab1 (e.g., cyprizumab).

[0033] [Figure 3] CD2-binding molecule 1 (deglycosylated CD2-binding molecule) and anti-CD2 Ab1 (e.g., cyprizumab) exhibit equivalent ability to induce cells important in immune system modulation. This ability to modulate the immune response is measured by the increase in the percentage of regulatory T (Treg) cells upon interaction with CD2-binding molecule 1 or anti-CD2 Ab1 (e.g., cyprizumab).

[0034] [Figure 4] A demonstrates the ability of CD2-binding molecule 1 (deglycosylated CD2-binding molecule) to inhibit NK cell activation (induction of CD69 expression on NK cells) compared with anti-CD2 Ab1 (e.g., cyprizumab) in autologous mixed lymphocyte response (MLR). B demonstrates the ability of CD2-binding molecule 1 (deglycosylated CD2-binding molecule) to inhibit NK cell activation (induction of CD69 expression on NK cells) compared with anti-CD2 Ab1 (e.g., cyprizumab) in allogeneic mixed lymphocyte response (MLR).

[0035] [Figure 5] This study demonstrates the absence of FcγRIIA signaling induced by CD2-binding molecule 1 (a deglycosylated CD2-binding molecule) compared to Fcγ receptor (FcγR)IIA signaling with anti-CD2 Ab1 (e.g., cyprizumab (MEDI-507)). In vivo, cells expressing FcγRIIA are major mediators of antibody-dependent cell phagocytosis (ADCP). Without FcγRIIA binding and signaling, CD2-expressing cells bound to CD2-binding molecule 1 cannot be depleted via ADCP.

[0036] [Figure 6] The immunomodulatory activity of antibodies and fragments is shown by their ability to inhibit the activation of CD69+ T cells. Anti-CD2 Ab1 (e.g., cyprizumab)Fab fragment did not inhibit CD69+ T cell activation compared to the control, while both anti-CD2 Ab1 (e.g., cyprizumab) and CD2-binding molecule 1 (deglycosylated CD2-binding molecule) inhibited activation. The immunomodulatory activity of CD2-binding molecule 1 was maintained, but its ADCC activity was eliminated.

[0037] [Figure 7] This demonstrates the construction of expanded anti-CD2 variants by adding either an scFv, CH2-, or CH3- region to the Fc portion of a genetically modified IgG2 or IgG4 type of cyprizumab (IgG1).

[0038] [Figure 8] This shows an expanded anti-CD2 variant. A represents molecules 5A(IgG2) and 5B(IgG4). B represents molecules 6A(IgG2) and 6B(IgG4). C represents molecules 7A(IgG2) and 7B(IgG4).

[0039] [Figure 9]A shows Jurkat reporter cells (Promega) stably expressing Fcγ receptor (FcγR)I, B shows Jurkat reporter cells (Promega) stably expressing FcγRIIA, and C shows Jurkat reporter cells (Promega) stably expressing FcγRIIIA. Each cell was incubated with increasing concentrations of anti-CD2 antibody. Data (mean ± SD; n=3) are normalized to the luminescence induced by the highest concentration of anti-CD2 Ab1 (e.g., cyprizumab). Reporter cells bind the Fc fragment of the target-binding IgG antibody to their FcγR, thereby inducing the expression of the luciferase reporter gene and generating a luminescence signal upon addition of the assay substrate (Promega). Cells were incubated with increasing doses of anti-CD2 Ab1 (e.g., cyprizumab), CD2-binding molecule 1 (deglycosylated CD2-binding molecule), CD2-binding molecule 2 (Fc-silent (FcS) anti-CD2 IgG1), CD2-binding molecule 3 (FcS anti-CD2 IgG2), and CD2-binding molecule 4 (FcS anti-CD2 IgG4), respectively.

[0040] [Figure 10] This shows CD2 expression on different lymphocyte (sub)populations. Data are presented as mean fluorescence intensity median ± SEM (n=5; *p<0.05, **p<0.01). A shows CD2 expression on different T cell subpopulations and NK cell subpopulations. CD56brigh tNK cells express CD2 at levels comparable to T cells. In contrast, CD56dim and CD56negNK cells express significantly lower levels of CD2 (p=0.0074 and p=0.0111, respectively, repeated measures one-way ANOVA followed by Dunnett's multiple comparison test). B shows CD2 expression on resting and active lymphocyte populations. CD2 expression was significantly upregulated after activation in T cells (p=0.0034), CD56dimNK cells (p=0.0024), CD56brightNK cells (p=0.017), and CD56negCD16+NK cells (0.0029). No difference was observed in B cells (paired two-sided t-test).

[0041] [Figure 11] This shows the expression of Fcγ receptor (FcγR)II (CD32) and FcγRIII (CD16) on NK cells. On average, 91.0% of NK cells express FcγRIII and 19.2% express FcγRII (n=9). The mean is shown as a horizontal line (A). Representative plots of FcγRII and FcγRIII expression on NK cells (CD3- CD56+ and / or CD16+ lymphocytes). The upper panel shows representative plots of NK cells from donors with relatively low CD32 expression, and the lower panel shows representative plots of NK cells from donors with relatively high CD32 expression (B).

[0042] [Figure 12] This report shows the time course of CD69 expression on NK cells in mixed lymphocyte reactions (MLR) and autologous lymphocyte cultures (ALC). CD69 expression was evaluated by flow cytometry at baseline (day 0) and at days 1, 2, 4, and 7, both without and with antibody treatment. Significance testing was performed via two-way ANOVA with an untreated control (no antibody) as the comparative dataset (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Anti-CD2 Ab1 (e.g., cyprizumab) and CD2-binding molecule 1 (deglycosylated CD2-binding molecule) were used at 10 μg / mL. This dose was pre-determined to saturate the target antigen over 7 days. Data are presented as mean ± SD (n=12). A represents the percentage of CD69+ NK cells in the MLR over time. B shows the percentage of CD69+ NK cells in ALC over time.

[0043] [Figure 13]This shows the expression of CD69 and CD2 on NK cells after a 7-day mixed lymphocyte reaction (MLR). Significance testing was performed via one-dimensional ANOVA with an untreated control (no antibody) as the comparative dataset (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Anti-CD2 Ab1 (e.g., cyprizumab), CD2-binding molecule 1 (deglycosylated CD2-binding molecule), CD2-binding molecule 2 (Fc-silent (FcS) anti-CD2 IgG1), CD2-binding molecule 3 (FcS anti-CD2 IgG2), and CD2-binding molecule 4 (FcS anti-CD2 IgG4) were used at concentrations of 0.0001 to 10 μg / mL. Data are presented as mean percentage of CD69+ NK cells ± SD (A) or mean median CD2 fluorescence intensity + SD (CD2 MFI; n=9) (B). Representative dot plots (C) of CD2 and CD69 expression on NK cells in untreated control (no antibody) or in anti-CD2 at 10 μg / mL.

[0044] [Figure 14] This shows NK cell fracturing. Purified NK cells were incubated overnight with no antibody, 0.001–10 μg / mL of anti-CD2 Ab1 (e.g., cyprizumab), or 0.001–10 μg / mL of CD2-binding molecule 2, 3, or 4 (FcS anti-CD2 IgG antibody). Significance testing was performed via one-dimensional ANOVA with untreated controls (no antibody) as the comparison dataset (N=6; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). A represents NK cell lysis; mean percentage of 7-AAD+ NK cells + SD. B represents NK cell count; mean normalized NK cell count + SD. C represents CD56dimNK cell count; mean normalized CD56dimNK cell count + SD. D represents CD56brightNK cell count; mean normalized CD56brightNK cell count + SD.

[0045] [Figure 15]This shows NK cell degranulation and ADCC in purified NK cell cultures. Purified NK cells were incubated with no antibody, 0.001–10 μg / mL of anti-CD2 Ab1 (e.g., cyprizumab), or 0.001–10 μg / mL of CD2-binding molecule 2, 3, or 4 (FcS anti-CD2 IgG antibody). Significance testing was performed via one-dimensional ANOVA with untreated controls (no antibody) as the comparison dataset (N=6; *p<0.05, **p<0.01, ***p<0.001). A shows NK cell degranulation; mean percentage + SD of CD107a+ NK cells. B shows CD16 expression on NK cells; mean median + SD of CD16 fluorescence intensity on NK cells. A shows a representative heatmap dot plot illustrating CD16 downregulation and NK cell degranulation when the dose of anti-CD2 Ab1 (e.g., cyprizumab) is increased in purified NK cell cultures.

[0046] [Figure 16] This study demonstrates the cytotoxicity of native NK cells. Purified NK cells were pre-incubated for 30 minutes (A) or 2 days (B) with no antibody, 0.001–10 μg / mL anti-CD2 Ab1 (e.g., cyprizumab), or 0.001–10 μg / mL of CD2-binding molecule 2, 3, or 4 (FcSilent (FcS) anti-CD2 IgG antibody), followed by the addition of HLA class I target cells (SPI-801). Significance testing was performed via one-dimensional ANOVA with an untreated control (no antibody) as the comparative dataset (N=6; *p<0.05, **p<0.01, ***p<0.001). C shows a representative histogram of NK cell degranulation in response to HLA class I target cells, without antibody addition (NK+SPI-801), without antibody and HLA class I target cells (NK), or in the presence of anti-CD2 Ab1 (e.g., cyprizumab) / CD2 binding molecule 2 (FcS anti-CD2 IgG1).

[0047] [Figure 17]Antibody-dependent cytotoxicity was observed. Purified NK cells were pre-incubated with no antibody or a saturated dose of anti-CD2 Ab1 (e.g., cyprizumab) / CD2-binding molecule 2, 3, or 4 (FcS anti-CD2 antibody), followed by the addition of titrations of anti-CD2 Ab1 (e.g., cyprizumab) and CD20+ target cells (Daudi). Significance testing was performed via one-dimensional ANOVA with untreated controls (no antibody) as the comparison dataset (N=6; (*)p<0.1, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). A represents NK cell degranulation; mean percentage of CD107a+ NK cells + SD. B represents target cell depletion; mean normalized target cell number + SD. C represents CD2 expression; mean median CD2 fluorescence intensity on NK cells + SD. D shows a representative dot plot illustrating the increased CD2 expression on NK cells that leads to ADCC induction.

[0048] [Figure 18A]Figures 18A–H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. The graphs in Figures 18A–H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18A shows the mean CD4 T cell proliferation after 7 days of mixed lymphocyte reaction (MLR). The MLR was supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18B]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18B shows the mean CD8 T cell proliferation after 7 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18C]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18C shows the mean CD4 T cell proliferation after 10 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18D]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18D shows the mean CD8 T cell proliferation after 10 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18E]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18E shows the mean CD4 T cell proliferation after 7 days of mixed lymphocyte reaction (MLR). The MLR was supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18F]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18F shows the mean CD8 T cell proliferation after 7 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18G]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18G shows the mean CD4 T cell proliferation after 10 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone. [Figure 18H]Figures 18A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 18A-H show the mean percentage + standard deviation (SD) of proliferating T cells in the mixed lymphocyte reaction (MLR) (n=6). Figure 18H shows the mean CD8 T cell proliferation after 10 days of MLR. MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A series of titrations of anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) were supplemented with 100 μg / mL abatacept or 100 μg / mL belatacept. Using an untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Treatment with the combination of anti-CD2 antibody 1 and belatacept, or the combination of anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of viable cells compared to treatment with belatacept or abatacept alone.

[0049] [Figure 19A]Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 19A-D show the mean percentage + SD of proliferated T cells in the MLR (n=9). Figure 19A shows the mean CD4 T cell proliferation after 7 days of mixed lymphocyte reaction (MLR). The MLR was supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A titration series of abatacept or beratacept (1 x 10⁻⁷ to 100 μg / mL) was treated with 1 μg / mL anti-CD2 antibody 1 throughout the entire titration series. An untreated control (no antibody) was used as the comparison dataset. After one-way ANOVA, statistical analysis was performed using Dunnett's multiple comparison test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19B] Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 19A-D show the mean percentage + SD of T cells proliferated in the MLR (n=9). Figure 19B shows the mean CD8 T cell proliferation after 7 days of MLR. The MLR was supplemented with abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) at increasing concentrations. A titration series of abatacept or beratacept (1 x 10⁻⁷ to 100 μg / mL) was treated with 1 μg / mL anti-CD2 antibody 1 throughout the entire titration series. An untreated control (no antibody) was used as the comparison dataset. After one-way ANOVA, statistical analysis was performed using Dunnett's multiple comparison test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19C]Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 19A-D show the mean percentage + SD of proliferated T cells in the MLR (n=9). Figure 19C shows the mean CD4 T cell proliferation after 10 days of MLR. The MLR was supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A titration series of abatacept or beratacept (1 x 10⁻⁷ to 100 μg / mL) was treated with 1 μg / mL anti-CD2 antibody 1 throughout the entire titration series. An untreated control (no antibody) was used as the comparison dataset. After one-way ANOVA, statistical analysis was performed using Dunnett's multiple comparison test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19D] Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Figures 19A-D show the mean percentage + SD of T cells proliferated in the MLR (n=9). Figure 19D shows the mean CD8 T cell proliferation after 10 days of MLR. The MLR was supplemented with abatacept (1 x 10⁻⁷ to 100 μg / mL), belatacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL) at increasing concentrations. A titration series of abatacept or beratacept (1 x 10⁻⁷ to 100 μg / mL) was treated with 1 μg / mL anti-CD2 antibody 1 throughout the entire titration series. An untreated control (no antibody) was used as the comparison dataset. After one-way ANOVA, statistical analysis was performed using Dunnett's multiple comparison test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19E]Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with cells as control, anti-CD2 antibody 1, beratacept, abatacept, a combination of anti-CD2 antibody 1 and beratacept, or a combination of anti-CD2 antibody 1 and abatacept. Figure 19E shows the mean CD4 T cell proliferation after 7 days of mixed lymphocyte reaction (MLR). MLRs were supplemented with increasing concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), beratacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). 1 μg / mL of anti-CD2 antibody 1 was added throughout the titration series to abatacept or beratacept titration series (1 x 10⁻⁷ to 100 μg / mL). Using the untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19F] Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with cells in combination with control, anti-CD2 antibody 1, beratacept, abatacept, a combination of anti-CD2 antibody 1 and beratacept, or a combination of anti-CD2 antibody 1 and abatacept. Figure 19F shows the mean CD8 T cell proliferation after 7 days of MLR. MLR was supplemented with increasing concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), beratacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). 1 μg / mL of anti-CD2 antibody 1 was added throughout the titration series to abatacept or beratacept titration series (1 x 10⁻⁷ to 100 μg / mL). Using the untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19G]Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with cells as control, anti-CD2 antibody 1, beratacept, abatacept, a combination of anti-CD2 antibody 1 and beratacept, or a combination of anti-CD2 antibody 1 and abatacept. Figure 19G shows the mean CD4 T cell proliferation after 10 days of MLR. MLR was supplemented with increasing concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), beratacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). 1 μg / mL of anti-CD2 antibody 1 was added throughout the titration series to abatacept or beratacept titration series (1 x 10⁻⁷ to 100 μg / mL). Using the untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 19H] Figures 19A-H show the mean T cell (CD4 and CD8) proliferation after incubation for 7 or 10 days with cells as control, anti-CD2 antibody 1, beratacept, abatacept, a combination of anti-CD2 antibody 1 and beratacept, or a combination of anti-CD2 antibody 1 and abatacept. Figure 19H shows the mean CD8 T cell proliferation after 10 days of MLR. MLR was supplemented with increasing concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), beratacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). 1 μg / mL of anti-CD2 antibody 1 was added throughout the titration series to abatacept or beratacept titration series (1 x 10⁻⁷ to 100 μg / mL). Using the untreated control (no antibody) as the comparison dataset, statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0050] [Figure 20] Representative histograms showing inhibition of CD4 T cell proliferation 10 days after MLR in different treatment groups are shown.

[0051] [Figure 21] The graph shows the enhancement of regulatory T cells (Tregs). MLRs were supplemented with increased concentrations of abatacept (1 x 10⁻⁷ to 100 μg / mL), beratacept (1 x 10⁻⁷ to 100 μg / mL), and anti-CD2 antibody 1 (5.08 x 10⁻⁵ to 1 μg / mL). A titration series of abatacept or beratacept (1 x 10⁻⁷ to 100 μg / mL) was supplemented with 1 μg / mL of anti-CD2 antibody 1 throughout the titration series. An untreated control (no antibody) was used as the comparison dataset. Statistical analysis was performed using Dunnett's multiple comparison test after one-way ANOVA (*p<0.05, **p<0.01, ***p<0.001).

[0052] [Figure 22] The mean CD2 levels of cells after incubation for 7 or 10 days with control, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept are shown. Treatment with a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept, resulted in lower CD2 levels compared to treatment with belatacept or abatacept alone.

[0053] [Figure 23] The T cell count is shown after incubation for 7 or 10 days with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept. Treatment with a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept, resulted in a lower T cell count compared to treatment with belatacept or abatacept alone.

[0054] [Figure 24]The mean levels of CD2 or CD28 after incubation of cells with control, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept are shown. Treatment with a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept, resulted in lower levels of CD2 and CD28 compared to treatment with belatacept or abatacept alone.

[0055] [Figure 25] Flow cytometry graphs are shown using Violet Proliferation Dye 450 (VPD450) low T cells after incubation with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept.

[0056] [Figure 26] Flow cytometry graphs are shown using Violet Proliferation Dye 450 (VPD450) high T cells after incubation with control cells, anti-CD2 antibody 1, belatacept, abatacept, a combination of anti-CD2 antibody 1 and belatacept, or a combination of anti-CD2 antibody 1 and abatacept.

[0057] [Figure 27] The mean T cell (CD4 and CD8) proliferation is shown after incubation for 7 or 10 days with control cells, FcSilent anti-CD2 (IgG4), belatacept, abatacept, a combination of FcSilent anti-CD2 antibody 1 (IgG4) and belatacept, or a combination of FcSilent anti-CD2 antibody 1 (IgG4) and abatacept. Treatment with the combination of FcSilent anti-CD2 antibody 1 and belatacept, or the combination of FcSilent anti-CD2 antibody 1 and abatacept, resulted in a lower percentage of cells compared to treatment with belatacept or abatacept alone.

[0058] [Figure 28] The cell-based FcγR binding assays are shown. For FcγRI, FcγRIIA, and FcγRIIIA binding assays, antibodies at concentrations such as anti-CD2 antibody (or ciprizumab), FcSilent anti-CD2 Ab-1, FcSilent anti-CD2 Ab-2, FcSilent anti-CD2 Ab-3, FcSilent anti-CD2 Ab-4, FcSilent anti-CD2 Ab-5, FcSilent anti-CD2 Ab-6, or FcSilent anti-CD2 Ab-7) were tested.

[0059] [Figure 29] A shows the mean T cell (CD4 and CD8) proliferation after incubation for 7 days with cells with control, FcSilent anti-CD2 Ab-5, belatacept, or a combination of FcSilent anti-CD2 Ab-5 and belatacept (n=6; 3 independent MLRs). B shows the mean T cell (CD4 and CD8) proliferation after incubation for 10 days with cells with control, FcSilent anti-CD2 Ab-5, belatacept, or a combination of FcSilent anti-CD2 Ab-5 and belatacept (n=6; 3 independent MLRs).

[0060] [Figure 30] A shows the mean T cell (CD4 and CD8) proliferation after incubation for 7 days with cells with control, FcSilent anti-CD2 Ab-7, belatacept, or a combination of FcSilent anti-CD2 Ab-7 and belatacept (n=6; 3 independent MLRs). B shows the mean T cell (CD4 and CD8) proliferation after incubation for 10 days with cells with control, FcSilent anti-CD2 Ab-7, belatacept, or a combination of FcSilent anti-CD2 Ab-7 and belatacept (n=6; 3 independent MLRs).

[0061] [Figure 31]A shows the mean T cell activation (CD69+ and HLA-DR+) after incubation with cells with control, FcSilent anti-CD2 Ab-5, belatacept, or a combination of FcSilent anti-CD2 Ab-5 and belatacept (n=6; 3 independent MLRs). B shows the mean T cell activation (CD69+ and HLA-DR+) after incubation with control, FcSilent anti-CD2 Ab-7, belatacept, or a combination of FcSilent anti-CD2 Ab-7 and belatacept (n=6; 3 independent MLRs).

[0062] [Figure 32] A shows mean T cell (CD4 and CD8) proliferation after 7 days of incubation with cells as a control, FcSilent Anti-CD2 Ab7, belatacept, abatacept, a combination of FcSilent Anti-CD2 Ab7 and belatacept, or a combination of FcSilent Anti-CD2 Ab7 and abatacept. B shows mean T cell (CD4 and CD8) proliferation after 10 days of incubation with cells as a control, FcSilent Anti-CD2 Ab7, belatacept, abatacept, a combination of FcSilent Anti-CD2 Ab7 and belatacept, or a combination of FcSilent Anti-CD2 Ab7 and abatacept. Treatment with the combination of FcSilent Anti-CD2 Ab7 and belatacept, or the combination of FcSilent Anti-CD2 Ab7 and abatacept, resulted in a lower percentage of cells compared to treatment with belatacept alone, abatacept alone, or FcSilent Anti-CD2 Ab7 alone (n=6; 2 independent MLRs). Detailed description of the invention

[0063] 5. Detailed Description of the Invention This specification describes CD2-binding molecules (or anti-CD2 antibodies or their antigenic binding molecules). This molecule is a composite fragment, and its ability to mediate antibody-dependent cell damage is due to the molecule's immunomodulatory activity. While being maintained, it is reduced or eliminated. CD2 binding molecules as described herein (ma Or anti-CD2 antibodies or their antigen-binding fragments) are used to treat chronic diseases of the immune system. Alternatively, it can be administered to patients long-term in order to perform transplants.

[0064] For CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments), SECSY It is described in section 5.1. Specifically, a CD2-binding molecule (or an anti-CD2 antibody or The binding specificity of its antigen-binding fragment is described in Section 5.1.1; CD2-binding molecule The non-depletion activity of (or anti-CD2 antibody or its antigen-binding fragment) is shown in Section Erro r!Reference source not found. (As described in the CD2 combined section) The immunomodulatory activity of the child (or anti-CD2 antibody or its antigen-binding fragment) is described in Section 5. As described in 1.3; the mechanism of CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) Active modifications are described in Section 5.1.4. CD2-binding molecules (or anti-CD2 anti- Methods for generating the body or its antigen-binding fragments are described in Section 5.2. Therapeutic use of CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) and The method is described in Section 5.3. CD2 binding molecule (or anti-CD2 antibody or The pharmaceutical composition of the antigen-binding fragment is described in Section 5.4. This is described in Section 5.5. Those who evaluate the clinical outcomes of the methods described herein. The law is described in Section 5.6. Examples of the methods provided herein are provided in Section 5.6. It is described in section 6.

[0065] 5.1 CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are , coupled to CD2 as detailed in Section 5.1.1. As described herein, The CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) may be an antibody. As described herein, CD2 binding molecules (or anti-CD2 antibodies or their antigen binding cleavage) A fragment may be an antigen-binding fragment. As defined herein, antibodies are IgG, Ig This refers to immunoglobulins such as M, IgE, IgA, and IgD. The antibodies described herein are They may be monoclonal antibodies or polyclonal antibodies. In some embodiments, The antibody may be a chimeric antibody. In some embodiments, the antibody may be a humanized antibody. In certain embodiments, the antibody is a recombinant antibody. In certain embodiments, the antibody is a recombinant antibody. It is a whole-human antibody. In certain embodiments, the CD2-binding molecule (or anti-C) described herein is used. The D2 antibody (or its antigen-binding fragment) is IgG. In one embodiment, IgG is It may be IgG1, IgG2, IgG3, or IgG4. In certain embodiments, the present invention The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the document is Ig It is G1, IgG2, or IgG4. As described herein, C as described herein The D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is an antigen-binding fragment. Obtained. In one embodiment, the antigen-binding fragment is Fab, F(ab')2, scFv(VL) It may be a fused VH, or sdAb, or may contain them.

[0066] In some embodiments, the term "anti-CD2 antibody or its antigen-binding fragment" means " The term is used synonymously with "CD2-binding molecule." In some embodiments, this method and CD2 binding molecules (or anti-CD2 antibodies or their antigen binding cleavage) for use in compositions. One of the samples has the CDR sequence of the rat anti-CD2 monoclonal antibody BTI-322. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) This could be the humanized IgG1 type of BTI-322 (cyprizumab; MEDI-507). In some embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding molecule) is used. The fragment is an Fc silent anti-CD2 antibody or its antigen-binding fragment. Several implementations Morphologically, the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is BTI -322 or its antigen-binding fragment. In some embodiments, a CD2-binding molecule ( (or anti-CD2 antibody or its antigen-binding fragment) CB.219 or its antigen-binding fragment In some embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its anti- The proto-binding fragment is LO-CD2b or its antigen-binding fragment. In some embodiments, The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is cyprizumab. or its antigen-binding fragment. In some embodiments, a CD2-binding molecule (or anti-C2 molecule) is used. A D2 antibody (or its antigen-binding fragment) is an anti-CD2 antibody 1 or its antigen-binding fragment. In some embodiments, the anti-CD2 antibody 1 of the present disclosure is cyprizumab or its antigenic It is a composite fragment. In some embodiments, the method described herein is at least one, few At least two, at least three, or more than three CD2-binding molecules (or This includes administering an anti-CD2 antibody or its antigen-binding fragment. In some embodiments, The methods described herein include one or more CD2-binding molecules (or anti-CD2 antibodies). This includes administering (or its antigen-binding fragment). In some embodiments, the method described herein The method involves applying a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) to CTLA- 4. This includes administering the agent to the target patient in combination with a costimulatory blocker.

[0067] The antibodies described herein consist of two heavy chains linked by disulfide bonds and two It may consist of light chains. Each heavy chain may include a variable region (VH) and a constant region. Each light chain is It may include a variable region (VL) and a constant region. Both the heavy chain and light chain variable regions of the antibody It directs binding to the antigen. The complementarity-determining region (CDR) is located on the variable regions of the heavy and light chains. It is a variable loop. Each heavy chain has 3 CDRs, and each light chain has 3 CDRs. In one embodiment, the antibody described herein binds to CD2. Section 5.1.1 Please refer to the following.

[0068] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. Administration of the antigen-binding fragment does not result in target cell depletion. See Section 5.1.2. Please refer to the following. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody) described herein is used. (or its antigen-binding fragment) exhibits immunomodulatory activity. See Section 5.1.3. In certain embodiments, the CD2-binding molecule (or anti-CD2 antibody) described herein may also be used. The ability of these antigen-binding fragments to suppress the depletion of target cells while maintaining immunomodulatory activity. This is achieved by eliminating glycosylation of the Fc region; Section 5.1.4 Please refer to the following.

[0069] 5.1.1 Binding characteristics of CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) opposite sex The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are CD2 (also known as T11, SRBC (sheep red blood cell receptor), and LFA-2) It binds specifically. In certain embodiments, the CD2 binding molecule (or anti-C) described herein is used. D2 antibody or its antigen-binding fragment is human CD2 (GenBank accession number) No. NM_001328609.1 (Isoform 1); NM_001767.5 (I It binds to Soform 2). In one embodiment, the CD2 binding molecule provided herein (Or an anti-CD2 antibody or its antigen-binding fragment) competitively binds to cyprizumab. (Medlmmune Inc.; International Publication Number WO02 / 098370) (No.) Ciprizumab (MEDI-507) is a CD2-specific rat antibody derived from BTI-322. Humanized version (Medlmmune Inc.; International Publication Number WO02 / 09837) (No. 0). Ciprizumab is a monoclonal antibody of the IgG1κ class, and is used to treat human T cells and It binds to CD2, which is found in human NK cells. Ciprizumab has two heavy chains (approximately 50kD). a) It consists of two light chains (approximately 25 kDa).

[0070] As defined herein, an epitope is an antigen to which an antibody or antigen-binding fragment binds. This is the region. In some embodiments, the epitope may be linear. Other embodiments Therefore, an epitope can be a conformation. In some embodiments, an epitope The epitope may be formed by a series of amino acids. In other embodiments, the epitope may be discontinuous. It can be formed by amino acids. In one embodiment, the CD2 binding molecule described herein ( Alternatively, an anti-CD2 antibody or its antigen-binding fragment binds to an epitope on CD2. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment binds to the same CD2 epitope as cyprizumab. In one embodiment, This refers to the CD2-binding molecule (or anti-CD2 antibody or its antigen binding cleavage) provided herein. (One side) Clark et al., J Exp Med. 1988 Jun 1;16 Appropriate in vitro competitions, such as those detailed in 7(6):1861-72. In the binding assay, it can competitively bind to cyprizumab. In one embodiment, The CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) provided in the details is, Same IC as ciprizumab 50 The value is approximately 1 nM (Branco et al., Tr ansplantation.1999 Nov 27;68(10):1588-96 ). In one embodiment, the CD2-binding molecule (or anti-CD2 antibody) provided herein may also be used. (Its antigen-binding fragment) has a lower IC than cyprizumab. 50 It has a value. In one embodiment Therefore, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding) provided herein is... (The fragment) has a higher IC than cyprizumab. 50 It has a value. In one embodiment, as specified herein The provided CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is 0.5 nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1.0nM, 1.1nM, 1 .2nM, 1.3nM, 1.4nM, 1.5nM, 0.5nM~0.8nM, 0.6nM ~0.9nM, 0.7nM~1.0nM, 0.8nM~1.1nM, 0.9nM~1.2 nM, 1.0nM~1.3nM, 1.1nM~1.4nM, or 1.2nM~1.5n M IC 50 It has a value.

