Methods of treating inclusion body myositis (IBM)

Abstract

The present disclosure relates to methods of treating inclusion body myositis with antibodies, or antigen-binding fragments thereof, that specifically bind to killer cell lectin-like receptor G1 (KLRG1), and methods for maintaining remission of inclusion body myositis in a patient.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of United States Provisional Application No. 63 / 617,063, filed January 2. 2024 and United States Provisional Application No. 63 / 707,402 filed October 15, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] Cytotoxic T cells or NK cells may result in disease either through inappropriate cellular injury (e.g., autoimmunity) or through uncontrolled proliferation (e.g., certain leukemias and lymphomas involving cytotoxic T cells or NK cells). Injury to tissues by cytotoxic T cells are implicated in autoimmune diseases, type 1 diabetes, solid organ transplant rejection, and graft versus host disease. Killer cell lectin-like receptor G1 (KLRG1), a cell surface marker known to be present on mature cytotoxic T cells, has been demonstrated to be present on cytotoxic T cells with high-killing potential (WO2018053264).

[0003] Cellular injury occurs in many diseases as a consequence of cytotoxic T cell attack. For example, pathogenic cytotoxic T cells are a key element in the destruction of muscle that occurs in the disease inclusion body myositis. Similar mechanisms of injury to tissues by cytotoxic T cells are implicated in other autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes, alopecia areata, Bechet's disease, ankylosing spondylitis, and primary biliary cirrhosis.

[0004] KLRG1 is a cell surface marker known to be present on senescent cytotoxic T cells. For example, in the case of inclusion body myositis, cell surface KLRG1 marks T cells that are directly killing healthy muscle cells. Unlike the teachings of prior studies regarding the senescent and inactive nature of KLRG1-expressing T cells in the blood of mice and humans, KLRG1-expressing T cells can be active and pathogenic, rendering them an advantageous target for cell depletion therapy.

[0005] Such cell depletion therapy comprises, in one example, administering to a subject in need thereof an effective amount of KLRG1 depleting agent (e.g., a KLRG1-expressing-cell depleting agent). The KLRG1 depleting agent can target the extracellular domain of KLRG1, comprising antibody dependent cellular cytotoxicity (ADCC) effector function, and can eliminate or reduce the number of cytotoxic T cells and / or NK cells injuring healthy cells.

[0006] KLRG1 is type II transmembrane protein and is a co-inhibitory receptor modulating the activity of T and NK cells. Its extracellular portion contains a C-type lectin domain whose known ligands are cadherins and its intracellular portion contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) domain responsible for co-inhibition of T cell receptor (TCR) mediated signaling. In various embodiments, the ligand can be E-cadherin, N-cadherin, R-cadherin, or a combination thereof.

[0007] Therefore, there is a need in the autoimmune art which uses a KLRG1 binding agent to deplete pathogenic T cells and / or NK cells attacking self-tissues.

[0008] Therefore, there is a need in the art for treating patients with inclusion body myositis with a KLRG1 binding agent to deplete pathogenic T cells. Expedient and accurate treatment decisions lead to effective management of the disease. Optimized dosing regimens are essential for treatment success. SUMMARY

[0009] The receptor killer cell lectin-like receptor G1 (KLRG1) is expressed on T and NK cells which binds to ligands on epithelial and mesenchymal cells. The ligands for KLRG1 expressed on T and NK cells have been described to be E-cadherin, N-cadherin, and R-cadherin. The present disclosure relates to antibodies, or antigen-binding fragments thereof, that specifically bind to killer cell lectin-like receptor G1 (KLRG1); methods of treating inclusion body myositis with a KLRG1 binding agent; and methods for maintaining remission of inclusion body myositis in a patient.

[0010] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity' determining regions (CDRs) comprising SEQ ID N0:8 (CDR-H1), SEQ IDN0:9 (CDR-H2), and SEQ ID NO: 10 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO: 11 (CDR-L1), SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3).

[0011] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:21 (CDR-H1), SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ IDNO:24 (CDR-L1), SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3).

[0012] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO: 33 (CDR-H1), SEQ ID NO: 34 (CDR-H2), and SEQ ID NO:35 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:36 (CDR-L1). SEQ ID NO:37 (CDR-L2), and SEQ ID NO:38 (CDR-L3)

[0013] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:8 (CDR-H1), SEQ IDNO:9 (CDR-H2), and SEQ ID NO: 10 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO: 11 (CDR-L1), SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3).

[0014] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:21 (CDR-H1), SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:24 (CDR-L1). SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3)

[0015] Described herein are methods of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising: administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises: a heavy chain variable region comprising three complementarity' determining regions (CDRs) comprising SEQ ID NO: 33 (CDR-H1), SEQ ID NO: 34 (CDR-H2), and SEQ ID NO:35 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ IDNO:36 (CDR-L1), SEQ ID NO:37 (CDR-L2), and SEQ ID NO:38 (CDR-L3).

[0016] The antibody or fragment thereof can comprise a heavy chain variable region comprising SEQ ID NO:4.

[0017] The antibody or fragment thereof can comprise a light chain variable region comprising SEQ ID NO: 5.

[0018] The antibody or fragment thereof can comprise a heavy chain comprising SEQ ID NO:6 and a light chain comprising SEQ ID NO:7.

[0019] The antibody, or fragment thereof, can be a monoclonal antibody, or a fragment or derivative thereof. The antibody, or fragment thereof, can be a humanized antibody, or a fragment thereof.

[0020] The antibody, or fragment thereof, can be an afucosylated antibody.

[0021] The antibody, or fragment thereof, can bind human KLRG1 or cynomolgus KLRG1.

[0022] The dose of the antibody can be 0.5 mg / kg. The dose of the antibody, or fragment thereof can be 2.0 mg / kg.

[0023] The doses can be administered at eight week intervals. The doses can be administered until clinical response and / or remission is achieved. The doses can be administered until KLRG1+ cells remaining in the blood are decreased by at least 20%. BRIEF DESCRIPTION OF DRAWINGS

[0024] FIG. 1 shows the pharmacodynamic response of human blood CD8+KLRG1+ T cells over 168 days (24 weeks) after single doses of ABC008 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg were administered in patients with inclusion body myositis (IBM) in the phase 1 single ascending dose study of ABC008.

[0025] FIGs. 2A and 2B shows the results of the inclusion body myositis functional rating scale (IBMFRS) and manual muscle testing (MMT12) in IBM patients in the phase 1 single ascending dose study of ABC008 from dosing at week 0 through 24 weeks. IBMFRS was assessed in 11 patients and the mean and standard deviation shown (FIG. 2A). MMT12 was assessed in 8 patients and the mean and standard deviation shown (FIG. 2B).

[0026] FIGs. 3A-3C show the selective depletion of CD8+ KLRG1+ T cells after subcutaneous (sc) administration of six Q8W (every eight weeks) doses of ulviprubart (ABC008). Cohort 1 (n=3) was 0.1 mg / kg doses of ulviprubart over 48 weeks of treatment. Cohort 2 (n=l) was administered 0.5 mg / kg doses of ulviprubart over 48 weeks of treatment. Cohort 3 (n=4) was administered 2.0 mg / kg doses of ulviprubart over 48 w eeks of treatment.

[0027] FIG. 4 is a graph showing the mean change in IBM Functional Rating Scale (IBMFRS) as compared to natural history / placebo-controlled cohorts for sixteen (16) patients over time.

[0028] FIGs. 5A-5D are graphs showing multiple clinical functional assessments obtained from 16 patients that received ulviprubart. FIG. 5A shows data relating to the manual muscles testing (MMT12). FIG. 5B shows data relating to right hand grip dynamometry. FIG. 5C shows data relating to right quad dynamometry. FIG. 5D shows data related to Modified Timed Up and Go test (mTUG). DETAILED DESCRIPTION

[0029] The present disclosure relates to antibodies, or antigen-binding fragments thereof, that specifically bind to killer cell lectin-like receptor G1 (KLRG1); methods of treating inclusion body myositis with a KLRG1 binding agent; and methods for maintaining remission of inclusion body myositis in a patient. Certain exemplary embodiments will now be described to provide an overall understanding of the use of the antibodies and related methods and therapies disclosed herein. Those skilled in the art will understand that the disclosures described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present disclosure is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure.

[0030] Killer cell lectin-like receptor G1 (KLRG1) is a ty pe II transmembrane protein which can function as co-inhibitory receptor by modulating the activity of T and NK cells. The extracellular portion of KLRG1 contains a C-type lectin domain whose known ligands are cadherins. The intracellular portion of KLRG1 contains an immunoreceptor tyrosine-based inhibitory' motif (ITIM) domain responsible for co-inhibition of T cell receptor (TCR) mediated signaling. KLRG1 ligands include E-cadherin, N-cadherin. R-cadherin, and combinations thereof.

[0031] The receptor killer cell lectin-like receptor G1 (KLRG1) is expressed on T and NK cells which bind to ligands on epithelial and mesenchymal cells. The ligands for KLRG1 can be E-cadherin, N-cadherin, and R-cadherin.

[0032] In humans, KLRG1 expression is generally confined to cells of the immune systems, and specifically to CD8 positive T cells, NK cells, and, to a lesser extent, CD4 positive T cells. KLRG1 expression has been associated with the late differentiated phenotype. As antigen specific T cells differentiate they can acquire increased expression of cytotoxic molecules, and therefore can have increased cytotoxic potential.

[0033] The present disclosure is based, at least in part, on the discovery described in WO2018 / 053264, that KLRG1, a cell surface marker known to be present on senescent cytotoxic T cells. For example, in the case of inclusion body myositis, KLRG1 can mark T cells that are directly killing healthy muscle cells. The present disclosure is also based, at least in part, on the discovery described in WO2020 / 210512 and PCT / US2022 / 038310, that KLRG1 is also present on cytotoxic T cells with high-killing potential.

[0034] Thus, KLRG1-expressing T cells and / or NK cells can be pathogenic and are therefore an advantageous target for cell depletion therapy. For example, administering to a subject in need of an effective amount of KLRG1 depleting agent (e.g., a KLRG1 -expressingcell depleting agent) with antibody dependent cellular cytotoxicity (ADCC) effector function can eliminate or reduce the number of cytotoxic T cells and / or NK cells injuring healthy cells as, for example, for the treatment of an autoimmune disease, such as inclusion body myositis.

[0035] A prominent biological function of cell surface KLRG1 is to inhibit cytotoxicity and proliferation of cytotoxic T cells and / or NK cells by functioning as a lymphocyte co-inhibitory receptor. Lymphocyte co-inhibitory receptors modulate the action of the adaptive immune system, e.g., T cells and NK cells, in response to activating signals such as antigenic peptides in the context of the major histocompatibility complex (MHC) binding to the T cell receptor (TCR). Other co-inhibitory receptors known in the art include PD-1, LAG-3. TIM-3, and CTLA4. The action of co-inhibitory receptors can generally be carried out by binding a ligand to the extracellular domain of the co-inhibitoiy receptor, followed by recruitment of intracellular phosphatases by an immune-receptor tyrosine-based inhibition motif (ITIM) located in the intracellular domain of the co-inhibitory receptor. The action of co-inhibitory receptors is generally to dampen the immune response of TCR engagement.

[0036] By not interfering with the binding of E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRGL the function of KLRG1 as a lymphocyte co-inhibitory receptor can be maintained. Because the KLRG1 binding agent does not release the checkpoint inhibition, the inhibition of the activation of potentially pathogenic CD8+ cytotoxic T and / or NK cells can be maintained.

[0037] The targeted depletion of KLRG1 expressing T cells and / or KLRG1 expressing NK cells and / or KLRG1 expressing cells in a subject can be mediated by the Fc region of the KLRG1 specific antibody or antigen binding fragment thereof and / or by an Fc peptide conjugated to a KLRG1 specific antigen binding fragment thereof, and / or by a cytotoxic agent conjugated to a KLRG1 specific antibody or antigen binding fragment thereof. International Patent Application Publication No. WO2002 / 44215 describes binding molecules which comprise or consist of the antigen binding site of an antibody and a peptide binding Fc-effector molecule. Selected Embodiments of the Present Disclosure

[0038] Disclosed herein are methods of treating inclusion body myositis (IBM) in a subject in need of treatment. Methods provided for herein include delivering to a subject in need of treatment an effective amount of a KLRG1 depleting agent, such as an antibody, or a fragment thereof, thereby treating inclusion body myositis by depleting KLRG1 expressing T cells in the subject.

