Anti-BTLA antibodies and uses of the same

Abstract

Described herein are treatments and preventions for autoimmune disease or inflammatory disease using agonistic antibodies that bind to BTLA, and uses of an anti-BTLA antibody in the manufacture of a medicament for the treatment or prevention of an autoimmune disease or inflammatory disease. Also described herein are methods of agonizing BTLA activity without blocking or preventing the binding of HVEM to BTLA by administering an agonistic antibody that binds to BTLA.

Description

Attorney Docket No: 210196-224003 / PCTANTI-BTLA ANTIBODIES AND USES OF THE SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 690,046, filed September 3, 2024, the entire disclosure of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing, which has been submitted via Patent Center. The Sequence Listing titled 210196-224003 / PCT. xml, which was created on August 29, 2025 and is 27,213 bytes in size, is hereby incorporated by reference in its entirety.FIELD

[0003] Described herein are treatments and preventions for autoimmune diseases or inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, using agonistic antibodies that bind to B- and T-lymphocyte attenuator (BTLA), and uses of an agonistic anti- BTLA antibody in the manufacture of a medicament for the treatment or prevention of autoimmune diseases or inflammatory diseases. Also described herein are methods of agonizing BTLA and enhancing inhibitory signaling on T cells.BACKGROUND

[0004] The following discussion is provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto.

[0005] BTLA or CD272 is an inhibitory receptor expressed on the surface of immune cells. It consists of a single extracellular immunoglobulin (Ig)-like domain, a transmembrane region and a cytoplasmic tail that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) (Watanabe et al., 2003). When the receptor is engaged by a ligand, the ITIM motif is phosphorylated leading to the recruitment of protein phosphatases, such as Src homology region 2 domain-containing phosphatase- 1 (SHP1) and SHP2, which in turn block kinase cascades downstream of activating receptors at the cell surface (Xu et al., 2020). In this way BTLA acts as a brake on immune cell activation. BTLA binds to a ligand that is a member of the tumor necrosis factor (TNF) receptor superfamily, called herpes virus entry mediator (HVEM) or TNFRSF14 (Sedy et al., 2005).1ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0006] BTLA is only expressed on specific populations of immune cells, including the majority of B and T cells and some subsets of dendritic cells (Han et al., 2004). Within the T cell compartment, BTLA is expressed more highly on CD4+cells than on CD8+cells and, unusually for an immune checkpoint receptor, it is expressed across the spectrum of T cell differentiation with highest expression is observed on naive cells (Fuertes Marraco et al., 2015). This feature of BTLA suggests that, in addition to controlling the effector function of previously primed T cells, this receptor could play a role in determining the fate of naive cells encountering antigen for the first time, and so limit the antigen spreading that contributes to the progression of autoimmune disease (Tuohy and Kinkel, 2000).

[0007] Genetic evidence for BTLA’s role as a key regulator of immune responses arises from human disease association data. Single nucleotide polymorphisms (SNPs) in the BTLA gene, one of which has been shown to reduce its inhibitory function, are associated with risk of developing severe rheumatoid arthritis (Lin, Kuo and Chan, 2006; Oki et al., 2011). In genome wide association studies, the ligand for BTLA, HVEM, has been highlighted as a potential risk gene for ulcerative colitis (UC) (Jostins et al., 2012; Anderson, Boucher and Lees, 2017), rheumatoid arthritis (RA) and coeliac disease (Coenen et al., 2009), multiple sclerosis (MS) (Sawcer et al., 2011) and primary sclerosing cholangitis (PSC) (Folseraas et al., 2012).

[0008] Studies in transgenic mice provide further evidence for BTLA’s regulatory role. Mice that lack the receptor develop multi-organ inflammatory infiltrates in old age (Oya et al., 2008) and have heightened susceptibility to disease in models of autoimmunity (Watanabe et al., 2003; Deppong et al., 2006; Bekiaris et al., 2013). Mice that lack the ligand HVEM are also more susceptible to autoimmune disease, suggesting that BTLA’s negative role dominates over HVEM’s activating functions (Wang et al., 2005; Steinberg et al., 2008). BTLA is not just involved in the regulation of conventional T-cell responses but has also been shown to negatively regulate y5 T-cell function in psoriasis models (Bekiaris et al., 2013), as well as regulating natural killer T cell (NKT) activation (Miller, Sun and Fu, 2009). Furthermore, expression on dendritic cells can promote their tolerogenic function (Jones et al., 2016) and dampen inflammation via regulation of TLR4 signaling (Kobayashi et al., 2013). The prominent inhibitory roles of BTLA across a spectrum of immune cell types suggest that it has evolved as a crucial checkpoint to prevent excessive activation.

[0009] To date there are no published clinical data exploring BTLA targeted therapeutics in human autoimmunity, but observational and functional experiments on human immune cells ex vivo suggest that the biology of the human receptor matches that of its murine counterpart. BTLA 2ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT agonist antibodies are able to inhibit T cell responses from healthy donors (Otsuki et al., 2006), as well as from patients with ANCA associated vasculitis (Werner et al., 2019) and Behcet’s disease (Ye et al., 2016). In patients with MS the drug fmgolimod induces upregulation of BTLA in B cells, which is correlated with reduction in disease severity (Piancone et al., 2016). Similarly, control of renal transplant rejection by the drug sirolimus is in part due to it upregulating BTLA on T cells (Bai et al., 2013).

[0010] There remains a need for developing effective treatment regimens for treating autoimmune diseases or inflammatory diseases using agonistic anti-BTLA antibodies.SUMMARY

[0011] Described herein are methods and uses for anti-BTLA antibodies.

[0012] For example, described herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease and / or an inflammatory disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0013] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease and / or an inflammatory disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.3ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0014] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease and / or an inflammatory disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0015] In some embodiments, the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), Sjogren’s syndrome, systemic sclerosis (SSc), ankylosing spondylitis (AS), dermatomyositis, psoriatic arthritis (PsA), ANCA vasculitis, IgG4-related disease, nonradiographic axial spondyloarthritis (nr-AxSpA), polymyositis, Takayasu arteritis, cutaneous lupus erythematosus (CLE) types: chronic CLE (including discoid), subacute CLE, acute CLE, seropositive RA, seronegative RA, juvenile idiopathic arthritis (JIA), primary OA, secondary OA, cervical and lumbar spinal OA, hip OA, knee OA, erosive OA, ulcerative colitis (UC), Crohn’s disease (CD), and graft vs. host disease (GVHD). In some embodiments, the autoimmune disease or inflammatory disease is RA. In some embodiments, the autoimmune disease or inflammatory disease is SLE. In some embodiments, the autoimmune disease or inflammatory disease is UC. In some embodiments, the autoimmune disease or inflammatory disease is CD. In some embodiments, the autoimmune disease or inflammatory disease is GVHD.

[0016] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light4ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0017] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0018] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0019] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.5ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0020] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0021] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0022] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0023] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, 6ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0024] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0025] In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subj ect is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents7ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone.

[0026] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0027] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0028] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody8ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0029] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0030] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0031] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0032] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-9ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0033] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0034] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0035] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0036] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0037] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy 10ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0038] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0039] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0040] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0041] In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some11ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9, wherein the X is absent. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9, wherein the X is lysine (K). In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9, wherein the X is absent. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9, wherein the X is lysine (K).

[0042] In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant region (CH) sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant region (CH) sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0043] In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a light chain constant region (CL) sequence comprising SEQ ID NO: 20. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant region (CL) sequence12ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0044] In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl. In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region.

[0045] In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

[0046] In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of 13ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subj ect is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone.

[0047] In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 1500 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 1000 mg. In some embodiments, the amount or dose of the anti- BTLA antibody is between about 1 mg to about 900 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 800 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 700 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 600 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 500 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 450 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 400 mg. In some embodiments, the amount or dose of the anti- BTLA antibody is between about 1 mg to about 300 mg. In some embodiments, the amount or14ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT dose of the anti-BTLA antibody is between about 1 mg to about 200 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is between about 1 mg to about 150 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 1 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 2 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 3 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 4 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 5 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 10 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 15 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 20 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 25 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 30 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 35 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 40 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is at least about 50 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 1000 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 900 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 800 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 700 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 600 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 500 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 450 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 400 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 300 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 200 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 150 mg. In some embodiments, the amount or dose of the anti-BTLA antibody is less than about 100 mg.

[0048] In some embodiments, the anti-BTLA antibody is administered by one or more routes of administration selected from oral, parenteral, topical, or by inhalation. In some embodiments, parenteral administration comprises intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration. In some embodiments, the anti-BTLA antibody is administered by subcutaneous administration.15ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0049] In some embodiments, two or more doses of the anti-BTLA antibody are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 or more days apart. In some embodiments, two or more doses of the anti-BTLA antibody are administered at least about 7 days apart. In some embodiments, two or more doses of the anti- BTLA antibody are administered at least about 14 days apart. In some embodiments, two or more doses of the anti-BTLA antibody are administered at least about 21 days apart. In some embodiments, two or more doses of the anti-BTLA antibody are administered at least about 30 days apart. In some embodiments, the anti-BTLA antibody is administered at least every week. In some embodiments, the anti-BTLA antibody is administered at least every 2 weeks. In some embodiments, the anti-BTLA antibody is administered at least every 3 weeks. In some embodiments, the anti-BTLA antibody is administered at least every 4 weeks. In some embodiments, the anti-BTLA antibody is administered at least every 5 weeks. In some embodiments, the anti-BTLA antibody is administered at least every 6 weeks.

[0050] In some embodiments, the anti-BTLA antibody is administered for a period of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or more weeks. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or more months. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 4 weeks. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 8 weeks. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 16 weeks. In some embodiments, the anti-BTLA antibody is administered for a period of at least about 20 weeks.