[0071] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The sequence of the VH region of the antigen-binding fragment is sequence number 01 and 80%, 85%, 90%, 91%. , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% One. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody) described herein is also used. The sequence of the VL region of the antigen-binding fragment is 80%, 85%, and 90% of sequence number 02. , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 1 They are 00% identical. In one embodiment, the CD2 binding molecule (or anti-CD) described herein is used. The sequence of VH CDR1 of the antibody (or its antigen-binding fragment) may be sequence number 03. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or similar) described herein is used. The sequence of VH CDR2 (antigen-binding fragment) may be sequence number 04. In one embodiment This refers to the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. The sequence of VH CDR3 may be sequence number 05. In some embodiments, as described herein The VL CDR1 of the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) The sequence may be sequence number 06. In one embodiment, the CD2 binding component described herein The VL CDR2 sequence of the child (or anti-CD2 antibody or its antigen-binding fragment) is, It may be No. 07. In some embodiments, the CD2 binding molecule (or anti-CD) described herein is used. The VL CDR3 sequence of the antibody (or its antigen-binding fragment) may be sequence number 08. These sequences are shown in Table 1.

[0072] In one embodiment, a CD2-binding molecule for use in the method provided herein (and (These are anti-CD2 antibodies or their antigen-binding fragments) and VH CDRs, respectively, numbered 3-5. and has a heavy chain variable region including VL of SEQ ID NO: 2. In one embodiment, provided herein CD2 binding molecules (or anti-CD2 antibodies or their antigen binding) for use in the method described above. The fragments each contain a heavy-chain variable VL CDR (SEQ ID NOs. 6-8) and a VH (SEQ ID NO. 1), respectively. It has a domain.

[0073] In one embodiment, a CD2-binding molecule for use in the method provided herein (and (Anti-CD2 antibody or its antigen-binding fragment) is the heavy chain variable region CDR1 of SEQ ID NO: 3; Heavy chain variable region CDR2 of column number 4; heavy chain variable region CDR3 of sequence number 5; light chain variable region of sequence number 6 Chain variable region CDR1; Light chain variable region CDR2 of SEQ ID NO: 7; Light chain variable region C of SEQ ID NO: 8 Includes DR3. In one embodiment, CD2 connection for use in the method provided herein. The synthesizer (or anti-CD2 antibody or its antigen-binding fragment) is at least approximately [number missing]% of SEQ ID NO: 3. 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 1 00% or approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 9 Heavy chain variable region CDR1 containing sequences that are 9% or 100% identical; less than sequence number 4. Approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and more. Or 100%, or approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, Heavy chain variable region CDR2 containing sequences that are 98%, 99%, or 100% identical; sequence number Number 5 and at least approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% 99%, or 100%, or approximately 75%, 80%, 85%, 90%, 95%, 96% Heavy chain variable region CD containing sequences that are 97%, 98%, 99%, or 100% identical. R3; Array No. 6 and at least approximately 75%, 80%, 85%, 90%, 95%, 96%, 9 7%, 98%, 99%, or 100%, or approximately 75%, 80%, 85%, 90%, Light chains containing sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical. Variable region CDR1; SEQ ID NO: 7 and at least approximately 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99%, or 100%, or approximately 75%, 80%, 85% Distributions that are identical in %, 90%, 95%, 96%, 97%, 98%, 99%, or 100% Light chain variable region CDR2 including column; and / or sequence number 8 and at least about 75%, 80% , 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%, also Approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, if It has a light chain variable region CDR3 containing sequences that are 100% identical.

[0074] In one embodiment, a CD2-binding molecule for use in the method provided herein (and (Anti-CD2 antibody or its antigen-binding fragment) is present in approximately one or fewer units relative to SEQ ID NO: 3. At most about 1 amino acid substitution, about 2 or at least about 2 amino acid substitutions, about 3 or at least approximately 3 amino acid substitutions, approximately 4 or at least approximately 4 amino acid substitutions, Or a heavy chain variable region CDR1 containing a sequence with at least approximately 4 or more amino acid substitutions. For SEQ ID NO: 4, approximately 1 or at least approximately 1 amino acid substitution, approximately 2 or fewer amino acid substitutions. At least two amino acid substitutions, about three or at least about three amino acid substitutions, about four Or at least approximately 4 amino acid substitutions, or at least more than approximately 4 amino acid substitutions Heavy chain variable region CDR2 containing a sequence having approximately one or fewer elements in sequence number 5. Approximately 1 amino acid substitution, approximately 2 or at least approximately 2 amino acid substitutions, approximately 3 or At least approximately 3 amino acid substitutions, approximately 4 or at least approximately 4 amino acid substitutions, The heavy chain variable region CDR3 contains a sequence with at least approximately 4 or more amino acid substitutions; For row number 6, approximately 1 or at least approximately 1 amino acid substitution, approximately 2 or fewer. Both involve approximately 2 amino acid substitutions, approximately 3 or at least approximately 3 amino acid substitutions, and approximately 4 or It has at least approximately 4 amino acid substitutions, or at least more than approximately 4 amino acid substitutions. Light chain variable region CDR1 containing the sequence; for sequence number 7, approximately 1 or at least approximately 1 amino acid substitution, approximately 2 or at least approximately 2 amino acid substitutions, approximately 3 or fewer At most about 3 amino acid substitutions, about 4 or at least about 4 amino acid substitutions, or a small number Light chain variable region CDR2 containing sequences with at least 4 or more amino acid substitutions; and / Or, for SEQ ID NO: 8, approximately one or at least approximately one amino acid substitution, approximately two or is at least about 2 amino acid substitutions, about 3 or at least about 3 amino acid substitutions, about Four amino acid substitutions or at least approximately four amino acid substitutions, or at least more than approximately four amino acid substitutions. It has a light chain variable region CDR3 containing a sequence with substitutions.

[0075] In some embodiments, the amino acid substitutions are conservative substitutions. A specific example of substitution is amino acid substitution that maintains the structural and / or functional properties of the side chain of an amino acid. For example, aromatic amino acids are substituted for other aromatic amino acids, and acidic amino acids are substituted for other aromatic amino acids. Substituted with another acidic amino acid, basic amino acids are substituted with another basic amino acid, fat The aliphatic amino acid is substituted with another aliphatic amino acid. In some embodiments, the conservative amino acid Acid substitution occurs when an amino acid residue is replaced by an amino acid residue that has a side chain with a similar charge. This is the case. A family of amino acid residues having side chains with similar charges is the technical component. These are defined in the field. These families include amino acids with basic side chains (for example) (For example, lysine, arginine, histidine), amino acids with acidic side chains (e.g., asparagus) (Ginic acid, glutamic acid), amino acids having non-charged side chains (e.g., asparagine, glycerin) (Lutamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains (For example, glycine, alanine, valine, leucine, isoleucine, proline, phenyl Alanine, methionine, tryptophan), amino acids having β-branched side chains (e.g., tre (onine, valine, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine) Examples include phenylalanine, tryptophan, and histidine. In contrast, non-preserved a An example of amino acid exchange is the amino acid exchange that does not maintain the structural and / or functional properties of the side chain of the amino acid. This is an acid substitution, where, for example, an aromatic amino acid is substituted for a basic, acidic, or aliphatic amino acid. Furthermore, the acidic amino acid is substituted with an aromatic, basic, or aliphatic amino acid, and the basic amino acid The ano acid is substituted with an acidic, aromatic, or aliphatic amino acid, and the aliphatic amino acid is substituted with an aromatic, acidic, or aliphatic amino acid. It is substituted with a sex or basic amino acid.

[0076] In one embodiment, a CD2-binding molecule (or an anti-CD2 molecule) for use with the method and composition is used in conjunction with this method and composition. CD2 antibody or its antigen-binding fragment) is the heavy chain C of BTI-322 or cyprizumab. It comprises one, two, or three DRs. In some embodiments, it is used in conjunction with the method and composition. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) used for this purpose is BTI -322 or one, two, or three light chain CDRs of ciprizumab. A certain implementation In this state, a CD2-binding molecule (or anti-CD2 antibody) for use with this method and composition is also included. The antigen-binding fragment is one or two of the CDRs of BTI-322 or cyprizumab. , including all three, four, five or six CDRs. In some embodiments, as described herein CD2 binding molecules (or anti-CD2 antibodies or their antigen binding cleavage) for use in the method described above. (One) is described in Error!Reference source not found. This includes one, two, three, four, five, or all six CDRs. In one embodiment, this includes one, two, three, four, five, or all six CDRs. , one, two, three, four, five CDRs of BTI-322 or ciprizumab, and / Or all six are amino acid substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. It has. In a more specific embodiment, such amino acid substitutions are conservative amino acid substitutions. That is the case. [Table 1]

[0077] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment has the same six CDR sequences as cyprizumab. In one embodiment, The CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are , it can share five of the six CDR sequences of cyprizumab. In one embodiment, CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) as described in the detailed document CDR One of them, unlike the corresponding CDR of cyprizumab, has a CDR sequence that is one ami The anoacids are different. In some embodiments, the CD2 binding molecule (or anti-CD2 anti) described herein is used. Differences between the CDR sequence of the body or its antigen-binding fragment and the corresponding CDR of cyprizumab This is a conservative amino acid substitution. For example, CD2-binding molecules (or anti-CD2 antibodies or The antigen-binding fragment) is compared to the set of six CDRs of cyprizumab, or cypri Compared to the set of three CDRs in the heavy chain of zumab, or the three in the light chain of cyprizumab Compared to the set of CDRs, 1, 2, 3, 4, 5, or 6 conservative amino acid substitutions It is possible to have.

[0078] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments (VL CDR1, VL CDR2, or VL CDR3) are their This is a different CDR from the prismab-compatible product. In other embodiments, CD2 as described herein. The binding molecule (or anti-CD2 antibody or its antigen-binding fragment) VH CDR1, VH C DR2, or VH CDR3, is a different CDR from its ciprizumab counterpart. In the embodiments described herein, the CD2 binding molecule (or anti-CD2 antibody or its anti- The different CDRs of the original binding fragment are longer than the sequences of their cyprizumab counterparts. Other implementations In this state, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding cleavage) described herein is used. The different CDRs (one) are shorter than the sequences of their cyprizumab counterparts.

[0079] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The sequence of the heavy chain constant region (CH) of the antigen-binding fragment is sequence number 09 and 80%, 85%, 9 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% also They are 100% identical. In one embodiment, the CD2 binding molecule (or anti) described herein is used. The sequence of the heavy chain constant region of the CD2 antibody (or its antigen-binding fragment) is 80% of SEQ ID NO. 10. 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , 99% or 100% identical. In one embodiment, the CD2 bonded component described herein The sequence of the heavy chain constant region of the child (or anti-CD2 antibody or its antigen-binding fragment) is the sequence number. 11 and 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 9 They are 7%, 98%, 99%, or 100% identical. In some embodiments, as described herein Sequence of the heavy chain constant region of a CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) This is sequence number 12 and 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% They are 96%, 97%, 98%, 99%, or 100% identical. In one embodiment, the present invention Heavy chain determination of the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the detailed document. The sequence of the normal region is sequence number 13 and 80%, 85%, 90%, 91%, 92%, 93%, 9 It is 4%, 95%, 96%, 97%, 98%, 99% or 100% identical. In certain embodiments the sequence of the light chain constant region (CL) of the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein is 80%, 85%, 90%, 91% with SEQ ID NO: 14, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In certain embodiments, the sequence of the light chain constant region of the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein is 80%, 85%, 9 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 15. In certain embodiments, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein can be directed to three regions of human CD2 known in the art as T111, T112, and T113 (Peterson, A., Seed, B., 1987. Nature 329, 842-846; Branco et al.

[0080] , 1999. Transplantation 68, 1588-1596; Arula nandam, A.R., et al., 1993. Proc. Natl. Acad. S ci. U.S.A. 90, 11613-11617; Damschroder et a l., 2004. Molecular Immunology 41, 985-1000 ). Three residues in the adhesion domain of human CD2 important for binding to sipuleucel-T are N18 , K55, and T5 (Damschroder et al., 2004. Mol ecular Immunology 41, 985-1000). In certain embodiments ). ). ​​Residues N18, K55, and T59 in the extracellular CD2 domain are essential for human CD2. The binding parent of the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the details. It is an important residue in terms of compatibility. In one embodiment, the CD2 binding molecule described herein ( (or an anti-CD2 antibody or its antigen-binding fragment) binds to the same epitope as cyprizumab. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody) described herein may also be used. The antigen-binding fragment (or its equivalent) binds competitively to human CD2 with cyprizumab.

[0081] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) The DNA sequence can be modified to optimize the yield of the product during manufacturing. The resulting amino acid sequence will be the same as that listed in Table 1, and through sequence optimization, during production Product yield increases without affecting the secretion of molecular product quality. CD2 binding component Optimized DN of the heavy and light chains of the child (or anti-CD2 antibody or its antigen-binding fragment) The A sequence is shown in Table 2. [Table 2] TIFF2026053445000005.tif100165

[0082] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The heavy chain sequence of the antigen-binding fragment is sequence number 16 and 80%, 85%, 90%, 91%, 9 2%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical Yes. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody) described herein is used. The sequence of the light chain of its antigen-binding fragment is sequence number 17 and 80%, 85%, 90%, 91%. , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% It is one.

[0083] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) This interferes with the CD58 / CD2 signaling cascade. In one embodiment, the CD2 signaling cascade The compound molecule (or anti-CD2 antibody or its antigen-binding fragment) blocks CD58. An example of a compound that inhibits the 58 / CD2 pathway is alefacept.

[0084] In one embodiment, cyprizumab depletion may be used to treat autoimmune diseases.

[0085] 5.1.2 Decreased or absent ADCC activity In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments of the antigen do not have antibody-dependent cell-mediated cytotoxicity ("ADCC") or reduce it. CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) are involved with these. Not limited to, Fc silencing, subclass switching, deglycosylation, and Using methods such as other mutations or modifications in the Fc region, a reduction or absence of ADCC can be observed. These can be produced in the manner described herein. Non-limiting examples of CD2-binding molecules obtained (or anti-CD2 antibodies or their antigen-binding fragments) For example, U.S. Provisional Application No. 63 / 135,381 (the entire application is referred to herein) These methods are described in Section 5.1.4 (which is incorporated into the document). Further details are provided in sections 5.2.2, 5.2.3, and the examples.

[0086] The ADCC activity can be determined by any commercially available kit (e.g., Promega ADCC Repo rter Bioassay, CoreKit (catalog #G7010, G7018), or any suitable assay. Such assays include, but are not limited to, assays based on flow cytometry, fluorescence assays, or bioluminescence reporter assays.

[0087] In certain embodiments, the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein exhibits up to 90% of the ADCC activity of rituximab in in vitro assays. Examples of such assays are described in the method of Golay et al., Haem atologica. January 2003;88:1002-1012. Specifically, the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) provided herein exhibits up to 0%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or up to 90% of the ADC C activity compared to rituximab.

[0088] In certain embodiments, the in vivo administration of the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) provided herein exhibits up to 90% of the A DCC activity compared to the in vivo administration of rituximab in humanized mouse models or in human subjects in a clinical setting. Specifically, the in vivo administration of the CD2-binding molecule (or anti-CD 2 antibody or its antigen-binding fragment) provided herein is in humanized mouse models or In human subjects in clinical settings, the maximum in vivo administration of ciprizumab was 0%. 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or maximum It exhibits 90% ADCC activity.

[0089] 5.1.3 Maintenance of immunomodulatory activity In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) provided herein (Its antigen-binding fragment) is present even though ADCC is absent or reduced. It exhibits immunomodulatory activity. CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) ) are not limited to these, but include Fc silencing, subclass switching, degling Methods such as cosylation and other mutations or modifications of the Fc region are used to reduce ADCC Alternatively, it can be generated to exhibit absence. These methods are described in Section 5. Further details are provided in sections 1.4, 5.2.2, 5.2.3 and the examples.

[0090] The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein Therefore, the immunomodulatory activity exhibited is not limited to these, but includes CD4+ / CD25+ Inhibition of T cell activation and proliferation, FOXP3 + Percentage of regulatory T cells Possible effects include an increase and suppression of CD69+ NK cells. In some embodiments, as described herein. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is cyprizumab. It exhibits the same immunomodulatory activity (e.g., the same type and level). The determination can be achieved by any suitable method known in the art. Our methods, though not limited to these, include cell proliferation assays and T cell activation function assays. SEI, ELISPOT assay, intracellular staining, cytokine capture, tetramer staining, spectroscopy Examples include typing assays and biosensor assays. One example is T cell assays. Activation can be performed using any commercially available assay kit (e.g., Promega T Cell Ac). Tivation Bioassay (NFAT or IL-2) (Catalog #J162) It can be determined by 1 or J1651)) or any suitable assay, Simply put, the assay plate is coated with an anti-CD3 antibody, and human PBMCs or Mouse peripheral target cells were added, anti-CD28 was added to the cells, and their proliferation was quantified.

[0091] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments (of the in vitro) activate and proliferate CD4+ / CD25+ T cells. In the assay, at least 50% of the level achieved by cyprizumab. It can inhibit down to a certain level. An example of such an assay is Ng et al., B. The method is described in lood.2001;98:2736-2744. Specifically, The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are The activation and proliferation of CD4+ / CD25+ T cells were stimulated in vitro by cyprix At least 50%, 55%, 60%, 65%, and 70% of the levels achieved by Mab, Inhibits up to a level of 75%, 80%, 85%, 90%, 95%, or 100%. It is possible.

[0092] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) provided herein In vivo administration of its antigen-binding fragment is performed in humanized mouse models or clinical settings. In human subjects, compared to in vivo administration of ciprizumab, at least 50 It exhibits a % level of CD4+ / CD25+ T cell activation / proliferation. Specifically, this specification The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) provided in the book In vivo administration is performed in humanized mouse models or human subjects in clinical settings. Compared to in vivo administration of lizumab, at least 50%, 55%, 60%, and 65% CD4 at levels of 70%, 75%, 80%, 85%, 90%, 95%, or 100% It exhibits activation / proliferation of + / CD25+ T cells.

[0093] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment of FOXP3 is superior to cyprizumab. + Increase the amount of regulatory T cells In one embodiment, the CD2 binding molecule (or anti-CD) described herein can be used. 2. Antibodies or their antigen-binding fragments) are used in in vitro assays to detect FOXP3 + The amount of regulatory T cells is increased to at least 50% of the amount achieved by cyprizumab. It can be increased to this extent. An example of such an assay is Sambucci et al. The method is described in l., Scientific Reports. 8:3674 (2018). Specifically, the CD2 binding molecule (or anti-CD2 antibody) described herein (Its antigen-binding fragment) is used in vitro with FOXP3 + The amount of regulatory T cells , FOXP3 achieved by sipuleucel-T + at least 50% of the amount of regulatory T cells, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 1 00% levels can be increased.

[0094] In certain embodiments, in vivo administration of the CD2 binding molecule (or anti-CD2 antibody or an antigen-binding fragment thereof) described herein results in at least 50% more regulatory T cells expressing FOXP3 in a humanized mouse model or human subject in a clinical setting compared to in vivo administration of sipuleucel-T. Specifically, in vivo administration of the CD2 binding + molecule (or anti-CD2 antibody or an antigen-binding fragment thereof) described herein results in at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more regulatory T cells expressing FOXP3 in a humanized mouse model or human subject in a clinical setting compared to in vivo administration of sipuleucel-T. + In certain embodiments, the CD2 binding molecule (or anti-CD2 antibody or an antigen-binding fragment thereof) described herein can inhibit the expression of CD69+ NK cells compared to sipuleucel-T. In certain

[0095] embodiments, the CD2 binding molecule (or anti-CD2 antibody or an antigen-binding fragment thereof) provided herein exhibits up to 50% less expression of CD69+ NK cells in an in vitro assay compared to sipuleucel-T. Examples of such assays are described in Thum et al., Human Reproduction. 19: ​​​​This is described in the method in 10, pp. 2395-2400, 2004. Specifically, Honmei The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the document is in In vitro, compared to cyprizumab, up to 10%, 20%, 30%, and 40% , exhibiting 50%, 60%, 70%, 80%, or up to 90% CD69+ NK cell expression. do.

[0096] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) provided herein In vivo administration of its antigen-binding fragment is performed in humanized mouse models or clinical settings. In human subjects, compared to in vivo administration of ciprizumab, up to 50% C It exhibits D69+ NK cell expression. Specifically, the CD2 binding molecule provided herein ( In vivo administration of anti-CD2 antibodies or their antigen-binding fragments is used in humanized mice. In human subjects in model or clinical settings, in vivo administration of cyprizumab and Compared to the previous figures, the maximum percentages were 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and so on. Alternatively, it can exhibit up to 90% CD69+ NK cell expression.

[0097] In certain embodiments, the CD2 binding molecule described herein (or anti-CD2 antibody or The antigen-binding fragment can perform one of these immunomodulatory activities. In the embodiments, the CD2 binding molecule described herein (or an anti-CD2 antibody or its antigen) is used. The binding fragment can perform two or more of these immunomodulatory activities. In terms of form, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding) as described herein. The fragment can perform all of these immunomodulatory activities. In certain embodiments, the present invention The administration of the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the detailed document is , while maintaining immunomodulatory activity, completely inactivates ADCC activity in the recipient. .

[0098] 5.1.4 Modification of the Fc region In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is an IgG1 antibody having modifications in the Fc region. In one embodiment, This refers to the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. This is an IgG2 antibody having modifications in the Fc region. In some embodiments, as described herein The CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is an IgG3 antibody. and has modifications in the Fc region. In one embodiment, the CD2 bond component described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is an IgG4 antibody, and the Fc region It has modifications inside. In some embodiments, the CD2 binding molecule (or anti-CD) described herein is used. 2. The antibody or its antigen-binding fragment) has at least one mutation compared to cyprizumab. (For example, about one or at least one, about two or at least two, about three or a few) At least three, about four, or at least four, about five, or at least five, about six, at least 6, about 7 or at least 7, about 8 or at least 8, about 9 (or at least 9, about 10, or more than about 10 mutations) In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) described herein is used. The antigen-binding fragments) are associated with cyprizumab and have approximately one mutation, approximately two mutations, and approximately three mutations. , approximately 4 mutations, approximately 5 mutations, approximately 6 mutations, approximately 7 mutations, approximately 8 mutations, approximately 9 mutations, about 10 mutations, or more than 10 mutations (for example, the Fc region of cyprizumab) Includes mutations in the region. In some embodiments, the CD2 binding molecule (or anti-C) described herein. The D2 antibody (or its antigen-binding fragment) contains cyprizumab CDR in the IgG1 heavy chain, and a small amount At least one mutation (for example, about one or at least one, about two or at least two) 5 or less 5, about 6 or at least 6, about 7 or at least 7, about 8 or fewer At least 8, about 9 or at least 9, about 10 or at least 10, or about 10 Includes mutations exceeding 1.5. In some embodiments, the CD2 binding molecule (or anti-CD2) described herein is included. CD2 antibody or its antigen-binding fragment) contains cyprizumab CDR in the IgG double chain, and At least one mutation (for example, about one or at least one, about two or at least) 2, about 3 or at least 3, about 4 or at least 4, about 5 or fewer Five, about six or at least six, about seven or at least seven, about eight or fewer At least 8, about 9, or at least 9, about 10, or at least 10, or about 1 Includes mutations greater than 0. In some embodiments, the CD2 binding molecule described herein (or The anti-CD2 antibody (or its antigen-binding fragment) contains cyprizumab CDR in the IgG triple chain, and and at least one mutation (for example, about one or at least one, about two or at least one) Also two, about three or at least three, about four or at least four, about five or fewer At least 5, about 6 or at least 6, about 7 or at least 7, about 8 or At least 8, about 9, or at least 9, about 10, or at least 10, or about Includes more than 10 mutations. In some embodiments, the CD2 binding molecule described herein (and (Anti-CD2 antibody or its antigen-binding fragment) contains cyprizumab CDR in the IgG quadrilateral chain. and at least one mutation (e.g., about one or at least one, about two or fewer) Two, about three or at least three, about four or at least four, about five or fewer At least 5, about 6, or at least 6, about 7, or at least 7, about 8 at least 8, about 9 or at least 9, about 10 or at least 10, It contains more than 10 mutations. The mutations, compared to the wild-type counterpart, affect the CD2 binding molecule (and This involves at least one modification in the amino acid sequence of an anti-CD2 antibody or its antigen-binding fragment. Modifications may include a reduction or elimination of the binding of the Fc region to its homologous receptor. In some embodiments, the mutation is one or more mutations, at amino acid position L234, L 235th place, P329th place, V234th place, G237th place, P238th place, H268th place, V309th place , A330th, P331st, and / or S228th (e.g., Edelman (EU) (Based on numbering) Includes mutations. In some embodiments, a mutation is one or more mutations. These are different and include mutations at amino acid positions L234 and / or L235. In this embodiment, the mutation is one or more mutations, with amino acids at positions L234, L235 and / or includes a mutation at position P329. In some embodiments, the mutation is one or more mutations. They are different, with amino acid positions V234, G237, P238, H268, and V309. , including mutations at position A330 and / or position P331. In some embodiments, A mutation is one or more mutations, including a mutation at amino acid position S228. In the application morphology, the mutation is one or more mutations, and is present at amino acid positions S228, P329, and / or or includes a mutation at position L235. In some embodiments, the mutation is one or more mutations. This includes L234A (or another conserved amino acid mutation). In some embodiments, The mutation is one or more mutations, including L235A (or another conservative amino acid mutation). In some embodiments, the mutation is one or more mutations, P329G (or another retainer). (Constant amino acid mutations) are included. In some embodiments, the mutation is one or more mutations. It contains V234A (or another conserved amino acid mutation). In some embodiments, the mutation is , one or more mutations, including G237A (or another conserved amino acid mutation). In that embodiment, the mutation is one or more mutations, P238S (or another conservative ami) (Includes no-acid mutations). In some embodiments, the mutation is one or more mutations, H268 It contains A (or another conserved amino acid mutation). In some embodiments, the mutation is one or more The above mutation includes V309L (or another conserved amino acid mutation). Several implementations Morphologically, the mutation is one or more mutations, such as A330S (or another conserved amino acid mutation). ) includes. In some embodiments, the mutation is one or more mutations, including P331S(and (This includes another conserved amino acid mutation). In some embodiments, the mutation is one or more mutations. This includes S228P (or another conserved amino acid mutation). In some embodiments, The mutation is one or more mutations, including L235E (or another conserved amino acid mutation). In some embodiments, the mutations are L234A and L235A (or other conserved ami). (Includes no-acid mutations). In some embodiments, the mutations are P329G, L234A and L2 Includes 35A (or other conserved amino acid mutations). In some embodiments, the mutation is V 234A, G237A, P238S, H268A, V309L, A330S, and P33 Includes 1S (or other conserved amino acid mutations) (for example, for IgG2). In this embodiment, the mutation is one or more mutations, S228P (or another conserved amino acid) (For example, for IgG4) includes acid mutations. In some embodiments, the mutation is one The above mutations are P329G, S228P, and L235E (or another conservative amino acid). (including acid mutations) (for example, for IgG4). In some embodiments, the amino acid position This refers to any antibody numbering scheme (e.g., Edelman (EU) numbering). The position is based on Edelman (EU). In some embodiments, the amino acid position is Edelman (EU) )The position is based on numbering. In some embodiments, the amino acid position is Kab This is a position based on the at numbering scheme. In some embodiments, the amino acid position This is a position based on the Clothia numbering scheme. In some embodiments, The amino acid positions are based on the IMGT numbering scheme. The modifications are wild type. Compared to the Fc region, CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) The amino acid sequence of the Fc region may include at least one modification, and the modification is in the Fc region This results in a decrease or elimination of binding to its homologous receptor. Fc receptors are used by B cells and NK cells. It is found on immune effector cells such as cysts, macrophages, and neutrophils. Constrained by theory Although this is not the case, in wild-type IgG, due to Fc interaction with the Fc receptor (FcR), Downstream effector cell functions, such as stimulating the phagocytic or cytotoxic activity of immune cells. This results in a reduction or elimination of the Fc / FcR interaction, which eliminates the effector function. To bring about.

[0099] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) Compared to cyprizumab, it exhibits reduced binding to the FcγRIIIA receptor. In the application form, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is used by the ship. Compared to rizumab, it exhibits reduced binding to the FcγRIIA receptor. In one embodiment, The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is linked to cyprizumab. In comparison, it shows a decrease in binding to the FcγRI receptor. In one embodiment, the CD2 binding component Compared to cyprizumab, the child (or anti-CD2 antibody or its antigen-binding fragment) has Fc It exhibits increased binding to the γRIIIA receptor. In one embodiment, the CD2 binding molecule (and (Anti-CD2 antibody or its antigen-binding fragment) is compared to cyprizumab with FcγRII It exhibits increased binding to the A receptor. In one embodiment, it is a CD2-binding molecule (or anti-CD2). Antibodies or their antigen-binding fragments bind to FcγRI receptors more effectively than cyprizumab. It exhibits an increase in adhesion. In one embodiment, the CD2 binding molecule (or anti-CD) described herein is used. 2. The antibody or its antigen-binding fragment) has 0% of the binding ability shown by ciprizumab. 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 5 Combine at 5%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) described herein is used. The antigen-binding fragment is shown by cyprizumab (e.g., FcγRIIA, F Compared to the binding capacity for cγRIIIA and / or FcγRI, it is approximately 5%, 10 %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or less Approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% respectively. %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% % high binding ability (e.g., FcγRIIA, FcγRIIIA, and / or FcγRI It has (against C). In one embodiment, the CD2 binding molecule (or anti-C) described herein. D2 antibody or its antigen-binding fragment) is indicated by cyprizumab (e.g., Fc Compared to the binding ability (to γRIIA, FcγRIIIA, and / or FcγRI) , about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% , or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , or 95% lower binding ability (e.g., FcγRIIA, FcγRIIIA, and / or It has (or FcγRI) binding events. However not limited to these, enzyme-linked immunosorbent assays (ELISA) and / or Biac Examples include surface plasmon resonance (SPR) methods such as the ORE system.