[0039] In some embodiments of the methods, the antibody, or a fragment thereof, comprises a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:8 (CDR-H1), SEQ ID NO:9 (CDR-H2), and SEQ ID NO: 10 (CDR-H3), and a light chain variable region comprises three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:11 (CDR-L1), SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3). In some embodiments the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4. In some embodiments the antibody, or fragment thereof, comprises a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4 and a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. In some embodiments, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NO:7. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6 and a light chain comprising SEQ ID NO:7. In some embodiments, the antibody, or fragment thereof, specifically binds the epitope PLNFSRI (SEQ ID NO: 14), or a fragment thereof comprising at least five contiguous amino acids. The antibody, or fragment thereof, may be a monoclonal antibody, or a fragment or derivative thereof. The antibody, or fragment thereof, may be a humanized antibody, or a fragment thereof. The KLRG1 may be human KLRG1 or cynomolgus KLRG1.

[0040] In some embodiments of the methods, the antibody, or a fragment thereof, comprises a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:21 (CDR-H1), SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3), and a light chain variable region comprises three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:24 (CDR-L1), SEQ ID NO:25 (CDR-L2). and SEQ ID NO 26 (CDR-L3). In some embodiments the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4. In some embodiments the antibody, or fragment thereof, comprises a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy' chain variable region comprising SEQ ID NO:4 and a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. In some embodiments, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NO:7. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6 and a light chain comprising SEQ ID NO:7. In some embodiments, the antibody, or fragment thereof, specifically binds the epitope PLNFSRI (SEQ ID NO: 14). or a fragment thereof comprising at least five contiguous amino acids. The antibody, or fragment thereof, may be a monoclonal antibody, or a fragment or derivative thereof. The antibody, or fragment thereof, may be a humanized antibody, or a fragment thereof. The KLRG1 may be human KLRG1 or cynomolgus KLRG1.

[0041] In some embodiments of the methods, the antibody, or a fragment thereof, comprises a heavy chain variable region comprising three complementarity' determining regions (CDRs) comprising amino acid sequences SEQ ID NO:33 (CDR-H1). SEQ ID NO:34 (CDR-H2), and SEQ ID NO:35 (CDR-H3), and a light chain variable region comprises three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:36 (CDR-L1), SEQ ID NO:37 (CDR-L2), and SEQ ID NO 38 (CDR-L3). In some embodiments the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4. In some embodiments the antibody, or fragment thereof, comprises a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4 and a light chain variable region comprising SEQ ID NO:5. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. In some embodiments, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID N0:7. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID N0:6 and a light chain comprising SEQ ID N0:7. In some embodiments, the antibody, or fragment thereof, specifically binds the epitope PLNFSRI (SEQ ID NO: 14), or a fragment thereof comprising at least five contiguous amino acids. The antibody, or fragment thereof, may be a monoclonal antibody, or a fragment or derivative thereof. The antibody, or fragment thereof, may be a humanized antibody, or a fragment thereof. The KLRG1 may be human KLRG1 or cynomolgus KLRG1.

[0042] In some embodiments of the methods, the KLRG1 can be human KLRG1 or cynomolgus KLRG1.

[0043] Disclosed herein are methods of treating inclusion body myositis in a subject, wherein the pathogenic cells express KLRG1. The methods can include delivering to the subject a therapeutically effective amount of a KLRG1 depleting agent, such an antibody, or a fragment thereof, that specifically binds to the extracellular domain of KLRG1. The delivery to the subject can deplete the pathogenic cells expressing KLRG1. The delivery to the subject can deplete KLRG1 expressing pathogenic T cells and / or NK cells attacking selftissues in the subject.

[0044] Disclosed herein are methods of treating inclusion body myositis, in which the method includes delivering to the subject a therapeutically effective amount of a KLRG1 depleting agent.

[0045] Disclosed herein are methods of treating inclusion body myositis by depleting KLRG1 expressing cells in a mixed population of cells. The KLRG1 expressing cells can include one or more cells selected from a group consisting of T cells and / or NK cells. The method can include delivering to the mixed population of cells a dose of at least 0.5 mg / kg (e.g., 0.5 mg / kg, 2.0 mg / kg, 5.0 mg / kg) of a KLRG1 depleting agent, such as an antibody, or a fragment thereof, that specifically binds to KLRG1 and depletes KLRG1 expressing T cells and / or NK cells in a patient with inclusion body myositis, thereby depleting KLRG1 expressing T cells and / or NK cells in the mixed population of cells.

[0046] Disclosed herein are doses of pharmaceutical compositions that include one or more of the above antibodies, or a fragment thereof, and a pharmaceutically acceptable carrier. A person skilled in the art, in view of the present disclosure, will understand various pharmaceutically acceptable carriers that can be used, including but not limited to (1) sugars, such as lactose, glucose and sucrose: (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil. sesame oil. olive oil. com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) histidine buffered solutions; (21) other non-toxic compatible substances employed in pharmaceutical formulations; and (22) enzymes, such as hyaluronidase. Definitions

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this present disclosure belongs. The terminology used in the description of the present disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure and any invention(s) described or otherwise provided for herein.

[0048] Amino acids are represented herein by either the one-letter code, or the three-letter code, both in accordance with 37 C.F.R. §1.822 and established usage.

[0049] All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

[0050] As used in the description of the present disclosure and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0051] As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0052] The terms "about" and "approximately" as used herein when referring to a measurable value such as an amount of polypeptide, dose, time, temperature, enzymatic activity or other biological activity and the like, is meant to encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, + 0.5%, or even ±0.1% of the specified amount.

[0053] The transitional phrase "consisting essentially of means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. See In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP § 2111.03.

[0054] The term "consists essentially of (and grammatical fragments), as applied to a polynucleotide or polypeptide sequence of this present disclosure, means a polynucleotide or polypeptide that consists of both the recited sequence (e.g, SEQ ID NO) and a total of ten or less (e.g.. 1, 2, 3. 4, 5, 6, 7, 8, 9, or 10) additional amino acids on the N-terminal and / or C-terminal ends of the recited sequence such that the function of polypeptide is not materially altered. The total of ten or less additional amino acids can include the total number of additional amino acids on both ends added together.

[0055] An "effective amount" as used herein is an amount that provides a desired effect. The term ‘‘effective amount” refers to a dosage or amount that is sufficient to reduce the amount of KLRG1+ cells to result in amelioration of symptoms in a patient or to achieve a desired biological outcome, e.g., deplete KLRG1+ cells from blood and tissue.

[0056] A "therapeutically effective" amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a "therapeutically effective" amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0057] By the terms "treat," "treating," or "treatment of," it is intended that the severity of the condition of the subject is reduced, or at least partially improved or modified, and that some alleviation, mitigation, or decrease in at least one clinical symptom is achieved.

[0058] The term "deplete" as used herein with respect to T cells and / or NK cells and / or KLRG1 expressing pathogenic cells refers to a measurable decrease in the number of said cells in a subject or in a sample. The reduction can be at least about 10%, e.g.. at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more. In certain embodiments, the term refers to a decrease in the number of T cells and / or NK cells and / or KLRG1 expressing pathogenic cells in a subject or in a sample to an amount below detectable limits.

[0059] The term "isolated" can refer to a polypeptide that is substantially free of cellular material, viral material, and / or culture medium (when produced by recombinant DNA techniques), or chemical precursors or other chemicals (when chemically synthesized). Moreover, an "isolated fragment" is a fragment of a polypeptide that is not naturally occurring as a fragment and would not be found in the natural state. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to provide the polypeptide or nucleic acid in a form in which it can be used for the intended purpose. Thus, the term "isolated" refers to a molecule that is substantially free of its natural environment. For instance, an isolated protein is substantially free of cellular material or other proteins from the cell or tissue source from which it is derived. The term "isolated" also refers to preparations where the isolated protein is sufficiently pure to be administered as a pharmaceutical composition, or approximately at least 70-80% (w / w) pure, more preferably, approximately at least 80-90% (w / w) pure, even more preferably, approximately 90-95% pure; and, most preferably, approximately at least 95%, approximately at least 96%, approximately at least 97%, approximately at least 98%, approximately at least 99%, or approximately at least 100% (w / w) pure.

[0060] The term "fragment," as applied to a polypeptide, will be understood to mean an amino acid sequence of reduced length relative to a reference polypeptide or amino acid sequence and comprising, consisting essentially of, and / or consisting of an amino acid sequence of contiguous amino acids identical or almost identical (e.g., approximately 90%, approximately 92%, approximately 95%, approximately 98%, approximately 99% identical) to the reference polypeptide or amino acid sequence. Such a polypeptide fragment according to the present disclosure may be. where appropriate, included in a larger polypeptide of which it is a constituent. In some embodiments, such fragments can comprise, consist essentially of, and / or consist of peptides having a length of at least about 4, about 6, about 8, about 10, about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, 7 about 5, about 100. about 150, about 200, or more consecutive amino acids of a polypeptide or amino acid sequence according to the present disclosure.

[0061] As used herein, the terms "protein" and "polypeptide" are used interchangeably and encompass both peptides and proteins, unless indicated otherwise.

[0062] A "fusion protein" is a polypeptide produced when two heterologous nucleotide sequences or fragments thereof coding for two (or more) different polypeptides not found fused together in nature are fused together in the correct translational reading frame. Illustrative fusion polypeptides include fusions of a polypeptide of the present disclosure (or a fragment thereof) to all or a portion of glutathione s-transferase, maltose-binding protein, or a reporter protein (e.g, Green Fluorescent Protein, 0 -glucuronidase, 0-galactosidase, luciferase, etc.), hemagglutinin, c-myc, FLAG epitope, etc.

[0063] As used herein, a "functional" polypeptide or "functional fragment" is one that substantially retains at least one biological activity normally associated with that polypeptide (e.g., target protein binding). In particular embodiments, the "functional" polypeptide or "functional fragment" substantially retains all of the activities possessed by the unmodified peptide. By "substantially retains" biological activity, it is meant that the polypeptide retains at least about 20%, about 30%, about 40%, about 50%, about 60%, about 75%, about 85%, about 90%, about 95%, about 97%, about 98%, about 99%, or more, of the biological activity of the native polypeptide (and can even have a higher level of activity than the native polypeptide). A "non-functional" polypeptide is one that exhibits little or essentially no detectable biological activity normally associated with the polypeptide (e.g., at most, only an insignificant amount, e.g., less than about 10% or even less than about 5%). Biological activities such as protein binding can be measured using assays that are well known in the art and as described herein.

[0064] “Clinical remission” or “remission” as used herein with reference to subjects with inclusion body myositis, refers to stabilization of the inclusion body myositis functional rating scale (IBMFRS); or the sporadic inclusion body myositis functional assessment (sIFA); or quantitative dynamometry of the quadriceps or hand grip; or the manual muscle testing (MMT); or of the modified timed up and go (mTUG); or dysphagia as measured in various scales including the EAT-10.

[0065] A "clinical response" as used herein with reference to subjects with inclusion body myositis refers to a decline in the rate of progression, stabilization, or improvement of the inclusion body myositis functional rating scale (IBMFRS); or the sporadic inclusion body myositis functional assessment (sIFA); or quantitative dynamometry of the quadriceps or hand grip; or the manual muscle testing (MMT); or of the modified timed up and go (mTUG); or dysphagia as measured in various scales including the EAT-10. The terms "clinical response" and "response" e.g., alone without any adjective, are used interchangeably herein.

[0066] "Baseline" as used herein describes a value of a parameter which is measured prior to the initial dose of a treatment. It can refer to a measurement of a sample obtained the same day, the day before, during the week before initial treatment, i.e., at a time period before the first dose when little change is expected until after the first dose and values of the measurement obtained after the first dose can be compared to this baseline value to represent the change caused by the dose.

[0067] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disease as well as those in which the disease or its recurrence is to be prevented. Hence, the patient to be treated herein may have been diagnosed as having the disease or may be predisposed or susceptible to the disease. The terms "patient" and "subject" are used interchangeably herein. Treatment of Subjects with Inclusion Body Myositis with KLRG1 depleting agents

[0068] The present disclosure provides, in a first aspect, a method of treating inclusion body myositis (IBM) with a KLRG1 depleting agent comprising administering an anti-KLRGl antibody or functional fragment thereof described herein in an amount effective to treat IBM, e.g., in humans. The human patient or subject may be an adult (e.g., 18 years or older), an adolescent, or a child. A pharmaceutical composition comprising a KLRG1 depleting agent can be used as described herein for treating IBM in a subject suffering therefrom. In some embodiments, the treatment results in a decrease in KLRG1+ cells remaining in the patient's blood. In some embodiments, the treatment results in a decrease in KLRG1+ cells remaining in the patient’s muscle. In some embodiments, the treatment results in a decrease in KLRG1+ cells remaining in the patient’s blood and / or muscle. In some embodiments, the treatment results in clinical response and / or clinical remission of IBM. In some embodiments, the result of the treatment occurs by 4 weeks, by 8 weeks, by 12 weeks, by 16 weeks, by 20 weeks, by 24 weeks, by 28 weeks, by 32 weeks, by 36 weeks, by 40 weeks, by 44 weeks, by 48 weeks, by 52 weeks, by 56 weeks, by 60 weeks, by 64 weeks, by 68 weeks, by 72 weeks, by 76 weeks, or by 80 weeks of treatment. In some embodiments, the result of treatment, e.g., the response, is durable, e.g., a clinical response which is sustained overtime, e.g., the patient exhibits aclinical response by week 8 after initiation of treatment.