[0051] In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks for a period of at least about 12 weeks. In some16ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks for a period of at least about 12 weeks.BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG. 1A shows relative expression levels of BTLA on different immune cell subsets. FIG. IB shows relative expression levels of HVEM on different immune cell subsets. For FIGs. 1A- 1B, BTLA and HVEM expression levels are expressed as geometric mean fluorescence intensity after subtractions from the isotype control of each donor (n=6 donors). FIG. 1C shows expression level of BTLA on PBMCs including dendritic cell subsets. For FIG. 1C, BTLA expression levels are expressed as geometric mean fluorescence intensity (n = 6 donors). BTLA = B- and T- lymphocyte attenuator; CD = clusters of differentiation; DC = dendritic cell; PBMC = peripheral blood mononuclear cell; cDCl = conventional dendritic cell type 1; cDC2 = conventional dendritic cell type 2; pDC = plasmacytoid dendritic cell; HVEM = herpes virus entry mediator; NK = natural killer.

[0053] FIGs. 2A-2B show binding of anti-BTLA Antibody Clone 1 to normal B cells (FIG. 2A) and CD4+ T cells (FIG. 2B) (n = 2 donors).

[0054] FIGs. 3A-3B show HVEM-Fc binding to BTLA expressing Jurkat cells in the presence of increasing anti-BTLA Antibody Clone 1 (FIG. 3A) or 1151 (FIG. 3B) concentration.

[0055] FIGs. 4A-4D show anti-BTLA Antibody Clone 1 binding and inhibitory effect in T cell reporter assay. FIGs. 4A-4B shows anti-BTLA Antibody Clone 1 binding to human BTLA expressing cells (FIG. 4A) and cyno BTLA expressing cells (FIG. 4B). FIGs. 4C-4D show inhibition by anti-BTLA Antibody Clone 1 in human BTLA expressing cells (FIG. 4C) and cyno BTLA expressing cells (FIG. 4D). Activation, assessed by GFP geomean on the Jurkat reporter cells, is normalized to activation in the absence of test antibody. BTLA = B- and T-lymphocyte attenuator; CD = clusters of differentiation; ECso = half-maximal effective concentration; GFP = Green Fluorescent Protein; ICso = half-maximal inhibitory concentration.

[0056] FIGs. 5A-5F show dose response effect of anti-BTLA Antibody Clone 1 on CD25 expression by anti-CD3 and CD28 antibody stimulated CD4+ T cells. Dose response curves for individual donors are shown in FIGs. 5A-5E, while EC50 values for all donors are plotted in FIG.5F

[0057] FIG. 5G show the impact of anti-BTLA Antibody Clone 1 on anti-CD3 and CD28 antibody stimulated CD4+ T cell proliferation. FIG. 5H shows the impact of CTLA4-Ig on anti- 17ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTCD3 and CD28 antibody stimulated CD4+ T cell proliferation. CTLA4-Ig was used as a positive control. Significance was calculated with paired T test: ***(P<0.001), ****(P<0.0001). (n = 15 donors).

[0058] FIG. 6 shows anti-BTLA Antibody Clone 1 did not impair Treg capacity to release IL- 10. Incubations were performed in the presence of autologous CD 14+ monocytes. 2-way ANOVA multiple comparison was performed (n = 3 donors)

[0059] FIGs. 7A-7C show anti-BTLA Antibody Clone 1 did not induce production of TNF (FIG. 7A), IFNy (FIG. 7B) or IL6 (FIG. 7C) release beyond isotype control in human peripheral blood mononuclear cells, measured using BD™ Cytometric Bead Array (CBA) Human inflammatory cytokine kit. The positive controls are Anti-CD3 / CD28 or SEB.

[0060] FIGs. 8A-8C show effector activity of the anti-BTLA antibody clone 1. FIG. 8A shows treatment with Rituximab, but not anti-BTLA Antibody Clone 1, resulted in death in B cells from three donors (D1-D3). CDC assay (Cell Titer-Gio, Promega) (n = 3 donors). FIG. 8B shows treatment with Rituximab but not anti-BTLA Antibody Clone 1 or the isotype control results in primary B cell death. FIG. 8C shows Rituximab but not anti-BTLA Antibody Clone 1 or an isotype control promote Jurkat ADCC reporter activity through CD16A receptor (Promega CD16A Reporter assay).

[0061] FIGs. 9A-9D show the impact of anti-BTLA Antibody Clone 1 at a single dose in a rapid onset xenoGvHD model in mice. FIG. 9A shows survival curves for irradiated NSG mice injected IV with IxlO7human PBMCs (or PBS only) and treated with 200pg isotype control or anti-BTLA Antibody Clone 1 every other week from day 1. FIG. 9B shows weights of individual mice in each treatment group. FIG. 9C shows quantification of human immune cell infiltration by flow cytometry of different organs day 13 after cell transfer in a separate cohort of mice. Disease induction and treatment were the same as above, but these mice were not included in the survival analysis as they were sacrificed early to enable comparison of immune infiltration. FIG. 9B shows ratio of regulatory T cells to CD8 T cells within the human immune cell infiltration in each organ.

[0062] FIGs. 9E-9H show the impact of anti-BTLA Antibody Clone 1 at different doses in a slower onset XenoGvHD model in mice. Irradiated NSG mice were injected IV with 5xl06human PBMCs (or PBS only) and treated with different doses of isotype control or anti-BTLA Antibody Clone 1 as indicated every week from day 1. On day 21 mice were bled by tail vein venipuncture and levels of human cytokines in serum were quantified by cytometric bead array.18ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0063] FIGs. 9I-9J show the impact of anti -B TLA antibody clone 10 in a T cell driven mouse model of colitis. CD45RBhighCD25-CD4+ naive T-cells were isolated from the spleens of transgenic human BTLA donor mice and 4x105 cells were injected IP into RAGl' / _recipient mice on day 0. Mice were treated every other week from day 7 with 200pg anti-BTLA or mlgGl isotype control. Healthy control groups consisted of mice that received unfractionated donor CD4s (including disease preventing Tregs) or PBS only. FIG. 91 shows treatment with anti-BTLA antibody clone 10 led to significant reduction in weight loss compared to isotype control treated mice. FIG. 9J shows that anti-BTLA treated mice put on weight similarly to healthy controls. FIG. 9K demonstrates the use of colon weight-to-length ratio, which was measured at time of sacrifice, as a marker of whole colon inflammation. This was significantly reduced in anti-BTLA treated mice compared to isotype control treated mice.

[0064] FIGs. 10A-10B show pharmacokinetic (PK) profiles and the fitting of a 2-compartment model to the PK data. FIG. 10A shows anti-BTLA Antibody Clone 1 plasma concentration time profiles. FIG. 10B shows the 2-compartment model fitted to PK data. For FIGs. 10A-10B, the lowest line corresponds to the 3mg / kg IV + 19.6 mg / kg SC group, the 2ndline from the bottom corresponds to the 10 mg / kg IV group, the third line from the bottom corresponds to the 30 mg / kg IV qlw group, and the uppermost line (top line) corresponds to the 100 mg / kg IV qlw group.

[0065] FIG. 10C shows anti-BTLA Antibody Clone 1 exposure (individual animal) on days 1 and 22 following IV dosing at 100 mg / kg on days 1, 8, 15 & 22.

[0066] FIG. 10D shows anti-BTLA Antibody Clone 1 exposure (mean + SD) on days 1 and 85 following SC dosing at 1, 10 & 100 mg / kg / wk for 13 weeks. Animals with accelerated drug clearance secondary to ADA have been excluded.

[0067] FIG. 11 shows the study schema. PD = pharmacodynamic(s); PK = pharmacokinetic(s); Q2W = every 2 weeks; RA = rheumatoid arthritis; SC = subcutaneous; SLE = systemic lupus erythematosus; SRT = Safety Review Team. For the RA cohorts in Part A, 4 additional participants may be randomized into each cohort, with approval, based on review of emerging safety, PK, and PD data. Dosing will occur Q2W from Week 0 (Day 1) through Week 12 (Day 85). The follow-up duration is up to 16 weeks.

[0068] FIG. 12 shows a mean (SD) serum concentration of anti-BTLA Antibody Clone 1 versus time by intravenous (IV) Cohorts: Al to A6 (2.3-200 mg), A9 (400 mg), and A10 (800 mg) (PK Analysis Set).19ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0069] FIG. 13 shows a mean (SD) serum concentration of anti-BTLA Antibody Clone 1 versus time by subcutaneous (SC) Cohorts: A7 (20 mg) and A8 (200 mg) (PK Analysis Set).

[0070] FIG. 14 shows a full view of Trypsin / Lys-C Peptide Map for the heavy chain (SEQ ID NO: 9) and light chain (SEQ ID NO: 10) of anti-BTLA Ab clone 1. TIC stands for total ion current. The peaks are labeled by a peptide alias denoted by L for light chain and H for heavy chain followed by the theoretical peptide umber from cleavage with Trypsin / Lys-C beginning from the protein N-terminus (e.g., Hl). Peaks attributable to the carboxymethyl modification are denoted by an asterisk, -K = Lysine and pE = pyroglutamic acid.

[0071] FIG. 15 shows Peptide Map Coverage for the heavy chain (SEQ ID NO: 9) and light chain (SEQ ID NO: 10) of anti-BTLA Ab clone 1.DETAILED DESCRIPTION

[0072] Described herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0073] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-20ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0074] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0075] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0076] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.21ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0077] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0078] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0079] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0080] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising 22ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTSEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0081] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0082] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0083] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain23ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0084] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0085] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0086] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0087] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising24ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTSEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0088] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0089] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0090] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0091] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.25ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0092] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0093] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0094] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0095] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of ulcerative colitis (UC), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0096] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR326ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0097] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0098] Disclosed herein are uses of an anti-BTLA antibody for the manufacture of a medicament for treatment of graft vs host disease (GVHD), wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 16; and (III) a LCDR3 comprising SEQ ID NO: 6.

[0099] In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subj ect is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and 27ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone.