[0100] In one embodiment, the Fc region is modified by any suitable method known in the art. It can be modified. In one embodiment, the modification can result in Fc silencing. In one embodiment, the modification may include a mutation in the amino acid sequence of IgG Fc. Morphologically, the modification is a glycosylation site (N297) or a consensus compound containing N297. This may include mutations in the column. In one embodiment, the modification is a mutation that inhibits FcγR and C1q binding. May include variations. In one embodiment, these mutations are mutations K322A, L234A and L This may include any or all of 235A. In some embodiments, CD described herein The 2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) lacks Fc. b may be a CD2 binding molecule (or anti-CD2 anti) described herein. In some embodiments, the CD2 binding molecule (or anti-CD2 anti) described herein may be used. The antibody (either the body or its antigen-binding fragment) is an IgG4 antibody. This is not bound by theory. However, the IgG4 subclass lacks effector functions such as ADCC, so treatment Desirable for the purpose (Davies and Sutton, Immunol Rev.2) 015 Nov;268(1):139-15). In some embodiments, as described herein The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is an IgG2 antibody. While not bound by theory, the therapeutically beneficial characteristics of the IgG2 subclass include: IgG2 does not cross the placenta (Einarsdottir et al., PLo S One. 2014 Sep 24;9(9):e108319), and IgG2, Very low / absent Fc receptor binding ability (Vidarsson et al., F (For example, Ront Immunol. 2014; 5:520) is cited.

[0101] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment may have an antigen-binding variable region and an Fc region. In this state, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding cleavage) described herein is used. The Fc region of one antibody contains a glycosylation consensus sequence in each of the antibody's heavy chains. In one embodiment, the glycosylated consensus sequence is Asn-X-Ser. Morphologically, the glycosylation consensus sequence is Asn-X-Thr. In one embodiment So, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. ) is glycosylated with Asn297. In some embodiments, C described herein The D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is deglycosylated. In one embodiment, the sugar chain attached to the asparagine residue may be an N-linked sugar chain. In one embodiment, the sugar chain attached to the asparagine residue may be an O-linked sugar chain. In certain embodiments, the CD2 binding molecule described herein (or an anti-CD2 antibody or similar) The antigen-binding fragment may contain a single N-linked glycosylation site on Asn297 of the heavy chain. ru.

[0102] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment can be glycosylated with the Fc glycosylation consensus sequence. In the embodiments, the CD2 binding molecule described herein (or an anti-CD2 antibody or its antigen) is used. The binding fragment is deglycosylated. In one embodiment, the CD2 bond described herein is deglycosylated. Deglycosylation of a molecule (or anti-CD2 antibody or its antigen-binding fragment) involves the Fc region This is achieved by modification, specifically by introducing a point mutation at position N297. In one embodiment, the mutation introduced at position 297 (N297) is not limited to these. However, it could be N297G, N297Q, or N297A. This is constrained by theory. However, the N297 point mutation is associated with a lack of glycosylation and silensin in Fc signaling. This brings about a result. In one embodiment, the CD2 binding molecule (or anti-CD2 anti) described herein is used. Deglycosylation of the body or its antigen-binding fragment is a deglycosylation of the CD2-binding molecule (or anti-CD2 anti- This is achieved by chemical or enzymatic degradation of the sugar chain structure (of the body or its antigen-binding fragments). See Section 5.2.3. In certain embodiments, chemical methods of glycolysis or The enzymatic method preserves the Fc amino acid sequence.

[0103] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The constant region of the antigen-binding fragment is switchable between the constant regions of different antibody subclasses. It is not bound by theory, and the variable domain does not change, but the subclass switch Antibodies maintain their specific affinity while interacting with different effector molecules. Valenzuela and Schaub,Transplantation.20 18 Jan;102(1S Suppl 1):S7-S13). In one embodiment, The determination of CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) as described herein. The constant region can be switched with the constant region of a different antibody. In one embodiment, this Through itching, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) This results in an antibody of a different subclass from the original antibody. In one embodiment, the CD2 binding molecule ( The constant region of an anti-CD2 antibody or its antigen-binding fragment maintains specific binding of the variable region. While maintaining its properties, it can be switched with different antibodies. In one embodiment, a CD2-binding molecule The constant region of (or an anti-CD2 antibody or its antigen-binding fragment) is switched with a different antibody. This allows for the preservation of a specific variable region, where a CD2-binding molecule (or anti-CD2 antibody) can also be used. The VH region of the antigen-binding fragment is 80%, 85%, 90%, and 91% of sequence number 01. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% They are identical, and the VL region of the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) The range is 02 of sequence number and 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%. They are identical by %, 96%, 97%, 98%, 99%, or 100%.

[0104] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) It specifically binds to the same epitope within human CD2 as cyprizumab. In one embodiment, CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) are animal-specific anti- Body, human-specific antibody, chimeric antibody, humanized antibody, full-length antibody, antibody fragment, single-chain variable fragment ( scFv), natural antibodies, synthetic antibodies, manipulated antibodies, extended antibodies with additional components added to the Fc region CD2 variant (for example, components include scFv, CH2 domain, and / or CH3 domain) It may include a main component, or a combination thereof. In one embodiment, The antibody Fc region contains a point mutation (e.g., in N297) that results in Fc silencing. In one embodiment, the antibody is IgG1. In another embodiment, the antibody is IgG 2. In one embodiment, the antibody is IgG4. In another embodiment, the antibody is It has a native constant region different from prismab. In one embodiment, the antibody is cypri A native steady-state region different from zumab, and within the Fc region that brings about Fc silencing. It has point mutations. In some embodiments, it has a CD2 binding molecule (or an anti-CD2 antibody or The antigen-binding fragment is a humanized anti-CD2 monoclonal antibody. In certain embodiments, The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is cyprizumab. In one embodiment, the anti-CD2 binding molecule (or anti-CD2 antibody) described herein is also used. The antigen-binding fragment may have a modified Fc region, and modifications are not limited to these. It is not defined, but Fc silencing, switched native steady-state region, or Fc silencing This includes point mutations that result in a new native stationary region that is erased and switched. These combinations of different antibody subclasses and modifications are outlined in Table 3. This process produces different types of 2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments). In one embodiment, the CD2 binding molecule (or anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment may be an IgG1, IgG2, or IgG4 subclass of the antibody. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment may have a modified Fc region, and the modifications are not limited to these. However, Fc silencing, switched native steady-state region, or Fc silencing This may include point mutations that result in a new, switched native steady-state region. These combinations of antibody subclasses and modifications are outlined in Table 3 for CD2-binding molecules. To produce different types of (or anti-CD2 antibodies or their antigen-binding fragments). [Table 3]

[0105] Table 4 provides an overview of the comparison of CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments). do. [Table 4]

[0106] In one embodiment, the CD2-binding molecules described herein, including the example presented above (or Anti-CD2 antibodies (or their antigen-binding fragments) exhibit less ADCC activity compared to cyprizumab. They have little to no immunomodulatory effects, and also retain the immunomodulatory effects exhibited by cyprizumab. .

[0107] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody) provided herein The antigen-binding fragment may have a higher molecular weight than the unmodified IgG1 antibody. In some embodiments, this increase in molecular weight can be achieved by adding a replication region to the molecule. In some embodiments, these areas include means known in the art, and are not limited to them. However, through chemical conjugation, recombination fusion, and covalent bonding, It can be attached to CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments).

[0108] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) Additional regions that may attach to these include, but are not limited to, additional variable heavy chains (VH), additional volatile Modified Light Chain (VL), scFv including fusion of additional VH and additional VL, additional CH2 domain It may include a replication region of the molecule, such as an additional CH3 domain. In this state, the additional region is a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment). It can be attached to the Fc region of ).

[0109] In one embodiment, scFv is a CD2-binding molecule (or an anti-CD2 antibody or its anti- It can be attached to the Fc region of the original binding fragment. In one embodiment, scFv is cyprizumab This may include the fusion of VH and VL. In one embodiment, scFv is VH and VL It can include a fusion with, and VH can include the amino acid sequence of SEQ ID NO: 1, and VL This may include the amino acid sequence of SEQ ID NO: 2. In certain embodiments, scFv is It binds to CD2. In one embodiment, the CDR of scFv is the same as the CDR of cyprizumab. In one embodiment, the CD2 binding molecule (or anti-CD2 antibody) described herein is also used. The scFv attached to the Fc region of the antigen-binding fragment is an epitope on CD2. It binds to the CD2 binding molecule (or anti-CD2 antibody) described herein. In one embodiment, it binds to the CD2 binding molecule (or anti-CD2 antibody) described herein. The scFv attached to the Fc region of the antigen-binding fragment (or the same CD as cyprizumab) It binds to epitope 2. In one embodiment, scFv is an IgG2 antibody or IgG It can be produced from 4 antibodies.

[0110] In one embodiment, an additional CH2 domain may be attached to Fc. In one embodiment, The CH2 domain is at least 80% or 85% of the amino acid sequence of SEQ ID NO: 18 or 19. They may contain amino acid sequences that are 90%, 95%, 98%, or 99% identical. In one embodiment, additional CH2 domains are generated from an IgG2 antibody or an IgG4 antibody. This is possible. In one embodiment, additional CH3 domains can be attached to Fc. In one embodiment, the CH3 domain has at least the amino acid sequence of SEQ ID NO: 20 or 21 It also contains amino acid sequences that are 80%, 85%, 90%, 95%, 98%, or 99% identical. In one embodiment, an additional CH3 domain can be used with an IgG2 antibody or Ig It can be generated from a G4 antibody. In one embodiment, the additional domain is the C-terminus of Fc. They can be attached to the edges. In one embodiment, these domains are known in the art. Stages, including but not limited to chemical conjugations, recombinant fusions, and covalent bonds. Through attachment, CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) They can be attached. In some embodiments, these domains are made by means known in the art. This includes, but is not limited to, chemical conjugation, recombination fusion, and covalent bonding. Attachment occurs via adhesion to CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments). It is possible to do so. Examples of CD2 antibodies or their antigen-binding fragments that can be used in this disclosure and their manufacture are provided below. For example, it is described in U.S. Provisional Application No. 63 / 042,844, which is by reference in its entirety. This specification is incorporated herein.

[0111] 5.2 Production of CD2-binding molecules The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein A method for production is provided herein, where, compared to cyprizumab, antibody-dependent The ability of the molecule to mediate sex cell damage is reduced or eliminated, but the immunity of the molecule The regulatory activity is maintained. CD2 binding molecules (or anti-CD2 antibodies) as described herein are also maintained. Methods for producing the antigen-binding fragment include recombinant expression technology, selection methods, and Transformation into chief cells, and CD2 binding molecules (or anti-CD2 antibodies or their antigen binding cleavage). Purification of the CD2-binding molecule (also) is an example. See Section 5.2.1. (This refers to a fragment of an anti-CD2 antibody or its antigen-binding fragment) (see Section 5.2.2); degradation Lycosylated CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) (section See section 5.2.3; and the CD2-binding molecules (or anti-CD2 antibodies) described herein. Cells containing a vector for recombinant expression of the antigen-binding fragment (or its antigen-binding fragment) (Section 5.2 Methods for producing (see .4) are also provided herein.

[0112] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments are VH of SEQ ID NO: 01, VL of SEQ ID NO: 02, and CH of SEQ ID NO: 09. , and CL of SEQ ID NO: 14; VH of SEQ ID NO: 01; VL of SEQ ID NO: 02; SEQ ID NO: 10 CH, and CL of SEQ ID NO: 14; VH of SEQ ID NO: 01, VL of SEQ ID NO: 02, SEQ ID NO: 1 CH of 1, and CL of sequence number 14; VH of sequence number 01, VL of sequence number 02, sequence number CH of sequence number 12, and CL of sequence number 14; VH of sequence number 01, VL of sequence number 02, This may include CH in column number 13 and CL in sequence number 14. In some embodiments, this specification includes The CD2-binding molecule described (or anti-CD2 antibody or its antigen-binding fragment) is sequence number 0. VH of 1, VL of SEQ ID NO: 02, CH of SEQ ID NO: 09, and CL of SEQ ID NO: 15; sequence VH of sequence number 01, VL of sequence number 02, CH of sequence number 10, and CL of sequence number 15; VH in SEQ ID NO: 01, VL in SEQ ID NO: 02, CH in SEQ ID NO: 11, and C in SEQ ID NO: 15 L; VH of SEQ ID NO: 01, VL of SEQ ID NO: 02, CH of SEQ ID NO: 12, and SEQ ID NO: 15 CL of; VH of SEQ ID NO: 01, VL of SEQ ID NO: 02, CH of SEQ ID NO: 13, and SEQ ID NO: It may include 15 CLs.

[0113] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments are the heavy chain of SEQ ID NO: 16; the VL of SEQ ID NO: 02; and the C of SEQ ID NO: 14. L; Heavy chain of SEQ ID NO: 16; VL of SEQ ID NO: 02, and CL of SEQ ID NO: 15; SEQ ID NO: 01 VH of SEQ ID NO: 09 CH; and SEQ ID NO: 17 light chain; SEQ ID NO: 01 VH; SEQ ID NO: CH of 10; and light chain of SEQ ID NO: 17; VH of SEQ ID NO: 01; CH of SEQ ID NO: 11; and Light chain of SEQ ID NO: 17; VH of SEQ ID NO: 01; CH of SEQ ID NO: 12; and light chain of SEQ ID NO: 17 Chain; VH of SEQ ID NO: 01; CH of SEQ ID NO: 13; and light chain of SEQ ID NO: 17; or sequence number It may include the heavy chain of number 16 and the light chain of sequence number 17.

[0114] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) This may include expanded variants. In some embodiments, the CD2-binding molecule described herein ( The Fc of an anti-CD2 antibody or its antigen-binding fragment is the CD2 binding molecule (or anti-C The molecular weight of the D2 antibody (or its antigen-binding fragment) is 10kDa, 11kDa, or 12kDa. , 13kDa, 14kDa, 15kDa, 16kDa, 17kDa, 18kDa, 19k Da, 20kDa, 21kDa, 22kDa, 23kDa, 24kDa, 25kDa, 2 6kDa, 27kDa, 28kDa, 29kDa, 30kDa, 31kDa, 32kDa , 33kDa, 34kDa, 35kDa, 36kDa, 37kDa, 38kDa, 39k Da, 40kDa, 41kDa, 42kDa, 43kDa, 44kDa, 45kDa, 4 6kDa, 47kDa, 48kDa, 49kDa, 50kDa, 51kDa, 52kDa , 53kDa, 54kDa, 55kDa, 56kDa, 57kDa, 58kDa, 59k In some embodiments, the specification includes additional regions to increase Da, or 60kDa. The Fc of the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the book is: The molecular weight of the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is 10 kD a~15kDa, 11kDa~16kDa, 12kDa~17kDa, 13kDa~18 kDa, 14kDa~19kDa, 15kDa~20kDa, 16kDa~21kDa, 17kDa~22kDa, 18kDa~23kDa, 19kDa~24kDa, 20kDa a~25kDa, 21kDa~26kDa, 22kDa~27kDa, 23kDa~28 kDa, 24kDa~29kDa, 25kDa~30kDa, 26kDa~31kDa, 27kDa~32kDa, 28kDa~33kDa, 29kDa~34kDa, 30kDa a~35kDa, 31kDa~36kDa, 32kDa~37kDa, 33kDa~38 kDa, 34kDa~39kDa, 35kDa~40kDa, 36kDa~41kDa, 37kDa~42kDa, 38kDa~43kDa, 39kDa~44kDa, 40kDa a~45kDa, 41kDa~46kDa, 42kDa~47kDa, 43kDa~48 kDa, 44kDa~49kDa, 45kDa~50kDa, 46kDa~51kDa, 47kDa~52kDa, 48kDa~53kDa, 49kDa~54kDa, 50kDa a~55kDa, 51kDa~56kDa, 52kDa~57kDa, 53kDa~58 kDa, increasing in the range of 54kDa to 59kDa, or 55kDa to 60kDa. This includes additional areas.

[0115] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) The replicated region can be attached to the molecule to produce an expanded variant. In one embodiment, this Our domain includes, but is not limited to, means known in the art, chemical conjugates CD2-binding molecules (or anti-C) are formed through recombination, recombination fusion, and covalent attachment. It can be attached to the Fc region of a D2 antibody or its antigen-binding fragment.

[0116] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) The expanded variant can originate from IgG1, IgG2, or IgG4. In this embodiment, an additional scFv is added to a CD2 binding molecule (or an anti-CD2 antibody or its anti- It can be attached to the Fc of the original binding fragment to produce an expanded variant (Figure 7, Figure 8A). In this embodiment, scFv may include VH and VL, where VH is the ami of SEQ ID NO: 1 The ano acid sequence is at least 80%, 85%, 90%, 95%, 98%, or 99% identical. It may contain an amino acid sequence, and VL contains at least 80 amino acids from the amino acid sequence of SEQ ID NO: 2. Contains amino acid sequences that are identical by %, 85%, 90%, 95%, 98%, or 99%. It is possible.

[0117] In one embodiment, an additional CH2 domain is added to a CD2-binding molecule (or an anti-CD2 antibody). (The antigen-binding fragment) can be attached to the Fc to produce an expanded variant (Figures 7 and 8). B) In one embodiment, the additional CH2 domain is an amino acid of SEQ ID NO: 18 or 19. The sequence is at least 80%, 85%, 90%, 95%, 98%, or 99% identical to the sequence. It may contain a mino acid sequence. In one embodiment, an additional CH3 domain is CD2-bound. Attach to the Fc of the molecule (or anti-CD2 antibody or its antigen-binding fragment) to create an expanded barrier. It can produce a sequence (Figures 7 and 8C). In one embodiment, an additional CH3 domain is sequence Amino acid sequence number 20 or 21 and at least 80%, 85%, 90%, 95%, 98 It may include amino acid sequences that are % or 99% identical. In a preferred embodiment, Additional fragments or domains may be attached to the C-terminus of Fc. In one embodiment, expanded anti The CD2 variant may be an IgG2 antibody. In one embodiment, an extended anti-CD2 barrier The antibody may be an IgG4 antibody. Details of the expanded anti-CD2 variant are shown in Table 5.

[0118] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) The additional regions attached to it may contain unrelated or artificial amino acid sequences. Morphologically, it attaches to CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments). The additional regions may include fragments such as structural domains derived from other human proteins. In one embodiment, a CD2 binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) is attached to it. The additional region attached may contain a fragment of a domain derived from another human protein. In the application morphology, the addition of such additional regions in humans involves the parent CD2 binding molecule (and It does not interfere with the binding activity of anti-CD2 antibodies or their antigen-binding fragments, and / or This is obtained in relation to the parent CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment). It does not increase the immunogenicity of the CD2 binder. [Table 5]

[0119] 5.2.1 Recombinant expression system Method for producing CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) The method is described herein. CD2 binding molecules (or anti-CD2 antibodies) described herein are also The antigen-binding fragment (or its antigen-binding fragment) can be produced by any suitable expression method known in the art. It is possible to produce antibodies. These methods of producing antibodies are not limited to these, Hybridoma cells, bacteria, yeast cells, insect cells, transgenic animals, trans For phenic plants, phage displays, ribosome displays, and mammalian cell lines One example is the use of recombinant expression in the same manner as cyprizumab. A method for producing recombinant antibodies that bind to CD2 in an epitope involves the VH and V of the antibody. Isolating, amplifying, and cloning the L gene; joining the heavy chain fragment and the light chain fragment. This then involves cloning these strands into a special phage vector. During the process, the antibody is presented on the cell surface and selected by any suitable option known in the art. These methods can be used to select antibodies that have the desired binding specificity. These are not limited to, but include panning, the use of paramagnetic beads, and fluorescence-activated Celsius. FACS, enzyme-linked immunosorbent assay (ELISA), and / or Bi Examples include surface plasmon resonance (SPR) methods such as the acore system.

[0120] After selection, the antibody gene can be moved to an expression vector. In one embodiment, a powerful pro The motor is also inserted into the expression vector. The promoter is CMV or SV40, etc. Illus promoter; or elongation factor (EF)-1 promoter, UBC, PGK, also The expression vector may be a non-viral promoter such as the CAG promoter. The cell line is transformed and integrated into the host cell genome. In one embodiment, the host cell line This may include bacterial, yeast, or mammalian cell lines. In certain embodiments, recombinant The mammalian cell lines that can be used as host cell lines for antibody production are limited to these. Although not, Chinese hamster ovary (CHO) cell line, NS0 cell line, Sp2 / 0 Examples include cell lines, PER.C6 cell line, and human fetal kidney (HEK) cell line.

[0121] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments are recovered from host cell cultures and any appropriate method known in the art. It can be purified by various methods. Standard antibody purification methods are not limited to these. However, protein A affinity chromatography and Q-Sepharose anion chromatography are not available. Cation exchange chromatography, sulfopropyl Sepharose cation exchange chromatography, High-performance liquid chromatography (HPLC), protein G purification, ammonium sulfate or Ethanol precipitation, acid extraction, phosphocellulose chromatography, hydrophobic interaction chromatography Chromatography, affinity chromatography, hydroxyapatite chromatography Examples include roughy chromatography and lectin chromatography.

[0122] 5.2.2 Production of CD2-binding fragments In addition to the above procedure steps, perform deformation or additional steps to produce CD2 binding fragments. These CD2-binding molecular fragments (or anti-CD2 antibodies or their antigen-binding fragments) can be produced. ) are not limited to these, but include Fab, F(ab')2, scFv, and sdA b can be cited. In certain embodiments, the produced fragment is the same as cyprizumab. It binds to an epitope. In one embodiment, the procedure for producing CD2-bound scFv is In addition to the linker, the VH and VL genes of the antibody are isolated, amplified, and clonin This includes linking. A flexible peptide linker is necessary to join the VH and VL fragments. In one embodiment, the procedure for producing CD2-bound sdAb is performed using a camel or This includes isolating, amplifying, and cloning the VH region of sharks. This consists only of the VH region, which does not include the VL region attached to the steady-state region.

[0123] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment can be treated with papain to produce a Fab-binding fragment. In the embodiments, the CD2 binding molecule described herein (or an anti-CD2 antibody or its antigen) is used. The binding fragment can be treated with pepsin to produce F(ab')2. Specific implementation In form, VH of Fab, F(ab')2, scFv, or sdAb as described herein. The sequence of regions is sequence number 01 and 80%, 85%, 90%, 91%, 92%, 93%, 94 They are identical by %, 95%, 96%, 97%, 98%, 99%, or 100%. Specific implementation In terms of form, VL of Fab, F(ab')2, scFv, or sdAb as described herein. The sequence of regions is sequence number 02 and 80%, 85%, 90%, 91%, 92%, 93%, 94 They are identical by %, 95%, 96%, 97%, 98%, 99%, or 100%.

[0124] 5.2.3 Deglycosylation of CD2-binding antibodies This specification describes the deglycosylated CD described in Section 5.1.4. A method for producing a 2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) In some embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigenic binding molecule) is used. The sugar chain of the composite fragment is treated with chemicals such as trifluoromethanesulfonic acid (TFMS). It can be modified using the method. In another embodiment, a CD2-binding molecule (or anti-C) is used. The sugar chains of D2 antibodies or their antigen-binding fragments can be modified using enzymatic methods. In certain embodiments, the chemical or enzymatic method of glycolysis is used for CD2 as described herein. The Fc amino acid sequence of the binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is preserved. ru.

[0125] CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein Enzymes that can be used to modify sugar chains include, but are not limited to, peptide-N - Glycosidase F (PNGase F), peptide-N-glycosidase A (PNGas eA), endoglycosidase H, endoglycosidase F, endo-β-N-acetyl Glucosaminidase (EndoS), endo-α-N-acetylgalactosaminidase, Sialidase A, β1-4 galactosidase S, β-N-acetylhexosaminidase, And EndoS2 can be cited. In one embodiment, the CD2 connection described herein The compound molecule (or anti-CD2 antibody or its antigen-binding fragment) is processed by endoglycosidase. In certain embodiments, the CD2-binding molecule (or anti-CD2 antibody) described herein is used. Endoglycosiders used to break down the sugar chain structure of the antigen-binding fragment (or its antigen-binding fragment) Ze is EndoS (Sjogren et al., Glycobiology, (2015, vol.25, no.10, 1053-1063). In certain embodiments, this Glycans of CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) as described in the specification The endoglycosidase used to break down the structure is EndoS2 (Sjo gren et al.,Biochem.J.(2013)455,107-118) .

[0126] EndoS and EndoS secreted from Streptococcus pyogenes oS2 specifically removes N-linked glycans from the chitobiose core of human IgG heavy chains. EndoS, an endoglycosidase derived from Streptococcus pyogenes. Incubation with 2 revealed two GlcNAcs in the chitobiose core of the N-glycan. The residue is cleaved, but the core GlcNAc remains unchanged. In one embodiment, as specified herein The CD2-binding molecules described are treated with EndoS or EndoS2. Both EndoS2 and B remove complex glycans, but EndoS2 removes high mannose glycans. Remove.

[0127] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is an IgG antibody. In some embodiments, the CD2 antibody described herein is used. The synthesizer (or anti-CD2 antibody or its antigen-binding fragment) has at least one constant region of the heavy chain. It also has another consensus N-linked glycosylation site. In some embodiments, as specified herein The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the scheme It supports at least one of the following oligosaccharides shown in 1. In a particular embodiment, The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are It is treated with EndoS. In certain embodiments, the CD2 binding molecule described herein (and The anti-CD2 antibody (or its antigen-binding fragment) is treated with EndoS2. Specific implementation In terms of form, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding) as described herein. The fragment is deglycosylated. In certain embodiments, the CD2 bond described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is an IgG antibody, and cyprisma Compared to B, the ability of antibodies to mediate antibody-dependent cell damage is reduced or eliminated. However, the immunomodulatory activity of the antibodies is maintained. Scheme 1: [ka] White triangle: Fucose; White square: N-acetylglucosamine; Gray circle: Mannose; White circle: Galactose.

[0128] In one embodiment, the deglycosylation of the CD2-binding molecule described herein is performed in the Art of the Art. Deglycosylation can be determined by any suitable method known to be used. Standard methods include, but are not limited to, size exclusion chromatography. Analysis, tertiary structure analysis, thermal stability evaluation, denaturation with guanidine HCl, and papain digestion. The resistance and heavy chain as measured by liquid chromatography-mass spectrometry (LC-MS) Converted mass data is provided.

[0129] 5.2.4 Cells and Vectors The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein Cells expressing these molecules are provided herein. CD2-binding molecules (or anti-CD2 molecules) described herein are provided herein. Ex vivo cells that recombinantly express (2 antibodies or their antigen-binding fragments) are provided herein. Provided: CD2 binding molecules (or anti-CD2 antibodies or their antigen binding) as described herein. Expression vectors containing nucleotide sequences encoding fragments are also provided herein. In this embodiment, the cells are ex vivo cells.

[0130] In one embodiment, gene expression can be placed under the control of a promoter. The promoter is a viral promoter such as CMV or SV40; or an elongation factor (EF) - Nonviral promoters such as 1 promoter, UBC, PGK, or CAG promoter It may be a ter. In one embodiment, the CD2 binding molecule (or anti-CD2) described herein. A nucleotide sequence encoding an antibody (or its antigen-binding fragment) is crossed into a suitable vector. To perform. In one embodiment, the vector may be a mammalian vector. Morphologically, the vector can be a viral vector. In one embodiment, an expression vector The cells are transformed into cells (e.g., ex vivo cells). In one embodiment, the cells are The vector is expressed so that the nucleotide sequence is transcribed and translated by the host cell. In some embodiments, the host cell line may include a bacterial, yeast, or mammalian cell line. In certain embodiments, the host cell line is a mammalian cell. In some embodiments, These are the only mammalian cell lines that can be used as host cell lines for replacement antibody production. Although not definitively established, Chinese hamster ovary (CHO) cell line, NS0 cell line, Sp2 / Examples include the 0 cell line, the PER.C6 cell line, and the human fetal kidney (HEK) cell line.

[0131] In one embodiment, the host cell line may be genetically modified. In one embodiment, the modification is This can be done to improve the productivity of recombinant protein expression. In one embodiment, Modifications can be performed to act on recombinant proteins expressed by host cells. In a specific embodiment, the host cell line is configured to express the desired glycosyltransferase. It is genetically modified. In certain embodiments, the host cell line is EndoS or End The gene has been modified to express oS2.

[0132] 5.3 Therapeutic Use and Methods The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein Methods for use are provided herein, and hereby compared with cyprizumab, antibody-dependent The ability of the molecule to mediate sex cell damage is reduced or eliminated, but the immunity of the molecule The regulatory activity is maintained. Provided herein are chronic or acute immune system This is a method for treating human subjects with inflammatory disorders. Furthermore, in this specification, Methods are also provided to prevent elephants from developing chronic or acute inflammatory disorders of the immune system. In further embodiments, acute or chronic disorders of the immune system may be, but are not limited to, transferable. Graft-versus-host disease (GVHD), rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, psoriasis, ulcerative colitis Enteritis, inflammatory bowel disease (Crohn's disease), celiac disease, Sjögren's disease, lupus, multiple sclerosis Diseases, focal segmental glomerulosclerosis, atopic dermatitis, amyotrophic lateral sclerosis, primary biliary hepatitis These may include cirrhosis, primary sclerosing cholangitis, and severe asthma. In one embodiment, the method For human subjects with chronic or acute inflammatory disorders of the immune system, the CD2 binding described herein A molecule (or an anti-CD2 antibody or its antigen-binding fragment) or the CD2 antibody as described herein. Administering a pharmaceutical composition containing a compound molecule (or an anti-CD2 antibody or its antigen-binding fragment) This includes, in some embodiments, the CD2 binding molecule (or anti-CD2 antibody) described herein. A pharmaceutical composition containing (or its antigen-binding fragment) or the CD2 binding described herein is for patients It is administered for a long period of time.