[0069] The present disclosure provides a method for treating a patient having IBM with a KLRG1 depleting antibody or functional fragment thereof. In this aspect, the method comprises treating the patient with about 0.005 mg / kg, about 0.025 mg / kg, about 0.1 mg / kg. about 0.125 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, or about 5.0 mg / kg of the KLRG1 depleting antibody or functional fragment thereof. Multiple doses of a KLRG1 depleting antibody or fragment thereof may be administered to a patient in need thereof. For example, the KLRG1 depleting antibody, or fragment thereof, may be administered every week, every two weeks, every three weeks, every four weeks, every' six weeks, every eight weeks, or every- twelve weeks.

[0070] The present disclosure provides a method for treating a patient having IBM yvith a KLRG1 depleting antibody or functional fragment thereof. In this aspect, the method comprises treating the patient with 1 dose of 0.1 mg / kg. 0.5 mg / kg. 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, or 5.0 mg / kg via subcutaneous administration of the KLRG1 depleting antibody or functional fragment thereof. In other embodiments, a dose of the KLRG1 depleting antibody or functional fragment thereof is a subcutaneous dose of 0.5 mg / kg, 1.0 mg / kg. 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, or 5.0 mg / kg and further may be administered at a frequency of every 8 yveeks.

[0071] In another aspect, the present disclosure provides a method for treating IBM in a patient with a dose (e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg) of a KLRG1 depleting antibody or functional fragment thereof, following an initial dose (e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg). In some embodiments, the method of using aKLRGl depleting antibody or functional fragment thereof comprises the steps of administering three or more doses of a KLRG1 depleting antibody or functional fragment thereof to a patient suffering from IBM, wherein the second dose is administered about eight weeks after the first dose is administered to the patient; and administering one or more further doses (e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg) of a KLRG1 depleting antibody or functional fragment thereof to the patient if the patient's percentage depletion of CD8+KLRG1+ T cells in blood is less than about 100%, about 95%, about 90%, about 85%, about 80%. about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 1%. In some embodiments, the method of using a KLRG1 depleting antibody or functional fragment thereof comprises the steps of administering three or more doses of a KLRG1 depleting antibody or functional fragment thereof to a patient suffering from IBM, wherein the second dose is administered about eight weeks after the first dose is administered to the patient; and administering one or more further doses (e.g., 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg) of a KLRG1 depleting antibody or functional fragment thereof to the patient if the patient's percentage depletion of CD8+KLRG1+ T cells in blood is about 95-100%, about 9095%, about 85-90%, about 80-85%, about 75-80%, about 70-75%, about 65-70%, about 6065%, about 55-60%, about 50-55%, about 45-50%, about 40-45%, about 35-40%, about 3035%, about 25-30%, about 20-25%, about 15-20%, about 10-15%, about 5-10%, or about 15%. The patient's percentage depletion of CD8+KLRG1+ T cells in blood may be less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% after administration of the KLRG1 antibody. The patient's percentage depletion of CD8+KLRG1+ T cells in blood may be below 90% after administration of the KLRG1 depleting antibody.

[0072] In some embodiments, the method comprises the steps of administering two or more doses of a KLRG1 depleting antibody or functional fragment thereof to a patient suffering from IBM, wherein the second dose is administered about eight weeks after the first dose is administered to the patient. The administration may be chronic or continuous dosing every eight weeks for as long as the patient continues to experience symptoms of IBM.

[0073] A KLRG1 depleting antibody or functional fragment thereof may be administered by any suitable method, such as by one or more of intravenous injection, subcutaneous injection, or infusion. In some embodiments, the KLRG1 depleting antibody or functional fragment thereof is administered, for example subcutaneously, at a dose of 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg. 4.0 mg / kg, or 5.0 mg / kg. The KLRG1 depleting antibody or functional fragment thereof may be administered once every 30 days, once every 60 days, once every 90 days, once a month, once every two months, once every three months, once every four weeks, once every eight weeks, or once every twelve weeks.

[0074] In an embodiment, a KLRG1 depleting antibody or functional fragment thereof is administered subcutaneously every eight weeks. In another embodiment, 0.1 mg / kg of a KLRG1 depleting antibody or fragment thereof is administered subcutaneously every' eight weeks. In another embodiment, 0.5 mg / kg of a KLRG1 depleting antibody or fragment thereof is administered subcutaneously every' eight weeks. In another embodiment, 2.0 mg / kg of a KLRG1 depleting antibody or fragment thereof is administered subcutaneously every eight weeks.

[0075] In an embodiment, a KLRG1 depleting antibody or functional fragment thereof is administered until KLRG1+ cells remaining in the blood are decreased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0076] Treatment methods using a KLRG1 depleting antibody or functional fragment thereof are described in International Patent Application Publication WO2020 / 210512 and International Patent Application Publication WO / 2023 / 009498.

[0077] The method may further comprise measurement of patient body weight. Body weight may be determined prior to treatment with the KLRG1 depleting antibody or functional fragment thereof, i.e., at baseline, or may be measured at other times during treatment, e.g., when monitoring patient response. Antibodies and Compositions

[0078] The KLRG1 depleting antibodies for treating IBM specifically bind to the extracellular domain of KLRG1 of cells. Such antibodies can advantageously be used to deplete cells expressing cell surface KLRG1 in a subject, e.g., for research or therapeutic purposes. Such antibodies can be used to treat inclusion body myositis associated with pathogenic and autoimmune T cells expressing KLRG1. Accordingly, one aspect of the present disclosure relates to antibodies or fragments thereof that specifically bind to the extracellular domain of KLRG1 and depletes cells expressing KLRG1 when administered to a subject. In another aspect, the KLRG1 depleting antibody is a human or mouse antibody or aKLRGl binding protein using the CDRs provided in International Patent Application Publication WO / 2023 / 009498.

[0079] Intact antibodies, also known as immunoglobulins, are typically tetrameric glycosylated proteins composed of two light (L) chains of approximately 25 kDa each and two heavy (H) chains of approximately 50 kDa each. Two types of light chain, designated as the X chain and the k chain, are found in antibodies. Depending on the amino acid sequence of the constant domain of heavy chains, immunoglobulins can be assigned to five major classes: A, D, E, G, and M, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, andIgA2.

[0080] The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known in the art. Briefly, each light chain can be composed of an N-terminal variable domain (VL) and a constant domain (CL). Each heavy chain can be composed of an N-terminal variable domain (VH), three or four constant domains (CH), and a hinge region. The CH domain most proximal to VH is designated as CHI. The VH and VL domains consist or comprise of four regions of relatively conserved sequence called framework regions (FR1, FR2, FR3, and FR4), which form a scaffold for three regions of hypervariable sequence called complementarity determining regions (CDRs). The CDRs can contain most of the residues responsible for specific interactions with the antigen. The three CDRs are referred to as CDR1, CDR2, and CDR3. CDR constituents on the heavy chain are referred to as Hl, H2, and H3, while CDR constituents on the light chain are referred to as LI, L2, and L3, accordingly. CDR3 and particularly H3, are the greatest source of molecular diversity within the antigen-binding domain. H3, for example, can be as short as two amino acid residues or greater than 26 amino acids in length.

[0081] The Fab fragment (Fragment antigen-binding), or Fab, consists or comprises of the VH-CH1 and VL-CL domains covalently linked by a disulfide bond between the constant regions. Known to those skilled in the art, a Fab (50,000 daltons) is a monovalent fragment that is produced from IgG and IgM, consisting or comprising of the VH, CHI and VL, CL regions, linked by an intramolecular disulfide bond. To overcome the tendency of non-covalently linked VH and VL domains in the Fv to dissociate when co-expressed in a host cell, a so-called single chain (sc) Fv fragment (scFv) can be constructed. In a scFv, a flexible and adequately long polypeptide links either the C-terminus of the VH to the N-terminus of the VL, or the C-terminus of the VL to the N-terminus of the VH. Most commonly, a 15-residue (Gly4Ser)3 peptide can be used as a linker, but other linkers are also known in the art.

[0082] Antibody diversify is a result of combinatorial assembly of multiple germline genes encoding variable regions and a variety of somatic events. The somatic events can include recombination of variable gene segments with diversify (D) and joining (J) gene segments to make a complete VH region and the recombination of variable and joining gene segments to make a complete VL region. The recombination process itself is imprecise, resulting in the loss or addition of amino acids at the V(D)J junctions. These mechanisms of diversify occur in the developing B cell prior to antigen exposure. After antigenic stimulation, the expressed antibody genes in B cells can undergo somatic mutation.

[0083] Based on the estimated number of germline gene segments, the random recombination of these segments, and random VH-VL pairing, up to approximately 1.6* 107 different antibodies can be produced according to Fundamental Immunology, 3rd ed., ed. Paul, Raven Press, New York, N.Y.. 1993. When other processes which contribute to antibody diversify (such as somatic mutation) are taken into account, it is thought that upwards of approximately IxlO10 different antibodies could be potentially generated, as supported by Immunoglobulin Genes, 2nd ed., eds. Jonio et al., Academic Press, San Diego, Calif, 1995. Because of the many processes involved in antibody diversify, it is highly unlikely that independently generated antibodies will have identical amino acid sequences in the CDRs.

[0084] In one aspect, the KLRG1 depleting antibodies for use in the treatment of IBM contain CDRs derived from human immunoglobulin gene libraries, which are effective in depleting cells expressing cell surface KLRG1. The scaffold structure for carrying a CDR can generally be, though is not limited to, an antibody heavy or light chain, or a portion thereof, in which the CDR is located at a location corresponding to the CDR of naturally occurring VH and VL. The structures and locations of immunoglobulin variable domains may be determined, for example, as described in Kabat et al., Sequences of Proteins of Immunological Interest, No. 91-3242, National Institutes of Health Publications, Bethesda, Md., 1991.

[0085] In certain embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region that includes three heavy chain CDRs SEQ ID NO:8 (CDR-H1), SEQ ID NON (CDR-H2), and SEQ ID NO: 10 (CDR-H3), and alight chain variable region that comprises three light chain CDRs SEQ ID NO: 11 (CDR-L1). SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3). In some aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NON, and a light chain variable region comprising SEQ ID NO:5. In some aspects of these embodiments, the antibody or fragment thereof, comprises a heavy’ chain comprising SEQ ID NO:6. Alternatively, or additionally, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NO:7. In more specific aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6, and a light chain comprising SEQ ID NO:7.

[0086] In certain embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region that includes three heavy chain CDRs SEQ ID NO:21 (CDR-H1), SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3), and a light chain variable region that comprises three light chain CDRs SEQ ID NO:24 (CDR-L1). SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3). In some aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NON, and a light chain variable region comprising SEQ ID NO:5. In some aspects of these embodiments, the antibody or fragment thereof, comprises a heavy’ chain comprising SEQ ID NO:6. Alternatively, or additionally, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NON. In more specific aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6, and a light chain comprising SEQ ID NON.

[0087] In certain embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region that includes three heavy chain CDRs SEQ ID NO:33 (CDR-H1), SEQ ID NO:34 (CDR-H2), and SEQ ID NO:35 (CDR-H3), and a light chain variable region that comprises three light chain CDRs SEQ ID NO:36 (CDR-L1), SEQ ID NO:37 (CDR-L2), and SEQ ID NO: 38 (CDR-L3). In some aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4, and a light chain variable region comprising SEQ ID NO:5. In some aspects of these embodiments, the antibody or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. Alternatively, or additionally, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NO:7. In more specific aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6, and a light chain comprising SEQ ID NO:7.

[0088] In certain embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region that includes three heavy chain CDRs SEQ ID NO:27 (CDR-H1), SEQ ID NO:28 (CDR-H2), and SEQ ID NO:29 (CDR-H3), and a light chain variable region that comprises three light chain CDRs SEQ ID NO:30 (CDR-L1), SEQ ID NO:31 (CDR-L2), and SEQ ID NO: 32 (CDR-L3). In some aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4, and a light chain variable region comprising SEQ ID NO:5. In some aspects of these embodiments, the antibody or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. Alternatively, or additionally, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID NO:7. In more specific aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6, and a light chain comprising SEQ ID NO:7.