[0100] In some embodiments, the subject fulfills EULAR / ACR 2019 classification criteria for SLE at least 24 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the subject does not have highly active SLE. In some embodiments, highly active SLE is selected from lupus nephritis, neuropsychiatric SLE, or vasculitis. In some embodiments, the subject is not exposed to cyclophosphamide or any biologic lupus therapy within 8 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from hydroxychloroquine, steroids and corticosteroids, belimumab, azathioprine, methotrexate, cyclophosphamide, mycophenolate and mycophenolate mofetil, cyclosporine, leflunomide, voclosporin, abatacept, anifrolumab, rituximab, NSAIDS, antimalarial drugs, such as hydroxychloroquine, calcineurin inhibitors, and tacrolimus. In some embodiments, the steroid or corticosteroid is prednisone or methylprednisolone. In some embodiments, the NSAID is naproxen sodium or ibuprofen. In some embodiments, the antimalarial drug is selected from hydroxychloroquine, calcineurin inhibitors, and tacrolimus.I. Definitions

[0101] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.28ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0102] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Unless otherwise specified, materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein, based on the guidance provided herein. Where ranges are provided, they are inclusive of the boundary values and individual values within the range. For instance, a range of 1 to 5 is inclusive of the boundary values 1 and 5, as well as the values 2, 3, and 4.

[0103] As used herein, the singular terms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more.”

[0104] As used herein, “about” when used with a numerical value means the numerical value stated as well as plus or minus 10% of the numerical value. For example, “about 10” should be understood as both “10” and “9-11.”

[0105] Also 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”).

[0106] As used herein, a phrase in the form “A / B” or in the form “A and / or B” means (A), (B), or (A and B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0107] The term “antibody,” as used herein, is used in the broadest sense and encompasses various antibody and antibody-like structures that specifically bind to a single antigen or to multiple antigens (e.g., monospecific antibodies, multispecific antibodies, polyepitopic antibodies, etc.), including but not limited to full-length antibodies, antigen-binding fragments, heavy chain antibodies, single-chain antibodies, and higher order variants of single-chain antibodies. Thus, any reference to an antibody should be understood to refer to the antibody in intact form or an antigenbinding fragment unless the context requires otherwise. Preferably, but not necessarily, antibodies useful herein are isolated and can be produced recombinantly. The term “anti-BTLA antibody,” as used herein, refers to an antibody that specifically binds to BTLA.

[0108] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region.29ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0109] “Native antibodies” are naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (each about 25 kDa) and two identical heavy chains (each about 50-70 kDa) that are disulfide bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody’s isotype as IgG, IgM, IgA, IgD and IgE, respectively. The aminoterminal portion of each light and heavy chain includes a variable region of about 100 to 110 or more amino acid sequences primarily responsible for antigen recognition (VL and VH, respectively). The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acid sequences, with the heavy chain also including a “D” region of about 10 more amino acid sequences.

[0110] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain of an antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (CDRs). (See, e.g., Kindt et al., Kuby Immunology, 6thed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).[OHl] “Framework region” or “FR” refers to variable domain residues other than hypervariable region residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The FR domains of a heavy chain and a light chain may differ, as is known in the art.30ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0112] As used herein, the terms “hypervariable region” or “HVR”, also commonly referred to as “complementarity determining region” or “CDR”, are used interchangeably and refer to each of the regions of a variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops”) and / or contain the antigen-contacting residues (“antigen contacts”). Generally, antibodies comprise six CDRs: three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3). As used herein, “a CDR derived from a variable region” refers to a CDR that has no more than two amino acid substitutions, as compared to the corresponding CDR from the original variable region. Exemplary CDRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (LI), 50-52 (L2), 91 -96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987)); (b) CDRs occurring at amino acid residues 24- 34 (LI), 50-56 (L2), 89-97 (L3), 31 -35b (Hl), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); (c) antigen contacts occurring at amino acid residues 27c-36 (LI ), 46-55 (L2), 89-96 (L3), 30-35b (Hl ), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); and (d) combinations of (a), (b), and / or (c), as defined below for various antibodies of this disclosure. Unless otherwise indicated, CDR residues and other residues in the variable domain (e.g., FR residues) are Eu numbered herein according to Kabat et al., supra.

[0113] The term “isolated antibody” refers to an antibody that has been separated from a component of its natural environment. In some embodiments, an isolated antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis or chromatography (e.g., ion exchange or reverse phase HPLC).

[0114] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0115] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non- human antigen-binding residues. Human antibodies can 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. Also available for the preparation of human monoclonal antibodies are methods described in Cole et al. Monoclonal Antibodies and31ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTCancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al. J. Immunol., 147(l):86-95, 1991. See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368-74, 2001.

[0116] A “humanized” antibody refers to an antibody comprising amino acid residues from nonhuman CDRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. In certain aspects in which all or substantially all of the FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues from non-human FR(s), for example at one or more Vernier position residues of FRs, and / or at one or more other chosen residue. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization. A humanized antibody retains similar binding specificity and affinity as the starting non-human antibody.

[0117] The term “monoclonal antibody” refers to an antibody that is derived from a single copy or clone, including e.g., any eukaryotic, prokaryotic, or phage clone. The term “monoclonal antibody” is not limited to antibodies produced through hybridoma technology. Monoclonal antibodies can be produced using hybridoma techniques well known in the art, as well as recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies and other technologies readily known in the art.

[0118] The term “epitope” refers to the particular site on an antigen to which an antibody binds. The particular site on an antigen to which an antibody binds can be determined, for example, by crystallography. Methods such as hydroxyl radical protein footprinting and alanine scanning mutagenesis can also be used but may provide less resolution.

[0119] The term “Fc region” is used herein to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl- terminus thereof. The C-terminal lysine (residue 447 according to the Eu numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.32ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0120] A “functional Fc region” possesses an effector function of a native sequence Fc region. Exemplary effector functions include Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays disclosed herein or otherwise known in the art. A functional Fc region may possess effector function substantially similar to a wild-type IgG, reduced effector function compared to a wild-type IgG, or enhanced effector function compared to a wild-type IgG. For antibodies comprising a human Fc region, the comparison is typically to a wild-type human IgGl.

[0121] As used herein, the term “Fc-enabled antibody” refers to an antibody that has similar or enhanced binding to human FcyR as compared to wild-type (WT) human IgGl and triggers Fc effector functions. Fc effector functions include but are not limited to ADCC, CDC and ADCP.

[0122] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgGl Fc region (non- A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region as well as naturally occurring variants thereof.

[0123] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g., from about one to about ten amino acid modifications, and in some embodiments from about one to about five amino acid modifications), preferably one or more amino acid substitution(s). The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, preferably at least about 90% homology therewith, or preferably at least about 95% homology therewith. In some embodiments, variant Fc regions may possess reduced or enhanced effector function, as compared to a wild-type IgG. For antibodies comprising a human Fc region, the comparison is typically to a wild-type human IgGl.

[0124] “Fc component” as used herein refers to a hinge region, a CH2 domain or a CH3 domain of an Fc region.

[0125] “Hinge region” is generally defined as stretching from about residue 216 to 230 of an IgG (Eu numbering), from about residue 226 to 243 of an IgG (Kabat numbering), or from about residue 1 to 15 of an IgG (IMGT unique numbering).33ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0126] The term “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antigen-binding fragment include, without limitation, a diabody, a Fab, a Fab', a F(ab')2, a F(ab)c, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide stabilized diabody (ds diabody), a triabody, a tetrabody, a singlechain antibody, an scFv, an scFv dimer, a single domain antibody, a single-domain antibody, and a multivalent domain antibody. Typically, binding fragments compete with the intact antibody from which they were derived for specific binding. Binding fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.

[0127] The term “Fab” refers to that portion of an antibody consisting of a single light chain (both variable and constant regions) bound to the variable region and first constant region of a single heavy chain by a disulfide bond.

[0128] The term “Fab'” refers to a Fab fragment that includes a portion of the hinge region.

[0129] The term “F(ab')2” refers to a dimer of Fab'. F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0130] The term “Fv” refers to the smallest fragment of an antibody to bear the complete antigen binding site. An Fv fragment consists of the variable region of a single light chain bound to the variable region of a single heavy chain.

[0131] The term “single-chain antibody” refers to an antibody consisting of a heavy chain variable region and a light chain variable region connected by a linker. In most instances, but not all, the linker may be a peptide. The length of the linker varies depending upon the type of single-chain antibody. Covalently or non-covalently linking two or more single-chain antibodies together results in higher order forms. Single-chain antibodies, and their higher order forms, may include, but are not limited to, single-domain antibodies, multivalent domain antibodies, single chain variant fragments (scFvs), divalent scFvs (di-scFvs), trivalent scFvs (tri-scFvs), tetravalent scFvs (tetra- scFvs), diabodies, and triabodies and tetrabodies.

[0132] The terms “single-chain Fv antibody” and “scFv” are used herein interchangeably to refer to a single-chain antibody consisting of heavy variable region and a light chain variable region connected by a linker. In most instances, but not all, the linker may be a peptide. The linker peptide is preferably from about 5 to 30 amino acids in length, or from about 10 to 25 amino acids in34ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT length. Typically, the linker allows for stabilization of the variable domains without interfering with the proper folding and creation of an active binding site. In preferred embodiments, a linker peptide is rich in glycine, as well as serine or threonine. Covalently or non-covalently linking two or more scFvs together results in higher order forms di-scFvs, tri-scFvs, tetra- scFvs, etc. The antigen-binding sites of each scFv in a higher order form can target the same or different antigen or epitope.

[0133] The term “single-chain Fv-Fc antibody” or “scFv-Fc” refers to a full-length antibody consisting of a scFv connected to an Fc region.

[0134] A “diabody” is a higher order variant of a single-chain antibody consisting of two singlechain antibodies. For each single-chain antibody, a linker is used that is too short to allow pairing between the two domains on the same chain, forcing the domains to pair with the complementary domains of another chain, thereby creating two antigen-binding sites. In most instances, but not all, the linker may be a peptide. The antigen-binding sites can target the same or different antigens or epitopes. Triabodies (three single chain antibodies assembled to form three antigen-binding sites), tetrabodies (four single chain antibodies assembled to form four antigen-binding sites), and higher order variants can similarly be produced. See, for example, Holliger P. et al., Proc Natl Acad Sci USA. July 15; 90(14):6444-8 (1993); EP404097; WO93 / 11161.