[0133] Furthermore, this specification refers to the treatment of human subjects undergoing organ or bone marrow transplantation. A method is also provided. In one embodiment, this method involves the CD2-binding molecule described herein ( This includes administering an anti-CD2 antibody or its antigen-binding fragment to the organ to be transplanted. In one embodiment, the method involves applying the CD2-binding molecule (or antibody) described herein to a human subject. CD2 antibody or its antigen-binding fragment) or CD2-binding molecule as described herein (or The procedure includes administering a pharmaceutical composition containing an anti-CD2 antibody or its antigen-binding fragment.

[0134] The method provided herein involves applying an anti-CD2 antibody or its antigen-binding fragment to a target and CT This may include administering an LA-4 costimulator. In some embodiments, an anti-CD2 anti- The body or its antigen-binding fragments and CTLA-4 costimulatory blockers cause immune-related disorders in the subject. Alternatively, it is administered to a subject to prevent or treat a disease. In some embodiments, this The method provided in the specification involves applying an anti-CD2 antibody or its antigen-binding fragment to a target, CTLA- 4. The administration of a costimulator and another activator. In some embodiments, the target The patient has been diagnosed with at least one immune-related disorder or disease. In some embodiments, The subjects have at least one symptom related to an immune-related disorder or disease. In one embodiment, the method provided herein is used to treat an immune-related disorder or disease. To prevent the disease from developing in elephants. The method provided herein also involves an anti-CD2 antibody against the target. By administering the antigen-binding fragment and CTLA-4 costimulatory blocker to the transplant recipients... This may include maintaining immune tolerance to the target. In some embodiments, the target is immune-related There is a predisposition to developing a disability or disease, or a high probability of developing one. Several implementations Morphologically, the subjects have at least one immune-related disorder or disease, at least two, and fewer Both are diagnosed with three, at least four, or more than four immune-related disorders or diseases. They are diagnosed, highly likely to develop them, or have symptoms related to them. In some embodiments, immune-related disorders or diseases are acute or chronic disorders of the immune system. That is the case.

[0135] In some embodiments, the anti-CD2 antibody or its antigen-binding fragment is CTLA-4 co-stimulating. The stimulant blocker is administered to the target before, simultaneously with, or after the administration of the stimulant blocker. In several embodiments, the initial dose of the anti-CD2 antibody or its antigen-binding fragment is CTLA-4 Before, simultaneously with, or after the administration of the first dose of a costimulator to the subject Therapeutic agents (e.g., anti-CD2 antibodies or their antigen-binding fragments and CTLA-4 receptors) are administered. The dosage of the stimulant blocker is not limited to these, but depends on the type of tissue affected and the treatment being performed. The type of autoimmune disease, the severity of the disease, the patient's health status, and their response to drug treatment are all factors to consider. It depends on many factors, including the answer. Therefore, the dosage of the drug should be determined according to each target and method of administration. It may change. In some embodiments, a CTLA-4 costimulator is administered to the subject. If not present, the dose of anti-CD2 antibody or its antigen-binding fragment is not therapeutically effective. In that embodiment, if the anti-CD2 antibody or its antigen-binding fragment is not administered to the subject, C The dose of TLA-4 costimulators is not therapeutically effective. In some embodiments, CT When LA-4 costimulatory blockers are also administered, the anti-CD2 antibody or its antigen-binding fragment A smaller dose is administered to the target. In some embodiments, an anti-CD2 antibody or When antigen-binding fragments are also administered, a lower dose of CTLA-4 costimulator is effective. It is administered to elephants. In some embodiments, the dose is about 2%, 5%, 7%, 10%, 15% %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65 %, 70%, or more than 70%; less than or at least about 2%, 5%, or 7%. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% , 60%, 65%, 70%, or less than 70%. In some embodiments, The dosages are approximately 2 times, 5 times, 7 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, and 4 times. 0x, 45x, 50x, 55x, 60x, 65x, 70x, 80x, or more than 80x The amount obtained is small, or at least about 2 times, 5 times, 7 times, 10 times, 15 times, 20 times, 25 times x, 30x, 35x, 40x, 45x, 50x, 55x, 60x, 65x, 70x, 80x The amount is less than double or 80 times the original amount. In some embodiments, the dose is approximately 1 mg / kJ g, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 12mg / kg, 15mg / k g, 17 mg / kg, 20 mg / kg, or an amount less than 20 mg / kg, or at least about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 1 2 mg / kg, 15 mg / kg, 17 mg / kg, 20 mg / kg, or 20 mg / The amount exceeding kg is small. In some embodiments, the dose is approximately 5 mg, 10 mg, 20 mg g, 30mg, 40mg, 50mg, 75mg, 100mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500m g, or an amount less than 500 mg, or at least about 5 mg, 10 mg, 2 0mg, 30mg, 40mg, 50mg, 75mg, 100mg, 150mg, 175m g, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 50 0 mg, or a small amount exceeding 500 mg.

[0136] Examples of immune-related disorders or diseases that can be treated by the methods described herein include: These are not limited to systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, and many other conditions. Arthroid-type juvenile idiopathic arthritis (JIA), osteoarthritis, juvenile chronic arthritis, spondyloarthritis, all Physical scleroderma, idiopathic inflammatory muscle disease, Sjögren's syndrome, systemic vasculitis, sarcoidosis S, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus Immune-mediated renal disease, demyelinating diseases of the central or peripheral nervous system, idiopathic demyelinating polyneuropathy, Gira N'Barré syndrome, Lyme disease, chronic inflammatory demyelinating polyneuropathy, hepatobiliary disease, infectious or Autoimmune chronic active hepatitis, primary biliary cirrhosis, Goodpasture syndrome, granulomatous liver disease Inflammation, sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive bowel disease, Whipple's disease, autoimmune disease, This includes immune-mediated skin diseases, bullous skin diseases, erythema multiforme, contact dermatitis, psoriasis, and allergic diseases. Patients, asthma, allergic rhinitis, atopic dermatitis, food allergies, urticaria, multiple sclerosis, Uveitis, immune disorders of the lung, eosinophilic pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, and complications associated with organ transplantation. Diseases associated with tissue transplantation, graft rejection, graft-versus-host disease (GVHD), DeBic Diseases, acute disseminated encephalomyelitis, acute demyelinating optic neuritis, demyelinating transverse myelitis, Miller-Fischer - Syndrome, cerebrospinal radiculopathy, acute demyelinating polyneuropathy, tumor-like multiple sclerosis, Balo-type concentric sclerosis, alopecia areata, ankylosing spondylitis, Meniere's disease, antiphospholipid syndrome, mixed connective tissue disease, autoimmune Addison's disease, myasthenia gravis, autoimmune hepatitis, pemphigus vulgaris, Behçet's disease, bullous pemphigoid, polyarteritis nodosa, cardiomyopathy, polychondritis, celiac pruritus, polyglandular syndrome, chronic fatigue syndrome (CFID), polymyalgia rheumatica, chronic inflammatory demyelinating polymyositis and dermatomyositis, primary agammaglobulinitis Phosphateemia, Churg-Strauss syndrome, bullous pemphigoid, Crest syndrome, Raynaud's phenomenon, cold agglutinin disease, Reiter's syndrome, Crohn's disease, rheumatic fever, discoid rash, essential mixed cryoglobulinemia, fibromyalgia, scleroderma, Graves' disease, Sjögren's syndrome, Stiffman syndrome, Hashimoto's thyroiditis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, idiopathic thrombocytopenic purpura (ITP), ulcerative colitis, focal segmental glomerulosclerosis, IgA nephropathy, insulin-dependent diabetes mellitus (Type 1), lichen planus, and vitiligo are among the conditions that can be treated.

[0137] In some embodiments, the immune-related disorder or disease is rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis. Idiopathic arthritis (JIA) and / or psoriatic arthritis. In some embodiments, The immune-related disorder or disease is rheumatoid arthritis. In some embodiments, the immune-related disorder Harm or disease is a disorder or disease related to organ transplantation, or a disorder or disease related to tissue transplantation. It is a disease. In some embodiments, an immune-related disorder or disease affects any organ in the human body. It is a disorder or disease related to organ and / or tissue transplantation. In some embodiments, it is an immune disorder. Disease-related disorders or diseases include lung, kidney, pancreas, heart, liver, skin, stomach, intestine, and gastrointestinal tract transplants. / or disorders or diseases related to tissue transplantation from them. In some embodiments Immune-related disorders or diseases are disorders or diseases associated with liver transplantation and / or liver tissue transplantation. It is a disease.

[0138] In some embodiments, the methods provided herein involve obtaining organs and / or from a donor. Anti-CD2 antibodies or their antigen-binding fragments and CTLA-4 costimulation to tissue transplant recipients. This includes administering an inhibitor. When used herein, the donor is the organ to be transplanted. For example, an individual from which the liver or kidneys are taken. The donor is of the same species as the recipient. There is a possibility that the donor may be alive or dead. The donor is a receptive donor. In some cases, it may be related to the pient, and in other cases, it may not be related to the recipient. If used, the recipient shall have the transplanted organ (e.g., liver or kidney) and / or The recipient is the person who will receive the organ. The recipient may or may not be related to the donor. In some cases, this may not be the case. The recipient's HLA may match that of the donor, or it may not match. It is possible.

[0139] In some embodiments, the transplanted organ (e.g., liver or kidney) is the entire organ, or the organ itself. In some cases, it may be tissue or cells derived from an organ. In some embodiments, the whole organ ( For example, a liver or kidney is transplanted. In some embodiments, an organ (for example, a liver) is transplanted. Alternatively, a portion of a kidney may be transplanted.

[0140] In some embodiments, the methods described herein involve the binding of an anti-CD2 antibody or its antigen. The fragment and CTLA-4 costimulator were administered to subjects who had undergone splenectomy (for example, those who had received organ transplants). This includes administering the drug to patients who have undergone splenectomy prior to the procedure.

[0141] The procedure for obtaining and transplanting organs (e.g., liver or kidney) is well known to those skilled in the art. Any procedure for surgical removal from and surgical transplantation in the recipient is provided herein. It can be used in conjunction with the method of providing. In one embodiment, an organ (e.g., liver or The kidneys can be treated between removal and transplantation.

[0142] In one embodiment, the patient was at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or less Tomo 1st year, 2nd year, 3rd year, 4th year, 5th year, 6th year, 7th year, 8th year, 9th year, 10th year, 11th year, 12th year , 13, 14, 15, 16, 17, 18, 19, 20, or 20 years I will receive treatment for a long period of time.

[0143] In some embodiments, the methods described herein result in a reduction of cell proliferation. In some embodiments, the methods described herein include an anti-CD2 antibody or its antigen-binding fragment and After both the CTLA-4 costimulator and the CTLA-4 costimulator were administered to the subjects, biological samples obtained from the subjects were collected. This results in a decrease in the number of cells inside. In some embodiments, an anti-CD2 antibody or its antigenicity The decrease in cell count after administration of both the composite fragment and the CTLA-4 costimulator to the target was observed in the case of Prior to administration of anti-CD2 antibodies or their antigen-binding fragments to elephants, CTLA-4 costimulatory blockade is performed on the subjects. Before administering the agent, or both, the reduction in cell count and ratio in the biological sample obtained from the subject. It is relatively large. In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and CT The decrease in cell count after administration of both LA-4 costimulatory blockers to the target group was observed in comparable subjects. Compared to the reduction in cell count by equivalent methods used to treat immune-related disorders, In this equivalent method, an anti-CD2 antibody or its antigen-binding fragment and CTLA-4 costimulatory blockade are used. It does not include administering both the discontinuing agent. In some embodiments, equivalent subjects are the subject and Those who have been diagnosed with the same immune-related disorder, or those suspected of having the same immune-related disorder as the subject In some embodiments, equivalent subjects have at least one symptom common to the subject. In some embodiments, the reduction is approximately 5%, 10%, 15%, 20%, 25%, and 3%. 0%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 8 0%, 85%, 90%, 100%, or greater than or less than 100% Approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%. , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, if The percentage is greater than 100%. In some embodiments, the anti-CD2 antibody or its antigenicity The raw materials obtained from subjects after administration of both the composite fragment and the CTLA-4 costimulator were administered to the subjects. The number of cells in a somatic sample is determined by anti-CD2 antibody or its antigen-binding fragment and CTLA-4 costimulation. Before both blocking agents are administered to the target, or before the anti-CD2 antibody or its antigen-binding fragment is administered, This is obtained from subjects after one (but not both) of the CTLA-4 costimulators have been administered to them. Compared to the number of cells in the biological sample, approximately 5%, 10%, 15%, 20%, 25%, and 30%. %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 %, 85%, 90%, 95%, 100%, or less than 100% At least approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or less than 100%.

[0144] In some embodiments, the methods described herein result in a reduction in the level of CD2. In some embodiments, the methods described herein involve the binding of an anti-CD2 antibody or its antigen. After both the fragment and the CTLA-4 costimulator were administered to the subjects, the raw materials obtained from the subjects were... This results in a decrease in the level of CD2 in the body sample. In some embodiments, an anti-CD2 antibody is used. Or, CD after both the antigen-binding fragment and the CTLA-4 costimulatory blocker have been administered to the target. The decrease in level 2 is before administration of anti-CD2 antibody or its antigen-binding fragment to the subject, Before administration of a CTLA-4 costimulator, or both, biological samples obtained from the subject The decrease in CD2 levels is significant compared to the decrease in CD2 levels within the body. In some embodiments, an anti-CD2 antibody is used. or C after both the antigen-binding fragment and the CTLA-4 costimulatory blocker have been administered to the target. A decrease in D2 levels is used to treat immune-related disorders in comparable subjects. Compared to the decrease in CD2 levels using methods such as the above, this method is more effective than equivalent methods using anti-CD2 antibodies. or does not involve the administration of both the antigen-binding fragment and the CTLA-4 costimulator. In that embodiment, equivalent subjects are diagnosed with the same immune-related disorder as the subjects, or The subject is suspected of having the same immune-related disorder as the subject. In some embodiments, equivalent subjects are , having at least one symptom common to the subject. In some embodiments, the reduction is about 5 %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or 1 Greater than 00%, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, Larger than 80%, 85%, 90%, 100%, or over 100%. Several implementations Morphologically, both the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulatory blocker are The level of CD2 in biological samples obtained from subjects after administration to the subjects was also measured by the level of anti-CD2 antibodies. Or, before both the antigen-binding fragment and the CTLA-4 costimulatory blocker are administered to the target, Either an anti-CD2 antibody or its antigen-binding fragment, or one of the CTLA-4 costimulatory blockers (both) (Not by method) The level of CD2 in a biological sample obtained from the subject after administration and the ratio In comparison, approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or less than 100%, or at least about 5%, 10%, 15% %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65 %, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or 100% It's less than that.

[0145] In some embodiments, the methods described herein produce synergistic effects. In embodiments, the methods described herein involve an anti-CD2 antibody or its antigen-binding fragment and CT Both LA-4 costimulatory blockers, when administered to the subject, produce a synergistic effect within the subject. In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and CTLA-4 costimulatory blockade are used. Administering a discontinuing agent to the target is an anti-CD2 antibody or its antigen-binding fragment or CTLA-4 The effect is synergistic compared to administering a costimulator to only one of the factors rather than both. In some embodiments, the methods described herein result in a reduction of the alloimmune response. In some embodiments, the methods described herein involve an anti-CD2 antibody or its antigen-binding fragment. After both the CTLA-4 costimulatory blocker and the CTLA-4 costimulatory blocker were administered to the subjects, an alloimmune response occurred within the subjects. This results in a decrease. In some embodiments, an anti-CD2 antibody or its antigen-binding fragment and C The decrease in the alloimmune response after administration of both TLA-4 costimulatory blockers to the subjects indicates that Prior to administration of an anti-CD2 antibody or its antigen-binding fragment, administration of a CTLA-4 costimulator to the subject. This is greater compared to the decrease in the alloimmune response within the subject before administration, or both before administration. In one embodiment, an anti-CD2 antibody or its antigen-binding fragment and a CTLA-4 costimulatory blocker are used. A decrease in the alloimmune response after administration of both to the target group indicates an immune-related disorder in the same target group. The reduction in the alloimmune response is significantly greater compared to equivalent methods used to treat the condition. An equivalent method involves both an anti-CD2 antibody or its antigen-binding fragment and a CTLA-4 costimulator. It does not include administration to subjects. In some embodiments, equivalent subjects have the same immune response as the subject. The individual has been diagnosed with a related disorder, or is suspected of having the same immune-related disorder as the subject. In some embodiments, equivalent subjects have at least one symptom common to the subject. In several embodiments, the reduction is approximately 5%, 10%, 15%, 20%, 25%, 30%, and 3%. 5%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 8 5%, 90%, 100%, or greater than 100%, or at least about 5% 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or 10 It is greater than 0%. In some embodiments, the anti-CD2 antibody or its antigen-binding fragment and The allogeneic immune response within subjects after administration of both CTLA-4 costimulators was observed. Both anti-CD2 antibodies or their antigen-binding fragments and CTLA-4 costimulatory blockers are being administered to the target population. Before administration, or before use, anti-CD2 antibody or its antigen-binding fragment or CTLA-4 costimulatory blockade. Compared to the alloimmune response within a subject after administration of one (but not both) of the discontinuing agents to the subject. , about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% %, or less than 100%, or at least about 5%, 10%, 15%, 2% 0%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 7 0%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100% few.

[0146] 5.3.1 Treatment of patients with inflammatory immune disorders and suitable subjects for treatment This specification describes the treatment of human subjects with chronic or acute inflammatory disorders of the immune system. This is a method for treating an immune-related disorder or disease. This describes a method for treating human subjects. What is described herein is an immune response in a subject. This is a method for preventing a disorder or disease. Individuals with inflammatory immune disorders may have a disorder. For the purpose of treating symptoms, the methods described herein may be followed. In one embodiment, Acute or chronic disorders of the immune system include, but are not limited to, graft-versus-host disease (GVHD). Rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, psoriasis, ulcerative colitis, inflammatory bowel disease (Cholera) Sjögren's disease, celiac disease, Sjögren's disease, lupus, multiple sclerosis, focal segmental glomerulosclerosis Diseases, atopic dermatitis, amyotrophic lateral sclerosis, primary biliary cirrhosis, and primary sclerosing biliary disease This can be ductitis and severe asthma. In some embodiments, cyprizumab depletion is autoimmune. It can be used to treat diseases. In some embodiments, a depleted CD2 binding molecule ( (or anti-CD2 antibodies or their antigen-binding fragments) are used in combination with CTLA-4 costimulatory blockers. Used in combination with and / or other agents described herein (e.g., immunosuppressants) To treat subjects with chronic conditions such as chronic or acute inflammatory disorders of epidemic origin; or C (To treat subjects having a D8+ T cell-driven state). In some embodiments, non-depletion CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) are associated with CTLA-4 Use in combination with a stimulant blocker and / or in combination with another agent described herein. (For example, treating subjects with chronic conditions such as chronic or acute inflammatory disorders of the immune system) (To do so; or to treat subjects with a CD8+ T cell-driven state).

[0147] The terms “subject,” “recipient,” and “patient” are used synonymously in this specification. In some embodiments, the subject is a mammal. In some embodiments, The target population or those requiring this treatment are individuals who have or are suffering from immune-related disorders or diseases. The subject is one who is expected to develop or become ill. In some embodiments, the subject or The target population consists of individuals who have undergone or are scheduled to undergo transplant surgery. In terms of administration methods, the target or target requiring treatment is someone with chronic or acute inflammatory disorders of the immune system. The subject is primates. In some embodiments, the subject is primates. is human. In some embodiments, the subject is a human adult. In some embodiments, the subject is a child. In some embodiments, the subject is a pediatric patient. In some embodiments, the subject is a human minor. In some embodiments, the subject is a minor. At least 5, 10, 15, 18, 21, 50, 60, 65, 70 years old, or over 70 years old. In some embodiments, the subjects are up to 5 years old, 10 years old, 15 years old, 1 The subjects are 8 or 21 years of age. In some embodiments, the subjects have immune-related disorders or diseases. The patient has not received prior treatment. In some embodiments, the subject is subjected to an anti-CD2 antibody. or for one month prior to administration of the antigen-binding fragment and / or CTLA-4 costimulatory blocker, 2 In months, 3 months, 4 months, 5 months, 6 months, 9 months, 1 year, 2 years, or more than 2 years, The subject has not received prior treatment for an immune-related disorder or disease. In some embodiments, the subject is not It is a target for treatment. In some embodiments, the target is an immune-related disorder or disease. This is a treatment for untreated patients. In some embodiments, the subjects are untreated for methotrexate. It is a treatment. In some embodiments, the subject is an anti-CD2 antibody or its antigen-binding fragment and / or not prior to treatment with a CTLA-4 costimulator. In some embodiments The subject is resistant to treatment for immune-related disorders or diseases. Several embodiments Therefore, the target is anti-CD2 antibody or its antigen-binding fragment and / or CTLA-4 costimulatory blockade. If you are receiving or are being treated for an immune-related disorder or disease that is not a drug .

[0148] In some embodiments, subjects diagnosed with an immune-related disease or disorder, and also immune-related diseases. Alternatively, individuals who have a predisposition to developing the disorder, or who are highly likely to develop it, or those with immune-related conditions. Subjects experiencing at least one symptom related to a disease or disorder are provided herein. It may be suitable for treatment by the method described. In some embodiments, the subject is at least One, at least two, at least three, or more than three immune-related disorders or diagnosed with a disorder. Immune-related diseases or disorders that can be treated or prevented by the methods of this disclosure. Non-restrictive examples are given in Section 5.3.

[0149] Subjects who have received or are scheduled to receive organ and / or tissue transplants are provided herein. It may be suitable for treatment by the method described herein. The method described herein is suitable for any organ transplant and / or tissue transplantation (e.g., lungs, heart, kidneys, liver, stomach, intestines, pancreas, skin, or spleen) It can be used for those who have received or are scheduled to receive an injury, disease, or congenital condition. Individuals whose organs have been damaged due to abnormalities or other reasons may receive organ transplants (for example, liver or kidney transplants). The criteria are met and the treatment can be performed according to the methods described herein. Recipients who have received treatment according to the methods described may require an organ transplant for any reason. Generally, patients suffering from end-stage organ disease who undergo organ transplantation For patients whose life expectancy is expected to be extended beyond their expected life expectancy, organ transplantation should be considered. It is possible.

[0150] In certain embodiments, recipients treated according to the method described herein are genetically inherited. They are receiving organ transplants as needed due to their disease. In certain embodiments, organ transplants are performed. This is a whole-body organ transplant. In certain embodiments, the organ transplant is performed using organs from a deceased donor. Yes. In some embodiments, organ transplantation may be ABO-compatible transplantation. In some embodiments, organ transplantation may be ABO-incompatible transplantation. Recipients treated according to the methods described herein are less than 30, less than 20, or They may have an End-Stage Liver Disease Model (MELD) score of less than 10. Several implementations In terms of form, recipients treated according to the method described herein are Epstein-B - May be seropositive for the virus (EBV). In some embodiments, the recipe The patient has undergone a splenectomy before receiving the transplant. In some embodiments, the recipe The subject has not undergone splenectomy before receiving the transplant. In some embodiments, the subject is or have received a liver transplant. Examples of indications for liver transplantation include, for example, EASL. Clinical Practice Guidelines: Liver tran spplantation(J Hepatol.2016 Feb;64(2):433 (Described in -485.doi:10.1016 / j.jhep.2015.10.006) It is being done.

[0151] 5.3.2 Patient Dosage and Regimen (e.g., patients with inflammatory immune disorders) In one embodiment, a method for treating human subjects with chronic or acute inflammatory disorders of the immune system. The method uses the CD2-binding molecule (or anti-) described herein as a component of a long-term treatment regimen. CD2 antibody or its antigen-binding fragment) or CD2-binding molecule as described herein (or This includes administering a pharmaceutical composition containing an anti-CD2 antibody or its antigen-binding fragment to a target. In one embodiment, a method for treating a human subject having an immune-related disorder or disease is described in the present invention. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the document or this The specification includes a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) as described in the specification. This includes administering a pharmaceutical composition to a subject. In one embodiment, this method involves administering a pharmaceutical composition to a subject. This includes preventing immune-related disorders or diseases. In some embodiments, C as described herein A D2 binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) is used by the opponent that needs it. For elephants or patients with chronic or acute inflammatory immune disorders, 1000 mg, 1100 mg , 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700 mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 23 00mg, 2400mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400m g, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 400 0mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4 600mg, 4700mg, 4800mg, 4900mg, 5000mg, 1000mg ~1600mg, 1500mg~2100mg, 2000mg~2600mg, 2500 mg~3100mg, 3000mg~3600mg, 3500mg~4100mg, 40 It can be administered in doses of 00mg to 4600mg, or 4500mg to 5000mg. In certain embodiments, the CD2 binding molecule (or anti-CD2 antibody) described herein may be used. (Its antigen-binding fragment) is needed by targets or chronic or acute inflammatory immune disorders. It can be administered at a dose of 2400 mg to patients with the condition.

[0152] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is for those who require it or patients with chronic or acute inflammatory immune disorders. For the patient, 0.01 mg / kg / dose, 0.02 mg / kg / dose, 0.03 mg / kg / dose, 0 0.04 mg / kg / dose, 0.05 mg / kg / dose, 0.1 mg / kg / dose, 0.15 mg / kg / dose, 0.2mg / kg / dose, 0.25mg / kg / dose, 0.3mg / kg / dose, 0.35 mg / kg / dose, 0.4 mg / kg / dose, 0.45 mg / kg / dose, 0.5 mg / kg / dose, 0.55mg / kg / dose, 0.6mg / kg / dose, 0.65mg / kg / dose , 0.7 mg / kg / dose, 0.75 mg / kg / dose, 0.8 mg / kg / dose, 0.85 mg g / kg / dose, 0.9 mg / kg / dose, 0.95 mg / kg / dose, 1.0 mg / kg / dose 2.0 mg / kg / dose, 3.0 mg / kg / dose, 4.0 mg / kg / dose, 5.0 mg / kg / dose, 6.0 mg / kg / dose, 7.0 mg / kg / dose, 8.0 mg / kg / dose, 9. 0 mg / kg / dose, 10 mg / kg / dose, 11 mg / kg / dose, 12 mg / kg / dose, 1 3 mg / kg / dose, 14 mg / kg / dose, 15 mg / kg / dose, 16 mg / kg / dose, 1 7 mg / kg / dose, 18 mg / kg / dose, 19 mg / kg / dose, 20 mg / kg / dose, 2 1 mg / kg / dose, 22 mg / kg / dose, 23 mg / kg / dose, 24 mg / kg / dose, 2 5 mg / kg / dose, 26 mg / kg / dose, 27 mg / kg / dose, 28 mg / kg / dose, 2 9 mg / kg / dose, 30 mg / kg / dose, 31 mg / kg / dose, 32 mg / kg / dose, 3 3mg / kg / dose, 34mg / kg / dose, 35mg / kg / dose, 36mg / kg / dose, 3 7 mg / kg / dose, 38 mg / kg / dose, 39 mg / kg / dose, 40 mg / kg / dose, 4 1 mg / kg / dose, 42 mg / kg / dose, 43 mg / kg / dose, 44 mg / kg / dose, 4 5 mg / kg / dose, 46 mg / kg / dose, 47 mg / kg / dose, 48 mg / kg / dose, 4 It can be administered in doses of 9 mg / kg / dose or 50 mg / kg / dose. In one embodiment This refers to the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. This is for patients who require it or who have chronic or acute inflammatory immune disorders, at a dose of 0.1-0 0.3 mg / kg / dose, 0.2-0.4 mg / kg / dose, 0.3-0.5 mg / kg / dose 0.4~0.6mg / kg / time, 0.45~0.65mg / kg / time, 0.5~0.7m g / kg, 0.55~0.75mg / kg / dose, 0.6~0.8mg / kg / dose, 0.6 5-0.85 mg / kg / dose, 0.7-0.9 mg / kg / dose, 0.8-1.0 mg / kg g / dose, 1.0 mg / kg / dose to 6.0 mg / kg / dose, 5.0 mg / kg / dose to 10 mg g / kg / dose, 9.0 mg / kg / dose to 15 mg / kg / dose, 14 mg / kg / dose to 20 mg / kg / dose, 19 mg / kg / dose to 25 mg / kg / dose, 24 mg / kg / dose to 30 mg / kg / dose mg / kg / dose, 29 mg / kg / dose to 35 mg / kg / dose, 34 mg / kg / dose to 40 mg / kg / dose mg / kg / dose, 39 mg / kg / dose to 45 mg / kg / dose, or 44 mg / kg / dose It can be administered in doses ranging from ~50 mg / kg / dose. In certain embodiments, the present The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the document is necessary. For patients with chronic or acute inflammatory immune disorders, 0.1 mg / kg / It can be administered in a single dose. In certain embodiments, the CD2 binding component described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is used for the target or chronically affected individuals. In patients with acute inflammatory immune disorders, it may be administered at a dose of 0.6 mg / kg / dose. can.