[0089] In certain embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region that includes three heavy chain CDRs SEQ ID NO: 15 (CDR-H1), SEQ ID NO: 16 (CDR-H2), and SEQ ID NO: 17 (CDR-H3), and a light chain variable region that comprises three light chain CDRs SEQ ID NO: 18 (CDR-L1), SEQ ID NO: 19 (CDR-L2), and SEQ ID NO:20 (CDR-L3). In some aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain variable region comprising SEQ ID NO:4, and a light chain variable region comprising SEQ ID NO:5. In some aspects of these embodiments, the antibody or fragment thereof, comprises a heavy chain comprising SEQ ID NO:6. Alternatively, or additionally, the antibody, or fragment thereof, comprises a light chain comprising SEQ ID N0:7. In more specific aspects of these embodiments, the antibody, or fragment thereof, comprises a heavy chain comprising SEQ ID N0:6, and a light chain comprising SEQ ID N0:7. Table 1: The amino acid sequence of human KLRG1 ECD (SEQ ID NO: 1), cyno KLRG1 ECD (SEQ ID N0:2) and human E-cadherin ECD (SEQ ID N0:3). with epitope amino acid sequence PLNFSRI (SEQ ID NO: 14) underlined in human and cyno KLRG1. human KLRG1 extracellular domain (ECD) (SEQ ID NO:1), LCQGSNYSTCASCPSCPDRWMKYGNHCYYFSVEEKDWNSSLEFCLARDSHLLV ITDNQEMSLLQVFLSEAFCWIGLRNNSGWRWEDGSPLNFSRISSNSFVQTCGA INKNGLQASSCEVPLHWVCKKVRL cyno KLRG1 extracellular domain (ECD) (SEQ ID N0:2), LCQGSKYSTCASCPSCPDHWMKYGNHCYYFSVEKKDWISSLEFCLARDSHLLM ITDKQEMSLLQDFLSEAFHWVGLRNNSGWRWEDGSPLNFSRIYSNSLVQTCG AIN K NS LQASSCE VS LQWVCK KVS P human E-cadherin full length (SEQ ID N0:3) DWVIPPISCPENEKGPFPKNLVQIKSNKDKEGKVFYSITGQGADTPPVGVFIIER ETGWLKVTEPLDRERIATYTLFSHAVSSNGNAVEDPMEILITVTDQNDNKPEFT QEVFKGSVMEGALPGTSVMEVTATDADDDVNTYNAAIAYTILSQDPELPDKN M FTIN RNTG VISVVTTG LD RES F PTYTLVVQAAD LQG EG LSTTATAVITVTDTN DNPPIFNPTTYKGQVPENEANVVITTLKVTDADAPNTPAWEAVYTILNDDGGQ FVVTTNPVNNDGILKTAKGLDFEAKQQYILHVAVTNVVPFEVSLTTSTATVTVD VLDVNEAPIFVPPEKRVEVSEDFGVGQEITSYTAQEPDTFMEQKITYRIWRDTA NWLEINPDTGAISTRAELDREDFEHVKNSTYTALIIATDNGSPVATGTGTLLLILS DVNDNAPIPEPRTIFFCERNPKPQVINIIDADLPPNTSPFTAELTHGASANWTIQ YNDPTQESIILKPKMALEVGDYKINLKLMDNQNKDQVTTLEVSVCDCEGAAGV CRKAQPVEAGLQIPAILGILGGILALLILILLLLLFLRRRAVVKEPLLPPEDDTRDNV YYYDEEGGGEEDQDFDLSQLHRGLDARPEVTRNDVAPTLMSVPRYLPRPANP DEIGNFIDENLKAADTDPTAPPYDSLLVFDYEGSGSEAASLSSLNSSESDKDQDY DYLNEWGNRFKKLADMYGGGEDD Table 2: Amino acid sequences of CDRs and heavy and light chain variable regions for anti- KLRG1 antibodies. ABC008 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTDHNMHWVKQATGQGLEWFGFINPNTGVT RYNQKFQGRVTLTINKAISTAYLELSSLRSEDTAVYYCARDYYGSAWFAYWGQGTLVTVSS (SEQ. ID NO:4) ABC008 VL DIVMTQSPDSLAVSLGERATINCKSSQTLLYSSDQKNYLAWYQQKPGQPPKLLIYWASTRE SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNYPTFGGGTKVEIK (SEQ ID NO:5) ABC008 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTDHNMHWVKQATGQGLEWFGFINPNTGVT RYNQKFQGRVTLTINKAISTAYLELSSLRSEDTAVYYCARDYYGSAWFAYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:6) ABC008 LC DIVMTQSPDSLAVSLGERATINCKSSQTLLYSSDQKNYLAWYQQKPGQPPKLLIYWASTRE SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNYPTFGGGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:7) ABC008 HC CDR-H1 GYTFTDH (SEQ ID NO:8) CDR-H2 NPNTGV(SEQID NO:9) CDR-H3 DYYGSAWFAY (SEQ ID NOTO) ABC008 LC CDR-L1 KSSQTLLYSSDQKNYLA (SEQ ID NO:11) CDR-L2 WASTRES (SEQ ID NO:12) CDR-L3 QQYYNYPT (SEQ ID NO:13)

[0090] In some embodiments, an anti-KLRGl antibody comprises a combination of any six CDRs of any one of the antibodies described herein. In some embodiments, an anti-KLRGl antibody comprises (i) three heavy chain CDRs from Table 3 (i.e., a CDR-H1, a CDR-H2, and a CDR-H3), and (ii) three light chain CDRs from Table 3 (i.e., a CDR-L1, a CDR-L2, and a CDR-L3). Table 3: Amino acid sequences of CDRs and heavy and light chain variable regions for anti- KLRG1 antibodies. ABCOO 8 Chothia AbM Kabat Contact IMGT CDR- H1 GYTFTDH (SEQ ID NO:8) GYTFTDHNMH (SEQ ID NO:15) DHNMH (SEQID NO:21) TDHNMH (SEQ ID NO:27) GYTFTDHN (SEQ ID NO:33) CDR- H2 NPNTGV (SEQ ID NO:9) FINPNTGVTR (SEQ ID NO:16) FINPNTGVTRYNQKF QG (SEQ ID NO:22) WFGFINPNTGV TR (SEQ ID NO:28) INPNTGVT (SEQ ID NO:34) CDR- H3 DYYGSAWFAY (SEQ ID NO:10) DYYGSAWFAY (SEQ ID NO:17) DYYGSAWFAY (SEQ ID NO:23) ARDYYGSAWFA (SEQ ID NO:29) ARDYYGSAWF AY (SEQ ID NO:35) CDR- L1 KSSQTLLYSSDQKN YLA (SEQ ID NO:11) KSSQTLLYSSDQKN YLA (SEQ ID NO:18) KSSQTLLYSSDQKNY LA (SEQ ID NO:24) LYSSDQKNYLA WY (SEQ ID NQ:30) QTLLYSSDQKN Y (SEQ ID NO:36) CDR- L2 WASTRES (SEQ ID NO:12) WASTRES (SEQ ID NO:19) WASTRES (SEQ ID NO:25) LLIYWASTRE (SEQ ID NO:31) WA (SEQ ID NO:37) CDR- L3 QQYYNYPT (SEQ ID NO:13) QQYYNYPT (SEQ ID NQ:20) QQYYNYPT (SEQ ID NO:26) QQYYNYP (SEQ ID NO:32) QQYYNYPT (SEQ ID NO:378)

[0091] There are multiple antibody variable chain numbering schemes, including those proposed by Kabat (Wu and Kabat, 1970 , J Exp Med. (1970) 132:211-50.); Kabat EA, Te Wu T, Foeller C. Perry HM, Gottesman KS. Sequences of Proteins of Immunological Interest. Diane Publishing Company (1992)); Chothia(1987, Chothia C, Lesk aM. Canonical structures for the hypervanable regions of immunoglobulins. JMol Biol. (1987) 196:901-17); Al-Lazikani et ah, (1997 Standard conformations for the canonical structures of immunoglobulins. JMol Biol. (1997) 273:927-48), Lefranc (IMGT numbering; Lefranc, 1997 Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509; Lefranc et ah, 2005 IMGT- ONTOLOGY for immunogenetics and immunoinformatics. In Silico Biol. (2004) 4:17-29, and Honegger (Honegger and Pluckthun, 2001, Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool. JMol Biol. (2001) 309:657-70), which makes it more complex.

[0092] Chothia and his colleagues defined CDRs based on structure, i.e. the location of the loops (Chothia and Lesk, 1987 supra; Al-Lazikani et ah, 1997, supra).

[00075] Kabat and Wu originally defined the CDRs in the early 1970s by amino acid sequence variability analysis (Wu and Kabat, 1970, supra; Kabat and Wu, 1971, supra). Since then, detailed genetic analyses and three-dimensional structural analyses have more clearly defined the structural basis of the antigen combining site in terms of the HVLs / CDRs, leading to definitions of contact residues (MacCallum et al., 1996, Antibody-antigen interactions: contact analysis and binding site topography. JMol Biol. (1996) 262:732-745; Martin and Allen, 2007, Bioinformatics tools for antibody engineering. In: Diibel S, editor. Handbook of Therapeutic Antibodies. Weinheim: Wiley-VCH Verlag GmbH (2008). p. 95-117).

[0093] The AbM definition of CDRs, which was a compromise between the Kabat and Chothia definitions, was used in the AbM modeling software (Martin and Allen, 2007, supra). Martin and his colleagues also have formed a definition of CDRs based on the actual paratope, i.e. those residues that actually contact the antigen (Martin and Allen. 2007, supra), and have developed and tested an automated application called “Abnum” for variable chain numbering and CDR determination based on a correction of the Chothia approach (Abhinandan and Martin, 2008, Analysis and prediction of VH / VL packing in antibodies. Protein Eng Des Sei. (2010) 23:689-97).

[0094] The Contact definition of CDRs is based on the observation that only 20 to 33 % of the amino acids within the CDRs make direct contact with the antigen (Padlan EA. Anatomy of the antibody molecule. Mol Immunol. (1994) 31 : 169- 217. These residues, named “Specificity Determining Residues (SDR)’’, were first described by Padlan et al. (Padlan EA, Abergel C, Tipper JP. Identification of specificity-determining residues in antibodies. FASEB J OffPubl Fed Am Soc Exp Biol. (1995) 9:133-9). Their results show that these SDRs are involved in the interaction with the antigen and, in most cases, match with the most variable positions present in the CDRs. Using this SDR concept. MacCallum and co-workers suggested a new method to define the CDRs and re-named the SDRs “contact residues”. They also suggested that contact residues are more often located in the center of the paratope and, as Chothia mentioned before, non-contacting residues play a role in shaping the conformation of the CDR loops and therefore orientate the contact residues optimally for efficient and specific antigen binding.

[0095] The IMGT unique numbering for the V-REGION has allowed to redefine the limits of the Complementarity Determining Regions and Framework Regions, designated as CDR-IMGT and FR-IMGT, respectively in IMGT. The IMGT unique numbering for V- DOMAIN provides a standardized numbering for the CDR3-IMGT and FR4-IMGT of rearranged V-J-REGION and V-D-J-REGION.

[0096] A Complementarity Determining Region (CDR-IMGT) is a loop region of a V-DOMAIN (Variable (V) Domain), delimited according to the IMGT unique numbering for V domain (Lefranc M. et al.(2003) IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol 27:5577). There are three CDR-IMGT in a V-DOMAIN: CDR1-IMGT (loop BC), CDR2-IMGT (loop C'C"), and CDR3-IMGT (loop FG).

[0097] In a V-DOMAIN (V domain of the immunoglobulins (IG) or antibodies and T cell receptors (TR)), the amino acids of the CDR-IMGT bind to an antigen (Epitope) and confer the specificity to the IG and TR (Paratope, IMGT-ONTOLOGY, Specificity Type). The first two CDR-IMGT are part of the V-REGION (encoded by a variable (V) gene), whereas the CDR3- IMGT corresponds to the junction and results from the rearrangement between a V gene and a joining (J) gene (V-J rearrangement) or between a V gene, a diversity (D) gene, and a J gene (V- D-J rearrangement) (Immunoglobulin Synthesis).

[0098] In some embodiments, the KLRG1 bound by the disclosed antibodies or fragments thereof can be human KLRG1 or cyno KLRG1. In some embodiments, the antibody, or fragment thereof, can specifically bind the epitope PLNFSRI (SEQ ID NO: 14), or a fragment thereof, comprising at least five (5) contiguous amino acids.

[0099] In some embodiments, the antibodies can be expected to retain the specificity of binding and / or the ability to be KLRG1-expressing cell-depleting agents so long as the antibody amino acid sequences comprise a sequence which is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more identical to SEQ ID NO:4, 5, 6, or 7. In some aspects of these embodiments, the antibody or fragment thereof retains the heavy and light chain CDRs of SEQ ID NOs. 813. In some aspects of these embodiments, the antibody or fragment thereof retains the heavy and light chain CDRs of SEQ ID NOs. 21-26. In some aspects of these embodiments, the antibody or fragment thereof retains the heavy and light chain CDRs of SEQ ID NOs. 3338. The percent identity can be determined by standard alignment algorithms such as, for example. Basic Local Alignment Tool (BLAST) described in Altshul et al. (1990) J. Mol. Biol., 215: 403-410, the algorithm ofNeedleman et al. (1970) J. Mol. Biol., 48: 444-453, or the algorithm of Meyers et al. (1988) Comput. Appl. Biosci., 4: 11-17.