[0135] A “single-domain antibody” refers to an antibody fragment containing only the variable region of a heavy chain or the variable region of a light chain. In certain instances, two or more VH domains are covalently joined with a peptide linker to create a multivalent domain antibody. The two or more VH domains of a multivalent domain antibody can target the same or different antigens or epitopes.

[0136] The term “heavy chain antibody” refers to an antibody that consists of two heavy chains. A heavy chain antibody may be an IgG-like antibody from camels, llamas, alpacas, sharks, etc., or an IgNAR from a cartilaginous fish. See, for example, Riechmann L. and Muyldermans S., J Immunol Methods. December 10; 231(1-2): 25-38 (1999); Muyldermans S., J Biotechnol. June; 74(4):277-302 (2001); WO94 / 04678; WO94 / 25591; or U.S. Pat. No. 6,005,079. Heavy chain antibodies were originally derived from Camelidae (camels, dromedaries, and llamas). Although devoid of light chains, camelized antibodies have an authentic antigen-binding repertoire (Hamers-Casterman C. et al., Nature. June 3; 363(6428):446-8 (1993); Nguyen V. K. et al. “Heavy-chain antibodies in Camelidae; a case of evolutionary innovation,” Immunogenetics. April; 54(l):39-47 (2002); Nguyen V. K. et al. Immunology. May; 109(l):93-101 (2003)). The35ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT variable domain of a heavy chain antibody (VHH domain) represents the smallest known antigenbinding unit generated by adaptive immune responses (Koch-Nolte F. et al., FASEBJ. November; 21(13):3490-8. Epub 2007 Jun. 15 (2007)).

[0137] A “nanobody” refers to an antibody that consists of a VHH domain from a heavy chain antibody and two constant domains, CH2 and CH3.

[0138] “Percent (%) identity” with respect to a reference amino acid sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, or CLUSTAL software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Generally speaking, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A.

[0139] As used herein, the phrase “therapeutically effective amount” with reference to an anti- BTLA antibody means a dose regimen (i.e., amount and interval) of the antibody that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. For prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, including biochemical, histological and / or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with a disease, delay disease progression, prolong survival, decrease the dose of other medication(s) required to treat the disease, or a combination thereof.

[0140] The terms “treat,” “treatment,” or “treating” as used herein with reference to autoimmune disease or inflammatory disease refer to a course of action that eliminates, reduces, suppresses,36ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT mitigates, ameliorates, or prevents the worsening of, either temporarily or permanently, a disease, disorder or condition to which the term applies, or at least one of the symptoms associated therewith. Treatment includes alleviation of symptoms, diminishment of extent of disease, inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease, delaying or slowing of disease progression, improving the quality of life, and / or prolonging survival of a subject as compared to expected survival if not receiving treatment or as compared to a published standard of care therapy for a particular disease.

[0141] The term “in need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. For example, “treating an autoimmune disease or inflammatory disease in a subject in need of treatment”, sometimes phrased as “treating an autoimmune disease or inflammatory disease in a subject in need thereof’, refers to treating a subject that a physician or other caregiver has judged requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise, which may include a positive diagnosis of a disease, disorder or condition. In some examples, a physician or other caregiver may determine a subject requires or will benefit from treatment with an anti-BTLA antibody. In these instances, an additional decision is still required for effective treatment, namely which anti-BTLA antibody or group of anti-BTLA antibodies are suitable.

[0142] The terms “prevent”, “preventing”, “prevention”, “prophylaxis” and the like refer to a course of action initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition or a symptom associated therewith in order to prevent relapse of that disease, disorder, condition or symptom.

[0143] The term “in need of prevention” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from preventative care. This judgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise.37ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0144] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and refer to any individual human.II. BTLA and Immune Cells

[0145] BTLA (also called B- and T-lymphocyte attenuator or CD272) is an inhibitory receptor expressed on the surface of immune cells. BTLA consists of a single extracellular immunoglobulin (Ig)-like domain, a transmembrane region and a cytoplasmic tail that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) (Watanabe et al., 2003).

[0146] BTLA is only expressed on specific populations of immune cells, including the majority of B and T cells and some subsets of dendritic cells (Han et al., 2004). Within the T cell compartment, BTLA is expressed more highly on CD4+ cells than on CD8+ cells and, unusually for an immune checkpoint receptor, it is expressed across the spectrum of T cell differentiation with highest expression is observed on naive cells (Fuertes Marraco et al., 2015).III. Anti-BTLA Antibodies

[0147] To date, there are no published clinical data exploring BTLA targeted agonist therapeutics in human autoimmunity. There are two molecules in clinical development, one by Eli Lilly (LY3361237) and the second by AnaptysBio (ANB032). Eli Lilly has completed two phase 1 safety studies of LY3361237 and is currently recruiting for a Phase 2 study of LY3361237 in SLE patients (ClinicalTrials.gov identifier NCT05123586). According to an AnaptysBio press release ANB032 has also completed a Phase 1 safety study under an Australian Clinical Trial Notification in April 2022 (www.anaptysbio.com / pipeline / anb032 / ).

[0148] One monoclonal antibody (JS004 / TAB004) is currently in clinical development and has been evaluated in patients across a range of oncological indications. However, the mechanism of this antibody is different from the mechanism of the agonistic anti-BTLA antibody disclosed herein as JS004 / TAB004 blocks BTLA interacting with HVEM.

[0149] The agonistic anti-BTLA antibodies as described herein, for the purposes of the disclosed methods and pharmaceutical compositions, are antibodies or fragments thereof that bind to human BTLA but do not block the binding of HVEM ligand to BTLA. Exemplary agonistic anti-BTLA antibodies are shown in Table 1. Additional agonistic anti-BTLA antibodies are described in International Publication Nos. PCT / GB2019 / 053569 and PCT / GB2021 / 051452._ Table 1. Anti-BTLA Antibody Sequences _38ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT39ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT40ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT41ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0150] An agonistic anti-BTLA antibody suitable for use in the disclosed methods and pharmaceutical uses may be human, humanized, or chimeric, and it may be a full-length antibody or an antibody fragment. In some embodiments, a therapeutic antibody suitable for use in the disclosed methods and pharmaceutical uses comprises an Fc region. Those antibodies comprising an Fc region may be an IgA, IgG (i.e., IgGl, IgG2, IgG3, and IgG4), IgD, IgE, or IgM antibody or variant thereof, though in all instances the Fc region has reduced binding to one or more FcyRs (e.g., activating FcyRs) as compared to WT IgGl or an inability to bind one or more FcyRs (e.g., activating FcyRs).

[0151] Anti-BTLA antibodies of the present disclosure have an equilibrium dissociation constant (KD) of 10'8M or lower for human BTLA, measured by surface plasmon resonance (SPR) on a Biacore 8K. For example, the anti-BTLA antibodies of the present disclosure may have a KD for BTLA of 10'8M or lower, 10'9M or lower, IO'10M or lower, 10'11M or lower, 10'12M or lower, or 10'13M or lower, measured by SPR. In various embodiments, the anti-BTLA antibodies of the present disclosure have a KD for BTLA in the range of about IxlO'9M to about IxlO'13M, or about IxlO'9M to about IxlO'12M, or about IxlO'10M to about IxlO'13M, or about IxlO'10M to about IxlO'12M, or about IxlO'11M to about IxlO'13M, or about IxlO'10M to about IxlO'11M, or about IxlO'11M to about IxlO'12M. In some embodiments, the anti-BTLA antibodies of the present disclosure have a KD for human BTLA of about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 25 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM or lower. In some embodiments, the anti-BTLA antibodies of the present disclosure have a KD for human BTLA of between about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 1 nM to about 3 nM, about 1 nM to about 2 nM. In some embodiments, the anti-BTLA antibodies of the present disclosure have a KD for human BTLA of about 1.25 x 10'9M.

[0152] In one embodiment, an anti-BTLA antibody of the present disclosure comprises a heavy chain comprising a CDRH1 comprising the amino acid sequence of SYGMS (SEQ ID NO. 1), a42ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTCDRH2 comprising the amino acid sequence of SIRSDGQTYYPDSVKG (SEQ ID NO: 2), a CDRH3 comprising the amino acid sequence of GGYYGSSPYY (SEQ ID NO: 3); and (b) a light chain comprising a CDRL1 comprising the amino acid sequence of KSSQSLLYSSNQKNYLA (SEQ ID NO: 4), a CDRL2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5), and a CDRL3 of QQYYNYLT (SEQ ID NO: 6).

[0153] In another embodiment, an anti-BTLA antibody of the present disclosure comprises a heavy chain comprising a CDRH1 comprising the amino acid sequence of SYGMS (SEQ ID NO. 1), a CDRH2 comprising the amino acid sequence of SIRSEGQTYYPDSVKG (SEQ ID NO: 11), a CDRH3 comprising the amino acid sequence of GGYYGSSPYY (SEQ ID NO: 3); and (b) a light chain comprising a CDRL1 comprising the amino acid sequence of KSSQSLLYSSNQKNYLA (SEQ ID NO: 4), a CDRL2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5), and a CDRL3 of QQYYNYLT (SEQ ID NO: 6).

[0154] In another embodiment, an anti-BTLA antibody of the present disclosure comprises a heavy chain comprising a CDRH1 comprising the amino acid sequence of SYGMS (SEQ ID NO. 1), a CDRH2 comprising the amino acid sequence of SIRSDGNTYYPDSVKG (SEQ ID NO: 15), a CDRH3 comprising the amino acid sequence of GGYYGSSPYY (SEQ ID NO: 3); and (b) a light chain comprising a CDRL1 comprising the amino acid sequence of KSSQSLLYSSNQKNYLA (SEQ ID NO: 4), a CDRL2 comprising the amino acid sequence of WASTRDS (SEQ ID NO: 16), and a CDRL3 of QQYYNYLT (SEQ ID NO: 6).