[0153] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is for those who require it or patients with chronic or acute inflammatory immune disorders. For patients, administer 2 mg / kg / dose once a week for 6 weeks, then every 4 weeks thereafter; 5 weeks, then every 4 weeks. Every; every 4 weeks, then every 4 weeks; every 3 weeks, then every 4 weeks; or every 2 weeks, then every 4 weeks It can be administered weekly. In certain embodiments, the CD2 binding component described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is used for the target or chronically affected individuals. Alternatively, in patients with acute inflammatory immune disorders, a dose of 2 mg / kg / dose once a week for 4 weeks is administered. It can be administered every four weeks thereafter. Synthetic molecules (or anti-CD2 antibodies or their antigen-binding fragments) are needed for the target or chronic Alternatively, for patients with acute inflammatory immune disorders, administer 2.5 mg / kg once a week for 6 weeks. , then every 4 weeks; 5 weeks, then every 4 weeks; 4 weeks, then every 4 weeks; 3 weeks, It can then be administered every four weeks; or every two weeks, then every four weeks. In the application method, the CD2 binding molecule (or anti-CD2 antibody or its antigenic binding) described herein is used. The combined fragment is administered weekly to patients who require it or who have chronic or acute inflammatory immune disorders. It can be administered once at a dose of 2.5 mg / kg / dose for 4 weeks, and then every 4 weeks thereafter. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment is for those who require it or patients with chronic or acute inflammatory immune disorders. For patients, 3 mg / kg / dose once a week for 6 weeks, then every 4 weeks thereafter; 5 weeks, then every 4 weeks thereafter. Every; every 4 weeks, then every 4 weeks; every 3 weeks, then every 4 weeks; or every 2 weeks, then every 4 weeks It can be administered weekly. In certain embodiments, the CD2 binding component described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is used for the target or chronically affected individuals. Alternatively, in patients with acute inflammatory immune disorders, a dose of 3 mg / kg / dose once a week for 4 weeks is administered. It can be administered every four weeks thereafter. Synthetic molecules (or anti-CD2 antibodies or their antigen-binding fragments) are needed for the target or chronic Alternatively, for patients with acute inflammatory immune disorders, administer 3.5 mg / kg once a week for 6 weeks. , then every 4 weeks; 5 weeks, then every 4 weeks; 4 weeks, then every 4 weeks; 3 weeks, It can then be administered every four weeks; or every two weeks, then every four weeks. In the application method, the CD2 binding molecule (or anti-CD2 antibody or its antigenic binding) described herein is used. The combined fragment is administered weekly to patients who require it or who have chronic or acute inflammatory immune disorders. It can be administered once at a dose of 3.5 mg / kg / dose for 4 weeks, and then every 4 weeks thereafter. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment is for those who require it or patients with chronic or acute inflammatory immune disorders. For the patient, 3.75 mg / kg / dose once a week for 6 weeks, then every 4 weeks thereafter; then every 5 weeks thereafter. Every four weeks; every four weeks thereafter; every three weeks thereafter; or every two weeks thereafter. It can be administered every four weeks thereafter. In certain embodiments, CD2 as described herein The binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is used for the target or chronic condition. For patients with sexually transmitted or acute inflammatory immune disorders, the dose is 3.75 mg / kg / dose once a week. It can be administered for 4 weeks, and then every 4 weeks thereafter.

[0154] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) This includes subcutaneous, intravenous, intravascular, local, intra-arterial, intracranial, intramuscular, oral, intraorbital, inhalation, and percutaneous. , by administration routes that allow for T cell depletion in the peritoneal cavity or in the recipient, It can be administered to the subject by a suitable method known in the art. In certain embodiments, The anti-CD2 antibody or its antigen-binding fragment, or the CD2-binding molecule, is administered intravenously. .

[0155] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) This is a humanized monoclonal antibody. In certain embodiments, a CD2-binding molecule (or anti- The CD2 antibody (or its antigen-binding fragment) is cyprizumab (MEDI-507). In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) The dosage may be modified as described herein. In some embodiments, methylpred Nisolone is administered before the administration of a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment). It is given to a CD2-binding molecule (or an anti-CD2 antibody or Before administering the antigen-binding fragment, acetaminophen (e.g., 1000 mg) and / or Alternatively, take an antihistamine (for example, an H1 antagonist such as diphenhydramine, 25 mg). Administer.

[0156] While not bound by theory, the CD2 binding molecules (or anti-CD2) described herein are not limited to those described in this specification. Antibodies (or their antigen-binding fragments) increase the level of regulatory T cells in the recipient. It is administered in a dose sufficient to cause the effect. Specifically, the CD2 binding molecule described herein ( (or anti-CD2 antibody or its antigen-binding fragment) is used to control FOXP3+ in the recipient. The level of dominant T cells is determined by the CD2 binding molecule (or anti-CD2 antibody) described herein. Compared to FOXP3+ regulatory T cells that are not treated with the antigen-binding fragment, for example, At least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% , 100%, 125%, 150%, 175%, 200%, or at least 250% increase It is administered in a dose that is appropriate for this purpose.

[0157] The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are , as a component of the treatment regimen, the target or chronic or acute inflammatory immune disorder It can be administered to patients with adverse effects. In one embodiment, it is used in a therapeutic regimen. The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are It is the sole component of the treatment regimen. In certain embodiments, the treatment regimen is essential. This specification is intended for use in patients with the target population or those with chronic or acute inflammatory immune disorders. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described above is cypris Binds to the same epitope as mab.

[0158] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) It induces remission in patients who require it or who have chronic or acute inflammatory immune disorders. Administer a sufficiently high dose (loading dose) to induce the condition, and then, without limit, once a month. It can be administered at infrequently, such as once every two months or once every three months.

[0159] In certain embodiments, the CD2 binding molecule described herein (or anti-CD2 antibody or The antigen-binding fragment is needed by the target or has chronic or acute inflammatory immune disorder. It can be administered to patients at weekly intervals. In specific embodiments, as described herein. CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) are used to target the required target. It can be administered every other week to patients with chronic or acute inflammatory immune disorders. In certain embodiments, the CD2 binding molecule (or anti-CD2 antibody) described herein may be used. (Its antigen-binding fragment) is needed by the target or has chronic or acute inflammatory immune disorder. For patients, once daily until remission or cessation of the disease is induced, then once weekly thereafter. It can be administered by means of [method]. In certain embodiments, the CD2 binding molecule described herein (and (Anti-CD2 antibodies or their antigen-binding fragments) are needed for the target population or for chronic or acute conditions. For patients with inflammatory immune disorders, the drug is administered once a week for 12 weeks, followed by administration every other week. This is possible. In certain embodiments, the CD2 binding molecule (or anti-CD2) described herein may be used. Antibodies (or their antigen-binding fragments) are needed for targeting chronic or acute inflammatory immunity. It can be administered to patients with disabilities every other week, then once a month. Specific Embodiments So, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. ) is administered once every two weeks to patients who require it or who have chronic or acute inflammatory immune disorders. It can be administered at intervals between doses. In certain embodiments, the CD2 binding component described herein The child (or anti-CD2 antibody or its antigen-binding fragment) is used for the target or chronically affected individuals. It can be administered to patients with acute inflammatory immune disorders at intervals of three months.

[0160] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is for those who require it or patients with chronic or acute inflammatory immune disorders. It can be administered to patients, where the patient is at least 1 month, 2 months, 3 months, or 4 months 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, Or at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 1 1 year, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 2 They have been receiving treatment for a period of 1 year, 22 years, 23 years, 24 years, or at least 25 years. In one embodiment, the target population is the patient with chronic or acute inflammatory immune disorder. This is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months months, 10 months, 11 months, or 12 months, or at least 1 year, 2 years, 3 years, 4 Year, 5 year, 6 year, 7 year, 8 year, 9 year, 10 year, 11 year, 12 year, 13 year, 14 year, 15 year , 16, 17, 18, 19, 20, 21, 22, 23, 24, or For a period of at least 25 years, the CD2 binding molecule (or anti-CD2 antibody) described herein (Its antigen-binding fragment) or the CD2-binding molecule described herein (or anti-CD2 antibody) Treatment can be performed with a pharmaceutical composition containing the antigen-binding fragment.

[0161] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments are found subcutaneously, intravenously, intravascularly, locally, intra-arterially, intracranially, intramuscularly, Oral, intraorbital, intravitreous, inhaled, intraperitoneal, intraosseous, intratracheal, sublingual, buccal, rectal, intradermal, medullary cavity It can be formulated for internal, intramedullary, or transdermal administration routes. In certain embodiments, as specified herein The CD2-binding molecule described (or anti-CD2 antibody or its antigen-binding fragment) is chronic or Formulated for intravenous administration to patients with acute inflammatory immune disorders. Specific Embodiments So, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. ) is administered subcutaneously to those who require it, or to patients with chronic or acute inflammatory immune disorders. It is formulated for administration.

[0162] In one embodiment, the target subject or the subject having a chronic or acute inflammatory disorder of the immune system For patients, a therapeutically effective amount of the CD2-binding molecule (or anti-CD2 antibody) described herein is administered. A pharmaceutical composition containing the antigen-binding fragment can be administered. In one embodiment, A therapeutically effective amount of the CD2 binding molecule (or anti-CD2 antibody or its antigen binding) described herein. A pharmaceutical composition containing a fragment may be used for the treatment of chronic or acute inflammatory disorders of the immune system in the target population or immune system. It is included in a kit or system for administering to patients having the following condition. In one embodiment, The set contains a therapeutically effective amount of the CD2 binding described herein, contained in one or more containers. The pharmaceutical composition includes a molecule (or an anti-CD2 antibody or its antigen-binding fragment). Containers that can be used to package pharmaceutical compositions include, but are not limited to, these: Examples include bottles, bags, ampoules, tubes, inhalers, bags, vials, and containers. In one embodiment, the kit includes instructions for administering a pharmaceutical dose. In this state, the kit includes a device that can be used to administer the pharmaceutical composition of the present invention, and These devices include, but are not limited to, syringes, needleless syringes, IV bags, Examples include perfusion pumps, pumps, patches, and inhalers.

[0163] In one embodiment, as described herein, the subject or chronic or acute inflammatory disease CD2 binding molecules (or anti-CD2 antibodies or their antigenic bindings) are attached to the affected organs of patients with the disease. The combined fragments can be perfused. In a more specific embodiment, a perfusion pump can be used The affected organ is perfused with a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment). In one embodiment, CD2-binding molecules (or anti-CD2 antibodies) are perfused to the affected organ. The concentration of the antigen-binding fragment is at least 0.001 mg / liter, at least 0.005 mg / liter, at least 0.01 mg / liter, at least 0.05 mg g / liter, at least 0.1 mg / liter, at least 0.5 mg / liter, small At least 1.0 mg / liter, at least 5.0 mg / liter, at least 10 mg It is / liter, or at least 50 mg / liter.

[0164] 5.3.3 Concurrent therapy with immunosuppressants in patients with inflammatory immune disorders In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is administered concurrently with low-dose immunosuppressants as a component of long-term patient therapy. It is done. Although not bound by theory, the CD2 binding molecule (or anti-C) described herein is not limited to this specification. An immunosuppressant that can be used in combination with the administration of a D2 antibody or its antigen-binding fragment. However, these are not limited to, but include tacrolimus, cyclosporine, belatacept, and anti-CD3. 40 antibody, anti-OX40L antibody, anti-CD28 antibody, anti-CD27 antibody, anti-CD154 antibody, anti- ICOS antibody, anti- or agonist 4-1BB(CD137) antibody, BCL-2 inhibitor, Mycophenolate mofetil, mycophenolate derivatives, for example, Myfortic (intestinal (Sodium mycophenolate coated with thaw), sirolimus, everolimus, anti-thoracic Glandular globulin, basiliximab, prednisone, cyclophosphamide, fludarabine Examples include , and rituximab (Adams et al., J Immunol, 2 016,197(6)2045-2050;Kinnear et al.,Trans plantation.2013 Feb 27;95(4):527-535;Zha ng and Vignali,Immunity.2016 May 17;44(5 ):1034-51). In some embodiments, the CD2 binding molecule (or anti) described herein is used. CD2 antibodies (or their antigen-binding fragments) may be administered as part of a dual costimulatory blocker. In certain embodiments, the immunosuppressant is a CD2-binding molecule (or anti-CD2) as described herein. When administered simultaneously with an antibody or its antigen-binding fragment, it is necessary for the treatment to be effective. The dose of immunosuppressants is reduced. In one embodiment, the CD2 binding molecule (or anti CD2 antibodies (or their antigen-binding fragments) can be administered simultaneously with one immunosuppressant. In other embodiments, CD2 binding molecules (or anti-CD2 antibodies or their antigen binding cleavage) are used. One can be administered simultaneously with two or more immunosuppressants.

[0165] The relationship between a CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) and an immunosuppressant. Chloropreservation can be used to treat patients with chronic or acute inflammatory disorders of the immune system. This includes, but is not limited to, rheumatoid arthritis and juvenile idiopathic disease. Arthritis, psoriatic arthritis, autoimmune liver disease, Kawasaki disease, inflammatory bowel disease, ankylosing spondylitis, psoriasis Ulcerative colitis, sympathetic ophthalmitis, age-related macular degeneration, non-infectious posterior uveitis, Vogt- Koyanagi-Harada disease, sarcoidosis, type 1 diabetes, Crohn's disease, celiac disease, lupus, schew Glenn's syndrome, atopic dermatitis, multiple sclerosis, graft-versus-host disease (GVHD), focal lesions Segmental glomerulosclerosis can be cited as an example.

[0166] 5.3.4 Organ transplant patient population Having one or more organs that are damaged due to injury, disease, congenital abnormalities, etc. Individuals may meet the criteria for receiving organ transplants. Selected for organ transplantation. Individuals exhibit a mixed chimeric state in which hematopoietic cells from both the recipient and the donor coexist in the recipient. For the purpose of inducing a state, these methods described herein may be followed. Once a state of synchimeric phenomena is achieved, the need for long-term immunosuppressive therapy decreases.

[0167] In some embodiments, the recipient may have a highly sensitized immune system. The development of a sensitized immune system is a result of previous exposure to foreign tissues and their response to those tissues. This is caused by the production of antibodies. Causes of this exposure include blood transfusions and previous exposures. This can include planting or pregnancy. In a sensitized state, the immune system is highly vigilant and responsive to migration. It produces antibodies that will attack the implanted organ. In one embodiment, as described herein The recipient may have a sensitized or unsensitized immune system. In Piento, IdeS can be administered along with rituximab. IdeS is an enzyme that cleaves the heavy chain of IgG. IdeS is involved in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell-mediated cytotoxicity (CDC). It inhibits [the process]. In one embodiment, IdeS is administered in combination with rituximab. In one embodiment, another desensitization protocol is used alone, or rituximab, IdeS, Alternatively, it can be used in combination with other desensitization protocols. These include: While not limited to these, intravenous immunoglobulin, plasmapheresis, immunoadsorption, double filtration, Examples include roteasome inhibitors (e.g., bortezomib) and complement inhibitors.

[0168] 5.3.5 Organ transplantation treatment In one embodiment, the method involves transferring the CD2-binding molecule described herein to the organ to be transplanted (and This may include the direct injection of an anti-CD2 antibody or its antigen-binding fragment. The organs that can be transplanted using the provided method may be any solid organ. In some embodiments, the organ is the kidney, heart, intestine, liver, lung, pancreas, or as specified herein. Other organs that can be transplanted using the provided method may be organs. In some embodiments, organs The hands, feet, other limbs, and faces that can be transplanted using the methods provided herein. Alternatively, it may be a vascular composite allograft, such as another body part. In some embodiments, Organ grafts can be an entire organ, a part of an organ, or cells derived from an organ.

[0169] In one embodiment, the transplanted organ is subjected to the CD2 binding molecule (or anti-CD2) described herein. The body or its antigen-binding fragments can be injected directly. This injection is administered to the organ to be transplanted. Can it be performed in one part of the organ, or in multiple parts of the transplanted organ? This can be done. In one embodiment, the organ to be transplanted is a CD2 cell as described herein. Incubated in a bath containing a compound molecule (or anti-CD2 antibody or its antigen-binding fragment). This incubation can occur during transport to surgery or at the surgical site. Incubation involves the CD2-binding molecule (or anti-CD2 antibody) described herein. This incubation continues for a sufficient amount of time for the antigen-binding fragment to be taken up by the transplanted organ. The available durations are 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.25 hours, 1.5 hours, and 1.75 hours. Hours, 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 3.25 hours, 3. 5 hours, 3.75 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5 0.25 hours, 5.5 hours, 5.75 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 Hours: 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours Hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 1 5 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, 20 hours, 20.5 hours, 21 hours, 21.5 hours It can be done for 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours. In one embodiment, the CD2-binding molecule (or anti-CD2 antibody) described herein for injection. The dose of (or its antigen-binding fragment) is at least 0.01 mg / kg, at least 0. 0.5 mg / kg, at least 0.1 mg / kg, at least 0.5 mg / kg, at least Also 1 mg / kg, at least 5 mg / kg, at least 10 mg / kg, or less The dosage is 50 mg / kg.

[0170] In one embodiment, the transplanted organ is a CD2-binding molecule (or anti-C) as described herein. It is incubated in a bath containing a D2 antibody or its antigen-binding fragment. In this embodiment, the organ is removed from the donor until it is transplanted to the recipient. For the duration of the specified time, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding cleavage) described herein. It is maintained in a bath containing (one). In one embodiment, the CD2 ligaments described herein in an organ bath. The concentration of the compound molecule (or anti-CD2 antibody or its antigen-binding fragment) is at least 0.01 mg / liter, at least 0.05 mg / liter, at least 0.1 mg / liter , at least 0.5 mg / liter, at least 1 mg / liter, at least 5 mg / It is a liter, at least 10 mg / liter, or at least 50 mg / liter. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or similar) described herein is used. The antigen-binding fragments can be administered to the transplanted organ via the circulatory system. Specifically The catheter can be inserted into an adjacent blood vessel and attached to a pump. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein passes through blood vessels. It can then be pumped and delivered to organs.

[0171] In one embodiment, the transplanted organ is subjected to the CD2 binding molecule (or anti-C) described herein. D2 antibody or its antigen-binding fragment can be perfused. More specific embodiments So, using a perfusion pump, a CD2-binding molecule (or anti-CD2 antibody or The antigen-binding fragment is perfused. In one embodiment, the CD2-binding molecule is perfused to the organ. The concentration of (or anti-CD2 antibody or its antigen-binding fragment) is at least 0.001 mg / liter, at least 0.005 mg / liter, at least 0.01 mg / liter , at least 0.05 mg / liter, at least 0.1 mg / liter, at least 0 0.5 mg / liter, at least 1.0 mg / liter, at least 5.0 mg / liter The concentration is at least 10 mg / liter, or at least 50 mg / liter.

[0172] 5.3.6 Dosage and regimen (e.g., for organ transplant recipients) In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. (Antigen-binding fragment of) or the CD2-binding molecule described herein (or anti-CD2 antibody or A pharmaceutical composition containing the antigen-binding fragment (for example, C) can be used alone or with one or more other drugs (e.g., C When administered in combination with a TLA-4 costimulator, it is effective for those who require it. Methods for treating or preventing immune-related disorders or diseases in [the relevant field] are provided herein. In one embodiment, the method for treating a human subject undergoing organ transplantation is to treat the pre-transplant condition As components of the conditioning regimen, the CD2 bond described herein. A molecule (or an anti-CD2 antibody or its antigen-binding fragment) or the CD2 antibody as described herein. The target of administration is a pharmaceutical composition containing a compound molecule (or an anti-CD2 antibody or its antigen-binding fragment). This includes, in some embodiments, the CD2 binding molecule (or anti-CD2) described herein. Antibodies or their antigen-binding fragments are, for example, Massart, A et al. (Cl (in Exp Immunol. 2017;189(2):138-157) and New ell KA,Turka LA.(Curr Opin Organ Transpl. The assay outlined in the review article by ant.2015;20(4):400-405) As determined by, administered with the aim of inducing tolerance within the transplant recipient. These assays include, but are not limited to, T-cell reactivity and B-cell reactivity. Antigen-specific assays to determine the reaction, as well as assays to identify tolerance biomarkers. Examples include: In one embodiment, the therapeutic method provided herein is for a subject with an immune-related disorder. Or, before being diagnosed with the disease, CD2-binding molecules (or anti-CD2 antibodies or their antigenic binding molecules) This includes administering a composite fragment to a target. In one embodiment, the therapeutic method provided herein The law stipulates that after a subject is diagnosed with an immune-related disorder or disease, a CD2-binding molecule (or anti-CD2 molecule) must be administered. This includes administering two antibodies (or their antigen-binding fragments) to the target. In one embodiment, The treatment method provided in the specification involves administering a CD2-binding molecule (or anti-) to the transplant recipient before transplantation. This includes administering a CD2 antibody or its antigen-binding fragment. In some embodiments, this includes administering a CD2 antibody or its antigen-binding fragment. The CD2 binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are 1 day before transplant, 2 days before transplant, 3 days before transplant, 4 days before transplant, 5 days before transplant, 6 days before transplant, 7 days before transplant Days before transplant, 1 and 2 days before transplant, 2 and 3 days before transplant, 3 and 4 days before transplant, 1 day before transplant Recipe before, two days before, and three days before, or one day before, two days before, three days before, and four days before transplantation. It can be administered to the patient. In certain embodiments, the CD2 binding molecule described herein ( Alternatively, an anti-CD2 antibody or its antigen-binding fragment) should be administered to the recipient one and two days before transplantation. It can be administered to the body. In certain embodiments, the CD2 binding molecule described herein ( (or anti-CD2 antibody or its antigen-binding fragment) should be administered to the recipient one day and six days before transplantation. It can be administered to the following: In one embodiment, the CD2 binding molecule described herein (or A test dose of an anti-CD2 antibody (or its antigen-binding fragment) can be administered. In terms of form, the administration of the test dose is optional. In certain embodiments, the CD2 binding molecule (and The anti-CD2 antibody (or its antigen-binding fragment) is administered on the day of the transplant surgery. In this state, the CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) acts on the target. Administer at a sufficiently high dose (loading dose) to induce remission, and thereafter, not limited to these. However, it can be administered at a low frequency, such as once a month, once every two months, or once every three months.

[0173] In some embodiments, the CD2-binding molecule (or anti-CD2 antibody) described herein is also used. (or its antigen-binding fragment) should be taken one week before transplantation, two weeks before transplantation, three weeks before transplantation, or It can be administered to the recipient once a day for four weeks prior to transplantation. Several implementations In this state, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding cleavage) described herein is used. One side) is taken one week, two weeks, three weeks, or four weeks before the transplant. It can be administered to the recipient twice a week. In some embodiments, as described herein The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) should be taken one week before transplantation. During the period, three times a week, in the two weeks, three weeks, or four weeks before transplantation, the recipient It can be administered to the following: In some embodiments, the CD2 binding molecule described herein ( (or anti-CD2 antibody or its antigen-binding fragment) should be taken one week before transplantation, two weeks before transplantation. It can be administered to the recipient four times a week for three or four weeks prior to transplantation. In some embodiments, the CD2-binding molecule (or anti-CD2 antibody) described herein is also used. (or its antigen-binding fragment) is taken one week before transplantation, two weeks before transplantation, three weeks before transplantation, and It can be administered to the recipient five times a week for four weeks prior to transplantation. Several implementations In this state, the CD2 binding molecule (or anti-CD2 antibody or its antigen binding cleavage) described herein is used. One side) is taken one week, two weeks, three weeks, or four weeks before the transplant. It can be administered to the recipient six times a week. In one embodiment, C described herein The D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is administered on the day of transplantation. It is possible.

[0174] In certain embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) is used. ) can be administered to the subject at weekly intervals. In certain embodiments, the CD2 binding component The drug (or anti-CD2 antibody or its antigen-binding fragment) is administered to the target every other week. This can be done. In certain embodiments, a CD2 binding molecule (or an anti-CD2 antibody or its anti- The original binding fragment is administered once daily until remission or quiescence of the disease is induced, and then once a week thereafter. It can be administered to the target. In certain embodiments, a CD2 binding molecule (or anti-CD2 anti- The body or its antigen-binding fragments are administered once a week for 12 weeks, followed by treatment every other week. It can be administered to the patient. In certain embodiments, a CD2-binding molecule (or anti-CD2 antibody) may also be used. The antigen-binding fragment (or its equivalent) can be administered to the target every other week, and then at monthly intervals thereafter. In certain embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding cleavage) is used. The drug can be administered to the subject at intervals of once every two weeks. In certain embodiments, CD2 The binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is administered at intervals of 3 months. It can be administered to elephants.

[0175] In some embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding) is used. The fragment is administered when a CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is administered. 100 mg per day, per dose, per week, every other week, or per month 50mg, 500mg, 700mg, 1000mg, 1100mg, 1200mg, 13 00mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400m g, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 300 0mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3 600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg , 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700 mg, 4800mg, 4900mg, 5000mg, 1000mg~1600mg, 15 00mg~2100mg, 2000mg~2600mg, 2500mg~3100mg, 3000mg~3600mg, 3500mg~4100mg, 4000mg~4600m The drug is administered to the target individual in amounts of g, or 4500 mg to 5000 mg.

[0176] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is administered at approximately 0.01 mg / kg / dose, 0.02 mg / kg / dose, and 0.03 mg / kg. g / kg / dose, 0.04 mg / kg / dose, 0.05 mg / kg / dose, 0.1 mg / kg / doses, 0.15 mg / kg / dose, 0.2 mg / kg / dose, 0.25 mg / kg / dose, 0.3 mg / kg / dose, 0.35 mg / kg / dose, 0.4 mg / kg / dose, 0.45 mg / kg / dose, 0.5 mg / kg / dose, 0.55 mg / kg / dose, 0.6 mg / kg / dose, 0.6 5 mg / kg / dose, 0.7 mg / kg / dose, 0.75 mg / kg / dose, 0.8 mg / kg / dose, 0.85 mg / kg / dose, 0.9 mg / kg / dose, 0.95 mg / kg / dose, 1. 0 mg / kg / dose, 2.0 mg / kg / dose, 3.0 mg / kg / dose, 4.0 mg / kg / 5.0 mg / kg / dose, 6.0 mg / kg / dose, 7.0 mg / kg / dose, 8.0 mg / kg / dose, 9.0mg / kg / dose, 10mg / kg / dose, 11mg / kg / dose, 12m g / kg / dose, 13 mg / kg / dose, 14 mg / kg / dose, 15 mg / kg / dose, 16 mg g / kg / dose, 17 mg / kg / dose, 18 mg / kg / dose, 19 mg / kg / dose, 20 mg g / kg / dose, 21mg / kg / dose, 22mg / kg / dose, 23mg / kg / dose, 24m g / kg / dose, 25mg / kg / dose, 26mg / kg / dose, 27mg / kg / dose, 28m g / kg / dose, 29 mg / kg / dose, 30 mg / kg / dose, 31 mg / kg / dose, 32 mg g / kg / dose, 33mg / kg / dose, 34mg / kg / dose, 35mg / kg / dose, 36m g / kg / dose, 37 mg / kg / dose, 38 mg / kg / dose, 39 mg / kg / dose, 40 mg g / kg / dose, 41 mg / kg / dose, 42 mg / kg / dose, 43 mg / kg / dose, 44 mg g / kg / dose, 45 mg / kg / dose, 46 mg / kg / dose, 47 mg / kg / dose, 48 mg g / kg / dose, 49 mg / kg / dose, or 50 mg / kg / dose or at least approximately 0 0.01 mg / kg / dose, 0.02 mg / kg / dose, 0.03 mg / kg / dose, 0.04 mg g / kg / dose, 0.05mg / kg / dose, 0.1mg / kg / dose, 0.15mg / kg / dose doses, 0.2 mg / kg / dose, 0.25 mg / kg / dose, 0.3 mg / kg / dose, 0.35 mg / kg / dose, 0.4mg / kg / dose, 0.45mg / kg / dose, 0.5mg / kg / dose doses: 0.55 mg / kg / dose, 0.6 mg / kg / dose, 0.65 mg / kg / dose, 0.7 mg / kg / dose, 0.75 mg / kg / dose, 0.8 mg / kg / dose, 0.85 mg / kg / dose, 0.9 mg / kg / dose, 0.95 mg / kg / dose, 1.0 mg / kg / dose, 2.0 mg / kg / dose, 3.0 mg / kg / dose, 4.0 mg / kg / dose, 5.0 mg / kg / dose 6.0 mg / kg / dose, 7.0 mg / kg / dose, 8.0 mg / kg / dose, 9.0 mg / kg / dose, 10 mg / kg / dose, 11 mg / kg / dose, 12 mg / kg / dose, 13 mg / kg / dose, 14 mg / kg / dose, 15 mg / kg / dose, 16 mg / kg / dose, 17 mg / kg / dose, 18 mg / kg / dose, 19 mg / kg / dose, 20 mg / kg / dose, 21 mg / kg / dose, 22mg / kg / dose, 23mg / kg / dose, 24mg / kg / dose, 25mg / dose kg / dose, 26 mg / kg / dose, 27 mg / kg / dose, 28 mg / kg / dose, 29 mg / kg / dose, 30 mg / kg / dose, 31 mg / kg / dose, 32 mg / kg / dose, 33 mg / kg / dose, 34mg / kg / dose, 35mg / kg / dose, 36mg / kg / dose, 37mg / dose kg / dose, 38 mg / kg / dose, 39 mg / kg / dose, 40 mg / kg / dose, 41 mg / kg / dose, 42 mg / kg / dose, 43 mg / kg / dose, 44 mg / kg / dose, 45 mg / kg / dose, 46 mg / kg / dose, 47 mg / kg / dose, 48 mg / kg / dose, 49 mg / Administer to the subject or transplant recipient at a dose of kg / dose or 50 mg / kg / dose. This is possible. In one embodiment, the CD2 binding molecule (or anti-CD2 anti) described herein is used. The body or its antigen-binding fragments) are approximately 0.1 to 0.3 mg / kg / dose, approximately 0.2 to 0 .4mg / kg / dose, about 0.3 to about 0.5mg / kg / dose, about 0.4 to about 0.6mg / k g / dose, about 0.45 to about 0.65 mg / kg / dose, about 0.5 to about 0.7 mg / kg, about 0 0.55~approximately 0.75 mg / kg / dose, approximately 0.6~approximately 0.8 mg / kg / dose, approximately 0.65~ Approximately 0.85 mg / kg / dose, approximately 0.7 to approximately 0.9 mg / kg / dose, approximately 0.8 to approximately 1.0 m g / kg / dose, about 1 to about 1.5 mg / kg / dose, about 1.5 to about 2 mg / kg / dose, about 2 to about Approximately 2.5mg / kg / dose, approximately 2.5~3mg / kg / dose, approximately 3~3.5mg / kg / dose times, about 3.5 to about 4 mg / kg / time, about 4 to about 4.5 mg / kg / time, about 4.5 to about 5 m g / kg / dose, approximately 1.0 mg / kg / dose to approximately 6.0 mg / kg / dose, approximately 5.0 mg / kg / dose ~ approximately 10 mg / kg / dose, approximately 9.0 mg / kg / dose ~ approximately 15 mg / kg / dose, approximately 14 mg / kg / dose to approximately 20 mg / kg / dose, approximately 19 mg / kg / dose to approximately 25 mg / kg / dose Approximately 24 mg / kg / dose to approximately 30 mg / kg / dose, approximately 29 mg / kg / dose to approximately 35 mg / kg / dose, approximately 34 mg / kg / dose to approximately 40 mg / kg / dose, approximately 39 mg / kg / dose to approximately 4 5 mg / kg / dose, or in a dose range of approximately 44 mg / kg / dose to approximately 50 mg / kg / dose It can be administered to elephants or transplant recipients. In specific embodiments, as described herein. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) listed is 0.1 mg / It can be administered to the subject or transplant recipient in a dose of kg / dose. Specific Embodiments So, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. ) can be administered to the subject or transplant recipient at a dose of 0.6 mg / kg / dose. ru.