[0100] In some embodiments, the antibody, or fragment thereof, includes a monoclonal antibody. In some embodiments, the antibody, or fragment thereof, includes a chimeric antibody, or a fragment thereof. In some embodiments, the monoclonal antibody, or a fragment thereof, includes a humanized antibody, or a fragment thereof.

[0101] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes SEQ ID NO:4, a heavy chain that includes the amino acid sequence of SEQ ID NO:6, or a sequence having approximately at least 90% sequence identity thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto, and a light chain comprising light chain CDRs SEQ ID NO: 11 (CDR-L1), SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3). In some embodiments, the antibody, or fragment thereof, comprises a heavy chain that includes at least 50 contiguous amino acids of the amino acid sequence of SEQ ID NO:6. or a sequence approximately at least 90% identical thereto, e.g., to at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0102] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes SEQ ID NO:4, a heavy chain that includes the amino acid sequence of SEQ ID NO:6, or a sequence having approximately at least 90% sequence identity thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto, and alight chain comprising light chain CDRs SEQ ID NO:24 (CDR-L1), SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3). In some embodiments, the antibody, or fragment thereof, comprises a heavy chain that includes at least 50 contiguous amino acids of the amino acid sequence of SEQ ID N0:6. or a sequence approximately at least 90% identical thereto, e.g., to at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0103] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes SEQ ID NO:4. a heavy chain that includes the amino acid sequence of SEQ ID NO:6, or a sequence having approximately at least 90% sequence identity thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto, and alight chain comprising light chain CDRs SEQ ID NO:36 (CDR-L1), SEQ ID NO:37 (CDR-L2), and SEQ ID NO:38 (CDR-L3). In some embodiments, the antibody, or fragment thereof, comprises a heavy chain that includes at least 50 contiguous amino acids of the amino acid sequence of SEQ ID NO:6, or a sequence approximately at least 90% identical thereto, e.g., to at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0104] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes SEQ ID NO:4, a light chain variable region that includes the amino acid sequence of SEQ ID NO:5, or a sequence having approximately at least 90% sequence identity thereto, e.g.. at least about 95%. about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 4 or SEQ ID NO:5.

[0105] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes SEQ ID NON, a heavy chain that includes the amino acid sequence of SEQ ID NO:6, or a sequence having approximately at least 90% sequence identity' thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto, and comprises a light chain variable region that includes the amino acid sequence of SEQ ID NO:5, a light chain that includes the amino acid sequence of SEQ ID NO:7, or a sequence having approximately at least 90% sequence identity thereto, e.g.. at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto.

[0106] Anti-KLRGl antibodies may optionally comprise antibody constant regions or parts thereof. For example, a VL domain may have attached, at its C terminus, antibody light chain constant domains including human Ck or CZ chains. Similarly, a specific antigen-binding domain based on a VH domain may have attached all or part of an immunoglobulin heavy chain derived from any antibody isotope, e.g., IgG, IgA, IgE, and IgM and any of the isotope sub-classes, which include but are not limited to, IgGl and IgG4. The DNA and ammo acid sequences for the C-terminal fragment of are well known in the art.

[0107] In some embodiments, the antibody, or a fragment thereof, has a half-life of at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, or at least 28 days. In some embodiments, the antibody, or a fragment thereof, has ahalf-life of about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In some embodiments, the antibody, or a fragment thereof, has ahalf-life of about 10-28 days, about 11-28 days, about 12-28 days, about 13-28 days, about 14-28 days, about 15-28 days, about 16-28 days, about 17-28 days, about 18-28 days, about 19-28 days, about 20-28 days, about 21-28 days, about 22-28 days, about 23-28 days, about 24-28 days, about 25-28 days, about 26-28 days, about 27-28 days, or about 14-21 days. In one embodiment, the antibody, or a fragment thereof, has a half-life of 14-21 days.

[0108] In some embodiments, the antibody or fragment thereof is an afucosylated antibody (e.g., an afucosylated IgGl antibody). The afucosylation can increase the antibody or fragment thereof ADCC killing capability. Depletion of KLRG1 Expressing Cells

[0109] Antibodies, such as those described herein, exhibit at least two functions in the immune system. They bind antigens, e.g., KLRG1, and eliminate these antigens, including cells expressing the antigen, via the immunoglobulin effector functions, including but not limited to activation of the complement system or interaction with cellular receptors (Fc receptors) on phagocytic cells such as macrophages, and / or other immune cells such as NK cells, leukocytes, platelets, and placental trophoblasts.

[0110] Antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) are three well known antibody mediated mechanisms for killing, and thus depleting, target cells.

[0111] Though not bound by mechanism or theory, binding of the antibody to the target cell through the antigen binding region (variable domain) of the antibody can provide a linkage of the target cell to immune effectors through the Fc region(s) of the constant region of the antibody. In ADCC, typically the Fc region of the antibody binds to FcyRIIIa receptor on the immune effector cell, e.g., an NK cell, which can then kill the target cell. In ADCP, ty pically the Fc region of the antibody binds to FcyRIIa receptor on the immune effector cell, e.g, a macrophage cell, which can then engulf and kill the target cell. CDC is induced when the immune complex Cl q binds to the Fc region of the antibody bound to the target cell, triggering the formation of a membrane attack complex that punches holes into the surface of the target cell.

[0112] Thus, the constant region of the antibody mediates effector functions, including the activation of complement and interaction with Fc receptors, enabling effects such as ADCC, ADCP, or CDC. Neither CHI nor Ck or CZ domains mediate effector functions, which is the reason why Fabs do not show ADCC, ADCP, or CDC.

[0113] There are three classes of Fc gamma receptors, FcyRI (CD64), FcyRII (CD32), and FcyRIII (CD16). Only FcyRI is able to bind IgG in a monomeric form, and the affinity of FcyRI receptors compared to the immunoglobulin receptors FcyRII and FcyRIII is high. The high affinity receptor FcyRI is constitutively expressed on monocytes, macrophages, and dendritic cells, and expression can be induced on neutrophils and eosinophils. Thus, these cells can be recruited to a target cell through antibody or antibody fragment thereof comprising fc region, bound to the target cell.

[0114] The FcyRIIa receptor is found on macrophages, monocytes, and neutrophils, and the FcyRIIb receptor is found on B-cells, macrophages, mast cells, and eosinophils. The FcyRIIIa receptor is found on NK cells, macrophages, eosinophils, monocytes, and T cells, and the FcyRIIIb receptor is highly expressed on neutrophils. Again, these various cell types can be recruited to a target cell by an antibody bound to the target cell through an antibody or antibody fragment thereof comprising the fc region, bound to the target cell.

[0115] Thus, the KLRG1 binding molecules, including antibodies and antigen binding fragments thereof, and methods thereof, including those pertaining to KLRG1 depletion in a subject or in vitro, in some aspects comprise a KLRG1 antigen binding site together with an antibody constant domain or fragment thereof. This can function to mediate an effector function, including but not limited to ADCC, ADCP, or CDC. In some aspects the KLRG1 binding molecule consists or comprises of the antigen binding site of an antibody and a peptide binding Fc-effector molecules, as described in International Patent Application Publication No. WO 2002 / 44215. Immunotoxins as Means for Depletion of KLRG1 Expressing Cells

[0116] In some aspects, the antibodies and / or antigen binding fragments thereof provided for by the instant disclosure are conjugated to a toxic agent, and thus do not necessarily rely on endogenous effector cells in ADCC, ADCP, or CDC to deplete the target cells, e.g.. pathogenic cells expressing cell surface KLRG1.

[0117] Immunoconjugates which include one or more cytotoxins are referred to as "immunotoxins." Antibodies conjugated to a cytotoxic agent, drug, or the like are also known as antibody-drug conjugates (ADC). An immunoconjugate may have a half-life of sufficient periods of time for the antibody-drug conjugate to be internalized, degraded, and induce cell killing by the released toxin. A cytotoxin or cytotoxic agent can include any agent that is detrimental to (e.g., kills) cells. Suitable cytotoxic agents for forming immunoconjugates of the present disclosure include taxol, tubulysins, duostatins, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracindione, maytansine or an analog or derivative thereof, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin; calicheamicin or analogs or derivatives thereof, antimetabolites (such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, decarbazine, hydroxyurea, asparaginase, gemcitabine, cladribine), alkylating agents (such as mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BCNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C. cisplatin and other platinum derivatives, such as carboplatin; as well as duocarmycin A, duocarmycin SA, CC-1065 (a.k.a. rachelmycin), or analogs or derivatives of CC-1065), dolastatin, auristatin, pyrrolo[2,l-c][l,4]benzodiazepins (PBDs), indolinobenzodiazepine (IGNs) or analogues thereof, antibiotics (such as dactinomycin (formerly actinomycin), bleomycin, daunorubicin (formerly daunomycin), doxorubicin, idarubicin, mithramycin, mitomycin, mitoxantrone, plicamycin, anthramycin (AMC)), anti-mitotic agents (e.g., tubulin-targeting agents), such as diphtheria toxin and related molecules (such as diphtheria A chain and active fragments thereof and hybrid molecules); ricin toxin (such as ricin A or a deglycosylated ricin A chain toxin), cholera toxin, a Shiga-like toxin (SLT-I, SLT-IT, SLT-IIV), LT toxin, C3 toxin, Shiga toxin, pertussis toxin, tetanus toxin, soybean Bowman-Birk protease inhibitor, Pseudomonas exotoxin, alorin, saporin, modeccin, gelanin, abrin A chain, modeccin A chain, alpha-sarcin. Aleurites fordii proteins, dianthin proteins. Phytolacca americana proteins (PAPI. PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, and enomycin toxins. Other suitable conjugated molecules include antimicrobial / lytic peptides such as CLIP, Magainin 2, mellitin, Cecropin, and Pl8; ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, diphtheria toxin, and Pseudomonas endotoxin. Supplemental Therapeutic Agents

[0118] The antibodies of the present disclosure, including fragments thereof and conjugates thereof, can optionally be delivered to a patient in conjunction with other therapeutic agents. The additional therapeutic agents can be delivered concurrently with the antibodies of the present disclosure. As used herein, the word "concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other).

[0119] In some embodiments the antibodies of the present disclosure can be administered in conjunction with other IBM agents, such as alemtuzumab, immunoglobulin (e.g.. intravenous immunoglobulin (IVIG), subcutaneous immunoglobulin), methotrexate, azathioprine, mycophenolate mofetil, rituximab, tacrolimus, cyclophosphamide, or a combination thereof.

[0120] In some embodiments, the antibodies of the present disclosure can be administered in conjunction with immunosuppressive agents including, for example, cyclosporine A, rapamycin, glucocorticoids, azathioprine, mizoribine, aspirin derivatives, hydroxychloroquine, methotrexate, cyclophosphamide and FK506 (tacrolimus). Antibody-Related Definitions

[0121] The term "antibody" or "antibodies" as used herein refers to all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE. The antibody can be monoclonal or polyclonal and can be of any species of origin, including, for example, mouse, rat, rabbit, horse, goat, sheep, camel, or human, or can be a chimeric antibody. The antibodies can be recombinant monoclonal antibodies produced according to the methods disclosed, for example, in U.S. Patent No. 4,474,893 or U.S. Patent No. 4,816,567. The antibodies can also be chemically constructed, for example, according to the methods disclosed in U.S. Patent No. 4,676,980.

[0122] The terms "antigen-binding domain," "antigen-binding fragment," and "binding fragment" refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen. In instances where an antigen is large, the antigen-binding domain may only bind to a part of the antigen. A portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as "epitope" or "antigenic determinant."

[0123] Though an antigen-binding domain typically comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH), however, it does not necessarily have to comprise both. For example, a so-called Fd antibody fragment consists only of a VH domain, but still retains some antigen-binding function of the intact antibody.

[0124] Anti-KLRGl antibodies may optionally comprise antibody constant regions or parts thereof. For example, a VL domain may have attached, at its C terminus, antibody light chain constant domains including human Ck or CL chains. Similarly, a specific antigenbinding domain based on a VH domain may have attached all or part of an immunoglobulin heavy chain derived from any antibody isotope, e.g, IgG. IgA, IgE. and IgM and any of the isotope sub-classes, which include but are not limited to, IgGl and IgG4. The DNA and amino acid sequences for the C-terminal fragment of are well known in the art.

[0125] The term "repertoire" refers to a genetically diverse collection of nucleotides derived wholly or partially from sequences that encode expressed immunoglobulins. The sequences can be generated by in vivo rearrangement of, e.g., V, D, and J segments for H chains and, e.g., V and J segment for L chains. Alternatively, the sequences may be generated from a cell line by in vitro stimulation, in response to which the rearrangement occurs. Alternatively, part or all of the sequences may be obtained by combining, e.g., unrearranged V segments with D and J segments, by nucleotide synthesis, randomized mutagenesis, and other methods, for example as disclosed in U.S. Patent No. 5,565,332.