[0155] In another embodiment, an anti-BTLA antibody of the present disclosure comprises a heavy chain variable (VH) domain comprising the amino acid sequence of EVQLVESGGGLVKPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVASIRSDGQTY YPDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRGGYYGSSPYYWGQGTTVT VSS (SEQ ID NO: 7) and a variable light chain (VL) domain comprising the amino acid sequence of DIVMTQSPLSLPVTPGEPASISCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTR ESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYYNYLTFGGGTKVEIK (SEQ ID NO: 8). These VH and VL domains are humanized variants ofEVKLVESGGGLVKPGGSLKLSCAASGFTLSSYGMSWVRQIPEKRLEWVASIRSDGNTY YPDSVKGRFIISRDNARNILYLQMSSLRSEDTAMYYCTRGGYYGSSPYYWGQGTTLTVS S (SEQ ID NO: 13) andDIVMSQSPSSLPVSVGEKISMTCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWAST43ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTRDSGVPDRFIGSGSGTDFTLTINSVKAEDLAVYYCQQYYNYLTFGAGTKLELK (SEQ ID NO: 14), respectively.

[0156] In another embodiment, an anti-BTLA antibody of the present disclosure comprises a mature gamma heavy chain amino acid sequence of: EVQLVESGGGLVKPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVASIRSDGQTY YPDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRGGYYGSSPYYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGDSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX (SEQ ID NO: 9), wherein the X is absent or K; and the mature kappa light chain amino acid sequence of:DIVMTQSPLSLPVTPGEPASISCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTR ESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYYNYLTFGGGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0157] In some embodiments, an anti-BTLA antibody of the present disclosure is selected from: (i) antibodies with heavy chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 9, (ii) antibodies with light chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 10, (iii) antibodies with a heavy chain variable region comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7, (iv) antibodies with a light chain variable region comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 8, (v) antibodies with a heavy chain variable region comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least44ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 12, (vi) antibodies with CDRs comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequences of SEQ ID Nos: 1 to 6, (vii) antibodies with CDRs comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequences of SEQ ID Nos: 1, 11, and 3 to 6, (viii) a antibodies with CDRs comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequences of SEQ ID Nos: 1, 15, and 3, 4, 16, and 6, (ix) antibodies with heavy chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 23, (x) antibodies with light chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 24, and (xi) combinations thereof. Additional exemplary therapeutic antibodies are described, for example, in International Application Nos. PCT / GB2019 / 053569 and PCT / GB2021 / 051452. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K).

[0158] In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 7.45ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0159] In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 12.

[0160] In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 23.

[0161] In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some46ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the heavy chain of the anti- BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a heavy chain constant region (CH) sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 19.

[0162] In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K).

[0163] In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence comprising SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-47ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 25.

[0164] In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence comprising SEQ ID NO: 21. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full- length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibodies described herein comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 23.

[0165] In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA48ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT antibodies described herein comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0166] In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence comprising SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 14.

[0167] In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence comprising SEQ ID NO: 20. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the heavy chain of the anti- BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the heavy chain of the anti-BTLA antibodies disclosed herein comprises a light chain constant region (CL) sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 20.

[0168] In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, 49ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full- length light chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 10.

[0169] In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence comprising SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full- length light chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibodies described herein comprises a full-length light chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 24.

[0170] Disclosed herein is an anti-BTLA antibody comprising: (I) a heavy chain comprising: (a) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (b) a HCDR2 comprising SEQ ID NO: 2; and (c) a HCDR3 comprising SEQ ID NO: 3; and (II) a light50ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT chain comprising: (a) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (b) a LCDR2 comprising SEQ ID NO: 5; and (c) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full- length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K).In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti- BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a 51ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full- length light chain sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl . In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region.

[0171] Further disclosed herein is an anti-BTLA antibody comprising: (I) a heavy chain comprising: (a) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (b) a HCDR2 comprising SEQ ID NO: 11; and (c) a HCDR3 comprising SEQ ID NO: 3; and (II) a light chain comprising: (a) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (b) a LCDR2 comprising SEQ ID NO: 5; and (c) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is52ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT at least about 99% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 25. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl. In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody 53ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

[0172] Further disclosed herein is an anti-BTLA antibody comprising: (I) a heavy chain comprising: (a) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (b) a HCDR2 comprising SEQ ID NO: 15; and (c) a HCDR3 comprising SEQ ID NO: 3; and (II) a light chain comprising: (a) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (b) a LCDR2 comprising SEQ ID NO: 16; and (c) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the54ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence comprising SEQ ID NO: 20. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG 55ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT heavy chain comprises IgGl. In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

[0173] In another embodiment, an anti-BTLA antibody of the present disclosure comprises a light chain variable domain and heavy chain variable domain of an anti-BTLA antibody disclosed in International Application Nos. PCT / GB2019 / 053569 and PCT / GB2021 / 051452.56ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT

[0174] As stated above, anti-BTLA antibodies of the present disclosure have reduced binding to one or more FcyRs (e.g., activating FcyRs) as compared to WT IgGl or an inability to bind one or more FcyRs (e.g., activating FcyRs). Binding to FcyRs can be directly measured by the methods detailed in Example 8. Alternatively, or in addition, reduced binding to an activating FcyR can be demonstrated by showing an antibody has reduced Fc effector function, such as CDC, ADCC, and / or ADCP compared to WT IgGl .

[0175] In some embodiments, the anti-BTLA antibody used in the disclosed methods and treatments is an IgG, such as an IgGl (e.g., an Fc-modified IgGl) or an IgG4. The four subclasses of IgG — IgGl, IgG2, IgG3, and IgG4 — are highly conserved. The amino acid sequence of the constant regions of these peptides are known in the art, e.g., see Rutishauser, U. et al. (1968) “Amino acid sequence of the Fc region of a human gamma G-immunoglobulin” PNAS 61(4): 1414-1421; Shinoda et al. (1981) “Complete amino acid sequence of the Fc region of a human delta chain” PNAS 78(2):785-789; and Robinson et al. (1980) “Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511)” PNAS 77(8):4909-4913.

[0176] Anti-BTLA antibody clone 1 is an example of an anti-BTLA antibody with a reduced or abolished capacity to bind FcyRs, particularly activating FcyRs like FcyRI, FcyRIIA, and FcyRIIIA. Anti-BTLA antibody clone 1, for example, has an engineered IgGl Fc and reduced binding to one or more FcyRs (e.g., activating FcyRs) as compared to WT IgGl. The Fc domain of anti-BTLA Antibody Clone 1 is mutated at a single amino acid residue which profoundly reduces the affinity of activatory Fey receptors for the Fc domain, blocking their ability to mediate antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).

[0177] Anti-BTLA antibodies suitable for the disclosed methods may be antibodies from which one or several amino acids at the amino or carboxyl terminus of the light and / or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. Substitutions can be made in the constant regions of antibodies of the present disclosure to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004). Exemplary substitutions include a Gin at position 250 and / or a Leu at position 428 (Eu numbering) for increasing the half-life of an antibody.

[0178] In some embodiments, the antibody is a monoclonal antibody. In some embodiments of any of the embodiments disclosed herein, the antibody is chimeric, humanized, or veneered. In57ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0179] Variants of an anti-BTLA antibody disclosed in Section III and suitable therapeutic antibodies may be monoclonal or polyclonal antibodies, though are preferably monoclonal. Such monoclonal antibodies having BTLA-binding and / or agonizing activity can be obtained, for example, by the following procedure: anti-BTLA monoclonal antibodies can be prepared by using as an antigen BTLA or a fragment thereof that is derived from a mammal, such as human, by known methods, and then antibodies having BTLA-binding and / or agonizing activity are selected from the thus obtained anti-BTLA monoclonal antibodies. Specifically, a desired antigen or cells expressing the desired antigen are used as a sensitizing antigen for immunization according to conventional immunization methods. Anti-BTLA monoclonal antibodies can be prepared by fusing the obtained immune cells with known parental cells using conventional cell fusion methods and screening them for monoclonal antibody-producing cells (hybridomas) by conventional screening methods. Animals to be immunized include, for example, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses, and pigs. The antigen can be prepared using the known BTLA gene sequence according to known methods, for example, by methods using baculovirus. Variants of an anti-BTLA antibody disclosed in Section III and suitable therapeutic antibodies may also include intrabodies, peptibodies, nanobodies, single domain antibodies, multi-specific antibodies (e.g., bispecific antibodies, diabodies, triabodies, tetrabodies, tandem di-scFV, tandem tri-scFv), darpins, heavy chain monomers, heavy chain dimers, or single-domain antibodies (i.e., a VHH fragment or a “camelid-like” antibody), any of which may be derived from the sequence and / or binding domain of an anti-BTLA antibody disclosed in Section III.IV. Combinations with a Disclosed Anti-BTLA Antibody

[0180] The present disclosure contemplates the use of agonistic anti-BTLA antibodies with reduced or abolished Fc effector function (e.g., anti-BTLA antibodies of Section III) alone or in combination with one or more additional therapy. Each additional therapy can be a therapeutic agent or another treatment modality. In embodiments comprising one or more additional therapeutic agents, each agent may target a different, but complementary, mechanism of action. The additional therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA or fragments of such macromolecules; or cellular or gene therapies. Non-limiting examples of additional treatment modalities include surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic 58ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT therapy. The use of anti-BTLA antibodies with reduced or abolished Fc effector function in combination with one or more additional therapy may have a synergistic or additive therapeutic or a prophylactic effect on the underlying disease, disorder, or condition. In addition, or alternatively, the combination therapy may allow for a dose reduction of one or more of the therapies, thereby ameliorating, reducing or eliminating adverse effects associated with one or more of the therapies.