[0177] In certain embodiments, the CD2 binding molecule described herein (or anti-CD2 antibody or The antigen-binding fragment is administered at a dose of 10 mg / kg or approximately 10 mg / kg on the day of transplantation, for 2 days. Day 6, Day 14, Day 28, Day 42, Day 56, and every 28 days thereafter, 10m The dose is administered to the target individual or transplant recipient in a dose of g / kg or approximately 10 mg / kg. It can be provided. In certain embodiments, the CD2 binding molecule (or antibody) described herein can be provided. CD2 antibody (or its antigen-binding fragment) is administered at a dose of 30 mg / kg or approximately 30 mg on the day of transplantation. A dose of / kg, then 15mg / kg or approximately 15mg / kg on day 5, and then every 14 days In addition, a dose of 7.5 mg / kg or approximately 7.5 mg / kg is administered to the target patient or transplant recipient as needed. It can be administered sipiently. In certain embodiments, the CD2 binding described herein The molecule (or anti-CD2 antibody or its antigen-binding fragment) is administered at a dose of 30 mg / kg on the day of transplantation. The dose is approximately 30 mg / kg, and on the 5th day, the dose is 15 mg / kg or approximately 15 mg / kg. Thereafter, every 14 days, take a dose of 3.75 mg / kg or approximately 3.75 mg / kg as needed. It can be administered to the target or transplant recipient. In certain embodiments, as specified herein. The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein is 30 mg A loading dose of approximately 30 mg / kg or 30 mg / kg, followed by 5.625 mg / kg every 14 days. Alternatively, it can be administered at a dose of approximately 5.625 mg / kg to those who require it or to transplant recipients. It is possible.

[0178] While not bound by theory, the CD2 binding molecules (or anti-CD2) described herein are not limited to those described in this specification. Antibodies (or their antigen-binding fragments) increase the level of regulatory T cells in the recipient. It is administered in a dose sufficient to cause the effect. Specifically, the CD2 binding molecule described herein ( (or anti-CD2 antibody or its antigen-binding fragment) is used to control FOXP3+ in the recipient. The level of dominant T cells is controlled by the CD2 binding molecule (or anti-CD2 antibody) described herein. Compared to FOXP3+ regulatory T cells that are not treated with the antigen-binding fragment, for example, At least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% , 100%, 125%, 150%, 175%, 200%, or at least 250% increase It is possible.

[0179] The CD2-binding molecules (or anti-CD2 antibodies or their antigen-binding fragments) described herein are It can be administered to patients who require it or to transplant patients as a component of a postoperative treatment regimen. Yes, it is possible. In one embodiment, the CD2-binding molecule described herein is used in a postoperative regimen. (or an anti-CD2 antibody or its antigen-binding fragment) is administered in the conditioning regimen. It is the same as the given molecule. In some embodiments, the CD2-binding molecule described herein (and (Anti-CD2 antibodies or their antigen-binding fragments) are administered in the conditioning regimen. It is different from the molecule. In certain embodiments, the CD described herein is administered in a postoperative regimen. The 2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is the same as cyprizumab. It binds to a pitope.

[0180] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is used on the day of transplantation, 1 day later, 2 days later, 3 days later, 4 days later, and on the day of transplantation and 1 day later. , on the day of transplantation and 1 day and 2 days later, on the day of transplantation and 1 day, 2 days and 3 days later, on the day of transplantation and 1 day later, 2 days later, 3 days later, and 4 days later, on the day of transplantation, and 1 day later, 2 days later, and 3 days later. and 4 and 5 days later, the day of transplantation, and 1, 2, 3, 4 and 5 days later 6 days later, or on the day of the transplant surgery and 1 day, 2 days, 3 days, 4 days, and 5 days later and It may be administered after 6 and 7 days. In one embodiment, the therapeutic method provided herein After transplantation, a CD2-binding molecule (or anti-CD2) is applied to the target or transplant recipient as needed. This includes administering an antibody or its antigen-binding fragment. In some embodiments, CD The CD2-binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is administered 1 day after transplantation, and 2 days after transplantation. After, 3 days after transplantation, 4 days after transplantation, 5 days after transplantation, 6 days after transplantation, 7 days after transplantation, 8 days after transplantation, 9 days after transplantation, 10 days after transplantation, 11 days after transplantation, 12 days after transplantation, 13 days after transplantation, 14 days after transplantation, 15 days after transplantation, 16 days after transplantation, 17 days after transplantation, 18 days after transplantation, 19 days after transplantation, 20 days after transplantation , 21 days after transplantation, 22 days after transplantation, 23 days after transplantation, 24 days after transplantation, 25 days after transplantation, 26 days after transplantation The recipe is administered 27 days after transplantation, 28 days after transplantation, 29 days after transplantation, and / or 30 days after transplantation. It can be administered to the ent. In certain embodiments, a CD2 binding molecule (or anti-CD2) is used. Antibodies or their antigen-binding fragments are administered on the day of transplantation, 1 day after transplantation, 2 days after transplantation, and / or It is administered 4 days after transplantation. In one embodiment, the CD2 binding molecule described herein (or The anti-CD2 antibody (or its antigen-binding fragment) should be administered once daily, every other week, or once a month. In some embodiments, the CD2 binding molecule (or anti-CD2 antibody) described herein can also be used. The antigen-binding fragment (or its antigen-binding fragment) can be administered by injection or subcutaneous administration. In the embodiments, the CD2 binding molecule described herein (or an anti-CD2 antibody or its antigen) is used. The connecting fragments are taken one week after transplantation, two weeks after transplantation, three weeks after transplantation, or at the transplant site. It can be administered once a day for four weeks post-surgery. In certain embodiments, C as described herein The D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is used on the day of transplantation and 1 day after transplantation. It can be administered to the recipient after a few days. In certain embodiments, C as described herein The D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is used on the day of transplantation and 1 day after transplantation. It can be administered to the recipient after 7 days and 7 days. In certain embodiments, this specification The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the book is used during transplantation. It can be administered to the recipient on the day of transplantation and on the 1st, 8th, and 13th days after transplantation.

[0181] In one embodiment, the CD2 described herein is administered to the recipient in a postoperative regimen. The dose of the binding molecule (or anti-CD2 antibody or its antigen-binding fragment) is determined by the conditioner. The dose may be the same as that administered in Grezimen. In one embodiment, the regimen is used in the postoperative regimen. The CD2 binding molecule described herein (or anti-CD2 antibody or similar) administered to Piento The dose of the antigen-binding fragment may differ from the dose administered in the conditioning regimen. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or similar) described herein is used. The antigen-binding fragment is administered at doses of 0.01 mg / kg / dose, 0.02 mg / kg / dose, and 0.03 mg. / kg / dose, 0.04mg / kg / dose, 0.05mg / kg / dose, 0.1mg / kg / dose , 0.15mg / kg / dose, 0.2mg / kg / dose, 0.25mg / kg / dose, 0.3m g / kg / dose, 0.35 mg / kg / dose, 0.4 mg / kg / dose, 0.45 mg / kg / doses: 0.5 mg / kg / dose, 0.55 mg / kg / dose, 0.6 mg / kg / dose, 0.65 mg / kg / dose, 0.7mg / kg / dose, 0.75mg / kg / dose, 0.8mg / kg / doses: 0.85 mg / kg / dose, 0.9 mg / kg / dose, 0.95 mg / kg / dose, 1.0 mg / kg / dose, 2.0 mg / kg / dose, 3.0 mg / kg / dose, 4.0 mg / kg / dose 5.0 mg / kg / dose, 6.0 mg / kg / dose, 7.0 mg / kg / dose, 8.0 mg / kg / dose, 9.0 mg / kg / dose, 10 mg / kg / dose, 11 mg / kg / dose, 12 mg / kg / dose, 13mg / kg / dose, 14mg / kg / dose, 15mg / kg / dose, 16mg / kg / dose, 17mg / kg / dose, 18mg / kg / dose, 19mg / kg / dose, 20mg / kg / dose, 21mg / kg / dose, 22mg / kg / dose, 23mg / kg / dose, 24mg / kg / dose, 25mg / kg / dose, 26mg / kg / dose, 27mg / kg / dose, 28mg / kg / dose, 29mg / kg / dose, 30mg / kg / dose, 31mg / kg / dose, 32mg / kg / dose, 33mg / kg / dose, 34mg / kg / dose, 35mg / kg / dose, 36mg / kg / dose, 37mg / kg / dose, 38mg / kg / dose, 39mg / kg / dose, 40mg / kg / dose, 41mg / kg / dose, 42mg / kg / dose, 43mg / kg / dose, 44mg / kg / dose, 45mg / kg / dose, 46mg / kg / dose, 47mg / kg / dose, 48mg The transplant recipient receives doses of 49 mg / kg / dose, 49 mg / kg / dose, or 50 mg / kg / dose. It can be administered to the following: In one embodiment, the CD2 binding molecule described herein (or Anti-CD2 antibody or its antigen-binding fragment) is administered at 0.1-0.3 mg / kg / dose, 0.2- 0.4 mg / kg / dose, 0.3-0.5 mg / kg / dose, 0.4-0.6 mg / kg / dose , 0.45~0.65mg / kg / dose, 0.5~0.7mg / kg, 0.55~0.75 mg / kg / dose, 0.6-0.8 mg / kg / dose, 0.65-0.85 mg / kg / dose 0.7-0.9 mg / kg / dose, 0.8-1.0 mg / kg / dose, 1.0 mg / kg / dose ~6.0 mg / kg / dose, 5.0 mg / kg / dose ~10 mg / kg / dose, 9.0 mg / kg g / dose to 15 mg / kg / dose, 14 mg / kg / dose to 20 mg / kg / dose, 19 mg / kg g / dose~25mg / kg / dose, 24mg / kg / dose~30mg / kg / dose, 29mg / k g / dose to 35 mg / kg / dose, 34 mg / kg / dose to 40 mg / kg / dose, 39 mg / kg Dosage range: g / dose to 45 mg / kg / dose, or 44 mg / kg / dose to 50 mg / kg / dose Within the specified area, it can be administered to the target or transplant recipient as needed. Specific Embodiments So, the CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described herein. ) is administered at a dose of 0.6 mg / kg / dose to the target or transplant recipient who requires it. It is possible.

[0182] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment can be administered to those who require it, or to patients after transplant surgery. Here, the patient is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months 8 months, 9 months, 10 months, 11 months, or 12 months, or at least 1 year, 2 Year, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 1 4 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 2 The patient has been receiving treatment for a period of 4 years, or at least 25 years. In one embodiment, the patient, At least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months 10 months, 11 months, or 12 months, or at least 1 year, 2 years, 3 years, or 4 years. 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 1 6 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, or less For a period of at least 25 years, the CD2 binding molecule (or anti-CD2 antibody or similar) described herein may be used. (Antigen-binding fragment of) or the CD2-binding molecule described herein (or anti-CD2 antibody or Treatment can be performed with a pharmaceutical composition containing the antigen-binding fragment.

[0183] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragments are found subcutaneously, intravenously, intravascularly, locally, intra-arterially, intracranially, intramuscularly, Oral, intraorbital, intravitreous, inhaled, intraperitoneal, intraosseous, intratracheal, sublingual, buccal, rectal, intradermal, medullary cavity It can be formulated for internal, intramedullary, or transdermal administration routes. In certain embodiments, as specified herein The CD2 binding molecule described (or anti-CD2 antibody or its antigen-binding fragment) is required. It is formulated for intravenous administration to target patients or transplant patients. In certain embodiments, The CD2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) described in the specification is required It is formulated for subcutaneous administration to target patients or transplant surgery patients.

[0184] In one embodiment, the transplant surgery patient receives a therapeutically effective amount of CD2-binding molecule as described herein. Alternatively, a pharmaceutical composition containing an anti-CD2 antibody or its antigen-binding fragment may be administered. In the embodiment, a therapeutically effective amount of the CD2-binding molecule described herein (or anti-CD2 antibody) is also used. A pharmaceutical composition containing (or its antigen-binding fragment) is a kit for administration to transplant surgery patients. It is included in the system. In one embodiment, the kit is housed in one or more containers. a therapeutically effective amount of the CD2-binding molecule described herein (or an anti-CD2 antibody or its anti- It contains a pharmaceutical composition that includes a proto-binding fragment. It contains a pharmaceutical composition that can be packaged. The containers used are not limited to these, but include bottles, bags, ampoules, tubes, and inhalers. Examples include bags, vials, and containers. In one embodiment, the kit is pharmaceutical Includes instructions for administering the medication. In one embodiment, the kit is the pharmaceutical composition of the present invention. This includes, but is not limited to, devices that can be used to administer [the substance]. However, syringes, needleless syringes, IV bags, pumps, perfusion pumps, patches and inhalers are It can be listed.

[0185] 5.3.7 Concurrent therapy with immunosuppressants in organ transplant recipients In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is used as a component of long-term patient therapy after organ transplant surgery, along with low-dose immunosuppressants. It is administered simultaneously with the antiseptic. Although not bound by theory, the CD2 binding described herein is not limited to this specification. It can be used in combination with the administration of molecules (or anti-CD2 antibodies or their antigen-binding fragments). Immunosuppressants include, but are not limited to, tacrolimus, cyclosporine, and vera. Tacept, anti-CD40 antibody, anti-OX40L antibody, anti-CD28 antibody, anti-CD27 antibody, anti-C D154 antibody, anti-ICOS antibody, anti- or agonist 4-1BB (CD137) antibody, B CL-2 inhibitors, mycophenolate mofetil, mycophenolate derivatives, for example, My Fortic (enteric-coated sodium mycophenolate), sirolimus, E Belolimus, antithymocyte globulin, basiliximab, prednisone, cyclophosphamide Examples include fludarabine and rituximab (Adams et al., JI mmunol,2016,197(6)2045-2050;Kinnear et a l.,Transplantation.2013 Feb 27;95(4):527 -535;Zhang and Vignali,Immunity.2016 May 17;44(5):1034-51). In one embodiment, the CD2 connection described herein The compound molecule (or anti-CD2 antibody or its antigen-binding fragment) is part of the dual costimulatory blocker. It may be administered as follows. In certain embodiments, the immunosuppressant is a CD2-binding molecule as described herein. (Or when administered simultaneously with an anti-CD2 antibody or its antigen-binding fragment, post-transplant therapy) The dose of immunosuppressant required for therapeutic effectiveness as part of the regimen is reduced. ru.

[0186] In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or so described herein) is used. The antigen-binding fragment is administered concurrently with one immunosuppressant as part of a post-transplant therapy regimen. This is possible. In other embodiments, the CD2 binding molecule (or anti-CD) described herein may be used. Two antibodies (or their antigen-binding fragments) are used as part of a post-transplant therapy regimen, along with two or more antibodies. It can be administered simultaneously with disease control agents.

[0187] 5.3.8 CTLA-4 Co-stimulatory Blockers In some embodiments, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding) is used. By administering the fragment and CTLA-4 costimulatory blocker to the target, the immune response in the target is improved. Methods for treating or preventing related disorders or diseases are described herein. Specifically, C D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) and CTLA-4 costimulatory blockade The present invention is a method of treating or preventing immune-related disorders or diseases using a combination of anticonceptions. Provided in the details, this method involves using an anti-CD2 antibody or its antigen-binding fragment or CTLA -4 A synergistic effect is obtained compared to using the costimulator alone or without the other agent. In some embodiments, methods for treating or preventing immune-related disorders or diseases are available. , further comprising administering another drug (e.g., an immunosuppressant). In one embodiment, C D2 binding molecule (or anti-CD2 antibody or its antigen-binding fragment) and CTLA-4 costimulation Both blocking agents should be administered, but only one of the following should be used: an anti-CD2 antibody or a CTLA-4 costimulatory blocker. Compared to administration to the target population, it resulted in a greater reduction in the alloimmune response in the target population. In one embodiment, a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) is used. Administration of both ) and CTLA-4 costimulatory blockers can lead to the administration of CD2-binding molecules (or anti-CD2 antibodies). Targeting only one of the following: (or its antigen-binding fragment) or a CTLA-4 costimulatory blocker. This results in a greater decrease in CD2 levels compared to when administered. In one embodiment, This involves a CD2-binding molecule (or an anti-CD2 antibody or its antigen-binding fragment) and CTLA-4 Administration of a co-stimulus blocker to both targets involves a CD2 binding molecule (or an anti-CD2 antibody or similar). After administration, only one of the following will be targeted: antigen-binding fragments or CTLA-4 costimulatory blockers. Compared to the number of cells in the biological sample from the subject, the number of cells in the biological sample from the subject It will decrease.

[0188] In one embodiment, the method described herein involves an anti-CD2 antibody or its antigen-binding fragment This includes administering the agent to the target in combination with a CTLA-4 costimulator. Several implementations In this state, CTLA-4 costimulators target CD80 and / or CD86 in CT It is LA4-Ig. In some embodiments, the CTLA-4 costimulator is B7-1 And / or CTLA4-Ig variants with enhanced binding to B7-2. In this embodiment, the CTLA-4 costimulator is a CTLA-4 fusion protein. In some embodiments, the CTLA-4 co-stimulus blocker is CTLA-4 Ig (for example, A (Batacept). In some embodiments, the CTLA-4 costimulator is fused to Fc. It is the extracellular domain of the combined CTLA-4. In some embodiments, it is fused to Fc. The extracellular domain of CTLA-4 is belatacept (Nulojix®). In some embodiments, the extracellular domain of CTLA-4 fused to Fc is ava. Tasept (Orencia®). In some embodiments, CTLA- 4. Co-stimulus blockers include the A29Y / L104E variant of human CTLA4. How many? In that embodiment, the CTLA-4 co-stimulus blocker has affinity for B7-1 and B7-2. To enhance this, at least one small portion of the CTLA4 portion of the CTLA-4 fusion protein is needed. At least two, at least three, at least four, or more than four substitutions Includes. For example, CTLA-4 costimulators include A29K, A29N, A29E, and A29W. , A29F, A29Y, A29H, A29Q, A29R, T30D, T30V, T30A , T30N, T30E, T30H, T30R, E31I, E31M, E31T, E31V , E31D, R33F, R33T, R33M, R33W, R331, R33Y, R33L , R33E, R33Q, T35E, T35V, T35M, T35D, T35F, T35Y , A49T, A49F, A49Y, A49W, A49D, A49E, T51V, T51L , T51N, T51H, T51Q, T51E, T51S, T51R, T51D, M53E , M53Q, M53Y, M53W, M53F, M53H, T59V, T59L, T59N , T59Y, T59H, T59Q, T59I, L61D, L61E, L611, L61A , L61F, L61G, L61H, L61K, L61M, L61N, L61P, L61Q , L61R, L61S, L61T, L61V, L61W, L61Y, D63E, S64K , S64R, S64Y, K93D, K93E, K93F, K93H, K93Q, K93R , K93T, K93V, K93W, K93Y, K93N, K93S, E95D, E95Q , E95Y, E95H, E95L, M97F, M97D, M97N, M971, M97V , Y98F, Y98W, Y102F, Y102W, Y103F, Y103W, Y103H , Y103D, Y103E, Y103N, Y103Q, L104D, L104E, L10 4V, L104M, L104Y, L104W, L104F, L104H, G105D, G This includes, but is not limited to, one or more of 105E, I106E, and I106Y. Includes one or more substitutions. In some embodiments, the CTLA-4 costimulator is A29 H, A29K, A29Y, T51N, L61E, L61Q, K93Q, K93, L104 At least one CTLA4 selected from the group consisting of H, L104E, and Y103Q Includes substitution.

[0189] In some embodiments, the CTLA4 costimulator is an array identical to SEQ ID NO: 22. Includes. In some embodiments, the CTLA4 costimulator is SEQ ID NO: 22 and approximately 75% 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% %, or at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 9 It contains sequences that are 8%, 99%, or 100% identical. In some embodiments, CT LA4 costimulators are present in approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 units of SEQ ID NO: 22. , 15, 20, 25, 30, 35, or 40, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40, or up to approximately 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 This includes amino acid substitutions. In some embodiments, the CTLA4 costimulator is SEQ ID NO: It contains the same sequence as 23. In some embodiments, the CTLA4 costimulator is included Column number 23 and approximately 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 9 9%, or 100%, or at least approximately 75%, 80%, 85%, 90%, 95% Includes sequences that are 96%, 97%, 98%, 99%, or 100% identical. In this embodiment, the CTLA4 costimulator contains approximately 1, 2, 3, 4, 5 units in SEQ ID NO: 23. 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 , or up to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 The amino acid substitutions include 35, or 40 amino acid substitutions. In some embodiments, the amino acid substitutions are This is a conservative amino acid substitution.

[0190] In one embodiment, the therapeutic method provided herein is for an immune-related disorder or disease. This includes administering a CTLA4 costimulatory blocker to the target before a diagnosis is made. Therefore, the treatment methods provided herein are for when the subject has been diagnosed with an immune-related disorder or disease. This includes administering a CTLA4 costimulator to the target. In some embodiments, this specification The treatment method offered involves administering a CTLA4 costimulator to the transplant recipient before transplantation. This includes, in some embodiments, a CTLA4 costimulator is administered one day before transplantation, or after transplantation. 2 days before, 3 days before transplant, 4 days before transplant, 1 and 2 days before transplant, 2 and 3 days before transplant, transplant Three days and four days prior, one day, two days and three days prior to transplantation, or one day and two days prior to transplantation and It may be administered to the recipient 3 and 4 days prior. In certain embodiments, CTLA4 co-administered Stimulant blockers can be administered to the recipient one and two days before transplantation. Specific implementation Morphologically, CTLA4 costimulators are administered on the day of transplant surgery.

[0191] In one embodiment, the therapeutic method provided herein involves administering C to the transplant recipient after transplantation. This includes administering a TLA4 costimulator. In some embodiments, this involves administering a TLA4 costimulator. The stimulant is administered on day 1, day 2, day 3, day 4, day 5, and day 6 after transplantation. After, 7 days after transplantation, 8 days after transplantation, 9 days after transplantation, 10 days after transplantation, 11 days after transplantation, 12 days after transplantation , 13 days after transplantation, 14 days after transplantation, 15 days after transplantation, 16 days after transplantation, 17 days after transplantation, 18 days after transplantation Days after transplantation, 19 days after transplantation, 20 days after transplantation, 21 days after transplantation, 22 days after transplantation, 23 days after transplantation, 24 days after transplantation, 25 days after transplantation, 26 days after transplantation, 27 days after transplantation, 28 days after transplantation, 29 days after transplantation, It can be administered to the recipient 30 days after transplantation. In certain embodiments, CTLA4 costimulators are administered on the day of transplantation, 1 day after transplantation, 2 days after transplantation and / or 4 days after transplantation. It will be administered later.

[0192] In one embodiment, a test dose of a CTLA4 costimulator can be administered. In the embodiments, administration of the test dose is optional. In one embodiment, CTLA4 co-stimulation blockade is used. The discontinuation drug is administered to the subject at a dose high enough to induce remission (loading dose), and then... While not limited to these, it may be administered at a low frequency such as once a month, once every two months, or once every three months. Obtain. In some embodiments, CTLA4 costimulators are administered subcutaneously, intravenously, intravascularly, or locally. This technique includes local, intra-arterial, intracranial, intramuscular, oral, intraorbital, inhalation, percutaneous, or intraperitoneal administration. It is administered to the subject by an appropriate method known in the field. In some embodiments, CTLA 4. The costimulator is administered intravenously. In some embodiments, CTLA4 costimulators are blocked. The agent is administered intravenously as a 30-minute intravenous infusion. In some embodiments, CTL A4 costimulators are administered approximately 2 weeks and 4 weeks after the initial injection, and / or for 4 weeks thereafter. It is administered each time. In some embodiments, the CTLA4 costimulator is administered subcutaneously once a week. It is administered by injection. In some embodiments, CTLA4 costimulators are administered intravenously. It is initiated with or without an intravenous loading dose. In some embodiments, CTLA4 costimulators are initiated with a single intravenous infusion, followed by the first subcutaneous injection (for example) If necessary, administer a 125 mg injection, which should be given within one day of intravenous infusion. In this embodiment, the CTLA4 costimulator is approximately 500 mg (for example, for subjects weighing less than 60 kg). ), 750 mg (for example, for subjects weighing 60-100 kg), or 1000 mg (for example, 1 It is administered at a dose for subjects weighing over 00 kg. In some embodiments, CTLA4 co-administers. The stimulant blocker is supplied in a vial (e.g., a 250 mg vial). Several implementations In this form, the CTLA4 co-stimulus blocker is provided as a lyophilized powder. Several implementations In this state, after reconstitution of the CTLA4 costimulator, 25 mg (250) per milliliter. The present invention contains a CTLA4 costimulator (mg / 10mL). In some embodiments, CTLA 4. The costimulator is provided as a single-dose pre-filled glass syringe containing 125 mg / mL. It will be done.

[0193] In some embodiments, the CTLA4 costimulator is administered daily, once a day, or weekly. Approximately 100mg, 150mg, 200mg, 250mg, 3 per day or per month. 00mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg , 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950 mg, 1000 mg, or more than 1000 mg, or at least about 100 mg, 150 mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 5 00mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg , 850mg, 900mg, 950mg, 1000mg, or more than 1000mg, The maximum dosage is approximately 100mg, 150mg, 200mg, 250mg, 300mg, and 350mg. 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700m g, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, also Alternatively, it may be administered in doses exceeding 1000 mg.

[0194] In some embodiments, the dose of the CTLA4 costimulator is 0.0001 to 100 A range of mg / kg body weight or more, for example, 0.1 mg / kg body weight, 1 mg / kg body weight, 10 mg The dose is 1 / kg body weight, or 50 mg / kg body weight. In some embodiments, the dose is 1 The range is ~10 mg / kg. In some embodiments, a single CTLA4 costimulator is used. Only a single dose is administered to the subject. In some embodiments, multiple doses of CTLA4 are administered together. A stimulant blocker is administered to the subject. In some embodiments, the time elapsed between administrations is 1 hour. Less than 1 hour, approximately 1 hour, approximately 1-2 hours, approximately 2-3 hours, approximately 3-4 hours, approximately 6 hours, approximately 12 hours Approximately 24 hours, approximately 48 hours, approximately 2-4 days, approximately 4-6 days, approximately 1 week, approximately 2 weeks, or 2 weeks It is beyond the interval.