[0126] The terms "specific interaction" and "specific binding" refer to two molecules forming a complex that is relatively stable under physiologic conditions. Specific binding can be characterized by a high affinity and a low to moderate capacity, as distinguished from non-specific binding, which usually has a low affinity with a moderate to high capacity. Typically, binding is considered specific when the affinity constant KA is higher than approximately 106 M ', or more preferably higher than approximately 108 M f If necessary, non-specific binding can be reduced without substantially affecting specific binding, for example, by varying the binding conditions. The appropriate binding conditions such as concentration of antibodies, ionic strength of the solution, temperature, time allowed for binding, concentration of a blocking agent (e.g. serum albumin, milk casein), etc., may be optimized by a skilled artisan using routine techniques.

[0127] In certain embodiments, the antibodies can specifically bind an epitope within the extracellular domain (ECD) of human or mouse or monkey KLRG1, with an affinity, as expressed in KD. of at least about 2 nM. about Inm, about 100 pM. about 10 pM, or about 5 pM. Antibody Binding Specificity

[0128] It is contemplated that antibodies of the present disclosure may also bind with other proteins, including, for example, recombinant proteins comprising all or a portion of KLRG1.

[0129] One skilled in the art will recognize that the antibodies of this present disclosure may be used to detect, measure, and inhibit proteins that differ somewhat from KLRG1. The antibodies can be expected to retain the specificity' of binding so long as the target protein comprises a sequence which is at least about 60%, about 70%, about 80%, about 90%, about 95%. or more identical to any sequence of at least about 130, about 100, about 80, about 60, about 40, or about 20 of contiguous amino acids in the sequence set forth in SEQ ID NO: 1 or SEQ ID NO:2. The percent identity is determined by standard alignment algorithms such as, for example, Basic Local Alignment Tool (BLAST) described in Altshul et al. (1990) J. Mol. Biol.. 215: 403-410, the algorithm of Needleman et al. (1970) J. Mol. Biol., 48: 444-453. or the algorithm of Meyers et al. (1988) Comput. Appl. Biosci., 4: 11-17.

[0130] In addition to the sequence homology analyses, epitope mapping (see, e.g.. Epitope Mapping Protocols, ed. Morris, Humana Press, 1996) and secondary and tertiary structure analyses can be carried out to identify specific 3D structures assumed by the disclosed antibodies and their complexes with antigens. Such methods include, but are not limited to, X-ray crystallography (Engstom (1974) Biochem. Exp. Biol., 11:7-13) and computer modeling of virtual representations of the presently disclosed antibodies (Fletterick et al. (1986) Computer Graphics and Molecular Modeling, in Current Communications in Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). Antibody Fragments

[0131] This disclosure also provides methods for treating IBM with an antibody fragment specific for KLRG1. Complementarity-determining regions (CDRs) in such antibodies are not limited to the specific sequences of VH and VL disclosed herein, and may include fragments of these sequences that retain the ability to specifically bind KLRG1 while not interfering with the binding by KLRG1 and E-cadherin. N-cadherin, and R-cadherin. Such fragments may be derived from the sequences listed in Tables 1-3 by a skilled artisan using techniques well known in the art. For example, amino acid substitutions, deletions, or additions, can be made in the framew ork regions (FRs) and / or in CDRs. While changes in the FRs can usually be designed to improve stability and immunogenicity of the antibody, changes in the CDRs can typically be designed to increase affinity of the antibody for its target.

[0132] Changes to FRs include, but are not limited to, humanizing a non-human derived or engineering certain framework residues that are important for antigen contact or for stabilizing the binding site, e.g., changing the class or subclass of the constant region, changing specific amino acid residues which might alter the effector function such as Fc receptor binding, e.g., as described in U.S. Patent Nos. 5,624,821 and 5,648,260 and Lund et al. (1991) J. Immun. 147: 2657-2662 and Morgan et al. (1995) Immunology 86: 319-324, or changing the species from which the constant region is derived.

[0133] Fragments of FRs also include naturally occurring immunoglobulin allotypes. Such affinity-increasing changes may be determined empirically by routine techniques that involve altering the CDR and testing the affinity antibody for its target. For example, conservative amino acid substitutions can be made within any one of the disclosed CDRs. Various alterations can be made according to the methods described, for example, in Antibody Engineering, 2nd ed., Oxford University Press, ed. Borrebaeck, 1995. These include, but are not limited to, nucleotide sequences that are altered by the substitution of different codons that encode a functionally equivalent amino acid residue within the sequence, thus producing a “silent’’ change. For example, the nonpolar amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, try ptophan, and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine, and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs. Furthermore, any native residue in the polypeptide may also be substituted with alanine (see, e.g., MacLennan et al. (1998) Acta Physiol. Scand. Suppl. 643:55-67; Sasaki et al. (1998) Adv. Biophys. 35:1-24).

[0134] The phrase "substantially as set out" means that the relevant CDR, VH, or VL domain of the resent disclosure will be either identical to. or have only insubstantial differences in the specified regions (eg., a CDR) from the sequence of which is set out. Insubstantial differences include minor amino acid changes, such as substitutions of one (1) or two (2) out of any five (5) amino acids in the sequence of a specified region.

[0135] The term "KLRG1 activity" refers to one or more lymphocyte co-inhibitory activities associated with KLRG1. For example, KLRG1 activity7 may mean modulation of cytotoxic T and NK cell activation.

[0136] The term "modulate," and its cognates, refer to a reduction or an increase in the activity7 of KLRG1 associated with activation of T cells and NK cells due to its interaction with an anti-KLRGl antibody, wherein the reduction or increase is relative to the activity7 of KLRG1 in the absence of the same antibody. A reduction or an increase in activity is preferably at least about 10%, about 20%. about 30%. about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more. When KLRG1 activity is reduced, the terms "modulatory" and "modulate" are interchangeable with the terms "inhibitory" and "inhibit." When KLRG1 activity is increased, the terms "modulatory" and "modulate" are interchangeable with the terms "activating" and "activate."

[0137] Antibody fragments included within the scope of the present disclosure include, for example: Fab, Fab', F(ab')2, and Fv fragments; domain antibodies, diabodies: vaccibodies, linear antibodies: single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Such fragments can be produced by known techniques. For example, F(ab')2 fragments can be produced by pepsin digestion of the antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (see Huse et al, Science 1989 Dec 8;246(4935): 1275-1281).

[0138] Antibodies of the present disclosure may be altered or mutated for compatibility with species other than the species in which the antibody was produced. For example, antibodies may be humanized or camelized. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fabl, F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a nonhuman species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework residues of the human immunoglobulin can be replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions (i.e., the sequences between the CDR regions) are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also can comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0139] In certain embodiments, the VH and / or VL domains may be germlined, i.e.. the framework regions (FRs) of these domains are mutated using conventional molecular biology techniques to match those produced by the germline cells. In other embodiments, the framework sequences remain diverged from the consensus germline sequences.

[0140] Methods for humanizing non-human antibodies are well known in the art. The present disclosure, and any invention(s) provided for herein, is not limited to any particular source, species of origin, or method of production. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These nonhuman amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can essentially be performed following the method of Winter and co-workers (Jones et al, Nature 321:522 (1986); Riechmann et al, Nature 332:323 (1988); Verhoeyen et al, Science 239:1534 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues (e.g., all of the CDRs or a portion thereof), and possibly some FR residues, are substituted by residues from analogous sites in rodent antibodies.

[0141] Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol. 227:381 (1991); Marks et al, J. Mol Biol 222:581 (1991)). The techniques of Cole et al and Boemer et al are also available for the preparation of human monoclonal antibodies (Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boemer et al, J. Immunol. 147:86 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 9,434.782, 9,253,965, 5,545,807, 5,545,806, 5,569,825, 5.625,126, 5,633.425, and 5,661.016, and in the following scientific publications: Lee, E-Chiang et al. “Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery"’ Nature Biotechnology volume 32, pages 356-363 (2014); Marks et ah, Bio / Technology 10:779 (1992); Lonberg et 1, Nature 368:856 (1994); Morrison, Nature 368:812 (1994); Fishwild et ah, Nature Biotechnol. 14:M5 (1996); Neuberger, Nature Biotechnoh 14:826 (1 96); Lonberg and Huszar, Intern, Rev. Immunol 13:65 (1995).

[0142] Monoclonal antibodies used to carry out the present disclosure can be produced in a hybridoma cell line according to the technique of Kohler and Milstein, Nature 265:495 (1975). For example, a solution containing the appropriate antigen can be injected into a mouse and. after a sufficient time, the mouse sacrificed, and spleen cells obtained. The spleen cells can then be immortalized by fusing them, for example with myeloma cells or with lymphoma cells, typically in the presence of polyethylene glycol, to produce hybridoma cells. The hybridoma cells can then be grown in a suitable medium and the supernatant screened for monoclonal antibodies having the desired specificity. Monoclonal Fab fragments can be produced in E. coli by recombinant techniques known to those skilled in the art. Antibodies specific to the target polypeptide can also be obtained by phage display techniques known in the art.

[0143] Various immunoassays can be used for screening to identify antibodies having the desired specificity for the extracellular domain of KLRG1. Numerous protocols for competitive binding or immunoradiometric assays using monoclonal antibodies with established specificity are well known in the art. Such immunoassays typically involve the measurement of complex formation between an antigen and its specific antibody (e.g., antigen / antibody complex formation). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non- interfering epitopes on the polypeptides or peptides of this disclosure can be used as well as a competitive binding assay.

[0144] Anti-KLRGl antibodies described herein can be conjugated to a solid support (e.g., beads, plates, slides, or wells formed from materials such as latex or polystyrene) in accordance with know n techniques. Anti-KLRGl antibodies described herein can likewise be conjugated to detectable groups such as radiolabels (e.g., 33S, 1251,1?1I or "mTc, which may also be attached to antibodies using conventional chemistry), enzyme labels (e.g, horseradish peroxidase, alkaline phosphatase), and fluorescence labels (e.g., fluorescein) in accordance with known techniques. Detectable labels further include chemical moieties such as biotin, which may be detected via binding to a specific cognate detectable moiety', e.g., labeled avidin. Determination of the formation of an antibody / antigen complex in the methods of this disclosure can be by detection of, for example, precipitation, agglutination, flocculation, radioactivity, color development or change, fluorescence, luminescence, etc., and is well known in the art.

[0145] Anti-KLRGl antibodies described herein can be linked to another functional molecule, e.g., another peptide or protein (albumin, another antibody, etc ), toxin, radioisotope, cytotoxic or cytostatic agents. For example, the antibodies can be linked by chemical cross-linking or by recombinant methods. The antibodies may also be linked to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent No. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, and 4,179,337. The antibodies can be chemically modified by covalent conjugation to a polymer, for example, to increase their circulating half-life. Exemplary polymers and methods to attach them are also shown in U.S. Patent Nos. 4,766,106, 4,179,337, 4,495,285, and 4,609,546.

[0146] Anti-KLRGl antibodies described herein may also be altered to have a glycosylation pattern that differs from the native pattern. For example, one or more carbohydrate moieties can be deleted and / or one or more glycosylation sites added to the original antibody. Addition of glycosylation sites to the presently disclosed antibodies may be accomplished by altering the amino acid sequence to contain glycosylation site consensus sequences known in the art. Another means of increasing the number of carbohydrate moieties on the antibodies is by chemical or enzymatic coupling of glycosides to the amino acid residues of the antibody. Such methods are described in International Patent Application Publication No. WO 87 / 05330, and in Aplin et al. (1981) CRC Crit. Rev. Biochem, 22: 259-306. Removal of any carbohydrate moieties from the antibodies may be accomplished chemically or enzymatically, for example, as described by Hakimuddin et al. (1987) Arch. Biochem. Biophys., 259: 52; and Edge et al. (1981) Anal. Biochem., 118: 131 and by Thotakura et al. Further Embodiments

[0147] In certain embodiments, the antibody, or a fragment thereof, can be a chimeric antibody or a humanized antibody. In additional embodiments, the chimeric or humanized antibody comprises at least a portion of the CDRs of the antibody. As used herein, a "portion" of a CDR is defined as one or more of the three loops from each of the light and heavy chain that make up the CDRs (e.g.. from 1-6 of the CDRs) or one or more portions of a loop comprising, consisting essentially of, or consisting of at least three contiguous amino acids. For example, the chimeric or humanized antibody may comprise 1, 2, 3, 4, 5, or 6 CDR loops, portions of 1, 2, 3, 4, 5, or 6 CDR loops, or a mixture thereof, in any combination.