[0181] In embodiments comprising one or more additional treatment modality, the agonistic anti- BTLA antibodies with reduced or abolished Fc effector function can be administered before, after or during treatment with the additional treatment modality. In embodiments comprising one or more additional therapeutic agent, the therapeutic agent(s) used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and / or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0182] In some embodiments, the methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease or inflammatory disease in a subject in need thereof further comprise administering one or more of the additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents is selected from a 4- IBB ligand, 4- IBB ligand modulator, 5-HT 2a receptor antagonist, 5- HT 2b receptor antagonist, 5-HT 3 receptor antagonist, 5-HT 4 receptor agonist, 5-HT receptor agonist, 5 -Lipoxygenase inhibitor, Acetaldehyde dehydrogenase inhibitor, Actin antagonist, AD AMTS inhibitor, ADAMTS4 gene inhibitor, Adenosine Al receptor antagonist, Adenosine A2a receptor agonist, Adenosine A3 receptor agonist, Adenosine A3 receptor modulator, Adenosine deaminase stimulator, Adenosylhomocysteinase inhibitor, Adiponectin receptor modulator, ADP ribosyl cyclase- 1 inhibitor, ADP ribosyl cyclase- 1 modulator, ADP ribosylation factor 6 inhibitor, Adrenocorticotrophic hormone ligand, Aggrecan modulator, Aggrecanase-1 inhibitor, Aggrecanase-2 inhibitor, AIMP multi synthetase complex protein 1 stimulator, Albumin antagonist, Albumin modulator, Alk-2 protein kinase inhibitor, Alk-5 protein kinase inhibitor,59ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTAlpha crystallin chain B stimulator, Aminopeptidase N modulator, Amylin receptor agonist, Angiopoietin-related protein-3 stimulator, Angiotensin II AT -2 receptor agonist, Annexin Al inhibitor, Annexin A2 modulator, API transcription factor inhibitor, API transcription factor modulator, Apelin receptor agonist, Apolipoprotein B modulator, APRIL receptor antagonist, APRIL receptor modulator, Aryl hydrocarbon receptor agonist, B and T lymphocyte attenuator stimulator, B-lymphocyte antigen CD 19 inhibitor, B-lymphocyte antigen CD 19 modulator, B- lymphocyte antigen CD20 inhibitor, B-lymphocyte antigen CD20 modulator, B-lymphocyte cell adhesion molecule inhibitor, B-lymphocyte stimulator ligand inhibitor, B-lymphocyte stimulator ligand modulator, Basigin inhibitor, Bcl-2 protein inhibitor, Beta 2 adrenoceptor agonist, Beta amyloid antagonist, Beta-catenin modulator, Bifunctional aminoacyl tRNA synthetase inhibitor, Bone morphogenetic protein-7 ligand, Bone morphogenetic protein-7 ligand modulator, Brain derived neurotrophic factor ligand inhibitor, Branched amino acid aminotransferase 1 inhibitor, Bromodomain containing protein inhibitor, Btk tyrosine kinase inhibitor, C-type lectin domain protein 2D inhibitor, C-type lectin domain protein 4C inhibitor, C-type lectin domain protein 4C modulator, CACNA2D1 calcium channel subunit inhibitor, Cak tyrosine kinase receptor inhibitor, Calcineurin inhibitor, Calcitonin receptor agonist, Calcium channel inhibitor, Calcium channel inhibitor L-type, Calreticulin inhibitor, Cannabinoid CB1 receptor inverse agonist, Cannabinoid CB2 receptor agonist, Cannabinoid receptor agonist, Cannabinoid receptor modulator, Carbonic anhydrase inhibitor, Carbonic anhydrase- VIII stimulator, Caspase inhibitor, Cathepsin K inhibitor, CCR2 chemokine antagonist, CCR3 chemokine modulator, CCR3 gene modulator, CCR5 chemokine antagonist, CCR6 chemokine antagonist, CD 11b agonist, CD 11b antagonist, CD223 agonist, CD226 antigen inhibitor, CD29 modulator, CD3 modulator, CD30 modulator, CD4 modulator, CD40 ligand inhibitor, CD40 ligand receptor antagonist, CD45RC modulator, CD47 antagonist, CD49e modulator, CD70 antigen modulator, CD79b modulator, CD80 antagonist, CD80 modulator, CD86 antagonist, CD86 modulator, CDwl23 modulator, Cell division control 42 homolog inhibitor, Cell surface glycoprotein MUC18 inhibitor, Chaperonin modulator, Chemokine receptor-like 2 modulator, Cholesterol esterase inhibitor, Choline kinase inhibitor, CLIP associating protein 2 inhibitor, CLK2 protein kinase inhibitor, Collagen I agonist, Collagen I antagonist, Collagen II antagonist, Collagen modulator, Collagen VII antagonist, Complement Clq subcomponent inhibitor, Complement C3 inhibitor, Complement C5 factor inhibitor, Complement C5a receptor antagonist, Complement Factor B inhibitor, Complement Factor inhibitor, Complement cascade inhibitor, Complement cascade modulator, Complement factor C2 inhibitor, Complement factor D inhibitor, CXCR3 chemokine antagonist, CXCR4 chemokine modulator, CXCR5 chemokine antagonist, CXCR5 chemokine modulator, cyclic GMP AMP synthase inhibitor, Cyclin-dependent kinase inhibitor 1 inhibitor, Cyclin-dependent 60ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT kinase-2 inhibitor, Cyclin-dependent kinase-4 inhibitor, Cyclin-dependent kinase-5 inhibitor, Cyclin-dependent kinase-6 inhibitor, Cyclin-dependent kinase-7 inhibitor, Cyclin-dependent kinase-9 inhibitor, Cyclooxygenase 1 inhibitor, Cyclooxygenase 2 inhibitor, Cyclooxygenase inhibitor, Cytotoxic T-lymphocyte protein-4 modulator, Cytotoxic T-lymphocyte protein-4 stimulator, Deoxycytidine kinase inhibitor, Deoxyribonuclease I stimulator, Deoxyribonuclease gamma stimulator, Deoxyribonuclease modulator, DHFR inhibitor, Dihydroorotate dehydrogenase inhibitor, Dipeptidyl peptidase I inhibitor, Dipeptidyl peptidase IV inhibitor, DNA binding protein Ikaros inhibitor, DYRK-1 alpha protein kinase inhibitor, Early activation antigen CD69 inhibitor, EBV induce G protein coupled receptor 2 antagonist, Ectonucleotide pyrophosphatase-PDE-2 inhibitor, Elastin stimulator, Endoplasmin inhibitor, Endostatin modulator, Endothelin ET-A receptor antagonist, Endothelin ET-B receptor antagonist, Enolase 1 inhibitor, Eotaxin 2 ligand inhibitor, EP4 prostanoid receptor antagonist, Ephb2 tyrosine kinase receptor inhibitor, Ephrin B2 ligand inhibitor, Epidermal growth factor ligand inhibitor, Epidermal growth factor ligand modulator, Erbb3 tyrosine kinase receptor modulator, Erythropoietin receptor agonist, Exportin 1 inhibitor, Extracellular matrix protein modulator, Extracellular matrix protein stimulator, Factor Xlla antagonist, FGF receptor antagonist, FGF-18 ligand, FGF-2 ligand inhibitor, FGF 18 gene stimulator, FK506 binding protein inhibitor, FMLP related receptor I agonist, FMLP related receptor II agonist, Folate receptor antagonist, Folate receptor modulator, G protein coupled receptor 15 antagonist, GABA receptor agonist, Gap junction alpha- 1 protein inhibitor, Glucagon-like peptide 1 receptor agonist, Glucocorticoid receptor agonist, Glucocorticoid receptor modulator, GM-CSF ligand inhibitor, GM-CSF receptor modulator, GMP synthetase inhibitor, GroEL protein 2 inhibitor, Growth differentiation factor-5 modulator, Growth hormone receptor agonist, Growth hormone receptor antagonist, Guanylate cyclase receptor agonist, Guanylate cyclase stimulator, H+ K+ ATPase inhibitor, Heat shock protein gene stimulator, Histamine H4 receptor antagonist, Histone deacetylase inhibitor, Histone deacetylase- 6 inhibitor, Histone H2A modulator, Histone H4 modulator, HLA antigen modulator, HLA class II antigen DR-1 beta inhibitor, HLA class II antigen inhibitor, HLA class II antigen modulator, Hyaluronic acid receptor agonist, Hyaluronic acid receptor antagonist, Hyaluronic acid receptor modulator, Hyaluronidase stimulator, Hypoxia inducible factor stimulator, Lkappa B kinase beta inhibitor, Lkappa B kinase epsilon inhibitor, IFNB gene stimulator, IgG receptor FcRn large subunit p51 antagonist, IgG receptor FcRn large subunit p51 modulator, Ikaros family zinc finger protein inhibitor, IL-1 receptor accessory protein inhibitor, IL-1 receptor antagonist, IL-10 receptor agonist, IL-10 receptor antagonist, IL-12 receptor antagonist, IL-13 receptor modulator, IL- 17 antagonist, IL- 18 antagonist, IL- 18 receptor accessory protein antagonist, IL-2 receptor agonist, IL-2 receptor alpha subunit inhibitor, IL-2 receptor antagonist, IL-2 receptor modulator, 61ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTIL-23 antagonist, IL-3 receptor antagonist, IL-3 receptor modulator, IL-4 receptor modulator, IL- 6 receptor agonist, IL-6 receptor antagonist, IL-6 receptor modulator, IL-7 receptor modulator, IL1RA gene modulator, Immunoglobulin G agonist, Immunoglobulin G binding protein A modulator, Immunoglobulin G1 agonist, Immunoglobulin G1 modulator, Immunoglobulin agonist, Immunoglobulin antagonist, Immunoglobulin gamma Fc receptor II modulator, Immunoglobulin gamma Fc receptor IIB agonist, Immunoglobulin gamma Fc receptor IIB modulator, Immunoglobulin gamma Fc receptor antagonist, Immunoglobulin modulator, Indoleamine-pyrrole-2,3-dioxygenase stimulator, Inducible T-cell co-stimulator inhibitor, Inducible nitric oxide synthase inhibitor, Inosine monophosphate dehydrogenase inhibitor, Insulin-like growth factor 1 receptor antagonist, Insulin-like