[0195] In some embodiments, the CTLA-4 costimulator is administered once or multiple times. The drug is administered to the subject in a range of approximately 1 ng / kg body weight to approximately 100 mg / kg body weight. In this embodiment, the CTLA4 costimulator is administered to the person who receives the CTLA4 costimulator. Per day, per dose, per week, or per month, approximately 1 ng / kg body weight ~ approximately 1 0 mg / kg body weight, approximately 1 ng / kg body weight ~ approximately 1 mg / kg body weight, approximately 1 ng / kg body weight ~ approximately 100 μg / kg body weight, approximately 1 ng / kg body weight ~ approximately 10 μg / kg body weight, approximately 1 ng / kg body weight Weight ~ approx. 1 μg / kg body weight, approx. 1 ng / kg body weight ~ approx. 100 ng / kg body weight, approx. 1 ng / k g body weight ~ approx. 10 ng / kg body weight, approx. 10 ng / kg body weight ~ approx. 100 mg / kg body weight, approx. 1 0ng / kg body weight ~ approx. 10 mg / kg body weight, approx. 10 ng / kg body weight ~ approx. 1 mg / kg body weight , approximately 10ng / kg body weight ~ approximately 100μg / kg body weight, approximately 10ng / kg body weight ~ approximately 10μg / kg body weight, approximately 10ng / kg body weight ~ approximately 1μg / kg body weight, 10ng / kg body weight ~ approximately 10 0ng / kg body weight, approx. 100ng / kg body weight ~ approx. 100mg / kg body weight, approx. 100ng / kg body weight ~ approximately 10 mg / kg body weight, approximately 100 ng / kg body weight ~ approximately 1 mg / kg body weight, approximately 1 00ng / kg body weight ~ approx. 100μg / kg body weight, approx. 100ng / kg body weight ~ approx. 10μg / kg body weight, approx. 100ng / kg body weight ~ approx. 1μg / kg body weight, approx. 1μg / kg body weight ~ approx. 10 0mg / kg body weight, approx. 1μg / kg body weight ~ approx. 10mg / kg body weight, approx. 1μg / kg body weight ~ Approximately 1 mg / kg body weight, approximately 1 μg / kg body weight ~ approximately 100 μg / kg body weight, approximately 1 μg / kg body weight Weight ~ approx. 10 μg / kg body weight, approx. 10 μg / kg body weight ~ approx. 100 mg / kg body weight, approx. 10 μ g / kg body weight ~ approx. 10 mg / kg body weight, approx. 10 μg / kg body weight ~ approx. 1 mg / kg body weight, approx. 10μg / kg body weight ~ approx. 100μg / kg body weight, approx. 100μg / kg body weight ~ approx. 100mg / kg body weight, approximately 100 μg / kg body weight ~ approximately 10 mg / kg body weight, approximately 100 μg / kg body weight ~Approx. 1mg / kg body weight, approx. 1mg / kg body weight ~ Approx. 100mg / kg body weight, approx. 1mg / kg Within the range of body weight ~ approximately 10 mg / kg body weight, and approximately 10 mg / kg body weight ~ approximately 100 mg / kg body weight. It will be administered.

[0196] In some embodiments, the CTLA4 costimulator is 0.1 to 20 per patient / day. It is administered at a dose of 0 mg / kg body weight (for example, 0.5 to 10.0 mg / kg / day). In several embodiments, the CTLA-4 costimulator is present in an amount of approximately 0.1 to 100 mg / kg of the target substance. Weight, approximately 0.5-5 mg / kg target body weight, approximately 5-10 mg / kg target body weight, approximately 10-15 m g / kg target body weight, approximately 15-20 mg / kg target body weight, approximately 20-25 mg / kg target body weight Approximately 25-30 mg / kg of body weight, approximately 30-35 mg / kg of body weight, approximately 35-40 mg g / kg target body weight, approximately 40-45 mg / kg target, approximately 45-50 mg / kg target body weight, approximately 50-55 mg / kg of body weight, approximately 55-60 mg / kg of body weight, approximately 60-65 mg / Approximately 65-70 mg / kg of target body weight, approximately 70-75 mg / kg of target body weight, approximately 75-80 mg / kg of body weight, approximately 80-85 mg / kg of body weight, approximately 85-90 mg / Target body weight in kg, approximately 90-95 mg / kg target body weight, approximately 95-100 mg / kg target body weight, Approximately 2-10 mg / kg of body weight, approximately 0.1-4 mg / kg of body weight, approximately 0.1-0.5 m g / kg target body weight, approximately 0.5-1.0 mg / kg target body weight, approximately 1.0-1.5 mg / kg Target body weight, approximately 1.5-2.0 mg / kg Target body weight, approximately 2.0-2.5 mg / kg Target body weight Approximately 2.5-3.0 mg / kg of target body weight, approximately 3.0-3.5 mg / kg of target body weight, approximately 3. 5-4.0 mg / kg of target body weight, approximately 4.0-4.5 mg / kg of target body weight, approximately 4.5-5. 0 mg / kg of body weight, approximately 5.0-5.5 mg / kg of body weight, approximately 5.5-6.0 mg / Target body weight in kg: approximately 6.0-6.5 mg / kg; Target body weight: approximately 6.5-7.0 mg / kg Body weight, approximately 7.0-7.5 mg / kg Target body weight, approximately 7.5-8.0 mg / kg Target body weight, approximately 8.0-8.5 mg / kg target body weight, approximately 8.5-9.0 mg / kg target body weight, approximately 9.0- 9.5 mg / kg of body weight, approximately 9.5-10.0 mg / kg of body weight, approximately 0.1-2 mg / kg target body weight, approximately 2-4 mg / kg target body weight, approximately 4-6 mg / kg target body weight, approximately 6-8 mg / kg target body weight, approximately 8-10 mg / kg target body weight, approximately 10-12 mg / kg target body weight Approximately 12-14 mg / kg of body weight, approximately 14-16 mg / kg of body weight, approximately 16-18 mg g / kg target body weight, approximately 18-20 mg / kg target body weight, approximately 0.5 mg / kg target body weight, 2 mg / kg target body weight, 10 mg / kg target body weight, approximately 0.5 mg / kg to 100 target body weight, Approximately 0.5-10 mg / kg of body weight, approximately 0.1-20 mg / kg of body weight, body weight 60 kg For subjects under 10kg, approximately 500mg; for subjects weighing 60-100kg, 750mg; or 10 For subjects weighing over 0 kg, a dose of 1000 mg is administered.

[0197] In some embodiments, CTLA4 costimulators (e.g., beratacept and / or) Abatacept is used in combination therapy with an anti-CD2 antibody or its antigen-binding fragment, and is administered daily. Approximately 1 per dose, per week, or per month of CTLA4 costimulator blockers. 0 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg (or any integer between kg and kg), or at least about 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg (or any in between) (an integer amount of 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg) or up to approximately 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg It is administered in amounts of g / kg or 30 mg / kg (or any integer in between).

[0198] 5.3.9 Immunosuppressive therapy In some embodiments, the methods provided herein involve an anti-CD2 antibody or its antigen. This includes administering a fragment, a CTLA-4 costimulator, and another activator. In the application form, another activator is an anti-CD2 antibody or its antigen-binding fragment and / or CTL. A-4 The costimulator is administered before, during, or after the administration of costimulators to the target. Several implementations In terms of form, another activator is an anti-CD2 antibody or its antigen-binding fragment, before it is administered to the target. It is administered during or after. In some embodiments, another activator is CTLA-4 co-administered. The stimulant blocker is administered before, during, or after the administration of the stimulant blocker to the subject. In some embodiments, Other active agents include methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), and pain relievers. Medications for relief, corticosteroids, TNF blockers, azathioprine, chloroquine, Gold, hydroxychloroquine, leflunomide, sulfasalazine, and / or anakinla One or more of these can be cited. Examples of NSAIDs include, but are not limited to, Aspirin, ibuprofen, naproxen, fenoprofen, ketoprofen, flur Biprofen, oxaprozin, indomethacin, sulindac, etodolac, diclofenac Nak, Pyroxicam, Meloxicam, Tenoxicam, Doroxicam, Romoxicam (lo moxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, Tolfenamic acid, celecoxicab, rofecoxib, Valde Coxib, parecoxib, lumiracoxib, etoricoxib, nimeslid, lycofenac Examples include (licofenac) and diflumic acid. In some embodiments, another The activator is immunosuppressive therapy. Immunosuppressive therapy is used to treat immune-related disorders or diseases in the subject. It may be any FDA-approved treatment for treating or preventing (e.g., transplant rejection) (Those shown to reduce [something]). Non-limited examples of immunosuppressive therapy include calcinu - Phosphate inhibitors (e.g., tacrolimus or cyclosporine), antiproliferative agents (e.g., mycoplasma Phenolic acids, 6-mercaptopurine, or its prodrug azathioprine, etc. (Antimetabolites), cyclophosphamide, rapamycin mammalian targeted inhibitor (mTOR) For example, sirolimus, rapamycin), steroids (for example, prednisone), cell cycle Inhibitors (azathioprine or mycophenolate mofetil), lymphocyte scavengers (e.g.) (antibodies such as antithymocyte globulin, alemtuzumab, or basiliximab) and co Stimulant blockers are one example. For instance, Chung et al (2020)., Ann T ransl Med.Mar;8(6):409;van der Mark et a l.(2020), Eur Respir Rev;29:190132 and Benve Nuto et al. (2018), J Thorac Dis 10:3141-3 See page 155.

[0199] Immunosuppressive therapy is used as induction therapy (perioperative period or immediately after surgery), as a maintenance dose, and It can be administered for acute immune-related diseases (e.g., acute rejection). Induction therapy Generally, basiliximab, antithymocyte globulin, or alemtuzumab are used. For example, immunosuppressive therapy often needs to be continued for the patient's entire life. It can also be administered as maintenance therapy. As maintenance immunosuppressive therapy, calcium is usually used. Neurolin inhibitors (tacrolimus or cyclosporine), antiproliferative agents (mycophenolic acid) Examples include azathioprine and corticosteroids for acute rejection. Immunosuppressive therapies typically include thymoglobulin or mycophenolate. For example, Chung et al. (2020), Ann Transl Med.Mar ;8:409 and Benvenuto et al., (2018) J Thorac See Dis 10:3141-3155.

[0200] Non-limiting examples of immunosuppressants include (1) antimetabolites, such as purine synthesis inhibitors. For example, inosine monophosphate dehydrogenase (IMPDH) inhibitors, for example, azathiop Phosphorus, mycophenolic acid, and mycophenolic acid mofetil), pyrimidine synthesis inhibitors ( For example, leflunomide and teriflunomide), and folic acid antagonists (for example, methotrexate) (t); (2) Calcineurin inhibitors, for example, tacrolimus, cyclosporine A, pime Chlorimus and voclosporine; (3) TNF-α inhibitors, e.g., thalidomide and (4) IL-1 receptor antagonists, e.g., anakinra; (5) ra Pamycin mammalian target (mTOR) inhibitors, for example, rapamycin (sirolimus), Forolimus, everolimus, temsirolimus, zotalolimus, and biolimus A9; (6) corticosteroids, e.g., prednisone; and (7) numerous cell targets or blood For any one of the target cells (such as anti-lymphocyte globulin and anti-thymocyte globulin) Antibodies are one example.

[0201] Examples of non-exclusive cellular targets and their respective inhibitor compounds include, but are not limited to, these. It is not specified, but complement component 5 (e.g., eculizumab); tumor necrosis factor (TNF) (e.g., infliximab, adalimumab, certolizumab pegol, aferimomab and golim Mab); IL-5 (e.g., mepolizumab); IgE (e.g., omalizumab); BAY X (e.g., nerimomab); interferon (e.g., fararimomab (faral imomab); IL-6 (e.g., elcirimomab); IL-12 and IL-13 ( For example, lebrikizumab and ustekinumab); CD3 (for example, muromonab-CD3, Oterixizumab, teprizumab, bicilizumab; CD4 (e.g., clenoliximab) keriximab and zanorimumab); CDI1a (e.g., ephalizumab); CD1 8 (e.g., erulizumab); CD20 (e.g., aftuzumab, ocrelizumab, pas) Corizumab; CD23 (e.g., lumiliximab); CD40 (e.g., teneriximab) (e.g., tralizumab); CD62L / L-selectin (e.g., aselizumab (aseli zumab); CD80 (e.g., galiximab); CD147 / basigin (e.g., gavilimomab); CD154 (e.g., ruprizumab); B LyS (e.g., belimumab); CTLA-4 (e.g., ipilimumab, tremelimumab) );CAT(for example, bertilimumab, reldelimumab ( Metelimumab (Lerdelimumab); Integri (e.g., natalizumab); IL-6 receptor (e.g., tocilizumab); LFA-1 ( For example, odulimomab); and IL-2 receptor / CD25 (for example, basiliximab, Examples include daclizumab and inolimomab.

[0202] In some embodiments, immunosuppressive therapy involves disease-modifying antirheumatic drugs (DMARDs). Nonspecific cytotoxic immunosuppressants, such as methotrexate and inflix, are known as [unclear]. Simab, cyclophosphamide, azathioprine, cyclosporine A, sulfasalazine, Hydroxychloroquine, leflunomide, etanercept, and tumor necrosis factor alpha (T Examples include NFα) or other cytokine blockers or antagonists. In this embodiment, the amount of immunosuppressive therapy (e.g., DMARDS) administered to the subject is immunosuppressive On the day the antitherapy was administered, approximately 1 to 5000 mg / day, approximately 1 to 10 mg / day , about 10~50mg / day, about 50~100mg / day, about 100~150mg / day, about 15 0~200mg / day, approx. 200~250mg / day, approx. 250~300mg / day, approx. 300 ~350mg / day, approximately 350~400mg / day, approximately 400~450mg / day, approximately 450~ 500mg / day, about 500~550mg / day, about 550~600mg / day, about 600~6 50mg / day, about 650~700mg / day, about 700~750mg / day, about 750~80 0 mg / day, approximately 800-850 mg / day, approximately 850-900 mg / day, approximately 900-950 mg / day, about 950~1000mg / day, about 1000~1100mg / day, about 1100~ 1200mg / day, approx. 1200~1300mg / day, approx. 1300~1400mg / day, approx. 1400~1500mg / day, about 1500~1600mg / day, about 1600~1700m g / day, about 1700~1800mg / day, about 1800~1900mg / day, about 1900~ 2000mg / day, approx. 2000~2500mg / day, approx. 2500~3000mg / day, approx. 3000-3500 mg / day, approximately 3500-4000 mg / day, approximately 4000-4500 mg g / day, or approximately 4500-5000 mg / day, or at least approximately 1-5000 mg g / day, about 1~10mg / day, about 10~50mg / day, about 50~100mg / day, about 10 0~150mg / day, approx. 150~200mg / day, approx. 200~250mg / day, approx. 250 ~300mg / day, approximately 300~350mg / day, approximately 350~400mg / day, approximately 400~ 450mg / day, approximately 450-500mg / day, approximately 500-550mg / day, approximately 550-6 00mg / day, about 600~650mg / day, about 650~700mg / day, about 700~75 0 mg / day, approximately 750-800 mg / day, approximately 800-850 mg / day, approximately 850-900 mg / day, about 900~950mg / day, about 950~1000mg / day, about 1000~11 00mg / day, about 1100~1200mg / day, about 1200~1300mg / day, about 13 00~1400mg / day, about 1400~1500mg / day, about 1500~1600mg / day, about 1600~1700mg / day, about 1700~1800mg / day, about 1800~19 00mg / day, about 1900~2000mg / day, about 2000~2500mg / day, about 25 00~3000mg / day, about 3000~3500mg / day, about 3500~4000mg / The daily dose is approximately 4000-4500 mg, or approximately 4500-5000 mg.

[0203] In some embodiments, the immunosuppressive therapy (e.g., DMARDS) administered to the subject The dosage is approximately 0.1-40 mg / week, approximately 5-30 mg / week, approximately 0.1-5 mg / week, and approximately 5-1 0mg / week, approx. 10~15mg / week, approx. 15~20mg / week, approx. 20~25mg / week, approx. 25~30mg / week, about 30~35mg / week, about 35~40mg / week, about 10~30mg / week, approximately 10-100mg / week, approximately 50mg / week, approximately 0.1-50mg / kg body weight / week be.

[0204] 5.3.10 Cyclophosphamide The cyclophosphamide used herein is intended to suppress the immune system in recipients. The compound to be administered. In some embodiments, cyclophosphamide (2-[bis( 2-Chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2- Oxide monohydrate induces tolerance to transplanted organs (e.g., liver or kidney). It is administered for that purpose, and the brand names of cyclophosphamide include Cytoxan (registered trademark) and N Examples include eosar® and Endoxan®.

[0205] In one embodiment, the regimen provided herein involves administering cyclophosphamide before transplantation. This includes administering to a transplant recipient. In one embodiment, the regimen provided herein Men administers cyclophosphamide to treat or prevent immune-related disorders or diseases. This includes the following. In some embodiments, cyclophosphamide is administered 3 days after transplantation, 4 days after transplantation. , 5 days after transplantation, 6 days after transplantation, 3 and 4 days after transplantation, 5 and 6 days after transplantation, 3 days after transplantation Administered to the recipient 4 and 5 days after transplantation, or 4, 5 and 6 days after transplantation. It is possible. In certain embodiments, cyclophosphamide is administered 4 and 5 days after transplantation. It can be administered to the recipient. In certain embodiments, cyclophosphamide is It is first administered to the recipient 3, 4, 5, 6, or 7 days after transplantation. .

[0206] In certain embodiments, recipients treated according to the method described herein are 30 The above MELD score is present, and this method is used 1-2 days after transplantation, 2-4 days after transplantation, and 4 days after transplantation. 6 days after transplantation, 6-8 days after transplantation, 8-10 days after transplantation, 10-12 days after transplantation, 12-14 days after transplantation , 14-16 days after transplantation, 16-18 days after transplantation, 18-20 days after transplantation, 20-22 days after transplantation , 22-24 days after transplantation, 24-26 days after transplantation, 26-28 days after transplantation, 28-30 days after transplantation Alternatively, administer cyclophosphamide to the recipient first, 31 days or more after transplantation. include.

[0207] In certain embodiments, recipients treated according to the method described herein are 30 The following MELD scores are observed, and this method is used at 1 day after transplantation, 2 days after transplantation, 3 days after transplantation, and after transplantation. 4 days after transplantation, 5 days after transplantation, 6 days after transplantation, 7 days after transplantation, 8 days after transplantation, 9 days after transplantation, 10 days after transplantation , 11 days after transplantation, 12 days after transplantation, 13 days after transplantation, 14 days after transplantation, or 14 days after transplantation This includes administering cyclophosphamide to the recipient first.

[0208] In one embodiment, cyclophosphamide is administered at doses of 20 mg / kg / dose and 25 mg / kg / dose. 30 mg / kg / dose, 35 mg / kg / dose, 40 mg / kg / dose, 45 mg / kg / dose 50 mg / kg / dose, 55 mg / kg / dose, 56 mg / kg / dose, 57 mg / kg / dose 58 mg / kg / dose, 59 mg / kg / dose, 60 mg / kg / dose, 61 mg / kg / dose 62 mg / kg / dose, 63 mg / kg / dose, 64 mg / kg / dose, 65 mg / kg / dose , 70mg / kg / dose, 75mg / kg / dose, 80mg / kg / dose, 85mg / kg / dose It can be administered to transplant recipients at a dose of 90 mg / kg / dose, or It may be administered to treat or prevent immune-related disorders or diseases in the target population. In one embodiment, cyclophosphamide is administered at 20-30 mg / kg / dose, 25-3 5 mg / kg / dose, 30-40 mg / kg / dose, 35-45 mg / kg / dose, 40-50 mg / kg / dose, 45-55 mg / kg / dose, 50-60 mg / kg, 55-65 mg / kg / dose, 60~70mg / kg / dose, 65~75mg / kg / dose, 70~80mg / k Administer in the following dose ranges: g / dose, 75-85 mg / kg / dose, or 80-90 mg / kg / dose. This is possible. In certain embodiments, cyclophosphamide is 40 mg / kg / dose. It can be administered in the prescribed dose.

[0209] In one embodiment, cyclophosphamide is used by appropriate methods known in the art. For example, subcutaneous, intravenous, intravascular, local, intraarterial, intracranial, intramuscular, oral, orbital, inhalation This allows for the appropriate action of cyclophosphamide through percutaneous, intraperitoneal, or targeted administration. It can be administered via a specific route of administration. In a particular embodiment, cyclophosph Amid is administered intravenously. In certain embodiments, cyclophosphamide is administered over 1 hour. It is administered intravenously. In some embodiments, cyclophosphamide is also an anti-CD2 antibody. Before the antigen-binding fragment and / or CTLA-4 costimulatory blocker is administered to the target, or administered later. In some embodiments, cyclophosphamide is an anti-CD2 anti- The body or its antigen-binding fragments are administered before, during, or after administration to the target. In this embodiment, cyclophosphamide is administered to a target of a CTLA-4 costimulatory blocker. It is administered before, during, or after the drug.

[0210] 5.3.11 Calcineurin inhibitors (e.g., tacrolimus) In some embodiments, the therapeutic methods described herein target calcineurin inhibition. The further includes administering the agent. In certain embodiments, the calcineurin inhibitor is tac This refers to tacrolimus. As used herein, tacrolimus is used to target the immune system for suppression. It is a macrolide antibiotic that can be administered. Tacrolimus is a cyclosporine (CyA) antibiotic. A (another calcineurin inhibitor) has a similar mechanism of action and is traded as tacrolimus. Prograf (registered trademark), Adport (registered trademark), Advagraf (registered trademark) (Registered Trademark), Protopic (Registered Trademark), Astagraf XL (Registered Trademark), Mo Examples include digraf® and Envarsus XR®. Lucineurin inhibitors (e.g., tacrolimus) are used to treat immune-related diseases or disorders. It can be administered to the target for prevention, or in the recipient, the immune system It can be included in the postoperative treatment regimen to suppress graft-versus-host disease and inhibit its development. In some embodiments, the administration of a calcineurin inhibitor is followed by the administration of a calcineurin inhibitor to the subject. This includes a certain process involving the tapering process of neurolin inhibitors (e.g., tacrolimus). .

[0211] In one embodiment, the regimen provided herein involves administering cyclophosphamide , including treating or preventing immune-related disorders or diseases. In some embodiments, this specification The regimen provided in the book involves the use of a calcineurin inhibitor (e.g., tacrolimus) in the implantation This includes administering to a cypient. In one embodiment, a calcineurin inhibitor (e.g.) Tacrolimus is taken one day before transplantation, two days before transplantation, three days before transplantation, one day and two days before transplantation, and It can be administered for the first time one and three days before planting, or one, two, and three days before transplantation. In certain embodiments, calcineurin inhibitors (e.g., tacrolimus) can be used for transplantation. It can be administered to the recipient first one day prior. In certain embodiments, calcinu -Phoenix inhibitors (e.g., tacrolimus) are used during the period immediately preceding transplantation (i.e., before and after transplant surgery). ) is administered as early as possible. In certain embodiments, calcineurin inhibitors (e.g.) For example, tacrolimus is administered within 24 hours after reperfusion of an organ (e.g., liver) transplant. In one embodiment, the postoperative treatment regimen provided herein involves calcineurin inhibition. This includes administering a drug (e.g., tacrolimus) to the transplant recipient. In one embodiment, Calcineurin inhibitors (e.g., tacrolimus) are used on the day of transplantation and one day after transplantation surgery. 2 days later, 3 days later, 4 days later, 5 days later, 6 days later, 7 days later, 8 days later, 9 days later, 10 days later, 11 days later After, 12 days later, 13 days later, 14 days later, 15 days later, 16 days later, 17 days later, 18 days later, 19 days later After, 20 days later, 21 days later, 22 days later, 23 days later, 24 days later, 25 days later, 26 days later, 27 days later 28 days later, 29 days later, 30 days later, 1 month later, 2 months later, 3 months later, 4 months later, 5 months later Six months later, seven months later, eight months later, nine months later, ten months later, eleven months later, twelve months later, After 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months It may be permitted.

[0212] In one embodiment, a single dose of tacrolimus can be administered. It is possible to administer multiple doses of a calcineurin inhibitor (e.g., tacrolimus). In one embodiment, a certain dose of a calcineurin inhibitor (e.g., tacrolimus) In one embodiment, calcineurin inhibition of the tapering process is performed. An agent (e.g., tacrolimus) can be administered. In one embodiment, a certain dose of Lucineurin inhibitors (e.g., tacrolimus) followed by calcineurin inhibitors (e.g., The tapering process of tacrolimus can be administered.

[0213] In certain embodiments, a calcineurin inhibitor (e.g., tacrolimus) is administered once daily. It may be administered at a frequency of . In one embodiment, tacrolimus is administered at a frequency of twice a day. It is possible. In one embodiment, tacrolimus is administered (for example, starting on the day of transplantation) It can be administered twice a day. In one embodiment, a calcineurin inhibitor (e.g.) For example, tacrolimus is available in doses of 0.1 mg / kg / dose, 0.2 mg / kg / dose, and 0.3 mg / kg / kg / dose, 0.4 mg / kg / dose, 0.5 mg / kg / dose, 0.6 mg / kg / dose, 0. 7 mg / kg / dose, 0.8 mg / kg / dose, 0.9 mg / kg / dose, 1 mg / kg / dose, 0.1~0.5mg / kg / dose, 0.5~1mg / kg / dose, 0.2~0.6mg / kg / dose, 0.3-0.7 mg / kg / dose, 0.4-0.8 mg / kg / dose, or 0.1- It may be administered twice daily at a dose of 1 mg / kg / dose. In certain embodiments, calcinuri The inhibitor is tacrolimus, administered at a dose of at least 0.5 mg / kg / dose twice daily. It is administered orally.

[0214] In one embodiment, the calcineurin inhibitor (e.g., tacrolimus) is 1-5 ng / ml, 5~10ng / ml, 10~15ng / ml, 1~11ng / ml, 2~12n g / ml, 3~13ng / ml, 4~14ng / ml, 5~15ng / ml, 6~16n g / ml, 7~17ng / ml, 8~18ng / ml, 9~19ng / ml, 10~20 A dose sufficient to achieve a target blood trough concentration of ng / ml, or 15-20 ng / ml. It can be administered to the target. In certain embodiments, the target blood trough concentration is 10-1 It may be 5 ng / ml. In certain embodiments, the calcineurin inhibitor is tacrolim It is a dose sufficient to maintain serum trough concentration in the range of 4-11 ng / mL. It is administered to elephants.

[0215] In one embodiment, a calcineurin inhibitor (e.g., tacrolimus) is administered subcutaneously, intravenously, or via the veins. Internal, intravascular, local, intra-arterial, intracranial, intramuscular, oral, intraorbital, inhalation, percutaneous, intraperitoneal , or appropriate calcineurin inhibitors (e.g., tacrolimus) by the recipient The target is administered by an appropriate method known in the art, such as an administration route that enables the action. It can be administered. In certain embodiments, calcineurin inhibitors (e.g., tacroli) can be administered. Mus) can be administered orally. In certain embodiments, calcineurin inhibitors ( For example, tacrolimus can be administered intravenously.

[0216] In certain embodiments, the subject is an immune-related disease or After being diagnosed with a disorder, or when the subject has an immune-related disorder or disability as described herein, After receiving treatment for the harm, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1-2 months, 2-3 months, 3-4 months, 4-5 months, 5-6 months Months, 6-7 months, 7-8 months, 8-9 months, 9-10 months, 10-11 months, 11-1 2 months, 12-13 months, 13-14 months, 14-15 months, 15-16 months, 16-1 7 months, 17-18 months, 18-19 months, 19-20 months, 20-21 months, 21-2 At 2 months, 22-23 months, or 23-24 months, calcineurin inhibitors (for example, Detachment from tacrolimus. In certain embodiments, detachment occurs after the subject has received an organ transplant. after the subject has been diagnosed with an immune-related disease or disorder, or It is initiated 6 months after treatment for an immune-related disease or disorder, according to specific implementations. In this context, the withdrawal was due to the 2016 Banff Criteria (Demetris et al.). al.,Am J Transplant.2016 Oct;16(10):2816 As determined by (as described in -2835), samples taken from the recipient at 6 months of age are taken. If there is no rejection reaction to the biopsy specimen, and / or the recipient maintains stable transplant function, It will only start if you have it.

[0217] In certain embodiments, the dose of a calcineurin inhibitor (e.g., tacrolimus) is, The dosage should be reduced every 2, 3, 4, 5, or 6 months after the start of withdrawal.

[0218] In certain embodiments, the withdrawal protocol reduces the frequency of administration, for example, to twice a day. From once a day, from once a day to every other day, from once a day to three times a week, from three times a week to twice a week, weekly Reduce the frequency of administration from twice a day to once a week, or from once a week to every other week, or take one or more steps. Includes. In certain embodiments, the withdrawal protocol includes a calcineurin inhibitor (e.g., ta A step to reduce the daily dose of chlorimus, for example, by 10-20% of the initial daily dose. ~30%, 30~40%, 40~50%, 50~60%, 60~70%, 70~80%, The process includes a step of reducing by 80-90%, or more than 90%. In certain embodiments, the withdrawal process Lotocor reduces the daily dose of calcineurin inhibitors (e.g., tacrolimus) by approximately 25%. Includes steps to reduce the number of steps.

[0219] In certain embodiments, administration of a calcineurin inhibitor (e.g., tacrolimus) is used against After an elephant has received an organ transplant, after the subject has been diagnosed with an immune-related disease or disorder, or the subject is After receiving treatment for an immune-related disease or disorder in accordance with the method described herein, approximately 12-15 It will be stopped after 1 month, 15-18 months, 18-21 months, or 21-24 months. In terms of administration methods, the administration of calcineurin inhibitors (e.g., tacrolimus) is used when the target organ transfer is affected. After receiving the plant, after the subject is diagnosed with an immune-related disease or disorder, or after the subject is specified herein It is discontinued 18 months after treatment for an immune-related disorder or condition according to the method described. In certain embodiments, the administration of a calcineurin inhibitor (e.g., tacrolimus) is performed. metris et al.,Am J Transplant.2016 Oct;1 As described in 6(10):2816-2835, 2016 Banff Criter As determined by ia, the biopsy taken from the recipient at 18 months of age It will only stop if there is no rejection reaction.

[0220] An example withdrawal protocol is (i) 3 months (for example, from 6 to 9 months after transplantation) ) Then, the initial twice-daily dose of tacrolimus was reduced to once daily, and the daily dose was reduced to three-quarters. (ii) over a period of three months (for example, from the 9th to the 12th month after transplantation), increasing the dosage weekly. Further reduce to 3 times; (iii) 3 months (for example, from 12 to 15 months after transplantation) (iv) Reduce the dose to twice a week over a period of three months (for example, 15 days after transplantation); (iv) From the first month to the 18th month, further reduce the dose to once a week; and (v) the subjects After receiving an organ transplant, after being diagnosed with an immune-related disease or disorder, or after the subject has been diagnosed with an immune-related disease or disorder Eighteen months after receiving treatment for an immune-related disease or disorder in accordance with the method described in the details, This includes the step of discontinuing the administration of tacrolimus.