[0148] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain that includes the amino acid sequence of any one of SEQ ID NO: 4, 6, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%, about 96%, about 97%, about 98%. or about 99% identical thereto. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain that includes at least 50 contiguous amino acids of the amino acid sequence of any one of SEQ ID NOs: 4, 6, or a sequence approximately at least 90% identical thereto, e.g., at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0149] In some embodiments, the antibody, or a fragment thereof, comprises a light chain that includes the amino acid sequence of any one of SEQ ID NOs: 5, 7, 11, 12, or 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%, about 96%, about 97%. about 98%, or about 99% identical thereto. In some embodiments, the antibody, or fragment thereof, comprises a light chain that includes at least 50 contiguous amino acids of the amino acid sequence of any one of SEQ ID NOs: 5, 7, 11, 12, or 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0150] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain that includes the amino acid sequence of any one of SEQ ID NOs:4 or 6, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%. about 96%, about 97%, about 98%, or about 99% identical thereto, and a light chain that includes the amino acid sequence of any one of SEQ ID NOs: 5, 7, 11, 12, 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto. In some embodiments, the antibody, or fragment thereof, comprises a heavy chain that includes at least 50 contiguous amino acids of the amino acid sequence of any one of SEQ ID NOs: 4, 6, or a sequence approximately at least 90% identical thereto, e.g., at least about 100 or about 150 or about 200 or more contiguous amino acids, and a light chain that includes at least 50 contiguous amino acids of the amino acid sequence of SEQ ID NOs: 5, 7,11, 12, 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 100 or about 150 or about 200 or more contiguous amino acids.

[0151] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain that includes at least one CDR (e.g.. 1. 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 4, 6 or a sequence approximately at least 90% identical thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions (e.g, for humanization of a mouse antibody) are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[0152] In some embodiments, the antibody, or a fragment thereof, comprises a light chain that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 5, 7, 11, 12, 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto.

[0153] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain that includes at least one CDR (e.g., 1. 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 4. 6 or a sequence approximately at least 90% identical thereto. e.g., at least about 95%, about 96%, about 97%, about 98%, or about 99% identical thereto, and a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 5, 7, 11, 12, 13, or a sequence approximately at least 90% identical thereto, e.g., at least about 95%. about 96%, about 97%, about 98%, or about 99% identical thereto. Pharmaceutical Compositions and Methods of Administration

[0154] The disclosure provides compositions comprising KLRG1 depleting agents, anti-KLRG1 antibodies, and / or fragments thereof, and / or conjugates and fusion proteins thereof. The compositions of the present disclosure can optionally comprise medicinal agents, pharmaceutical agents, carriers, pharmaceutically acceptable carriers, adjuvants, dispersing agents, diluents, and the like. Such compositions may be suitable for pharmaceutical use and administration to patients. By "pharmaceutically acceptable" it is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects such as toxicity7. The compositions typically comprise one or more antibodies of the present disclosure and a pharmaceutically acceptable excipient. The phrase "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The pharmaceutical compositions may also be included in a container, pack, or dispenser, together with instructions for administration.

[0155] A person skilled in the art, with the benefit of the present disclosure in its entirety, will understand various pharmaceutically acceptable carriers can be used, including but not limited to sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide, aluminum hydroxide, and amino acids; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffered solutions; histidine buffered solutions; enzymes, such as hyaluronidase; and other non-toxic compatible substances employed in pharmaceutical formulations. Pharmaceutically acceptable carriers can include substances that are "‘generally regarded as safe” (GRAS), for example as designated by the FDA.

[0156] The compositions of the present disclosure can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. In the manufacture of a pharmaceutical formulation according to the present disclosure, the compound (including the physiologically acceptable salts thereof) can typically be admixed with, inter alia, an acceptable carrier. The carrier can be a solid or a liquid, or both, and can be formulated with the compound as a unit-dose formulation, for example, a tablet, which can contain from approximately 0.01% or approximately 0.5% to approximately 95% or approximately 99% by weight of the compound. One or more compounds can be incorporated in the formulations of the present disclosure, which can be prepared by any of the techniques of pharmacy known to those skilled in the art.

[0157] A pharmaceutical composition of the present disclosure can be formulated to be compatible w ith its intended route of administration. Methods to accomplish the administration are known to those skilled in the art. The administration may. for example, be intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, and / or trans dermal. It may also be possible to obtain compositions that may be administered in other manners, including topically or orally, or which may be capable of transmission across mucous membranes.

[0158] Solutions or suspensions used for intradermal or subcutaneous application typically include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid, or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; agents for the adjustment of tonicity, such as sodium chloride or dextrose; and enzy mes, such as hyaluronidase. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Such preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials, which can be made, for example, of glass or plastic.

[0159] Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.), dextrose 5% in water, or phosphate buffered saline (PBS). Typically, the composition should be sterile and should be fluid to the extent that easy syringeability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Prevention of the action of microorganisms can be achieved, for example, by various antibacterial and antifungal agents, including parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include in the composition isotonic agents, for example, sugars and / or polyalcohols, such as mannitol, sorbitol, and sodium chloride. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and / or by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate, and gelatin.

[0160] The compositions of the present disclosure can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. In the manufacture of a pharmaceutical formulation according to the present disclosure, the compound (including the physiologically acceptable salts thereof) can typically be admixed with, inter alia, an acceptable carrier. The carrier can be a solid or a liquid, or both, and can be formulated with the compound as a unit-dose formulation, for example, a tablet, which can contain from approximately 0.01% or approximately 0.5% to approximately 95% or approximately 99% by weight or by volume of the compound. One or more compounds can be incorporated in the formulations of the present disclosure, which can be prepared by any of the techniques of pharmacy known to those skilled in the art.

[0161] In certain embodiments, the presently disclosed antibodies can be prepared with carriers that are configured to protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, poly orthoesters, and / or polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions containing the presently disclosed antibodies can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0162] It may be advantageous to formulate parenteral compositions in a dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0163] Toxicity and therapeutic efficacy of the composition of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to approximately 50% of the population) and the ED50 (the dose therapeutically effective in approximately 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are typically preferred.

[0164] For any composition used in the present disclosure, or derivable from the present disclosure, the therapeutically effective dose can be estimated initially from cell culture assays. Examples of suitable bioassays include but are not limited to DNA replication assays, cytokine release assays, transcription-based assays, KLRGl / cadherin binding assays, immunological assays, and other assays, such as those described in the Examples below. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the antibody which achieves a half-maximal inhibition of symptoms). Circulating levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage lies preferably within a range of circulating concentrations with little or no toxicity. The dosage may vary depending, at least in part, upon the dosage form employed and the route of administration utilized. Alternatively, one can administer the presently disclosed antibodies, or those derivable from the present disclosure, in a local rather than systemic manner, for example, in a depot or sustained-release formulation.

[0165] A further aspect of the present disclosure relates to kits for use in the methods provided for herein or otherwise derivable in view of the present disclosures. A kit can comprise one or more antibodies of the present disclosure, and / or one or more antibodies derivable from the present disclosure, in a form suitable for administration to a subject, and / or in a form suitable for compounding into a formulation. The kit can further comprise other components, such as therapeutic agents, earners, buffers, containers, devices for administration, and the like. The kit can be designed for therapeutic use, diagnostic use, and / or research use, and the additional components can be those suitable for the intended use. A person skilled in the art will recognize various such components suitable for inclusion in kits of this nature. The kit can further comprise labels and / or instructions, e.g.. for treatment of a disorder. Such labeling and / or instructions can include, for example, information concerning the amount, frequency, and method of administration of the antibody. A person skilled in the art, in view of the present disclosures, will appreciate the types of instructions that may be included in conjunction as part of the kits. The instructions are provided for herein, or are otherwise derivable by a person skilled in the art in view of the present disclosures.

[0166] One skilled in the art will appreciate further features and advantages of the disclosure based on the above-described embodiments. Accordingly, the disclosure is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety. Citation of references is not an admission that these references are prior art to the present disclosure. WORKING EXAMPLES Example 1: Pharmacodynamic measurements during phase 1 single dose studies with KLRGl-Depleting Antibody (ABC008)

[0167] A phase 1 single ascending dose clinical study was conducted with inclusion body myositis (IBM) patients. Three cohorts were enrolled. Cohort 1 consisted of 3 patients who received 0.1 mg / kg, cohort 2 consisted of 3 patients who received 0.5 mg / kg, and cohort 3 consisted of 5 patients who received 2.0 mg / kg, all administered subcutaneously on Day 0. Patients were followed for 168 days. Blood sampling and flow cytometry' of peripheral blood mononuclear cells (PBMCs) was conducted. Flow cytometry reagents included Alexa Fluor 488 labelled anti-KLRGl (clone 13F12F2) and other antibodies (Table 4).

[0168] The results are shown in FIG. 1 and Table 5. Maximum mean values and timepoints of depletion of blood CD8+KLRG1+ T cells was achieved as follows: cohort 1 -69% at Day 21, cohort 2 -97% at Day 28, and cohort 3 -97% at Day 28. Accordingly, the cohort 1 dose of 0.1 mg / kg was considered insufficient. At Day 56, both cohorts 2 (-90%) and cohort 3 (-94%) continued to have sufficient blood CD8+KLRG1+ depletion. At Day 84, CD8+KLRG1+ T cell levels had increased in cohort 2 to -58% and in cohort 3 -76%. Table 4: Flow cytometry reagents used in pharmacodynamic assay Reagent Supplier Catalogue No KLRG1 AF488 eBioScience Cat. # 53-9488-42 CD3 PerCP-Cy5.5 BD Cat. # 552852 CD25 BV421 Biolegend Cat. # 302630 CD8BV510 BD Cat. # 563919 CD197 (CCR7) BV605 Biolegend Cat. # 353224 CD4 BV711 BD Cat. # 563913 CD16BV786 BD Cat. # 563690 CD57 APC Biolegend Cat. # 359610 CD45 AF700 BD Cat. # 560566 CD45RA APC-H7 BD Cat. # 561212 CD127 PE Biolegend Cat. # 351304 CD56 PE-Cy7 Biolegend Cat. # 318318 CD161 BUV395 BD Cat. # 748280 Table 5: Blood CD8+KLRG1+ cell% depletion in a phase 1 single ascending dose study of ABC008 in IBM Day Cohort 1 Cohort 2 Cohort 3 0 0% 0% 0% 1 -56% -77% -71% 2 -52% -76% -82% 3 -61% -81% -91% 6 -63% -91% -97% 9 -56% -92% -97% 14 -68% -96% -98% 21 -69% -97% -96% 28 -68% -97% -97% 56 -67% -90% -94% 84 -55% -58% -76% 112 -52% -58% -74% 140 -67% -58% -64% 168 -51% -64% -53% Example 2: Clinical outcome assessment of phase 1 inclusion body myositis (IBM) patients who received single doses of ABC008

[0169] Eleven inclusion body myositis (IBM) patients enrolled in the single ascending dose phase 1 study (cohort 1 N=3, cohort 2 N=3, cohort 3 N=5) were assessed with the clinical outcome assessments inclusion body myositis functional rating scale (IBMFRS) and manual muscle testing (MMT12). Both tools assess patient functional status and muscle strength, with higher scores indicating better performance.

[0170] The mean values across all patients for 24 weeks after a single dose of ABC008 is shown in FIG. 2A and FIG. 2B. The IBMFRS appeared to stabilize up to 8 weeks and then declined by 16 weeks. The MMT12 improved up to 8 weeks and then declined. Taken together, these data suggested that every 8-week dosing resulted in disease stabilization or improvement.

[0171] Thus Examples 1 and 2 taken together, indicated that every’ 8-week dosing of 0.5 mg / kg and 2.0 mg / kg resulted in an optimal pharmacodynamic response of CD8+ KLRG1+ T cell depletion > 90% at 8 weeks (Example 1) while the 8-week dosing interval was optimal for clinical measures of disease stabilization or improvement (Example 2). Example 2A: Clinical outcome assessment of phase 1 inclusion body myositis (IBM) patients who received multiple ascending doses of ABC008

[0172] Eight of the eleven inclusion body myositis (IBM) patients enrolled in the single ascending dose portion of the Phase I study were enrolled into the multiple ascending dosing (MAD) portion of the Phase 1 study (cohort 1 N=3, cohort 2 N=l, cohort 3 N=4). An additional eight (8) subjects were enrolled in an imaging sub-study evaluating ulviprubart (ABC008) at a dose of 2 mg / kg every 8 weeks.