growth factor 1 receptor modulator, Integrin alpha-4 / beta-l antagonist, Integrin alpha-V / beta-3 antagonist, Interferon alpha 1 ligand inhibitor, Interferon alpha 2 ligand, Interferon alpha ligand, Interferon alpha ligand inhibitor, Interferon alpha ligand modulator, Interferon beta ligand inhibitor, Interferon gamma ligand, Interferon gamma ligand inhibitor, Interferon type I receptor antagonist, Interleukin 1 delta ligand inhibitor, Interleukin 1 like receptor 2 inhibitor, Interleukin 17 ligand inhibitor, Interleukin 17A ligand inhibitor, Interleukin 17A ligand modulator, Interleukin 17F ligand inhibitor, Interleukin 17F ligand modulator, Interleukin 18 ligand inhibitor, Interleukin 23A inhibitor, Interleukin 33 ligand inhibitor, Interleukin ligand, Interleukin receptor 17A antagonist, Interleukin-1 alpha ligand inhibitor, Interleukin- 1 beta ligand inhibitor, Interleukin- 1 beta ligand modulator, Interleukin- 1 receptor antagonist inhibitor, Interleukin- 10 ligand, Interleukin-2 ligand, Interleukin-31 receptor modulator, Interleukin-6 ligand inhibitor, IRAK-1 protein kinase inhibitor, IRAK-4 protein kinase inhibitor, Itk tyrosine kinase inhibitor, JAK tyrosine kinase inhibitor, Jakl tyrosine kinase inhibitor, Jak2 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, Jun N terminal kinase inhibitor, KCNA voltage-gated potassium channel-3 inhibitor, KDM6B gene inhibitor, Kelch like ECH associated protein 1 modulator, Kit tyrosine kinase inhibitor, LanC like protein 2 stimulator, LDL receptor related protein- 1 stimulator, Lectin mannose binding protein inhibitor, Leukocyte Ig like receptor A4 modulator, Leukotriene D4 antagonist, Lipoxygenase inhibitor, LOXL2 gene inhibitor, Lysophosphatidate-1 receptor antagonist, Lysophospholipase inhibitor, Macrophage mannose receptor 1 modulator, Macrophage migration inhibitory factor inhibitor, Macrophage migration inhibitory factor modulator, MALT protein 1 inhibitor, Mannan- binding lectin serine protease-2 inhibitor, MAPKAPK2 inhibitor, Matrix extracell phosphoglycoprotein modulator, Matrix metalloprotease inhibitor, MCL1 gene inhibitor, MEKK- 5 protein kinase inhibitor, Melanocortin MCI receptor agonist, Melanocortin MC3 receptor agonist, Melanocortin receptor agonist, Membrane copper amine oxidase inhibitor, Metalloprotease-2 inhibitor, Metalloprotease-3 inhibitor, Metalloprotease-9 inhibitor, 62ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTMetalloproteinase inhibitor- 1 inhibitor, Metalloproteinase inhibitor-2 inhibitor, Mineralocorticoid receptor antagonist, Mitochondrial 10 kDa heat shock protein stimulator, MKL myocardin like protein inhibitor, MMP1 gene stimulator, Monocarboxylate transporter inhibitor, Motile sperm domain protein 2 inhibitor, mTOR inhibitor, Mucin stimulator, NACHT LRR PYD domain protein 3 inhibitor, Nek-7 protein kinase inhibitor, Nerve growth factor ligand inhibitor, Neuropilin 2 modulator, Neurotrophin-3 ligand inhibitor, Neurotrophin-4 ligand inhibitor, NGF receptor antagonist, NGF receptor modulator, Nicotinic acetylcholine receptor antagonist, NK1 receptor modulator, NKX3.2 gene stimulator, NMDA receptor modulator, Non receptor tyrosine kinase TYK2 antagonist, Nuclear erythroid 2-related factor 2 modulator, Nuclear erythroid 2- related factor 2 stimulator, Nuclear factor kappa B inducing kinase inhibitor, Nuclear factor kappa B inhibitor, Nuclear factor kappa B modulator, Nuclear pore complex protein modulator, Nuclease stimulator, Opioid receptor delta antagonist, Opioid receptor mu agonist, Osteoclast differentiation factor antagonist, Osteoclast differentiation factor ligand inhibitor, OX-40 receptor antagonist, 0X40 ligand modulator, Oxidoreductase inhibitor, P-selectin glycoprotein ligand- 1, P2X7 purinoceptor antagonist, p38 MAP kinase alpha inhibitor, p38 MAP kinase inhibitor, p53 tumor suppressor protein stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 4b inhibitor, PDE 5 inhibitor, PDGF receptor antagonist, PGE1 agonist, PGI2 agonist, Phosphoinositide-3 kinase delta inhibitor, Phospholipase A2 inhibitor, Phospholipase C inhibitor, Phospholipase D4 inhibitor, PIM-1 protein kinase inhibitor, PIM-1 protein kinase modulator, PIM-2 protein kinase inhibitor, PIM-3 protein kinase inhibitor, Plasminogen activator inhibitor 1 inhibitor, Plexin domain containing protein stimulator, PPAR gamma agonist, Programmed cell death protein 1 modulator, Programmed cell death protein 1 stimulator, Prostaglandin E synthase inhibitor, Prostaglandin E synthase- 1 inhibitor, Protease-activated receptor-2 antagonist, Proteasome beta-8 subunit modulator, Proteasome inhibitor, Protein arginine deiminase II inhibitor, Protein arginine deiminase IV inhibitor, Protein cereblon modulator, Protein kinase C theta inhibitor, Protein kinase inhibitor, Protein MB21D1 modulator, Protein NOV homolog modulator, Protein tyrosine kinase inhibitor, Protein tyrosine phosphatase-2C inhibitor, Proteoglycan 4 inhibitor, Proteoglycan 4 modulator, Proteoglycan 4 stimulator, Proteoglycan stimulator, Proto oncogene vav inhibitor, PurH purine biosynthesis protein inhibitor, RAC1 GTPase inhibitor, Retinoid X receptor agonist, Retinoid Z receptor gamma antagonist, Retinoid Z receptor gamma inverse agonist, Rev protein modulator, Rho associated protein kinase 1 inhibitor, Rho associated protein kinase 2 inhibitor, Rhomboid family member 2 inhibitor, RIP-1 kinase inhibitor, RUNX1 gene stimulator, SI 00 calcium binding protein A4 inhibitor, SCN10A sodium channel subunit inhibitor, SCN9A gene inhibitor, SCN9A sodium channel subunit inhibitor, Secretory phospholipase A2 receptor antagonist, Sepiapterin reductase inhibitor, Seprase inhibitor, Serine threonine protein 63ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT kinase TBK1 inhibitor, Serine threonine protein kinase TBK1 modulator, Serum amyloid A protein modulator, Signal transducer CD24 modulator, SIRT3 gene stimulator, SL cytokine ligand modulator, SMAD inhibitor, SMAD-2 stimulator, SMAD-3 stimulator, Small inducible cytokine A17 ligand inhibitor, SNAI1 transcription factor inhibitor, Somatostatin 4 receptor agonist, SOX gene stimulator, Sphingosine kinase 1 inhibitor, Sphingosine kinase 2 inhibitor, Sphingosine- 1- phosphate receptor-1 agonist, Sphingosine- 1 -phosphate receptor-1 modulator, Sphingosine- 1- phosphate receptor-5 modulator, Sphingosylphosphorylcholine receptor antagonist, Src tyrosine kinase inhibitor, STAT inhibitor, STAT-1 modulator, STAT-3 inhibitor, Stimulator of interferon genes protein inhibitor, Syk tyrosine kinase inhibitor, Synuclein alpha inhibitor, T cell receptor antagonist, T cell receptor modulator, T cell surface glycoprotein CD28 inhibitor, T-cell antigen CD7 modulator, T-cell differentiation antigen CD6 inhibitor, T-cell surface glycoprotein CD8 inhibitor, T-cell transcription factor NF AT modulator, TAK1 binding protein modulator, Talin modulator, TAT protein inhibitor, Tau aggregation inhibitor, Tec tyrosine kinase inhibitor, Telomerase stimulator, TGF alpha ligand inhibitor, TGF beta 1 ligand inhibitor, TGF beta 1 ligand modulator, TGF beta 3 ligand inhibitor, TGF beta 3 ligand modulator, TGF beta ligand inhibitor, TGF beta receptor agonist, TGF beta receptor antagonist, TGF-beta activated kinase-1 inhibitor, TGF -beta type II receptor antagonist, TGF-beta type III receptor antagonist, TGFB1 gene stimulator, Thromboxane A2 antagonist, Thromboxane synthetase inhibitor, Thymic stromal lymphopoietin ligand modulator, Thymic stromal lymphopoietin receptor modulator, TLR-4 antagonist, TLR-7 antagonist, TLR-7 modulator, TLR-8 antagonist, TLR-8 modulator, TLR-9 antagonist, TLR-9 modulator, TNF agonist, TNF alpha ligand inhibitor, TNF alpha ligand modulator, TNF antagonist, TNF binding agent, TNF gene modulator, TNF related apoptosis inducing ligand, TRAIL receptor agonist, Transcription factor modulator, Transcription factor p65 modulator, Transcription factor stimulator, Transferase stimulator, Transferrin modulator, Transmembrane 4 L6 family member 19 inhibitor, Transthyretin modulator, TRBV9 gene modulator, TREM receptor 1 antagonist, TrkA receptor antagonist, TRP cation channel Al inhibitor, TRP cation channel Cl inhibitor, TRP cation channel VI antagonist, TRP cation channel VI stimulator, TRP cation channel V4 stimulator, TRPV1 gene inhibitor, Tubulin polymerization protein inhibitor, Tumor necrosis factor 13B receptor modulator, Tumor necrosis factor 13C receptor antagonist, Tumor necrosis factor 13C receptor modulator, Tumor necrosis factor ligand 13 inhibitor, Tumor necrosis factor ligand inhibitor, Tyk2 tyrosine kinase inhibitor, Tyk2 tyrosine kinase modulator, Type I IL-1 receptor antagonist, Type I TNF receptor antagonist, Type II TNF receptor antagonist, Type II TNF receptor modulator, Ubiquitin ligase modulator, Vascular cell adhesion protein 1 antagonist, VEGF receptor modulator, Vimentin inhibitor, Wnt 1 ligand64ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT modulator, XPO1 gene modulator, Zap70 tyrosine kinase inhibitor, and zinc finger binding proteinAiolos inhibitor. In some embodiments