[0221] In some embodiments, alternative compounds can be used instead of calcineurin inhibitors. These compounds include sirolimus and everolimus. In this embodiment, the calcineurin inhibitor is cyclosporine (Gengraf (registered trademark) (Mark), Neoral (registered trademark), and Sandimmune (registered trademark)) This can be done and can be used as a substitute for tacrolimus. In some embodiments, Syneurin inhibitors are anti-CD2 antibodies or their antigen-binding fragments and / or CTLA- 4. The co-stimulus blocker is administered before, during, or after administration to the subject. Several embodiments So, calcineurin inhibitors are administered to targets using anti-CD2 antibodies or their antigen-binding fragments. It is administered before, during, or after. In some embodiments, a calcineurin inhibitor It is administered before, during, or after the administration of CTLA-4 costimulatory blockers to the target patient.

[0222] 5.3.12 Steroids Steroids, when used herein, are intended to treat immune-related immune disorders or diseases. These are compounds administered to a target for preventative purposes. In some embodiments, they suppress the immune system. To achieve this, steroids are administered to recipients of organ (e.g., liver or kidney) transplants. Prednisone is a corticosteroid, and its chemical name is 17,21-dihydrox. Cypregna-1,4-diene-3,11,20-trione(C 21 H 26 It is O5). Prednisone is sold under the brand names Deltasone (registered trademark) and Sterapred. (Registered Trademark), Rayos (Registered Trademark), Prednicot (Registered Trademark), and Met One example is icorten (registered trademark).

[0223] In one embodiment, the therapeutic method provided herein involves corticosteroids in an immune-related manner. To administer to a target for the treatment or prevention of an immune disorder or disease, or to transplantation This includes administering it to the patient. In one embodiment, the corticosteroid is administered on the day of transplantation. , after transplant surgery, 1 day later, 2 days later, 3 days later, 4 days later, 5 days later, 6 days later, 7 days later, 8 days later, 9 Days later, 10 days later, 11 days later, 12 days later, 13 days later, 14 days later, 15 days later, 16 days later, 17 Days later, 18 days later, 19 days later, 20 days later, 21 days later, 22 days later, 23 days later, 24 days later, 25 days later It can be administered on the 26th, 27th, 28th, 29th, or 30th day after administration. ru.

[0224] In one embodiment, corticosteroids were administered from the day of the transplant surgery until 5 days after the transplant surgery. From the day of the transplant surgery to 10 days after the transplant surgery, from the day of the transplant surgery to 15 days after the transplant surgery, transplant surgery From the day of the surgery until 20 days after the transplant surgery, from the day of the transplant surgery until 25 days after the transplant surgery, or transplant It can be administered from the day of surgery until 30 days after the transplant surgery. In certain embodiments, corticosterone The drug is administered on the day of the transplant surgery and 2 to 7 days after the transplant surgery. In certain embodiments, the patient The dosage of corticosteroids administered is gradually reduced from the day of transplantation until one month after transplantation.

[0225] In one embodiment, a single dose of corticosteroid may be administered. In one embodiment, Multiple doses of corticosteroids may be administered. In one embodiment, a certain dose of corticosteroids Tycosteroids may be administered. In one embodiment, a corticosteroid pulse is administered. It is possible. In one embodiment, a corticosteroid may be administered during the tapering process. In one embodiment, after a certain dose of corticosteroids, the corticosteroids are tapered. The process may be administered. In one embodiment, a certain dose of corticosteroids is administered to corticosteroids. It can be administered in conjunction with teroid pulse therapy and the tapering process of corticosteroids.

[0226] In one embodiment, the corticosteroid is 0.1 mg / kg, 0.2 mg / kg, 0 .3mg / kg, 0.4mg / kg, 0.5mg / kg, 0.6mg / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1.0mg / kg, 1.1mg / kg, 1.2mg / kg, 1.3mg / kg, 1.4mg / kg, 1.5mg / kg, 1.6m g / kg, 1.7mg / kg, 1.8mg / kg, 1.9mg / kg, 2.0mg / kg , 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5 mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / k It can be administered to the subject at a dose of g or 3.0 mg / kg. In certain embodiments Steroids may be administered to the subject at a dose of 2 mg / kg.

[0227] In one embodiment, the corticosteroid is 100 mg / dose, 200 mg / dose, 300 mg mg / dose, 400mg / dose, 500mg / dose, 600mg / dose, 700mg / dose, 800 The drug is administered to the target patient in pulse doses of mg / dose, 900 mg / dose, or 1000 mg / dose. This is possible. In certain embodiments, the corticosteroid is administered in pulse doses of 500 mg / dose. It can be administered as follows. In one embodiment, the corticosteroid pulse is administered on the day of transplantation. 1 day after transplantation, 2 days after transplantation, 3 days after transplantation, 4 days after transplantation, 5 days after transplantation, 6 days after transplantation, 7 days after transplantation After, 8 days after transplantation, 9 days after transplantation, 10 days after transplantation, 11 days after transplantation, 12 days after transplantation, 13 days after transplantation Also, 14 days after transplantation, 15 days after transplantation, the day of transplantation, and 1 and 2 days after transplantation, and 3 and 4 days after transplantation. and 5 days after transplantation, 6 days, 7 days, and 8 days after transplantation, 9 days, 10 days, and 11 days after transplantation, 10, 11, and 12 days after transplantation, 11, 12, and 13 days after transplantation, and It can be administered 13, 14, and 15 days after transplantation. In certain embodiments, Corticosteroid pulses are administered on the day of transplantation. In certain embodiments, cortico Steroid pulse therapy is administered 10, 11, and 12 days after transplantation.

[0228] In one embodiment, the steroid can be administered to the subject in a fixed dose. The duration of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, and This can be 10 days. In one embodiment, the corticosteroid administered to the subject is It can be parried and terminated. In one embodiment, this tapering process is 5 Sunday, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th Sunday, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th This can be done over 27, 28, 29, or 30 days, depending on the specific embodiment. The tapering process can be carried out over 10 days. In a particular embodiment, the taper The ringing process can be completed in 20 days.

[0229] In one embodiment, during the tapering process, the amount of corticosteroid administered to the subject is 0 0.01 mg / kg / day, 0.02 mg / kg / day, 0.03 mg / kg / day, 0.04 mg g / kg / day, 0.05 mg / kg / day, 0.06 mg / kg / day, 0.07 mg / kg / day, 0.08mg / kg / day, 0.09mg / kg / day, 0.1mg / kg / day, 0. 2mg / kg / day, 0.3mg / kg / day, 0.4mg / kg / day, 0.5mg / kg / 0.6 mg / kg / day, 0.7 mg / kg / day, 0.8 mg / kg / day, 0.9 mg / kg / day, 1.0mg / kg / day, 1.1mg / kg / day, 1.2mg / kg / day, 1 .3mg / kg / day, 1.4mg / kg / day, 1.5mg / kg / day, 1.6mg / kg / day, 1.7mg / kg / day, 1.8mg / kg / day, 1.9mg / kg / day, or 2 It can be reduced by 0.0 mg / kg / day.

[0230] An exemplary steroid administration regimen includes administering the following doses to the subject: (i) (ii) Transplant surgery 2 (iii) 250 mg of steroids administered orally three days later; (iii) 125 mg of steroids three days after transplant surgery. (iv) Oral administration of teroid; (iv) Oral administration of 75 mg of steroid four days after transplant surgery; and (v) Administer 60 mg of steroids orally 5 to 7 days after transplant surgery; and (vi) Administer 20 mg of steroid orally once a day from 7 days after the transplant surgery until 1 month later.

[0231] In one embodiment, corticosteroids are administered subcutaneously, intravenously, intravascularly, topically, intraarterially, and in the head. Intracavitary, intramuscular, oral, intraorbital, inhalation, percutaneous, intraperitoneal, or by the recipient This includes the administration route that enables the proper action of luticosteroids, as is known in the art. It can be administered to the target by an appropriate method. In certain embodiments, corticosterone The corticosteroid may be administered orally. In certain embodiments, the corticosteroid may be administered intravenously. obtain.

[0232] Examples of steroids that may be used in the methods described herein include Deltison ( (Registered trademark), Prednisolone EQL Pharma, and Prednisol Alternova is one example.

[0233] In certain embodiments, the corticosteroid is prednisone. In one embodiment, the corticosteroid pulse is methylprednisone. The administration of tycosteroids may be modified as described herein. In terms of administration, steroids are used with anti-CD2 antibodies or their antigen-binding fragments and / or CTLs. A-4 The costimulator is administered before, during, or after the administration of costimulators to the target. Several implementations In terms of form, steroids are administered to the target before the anti-CD2 antibody or its antigen-binding fragment is administered. It is administered during or after the treatment. In some embodiments, the steroid is administered via CTLA-4 receptors. It is administered before, during, or after the administration of a stimulant blocker to the target.

[0234] 5.3.13 Cyclosporine Cyclosporine (CyA) is used to treat immune-related immune disorders or diseases in subjects. It can be included for prevention. Cyclosporine (CyA) helps the recipient control odor. Therefore, to suppress the immune system and inhibit the development of graft-versus-host disease, it is included in the postoperative treatment regimen. The treatment regimen can be tapered after a certain course of CyA administration to the subject. It may include a certain degree. In one embodiment, cyclosporine is provided herein. In the law, it may be used as a substitute for calcineurin inhibitors (e.g., tacrolimus). In some embodiments, cyclosporine is harmful to calcineurin inhibitors. It can be used on objects that have experienced an event. In certain embodiments, cyclosporine is used in tacroli It may be used in patients who have experienced mucus-related adverse events.

[0235] In one embodiment, the postoperative treatm...

Claims

1. A recombinant anti-CD2 antibody, wherein the antibody is an IgG antibody, compared to cyprizumab. While the immunomodulatory activity of the antibody is maintained, the antibody mediates antibody-dependent cell-mediated cytotoxicity. The antibody whose ability is reduced or eliminated.

2. Recombinant anti-CD2 antibody, wherein the antibody is an IgG antibody and has a small amount of constant region in the heavy chain. The antibody wherein one consensus N glycosylation site is not glycosylated.

3. At least one consensus sequence is mutated so that it is not glycosylated any further. The antibody according to claim 1.

4. Recombinant anti-CD2 antibody, wherein the antibody is an IgG antibody and has a small amount of constant region in the heavy chain. Each consensus N-linked glycosylation site maintains one of the following oligosaccharides. To hold: 【Chemistry 1】 (Here, the symbols are as follows: white triangle: fucose, white square: N-acetylglucosa) Min, gray circle: mannose, white circle: galactose), the aforementioned antibody.

5. Recombinant anti-CD2 antibody, wherein the antibody is an IgG antibody expressed in mammalian cells. The antibody is treated with endoglycosidase.

6. The aforementioned mammalian cells are NS0 mouse myeloma cells, PER. C6® human cells, The antibody according to claim 5, or Chinese hamster ovary (CHO) cells.

7. The antibody according to claim 5, wherein the endoglycosidase is EndoS2.

8. The antibody according to any one of claims 1 to 7, wherein the amino acid residues N18, K55, and T59 of human CD2 determine the affinity of the antibody to human CD2.

9. The antibody according to any one of claims 1 to 8, wherein the immunomodulatory activity of the antibody is maintained, while the ability of the antibody to mediate antibody-dependent cell-mediated cytotoxicity is reduced or eliminated. body.

10. The immunomodulatory activity may include induction of CD4+ / CD25+ T cells, as described in claim 9. Antibodies of [the substance].

11. The antibody according to claim 9, wherein the immunomodulatory activity may include an increase in FoxP3 expression.

12. The antibody according to claim 9, wherein the immunomodulatory activity may include the suppression of CD69+ NK cells.

13. The antibody according to any one of claims 1 to 12, wherein the antibody is IgG1.

14. The antibody according to any one of claims 1 to 13, wherein the antibody is IgG2.

15. The antibody according to any one of claims 1 to 14, wherein the antibody is IgG4.

16. The antibody according to any one of claims 1 to 15, wherein the antibody is humanized.

17. The antibody according to any one of claims 1 to 16, wherein the antibody is fully human.

18. The antibody according to any one of claims 1 to 17, wherein the antibody comprises an additional antibody component in addition to IgG.

19. Claim 18, wherein the additional antibody component may be the replication region of the recombinant anti-CD2 antibody. The antibody described.

20. The claim states that an additional antibody component is ligated to the C-terminus of the Fc region of the recombinant anti-CD2 antibody. The antibody described in item 18.

21. The additional antibody component binds to the CD2, CH2, or CH3 domain. The antibody according to claim 18, which may contain cFv.

22. The scFv domain includes VH and VL, and the sequence of VH is the ami of SEQ ID NO: 1 The ano acid sequence is at least 80%, 85%, 90%, 95%, 98%, or 99% identical. Furthermore, the sequence of VL is at least 80%, 85%, and 90% different from the amino acid sequence of SEQ ID NO:

2. The antibody according to claim 21, which is 95%, 98%, or 99% identical.

23. The CH2 domain is at least 80% of the amino acid sequence of SEQ ID NO: 18 or 19. Claim comprising an amino acid sequence that is 85%, 90%, 95%, 98%, or 99% identical. The antibody described in 21.

24. The CH3 domain is at least 80% of the amino acid sequence of SEQ ID NO: 20 or 21. Claim comprising an amino acid sequence that is 85%, 90%, 95%, 98%, or 99% identical. The antibody described in 21.

25. a. The heavy chain variable region CDR1 of the antibody contains the amino acid sequence of SEQ ID NO: 3; b. The heavy chain variable region CDR2 of the antibody comprises the amino acid sequence of SEQ ID NO: 4; c. The heavy chain variable region CDR3 of the antibody comprises the amino acid sequence of SEQ ID NO: 5; d. The light chain variable region CDR1 of the antibody comprises the amino acid sequence of SEQ ID NO: 6; e. The light chain variable region CDR2 of the antibody comprises the amino acid sequence of SEQ ID NO: 7; f. The light chain variable region CDR3 of the antibody contains the amino acid sequence of SEQ ID NO:

8. The antibody according to any one of claims 1 to 24.

26. The Fc region of the antibody has one or more point mutations that result in Fc silencing. an antibody according to any one of claims 1 to 25.

27. The antibody according to claim 26, wherein the antibody is IgG1.

28. The antibody according to claim 26, wherein the antibody is IgG2.

29. The antibody according to claim 26, wherein the antibody is IgG4.

30. The antibody according to any one of claims 1 to 29, wherein the antibody has a native constant region different from cyprizumab.

31. The antibody according to any one of claims 1 to 30, wherein the antibody has a native constant region different from cyprizumab and has a point mutation within the Fc region that results in Fc silencing.

32. The heavy chain variable region is the amino acid sequence of SEQ ID NO: 1, or the amino acid sequence of SEQ ID NO: 1 and Amino acids that are at least 80%, 85%, 90%, 95%, 98%, or 99% identical The sequence includes; the light chain variable region is the amino acid sequence of SEQ ID NO: 2, or the amino acid sequence of SEQ ID NO:

2. The antibody according to any one of claims 1 to 31, comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, or 99% identical to the no-acid sequence.

33. The heavy chain constant region is the amino acid sequence of SEQ ID NOs. 9, 10, 11, 12, or 13, The amino acid sequence of SEQ ID NOs. 9, 10, 11, 12, or 13 is at least 80%, 85% , comprising an amino acid sequence that is 90%, 95%, 98%, or 99% identical; the light chain steady state The region is the amino acid sequence of SEQ ID NO: 14 or 15, or the amino acid sequence of SEQ ID NO: 14 or 15. The antibody according to any one of claims 1 to 32, comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, or 99% identical to the no-acid sequence.

34. The heavy chain is the nucleic acid sequence of SEQ ID NO: 16, or at least 80% of SEQ ID NO: 16, 85% Containing nucleic acid sequences that are identical by %, 90%, 95%, 98%, or 99%; the light chain is The nucleic acid sequence of sequence number 17, or sequence number 17 and at least 80%, 85%, 90%, 95% An antibody according to any one of claims 1 to 33, comprising nucleic acid sequences that are identical by %, 98%, or 99%.

35. Heavy chain variable region of SEQ ID NO: 1; Light chain variable region of SEQ ID NO: 2; SEQ ID NOs: 9, 10, 11, 1 A set comprising a heavy chain steady region of 2 or 13; and a light chain steady region of sequence number 14 or 15. Replacement anti-CD2 antibody.

36. Nucleic acid sequences including SEQ ID NOs. 16 and SEQ ID NOs.

17.

37. A pharmaceutical preparation comprising the antibody described in any one of claims 1 to 36.

38. The pharmaceutical preparation according to claim 36, wherein the preparation is suitable for long-term administration.

39. A method for treating an acute or chronic disorder of the immune system in a patient, comprising administering to the patient an antibody according to any one of claims 1 to 38.

40. The aforementioned patient has been at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or at least 1 year, 2 years , 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 Treatment for a period of 15, 16, 17, 18, 19 years, or at least 20 years. The method according to claim 39, which has been received.

41. A method for maintaining immune tolerance to transplantation in transplant recipients, according to claims 1 to The method comprising administering the antibody described in any one of item 38 to the transplant recipient. Law.

42. The aforementioned antibody lasts for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, and 7 months. 8 months, 9 months, 10 months, 11 months, or 12 months, or at least 1 year, 2 years , 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 For a period of 15, 16, 17, 18, 19, or at least 20 years, the aforementioned The method according to claim 41, administered to a transplant recipient.

43. The aforementioned acute or chronic disorder of the immune system is graft-versus-host disease (GVHD), rheumatoid arthritis Ankylosing spondylitis, type 1 diabetes, psoriasis, ulcerative colitis, inflammatory bowel disease (Crohn's disease), celery Ack's disease, Sjögren's disease, lupus, multiple sclerosis, focal segmental glomerulosclerosis, atopic dermatitis Dermatitis, amyotrophic lateral sclerosis, primary biliary cirrhosis, and primary sclerosing cholangitis, and severe The method according to claim 39 or 40, wherein the patient has asthma.

44. A method of treating or preventing immune-related disorders or diseases in those who require it. That is, a) Administering an anti-CD2 antibody or its antigen-binding fragment to the subject; b) Administering a CTLA-4 costimulator to the subject, The method, including the method described above.

45. The anti-CD2 antibody or its antigen-binding fragment is Fc Silent anti-CD2 antibody, BTI- 322, CB. 219, LO-CD2b, cyprizumab, and / or its antigen-binding fragments The method according to claim 44, comprising at least one of the following.

46. The anti-CD2 antibody or its antigen-binding fragment a) Heavy chain variable region CDR1 of Sequence ID No. 3; b) Heavy chain variable region CDR2 of Sequence ID No. 4; c) Heavy chain variable region CDR3 of Sequence ID No. 5; d) Light chain variable region CDR1 of sequence number 6; e) Light chain variable region CDR2 of Sequence ID No. 7; and f) Light chain variable region CDR3 of Sequence ID No. 8 The method according to claim 44, including the method described in claim 44.

47. The method according to any one of claims 44 to 47, wherein the anti-CD2 antibody is a humanized antibody. Law.

48. Claims 44-47, wherein the anti-CD2 antibody is cyprizumab or its antigen-binding fragment. The method described in any one of the items.

49. The CTLA-4 costimulator is the Fc fragment of human IgG1 immunoglobulin and CTL A fusion protein containing the extracellular domain of A4, according to any one of claims 44 to 49 Method of description.

50. The aforementioned CTLA-4 costimulator is approximately 80%, 85%, 90%, and 95% of the CTLA-4 costimulator (SEQ ID NO: 22). 98%, 99%, or 100%, or at least about 80%, 85%, 90%, 9 Claims 44 to 49 include sequences that are 5%, 98%, 99%, or 100% identical. The method described in item 1.

51. Claims 44-5, wherein the CTLA-4 costimulator contains the same sequence as SEQ ID NO:

22. The method described in any one of item 1.

52. Any of claims 44 to 51, wherein the CTLA-4 costimulator is beratacept. The method described in paragraph 1.

53. The aforementioned CTLA-4 costimulator is approximately 80%, 85%, 90%, and 95% of the CTLA-4 costimulator described in SEQ ID NO:

23. 98%, 99%, or 100%, or at least about 80%, 85%, 90%, 9 Claims 44 to 49 include sequences that are 5%, 98%, 99%, or 100% identical. The method described in item 1.

54. Claims 44-4, wherein the CTLA-4 costimulator contains the same sequence as SEQ ID NO:

23. The method described in either item 9 or 54.

55. Claims 44 to 49 or 54, wherein the CTLA-4 costimulator is abatacept. The method described in any one of items ~55.

56. The aforementioned immune-related disorders or diseases include systemic lupus erythematosus, rheumatoid arthritis, and psoriatic arthritis. Inflammation, polyarticular juvenile idiopathic arthritis (JIA), osteoarthritis, juvenile chronic arthritis, spinal arthritis Scleroderma, systemic scleroderma, idiopathic inflammatory muscle disease, Sjögren's syndrome, systemic vasculitis, sarcoplasmosis idosis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, thyroiditis, true Diabetes mellitus, immune-mediated renal disease, demyelinating diseases of the central or peripheral nervous system, idiopathic demyelinating polyneuropathy Inflammation, Guillain-Barré syndrome, Lyme disease, chronic inflammatory demyelinating polyneuropathy, hepatobiliary tract disease, infection Sexual or autoimmune chronic active hepatitis, primary biliary cirrhosis, Goodpasture syndrome, meat Blastomatous hepatitis, sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive bowel disease, Whipple's disease, autologous Immune or immune-mediated skin diseases, bullous skin diseases, erythema multiforme, contact dermatitis, psoriasis, allergies Ghee-related disorders, asthma, allergic rhinitis, atopic dermatitis, food allergies, urticaria, multiple Sclerosis, uveitis, pulmonary immune disorders, eosinophilic pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, organs Diseases associated with transplantation, diseases associated with tissue transplantation, graft rejection, graft-versus-host disease, Devic's disease, Acute disseminated encephalomyelitis, acute demyelinating optic neuritis, demyelinating transverse myelitis, Miller Fisher disease Syndrome, cerebrospinal radiculopathy, acute demyelinating polyneuropathy, tumor-like multiple sclerosis, Balo-type concentric sclerosis, alopecia areata, ankylosing spondylitis, Meniere's disease, antiphospholipid syndrome, mixed connective tissue disease, autoimmune Addison's disease, myasthenia gravis, autoimmune hepatitis, pemphigus vulgaris, Behçet's disease, bullous pemphigoid, polyarteritis nodosa, cardiomyopathy, polychondritis, celiac plue dermatitis, polyglandular syndrome, chronic fatigue syndrome (CFID), polymyalgia rheumatica, chronic inflammatory demyelinating polymyositis and dermatomyositis, primary agammaglobulinemia, Churg's disease The method according to any one of claims 44 to 56, wherein the condition is Trauss syndrome, bullous pemphigoid, Crest syndrome, Raynaud's phenomenon, cold agglutinin disease, Reiter's syndrome, Crohn's disease, rheumatic fever, discoid rash, essential mixed cryoglobulinemia, fibromyalgia, scleroderma, Graves' disease, Sjögren's syndrome, Stiffman syndrome, Hashimoto's thyroiditis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, idiopathic thrombocytopenic purpura (ITP), ulcerative colitis, IgA nephropathy, insulin-dependent diabetes mellitus (type 1), lichen planus, vitiligo, or any combination thereof.

57. The aforementioned immune-related disorder or disease is rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (JIA). ), psoriatic arthritis, or a combination thereof, any one of claims 44 to 56 Methods used.

58. The aforementioned immune-related disorders or diseases include organ transplant-related diseases and tissue transplant-related diseases. The method according to any one of claims 44 to 56, or a combination thereof.

59. If the CTLA-4 costimulator is not administered to the subject, the anti-CD2 antibody or The dose of the antigen-binding fragment is not therapeutically effective, according to any one of claims 44 to 61. Method of description.

60. If the anti-CD2 antibody or its antigen-binding fragment is not administered to the subject, the CTL A-4 The dosage of the costimulator is not therapeutically effective, according to any one of claims 44 to 61. Method of description.

61. Both the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulator are The number of cells in the biological sample obtained from the subject after administration to the subject is the number of cells in the subject. After administration of an anti-CD2 antibody or its antigen-binding fragment, or after CTLA-4 costimulation The number of cells in the biological sample obtained from the subject after the blocking agent has been administered (but not both) Compared to any one of claims 44 to 60, which is about 10% or at least about 10% less. The method described in section [section number].

62. The method according to any one of claims 44 to 60, wherein both the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulatory blocker are administered to the subject, resulting in a greater reduction in the number of cells in the biological sample obtained from the subject after administration to the subject, compared to the reduction in the number of cells in the biological sample obtained from the subject before at least one of administration of the anti-CD2 antibody or its antigen-binding fragment to the subject and / or administration of the CTLA-4 costimulatory blocker to the subject.

63. The method according to any one of claims 44 to 62, wherein both the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulatory blocker are administered to the subject, resulting in a greater decrease in the CD2 level in a biological sample obtained from the subject after administration to the subject, compared to the decrease in the CD2 level in a biological sample obtained from the subject before at least one of administration of the anti-CD2 antibody or its antigen-binding fragment to the subject and / or administration of the CTLA-4 costimulatory blocker to the subject.

64. The anti-CD2 antibody or its antigen-binding fragment or the CTLA-4 costimulator The CD2 level in the biological sample obtained from the subject after administration to the elephant (but not both) Compared to the decrease in the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4, The C in the biological sample obtained from the subject after both irritant-blocking agents have been administered to the subject. The method according to any one of claims 44 to 62, which results in a greater reduction in the D2 level. 。

65. Larger decreases than those mentioned above were approximately 5%, 10%, 15%, 20%, 25%, 30%, and 35%. ４０％、４５％、５０％、５５％、６０％、６５％、７０％、７５％、８０％、８５％、 90%, 100%, or greater than 100%, or at least about 5%, 10 ％、１５％、２０％、２５％、３０％、３５％、４０％、４５％、５０％、５５％、６０ %, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or 100% The method according to any one of claims 66 to 67, which is greater than or equal to.

66. The number of cells in the biological sample obtained from the subject is approximately 10%, 15%, 20%, 2 ５％、３０％、３５％、４０％、４５％、５０％、５５％、６０％、６５％、７０％、７ 5%, 80%, 85%, 90%, 100%, or less than 100%, or At least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, also The method according to claim 62, or less than 100%.

67. The subject has undergone organ transplantation and / or tissue transplantation, claims 44 to 56 or 58 The method described in any one of paragraphs 66.

68. The anti-CD2 antibody or its antigen-binding fragment is administered two weeks after organ transplantation and / or tissue transplantation. The method according to claim 70, wherein the subject is administered at least once within [number] days.

69. The anti-CD2 antibody or its antigen-binding fragment, on the day of organ and / or tissue transplantation, One day after transplantation of the organ and / or tissue, and / or four days after transplantation of the organ and / or tissue. The method according to claim 70 or 68, wherein the subject is administered the above-mentioned subject.

70. The anti-CD2 antibody or its antigen-binding fragment is administered intravenously or subcutaneously to the subject. or the method according to any one of claims 44 to 69.

71. Any one of claims 44 to 70 further comprises administering an additional drug to the subject. Methods used.

72. The aforementioned additional drugs include steroids, calcineurin inhibitors, cyclosporine, and cyclophorexate. Sphamide, antimetabolite therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and treatment for rheumatoid arthritis A drug used to treat and / or one or more mTOR inhibitors, please The method described in claim 71.

73. The aforementioned additional drugs include basiliximab inducer, mycophenolate mofetil, and corticosteroids. The method according to claim 71, comprising Lloyd's, or a combination thereof.

74. The initial dose of the anti-CD2 antibody or its antigen-binding fragment is the CTLA-4 costimulatory blockade. The method according to any one of claims 44 to 73, administered before the first dose of the agent.

75. The initial dose of the anti-CD2 antibody or its antigen-binding fragment is the CTLA-4 costimulatory blockade. The method according to any one of claims 44 to 73, administered after the initial dose of the agent.

76. The initial dose of the anti-CD2 antibody or its antigen-binding fragment is the CTLA-4 costimulatory blockade. The method according to any one of claims 44 to 73, administered simultaneously with the initial dose of the agent.

77. The method according to any one of claims 44 to 76, wherein the subject is an untreated subject.

78. Claims 44 to 44, wherein the subject is resistant to treatment of the immune-related disorder or disease. The method described in any one of paragraphs 76.

79. The anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulator are administered. This involves administering the anti-CD2 antibody to the subject or blocking the CTLA-4 costimulation. Compared to administering a discontinuing agent (but not both), the following claims 44-78 are synergistic. The method described in item 1.

80. The administration of the anti-CD2 antibody or its antigen-binding fragment and the CTLA-4 costimulator is , the administration of the anti-CD2 antibody to the subject or the CTLA-4 costimulator Compared to the reduction in alloimmune response after administration (not both), in the aforementioned subjects, alloimmunity The method according to any one of claims 44 to 79, which results in a greater reduction in response.

81. Larger decreases than those mentioned above were approximately 5%, 10%, 15%, 20%, 25%, 30%, and 35%. ４０％、４５％、５０％、５５％、６０％、６５％、７０％、７５％、８０％、８５％、 90%, 100%, or greater than 100%, or at least about 5%, 10 ％、１５％、２０％、２５％、３０％、３５％、４０％、４５％、５０％、５５％、６０ %, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or 100% The method according to claim 80, which is greater than or equal to.

82. The aforementioned alloimmune response is detected in an in vitro human T cell proliferation assay or a mixed lymphocyte assay. The method according to claim 80 or 81, determined using a response (MLR) assay.

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