[0173] The pharmacodynamic effect of ulviprubart (ABC008) was also evaluated during the 48-week period of the multiple-dose portion of the study. During the 48 weeks in which patients received 6 doses of ulviprubart (ABC008) Q8W, there was a selective and sustained depletion of KLRG1+ cells, with no recoveries observed in the 48 weeks. Ulviprubart (ABC008) treatment resulted in a dose-related reduction in CD8+ KLRG1+ T cells (FIG. 3A). Administration of 0.1 mg / kg resulted in a reduction of CD8+ KLRG1+ T-cells averaging 82%, while 0.5 and 2 mg / kg doses resulted in reductions averaging 98% and 93%. respectively. Cells that did not express KLRG1. such as regulatory T-cells (Tregs) (FIG. 3B) and B lymphocytes (FIG. 3C) were not impacted significantly by ulviprubart (ABC008).

[0174] In conclusion, profound depletions of KLRG1+ T cells were observed following single doses of 0.5 and 2 mg / kg of ulviprubart (ABC008). and Q8W dosing sustained this deep depletion throughout the study.

[0175] Importantly for preservation of homeostatic immune function, the depletion profile was restricted to subsets of T cells expressing KLRG1, with preservation of KLRG1-negative cells including subsets of T cells and regulatory T cells and B cells.

[0176] Several exploratory clinical functional assessment endpoints including IBM Functional Rating Scale (IBMFRS). Manual Muscle Testing (MMT12), dynamometry of dominant quadriceps and dominant hand grip, and Modified Timed Up and Go test (mTUG) were obtained for the 16 patients that received multiple doses of ulviprubart (8 patients from the SAD-MAD portion of the study and 8 patients from the imaging sub-study).

[0177] Mean change in IBMFRS vs natural histoiy / placebo-controlled cohorts for all 16 patients against time is shown in FIG. 4. MMT12, mTUG and dynamometry functional assessment data are shown in FIGs. 5A (MMT12); 5B (right hand grip dynamometry), 5C (right quad dynamometry) and 5D (mTUG).

[0178] In conclusion, comparisons of these data from all five clinical functional assessments with natural history and placebo control clinical trials are supportive of slowing of progression of IBM by ulviprubart treatment. Example 3: A Phase II / III Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of ABC008 in the Treatment of Subjects With Inclusion Body Myositis

[0179] The study is a blinded randomized study evaluating the efficacy and safety of two doses of ABC008, 0.5 mg / kg or 2 mg / kg vs. placebo in patients with IBM. The study is comprised of 3 parts. Part A. B, and C. Part A is a sentinel cohort of approximately 30 subjects who received the first three doses of the study drug at 0.5 mg / kg or 2 mg / kg or a matching placebo randomly assigned in a blinded manner. Safety data from subjects in Part A was evaluated by a Data and Safety7 Monitoring Board (DSMB) before initiation of enrollment in Part B. After completion of Part A or Part B, subjects have the option of enrolling in an open-label long-term extension study. For subjects who terminate treatment early from Part A or Part B they would roll over into Part C, to evaluate the recovery of the depletion of killer cell lectin-like receptor G1 (KLRG1)+ cells after the end of treatment with ABC008.

[0180] Efficacy, safety, health related quality of life (HRQoL), and health care resource utilization (HRU) assessments were conducted. Blood samples were obtained to evaluate the serum pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity7 of ABC008 throughout the study. Inclusion Criteria

[0181] Adult males and females age >40 years at the time of the first dose of study medication; Weight >40 and <150 kg; Diagnosis of either clinico-pathologically defined IBM, clinically defined IBM, or probable IBM according to the European Neuromuscular Centre (ENMC) IBM 2011 research diagnostic criteria (Rose et al., 2013). Documented histopathology results must be available prior to Baseline (Day 1) to confirm eligibility; able to arise from a chair (with armrests), with use of their arms but without support from another person or device (e.g., cane, walking stick), at Screening and Baseline (Day 1); able to walk 3 meters, turn around, walk back to the chair, and sit down, with or without assistive device. Once arisen from the chair, subject may use any w alking device but cannot be supported by another person, furniture, or a wall. Exclusion Criteria:

[0182] Any other form of myositis or myopathy other than IBM, e.g., metabolic or drug-induced myopathy, drug-induced myositis, anti-synthetase syndrome, polymyositis or dermatomyositis, cancer-associated myositis (myositis diagnosed within 3 years, either before or after), myositis in overlap with another autoimmune disease (e.g. systemic lupus, systemic sclerosis, rheumatoid arthritis), or muscular dystrophy; Any condition, e.g., severe degenerative arthritis with limited range of motion, which precludes the ability to quantitate muscle strength or perform functional assessments (e.g. mTUG), in the Investigator’s opinion; Presence of other autoimmune or autoinfl ammatory disease other than indication under study, e.g. g., rheumatoid arthritis, psoriatic arthritis, axial spondyloarthropathy, inflammatory’ bowel disease, systemic lupus erythematosus. Subjects with Sjogren's syndrome, T-cell large granular lymphocyte leukemia (T-LGLL). or well-controlled thyroid disease are permitted. STUDY ARMS: Active Comparator: 0.5 mg / kg ABC008

[0183] 1. Part A- ABC008 N=12; Part B-ABC008 N=67

[0184] 2. Interventions: Drug ABC008 Active Comparator: 2.0 mg / kg ABC008

[0185] 1. Part A-ABC008 N=12; Part B ABC008 N=67

[0186] 2. Interventions: Drug ABC008 Placebo Comparator: Placebo

[0187] Part A-Placebo N=6; Part B-Placebo N=67

[0188] Interventions: Drug: ABC008 Part A - To determine the safety and tolerability of recurrent dosing of ABC008 in subjects with IBM at 2 SC dose levels. [Time Frame: From Baseline (week 0) through week 20],

[0189] Safety as assessed by the incidence, type and severity of Treatment Emergent Adverse Events (TEAEs) Part B - To determine the efficacy of ABC008 in IBM at two SC dose levels as measured by IBM Functional Rating Scale (IBMFRS) at Week (W)76 [Time Frame: From Baseline (week 0) through study completion, an average of 76 weeks]

[0190] Mean change in IBM Functional Rating Scale (IBMFRS)

[0191] Part A - Treatment Emergent Serious Adverse Events (TESAEs) [Time Frame: From Baseline (Day 1) through study completion, an average of 80 weeks.] Incidence, type and severity of TESAEs

[0192] Part A - Treatment Emergent Adverse Events (TEAEs) onset within 24 hours of Study Medication Administration. [Time Frame: From Baseline (Day 1) through study completion, an average of 80 weeks.] Incidence, type, and severity of TEAEs with onset within 24 hours from the start of any of study medication administration

[0193] Part A - Treatment Emergent Adverse Events leading to study medication or study discontinuation. [Time Frame: From Baseline (Day 1) through study completion, an average of 80 weeks] Incidence of TEAEs leading to study medication or study discontinuation

[0194] Part A - Clinically significant changes in standard laboratory parameters, vital signs, and ECGs [Time Frame: From Baseline (Day 1) through study completion, an average of 80 weeks.] Incidence of clinically significant changes in standard laboratory parameters, vital signs, and ECGs

[0195] Part A - Adverse Events of Special Interest (AESI) [Time Frame: From Baseline (Day 1) through study completion, an average of 80 weeks.] Incidence of AES Is

[0196] Part B - Manual Muscle Test 12 (MMT 12) [Time Frame: From Baseline (Day 1) through study completion, an average of 76 weeks.]

[0197] Mean change in MMT 12

[0198] One skilled in the art will appreciate further features and advantages of the disclosure based on the above-described embodiments. Accordingly, the disclosure is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety. Citation of references is not an admission that these references are prior art to the present disclosure. REFERENCES 1. Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol. 2011; 11(4):289-95. 2. Amemiya K, Granger RP, Dalakas MC. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain: a journal of neurology. 2000; 123 ( Pt 10):2030-9. 3. Apetoh L, Smyth MJ, Drake CG, Abastado JP, Apte RN, Ayyoub M, et al. 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Association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Brain : a journal of neurology. 2016; 139: 1348-1360. 18. Guthmann MD, Tai M, Pecht I. A new member of the C-type lectin family is a modulator of the mast cell secretory response. Int Arch Allergy Immunol. 1995; 107(1-3):82-6. 19. Hijnen D. Knol EF, Gent YY, Giovannone B, Beijn SJ, Kupper TS, et al. CD8(+) T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-gamma, IL-13, IL-17, and IL-22. J Invest Dermatol. 2013; 133(4):973-9. 20. Hofmann M, Schweier O, Pircher H. Different inhibitory7 capacities of human and mouse KLRG1 are linked to distinct disulfide-mediated oligomerizations. Eur J Immunol. 2012; 42(9):2484-90. 21. Kita H. Autoreactive CD8-specific T-cell response in primary biliary cirrhosis. Hepatology research : the official journal of the Japan Society7 of Hepatology7. 2007; 37 Suppl 3:S402-5. 22. 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Tessmer MS, Fugere C, Stevenaert F, Naidenko OV, Chong HJ, Leclercq G, et al. KLRG1 binds cadherins and preferentially associates with SHIP-1. International immunology. 2007; 19(4):391-400. 31. Trevino MA, Teixeiro E, Bragado R. CD8+ T cells oligoclonally expanded in synovial fluid at onset of spondyloarthropathy selectively proliferate in response to self antigens characterization of cell specificities in nonclonal populations. The Journal of rheumatology-. 2004; 31(10): 1962-72. 32. Voehringer D, Koschella M, Pircher H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood. 2002;100(10):3698-702. 33. Xing L. Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014; 20(9): 1043-9. 34. Willinger, T. et al. Molecular Signatures Distinguish Human Central Memory from Effector Memory CD8 T Cell Subsets. 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Claims

1. A method of treating inclusion body myositis (IBM) in a subject in need thereof, themethod comprising:administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRGI and depletes KLRGI expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:8 (CDR-H1), SEQ ID NO:9 (CDR-H2), and SEQ ID NO: 10 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO: 11 (CDR-L1). SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3)2. A method of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising:administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRGI and depletes KLRGI expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:21 (CDR-H1). SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ IDNO:24 (CDR-L1), SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3).

3. A method of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising:administering a dose of at least 0.1 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRGI and depletes KLRGI expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:33 (CDR-H1), SEQ ID NO:34 (CDR-H2), and SEQ ID NO:35 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:36 (CDR-L1). SEQ ID NO:37 (CDR-L2), and SEQ ID NO:38 (CDR-L3).

4. A method of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising:administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:8 (CDR-H1), SEQ ID NO:9 (CDR-H2), and SEQ ID NO: 10 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO: 11 (CDR-L1), SEQ ID NO: 12 (CDR-L2), and SEQ ID NO: 13 (CDR-L3).

5. A method of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising:administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity determining regions (CDRs) comprising SEQ ID NO:21 (CDR-H1), SEQ ID NO:22 (CDR-H2), and SEQ ID NO:23 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ ID NO:24 (CDR-L1). SEQ ID NO:25 (CDR-L2), and SEQ ID NO:26 (CDR-L3)6. A method of treating inclusion body myositis (IBM) in a subject in need thereof, the method comprising:administering a dose of at least 0.5 mg / kg of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 and depletes KLRG1 expressing T cells, wherein the antibody, or a fragment thereof, comprises:a heavy chain variable region comprising three complementarity’ determining regions (CDRs) comprising SEQ ID NO:33 (CDR-H1), SEQ ID NO:34 (CDR-H2), and SEQ ID NO:35 (CDR-H3); and a light chain variable region comprising three complementarity determining regions (CDRs) comprising amino acid sequences SEQ IDNO:36 (CDR-L1), SEQ ID NO:37 (CDR-L2), and SEQ ID NO:38 (CDR-L3).

7. The method of any one of claims 1-6, wherein the antibody or fragment thereofcomprises a heavy chain variable region comprising SEQ ID NO:4.

8. The method of any one of claims 1-7, wherein the antibody or fragment thereof comprises a light chain variable region comprising SEQ ID NO: 5.

9. The method of any one of the preceding claims, wherein the antibody or fragment thereof comprises a heavy chain comprising SEQ ID NO: 6 and a light chain comprising SEQ ID NO:7.

10. The method of any one of the preceding claims, wherein the antibody, or fragment thereof, may be a monoclonal antibody, or a fragment or derivative thereof.

11. The method of any one of the preceding claims, wherein the antibody, or fragment thereof, may be a humanized antibody, or a fragment thereof.

12. The method of any one of the preceding claims, wherein the antibody, or fragment thereof, binds human KLRG1 or cynomolgus KLRG1.

13. The method of any one of the preceding claims, wherein the dose of antibody is 0.5 mg / kg.

14. The method of any one of claims 1 to 12, wherein the dose is 2.0 mg / kg.

15. The method of any one of the preceding claims, wherein the doses are administered ateight week intervals.

16. The method of any one of the preceding claims, wherein the doses are administered until clinical response and / or remission is achieved.

17. The method of any one of the preceding claims, wherein the doses are administered until KLRG1+ cells remaining in the blood are decreased by at least 20%.

18. The method of any one of the preceding claims, wherein the antibody, or fragment thereof, is an afucosylated antibody.

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