[0183] In some embodiments, the methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease or inflammatory disease in a subject in need thereof further comprise administering one or more of the additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents includes one or more of 608, 1,5-bisphenylpyrazole derivative, 19-CP-02, 2ccPA, 4P-022, 99mTc-maraciclatide, A-1619758, A-319, abatacept, ABBV-3373, Ab-IPL-IL-17, ABIS-45RC, AC-003, AC-0058, AC-201, acazicolcept, ACE-1334, aceclofenac, acloproxalap, actarit, adalimumab, adalimumab fosimdesonide, ADB-101, ADB-102, ademetionine, ADI-001, adipose tissue-derived autologous stem cell therapy, ADX-097, afimetoran, AJ-303, AK-101, AK-1830, AKL-4, aldesleukin, ALD-R491, ALLO-329, Allocetra, allogeneic CAR-iNK cell therapy, allogeneic umbilical cord derived mesenchymal stem cell therapy, allogeneic umbilical cord mesenchymal stem cells, Sclnow Biotechnology, allogenic mesenchymal stromal cell therapy, AlloJoin, AlloNK, AlloRx, alloSTEM-OA, ALMB-0166, Alnitak program, ALTB-168, AM- 1476, AM-411, AMG-329, Amilo-5MER, AMT-101, AMTX-100, AMTX-100 CF, anakinra, anandamide, ANB-101, anbalcabtagene autoleucel, aneratrigine, anifrolumab, annexin V-128, annexuzlimab, anti-CD19 CAR T cell therapy, anti-CD19 CAR-NK-cell therapy, anti-CD40 antibody-glucocorticoid conjugate, anti-CD7 CAR T-cell therapy, anti-fibroblast-activation protein (FAP) antibody radiotracers, anti-IL-lR7 canonical antibody, anti-PAD2 / anti-PAD4 bispecific humanized mAb, anti-TNF alpha antibody-glucocorticoid conjugate, Anti-VEGFR therapeutic, ANX-009, APB-R3, APC-201, apremilast, APT-101, AR-100DP1, ARG 00, ARF6 inhibitors, ARG-201, ARG-301, ARN-4079, arsenic tri oxi de, artenimol, ARTS-011, asengeprast, ASP-1617, AT-003, AT- 1001, ATA-3219, atacicept, ATB-1606, ATGC-200, ATGC-700, ATH- XX (Gene A), ATH-XX (Gene X), ATX-006, AUR-200, autologous adipose tissue-derived mesenchymal stem cells, autologous adipose-derived mesenchymal stem cells, autoSTEM-OA, avacopan, avenciguat, AVID-200, AVM-0703, AX-202, AXR-2102, AZD-1163, AZD-6912, baicalin + catechin, baricitinib, BAY- 1830839, bazlitoran, BCD- 180, BCMA-CD19 cCAR, begelomab, belantamab, belatacept, belimumab, belumosudil, bermekimab, bersiporocin dihydrochloride, betamethasone, BGS-1949, BG-T19, BG-2102, BHV-1300, BI-655064, Bifunctional complement inhibitor, BUB-068, bimekizumab, biosimilar monoclonal antibodies, BITT-CD4D11, BITT-CD4F10, BLI-1007, BLR-200, BLX-0631, BMS-986142, BMS-986325, BMS-986326, bone-marrow derived allogenic ischemia-tolerant MSCs, BOS-161721, bosentan, bovhyaluronidase azoximer, branched-chained aminotransferase- 1 inhibitors, branebrutinib,65ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT brensocatib, brentuximab vedotin, brepocitinib, briquilimab, BRL-301, BRM-521, brodalumab, budoprutug, buloxibutid, burfiralimab, BX-U001, BZ-068, CA-702, CABA-201, camoteskimab, CAN- 10, canakinumab, cannabidiol + tetrahydrocannabinol, cannabinoid, cannabinoid / celecoxib conjugate, capsaicin, CAR Treg-cell therapy, CartiLife-Allo, Cartistem, CB-010, CB2 receptor agonists, CB5138-3, CC-97540, C-CAR168, CCRL2 modulators, CD19-CAR-DNT, CD24-IgFc, CD4+CD1271o / -CD25+ polyclonal regulatory T cells, CEL-4000, celecoxib, celecoxib + tramadol hydrochloride, cell-free stem cell-derived extract formulation, Cellistem-OA, cenerimod, certolizumab pegol, CG-652, Chondrocell-Ex, chromene COX-2 inhibitors, ciclosporin, CIGB-258, CIT-013, CJRB-901, CKD-506, CLN-978, clodronic acid, CM-101, CNTX-6970, CNTY-101, colchicine, corticotropin, COYA-203, COYA-204, CPL-302415, CPL- 409116, CRB-0017, crovalimab, CS-12192, CS-20AT04, CT-02, CT-05, CT-15300, CT-732, CTI-156, CT-P17, CTX-112, cudetaxestat sodium, CUG-252, Cutaquig, CX-011, CX-1440, CXCR5 targeting antibody, CYP-004, Cyt-108, D4-107-01, DA-5202, dapirolizumab pegol, daratumumab, daxdilimab, dazodalibep, dazukibart, DB-2304, deflazacort, delgocitinib, DEN- 181, denosumab, dersimelagon, Descartes-08, deucravacitinib, dexamethasone, DFV-890, diacerein, diclofenac, diclofenac etalhyaluronate sodium, diclofenac sodium, dimethyl fumarate, divozilimab, DKM-412, DKM-420, DL-0309, DMXD-011, DNX-114, DNX-314, domase alfa, DS-7011, dual anti-CD19 / anti-BAFF CAR T-cell therapy, CD19-BCMA CAR-T, dual inhibitors of sphingosine kinase 1 and 2 (SPHK1 / 2) University, dual JAK3 / TEC inhibitor, duloxetine, DWP- 213388, DZ-2002, E1K, E-6742, ECC-0509, eculizumab, edecesertib, edralbrutinib, efgartigimod alfa, efzofitimod, EG-501, elapegademase, Elixcyte, elsubrutinib, emapalumab, emiplacel, empasiprubart, EN-2000, enekinragene inzadenovec, enpatoran, enteric-coated mycophenolate sodium, EOM-613, EP-9001A, eptotermin alfa, EQ-121, ER-000145, esflurbiprofen patch, ESK- 001, ET-901, etanercept, EtanerRel, etodolac, etoricoxib, etrinabdione, EV- 104b, EVT-401, ExoFlo, EYD-001, FB-704A, FBL-MTX, FCR-001, FCX-013, felzartamab, fenebrutinib, fepixnebart, filgotinib maleate, fipaxalparant, FKC-288, fluticasone propionate, FNS-007, forigerimod, fostamatinib disodium, frexalimab, froniglutide, FRTX-02, FT-819, FTC-001, FZ- 007, FZJ-003, G-001, GABA + antigen based therapy, gabapentin, GB-5313, GB-910, GB-930, GC-012, gefurulimab, Gensci-048, GF9-LPC loaded TREM-1 receptor inhibitor, GFH-312, GL- 7190, GLPG-3667, GNR-086, GNR-087, GNSC-001, golimumab, GPR15 antagonists, GQ-501, GR-1501, GR-1603, grapiprant, grapiprant (iv), GRI-0803, GS-0151, GS-6791, GSK-2618960, GSK-2646264, GSK-2982772, GSK-3117391, GSK-3858279, GSK-4347859, GT-TNF alpha- mAb 004, gumokimab, gusacitinib, guselkumab, GXCPC-1, H-018, HB00-17, HB-0034, HB- 0043, HB-1734, HE-009, HHT-109, Hizentra, HLA-DR1 / DR4 inhibitors, HLA-open conformerspecific monoclonal antibody, HMBD-011, HP-1901, HRF-2105, HRS-5965, HS-101, HS-10374, 66ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTHSK-39297, HuL-001, human adipose-derived mesenchymal stem cells, human-derived sertoli cell therapy, HWH-486, HY-021068, HY-071221, hyaluronate sodium, hyaluronic acid, hydroxychloroquine, IA-14069, ianalumab, iberdomide, IBI-355, IBIO-lOO, IBL-101, ibuprofenamine hydrochloride, icanbelimod, ICM-203, ICM-203-O, ICP-332, ICP-488, ICP-490, IDO-8, ifetroban, IFNalpha kinoide, IFN-ELP fusion protein, iguratimod, IHL-675A, IK-01, IL- 17 NanoAb, IL-2 fusion protein, IL-6 inhibitors, ILB-2107, iloprost, IMB-1001, IMB-1003, IMB- 1004, IMB-101, IMG-004, imidazole salicylate, immune globulin intravenous, Imotope, IMP- 761, implantable allogeneic chondrocyte cell therapy, IMPT-514, imrecoxib, imvotamab, IMVT- 1402, inaticabtagene autoleucel, INCB-054707, inebilizumab, infliximab, interferon gamma follow-on biologic, interferon-alpha, interleukin-2 follow-on biologic, INV-103, IPG-1094, IPG- 11406, iPSCs derived cell therapy, iptacopan, IQ-004, IRL-201805, IRX-4204, iscalimab, ISD- 017, itacitinib, itolizumab, ivarmacitinib sulfate, IVL-4001, IxCell hUC-MSC-O, ixekizumab, izokibep, izumerogant, JAK2 inhibitors, jaktinib dihydrochloride monohydrate, JBL 1044, JH- 013, JK-0003, JMJD3 siRNA, JMKX-000189, JMT-601, JNJ-2113, JNJ-67484703, JNJ- 78934804, JTA-004, JTE-051, JTE-451, JYP-0061, K-l l, Ka Shu Ning, KBP-336, KD-6005, KEM-2102, KEM-2104, ketoprofen + omeprazole, KF-0210, KF-041, KH-656, KIO-101, KK- 4277, KL-130008, KN-5501, KP-104, KPG-818, KPI-012, KPL-404, KT-294, KT-474, KYS- 202002A, KYV-101, KYV-201, L-608, LABP-69, LAT-8881, LB-600, LB-P8, LBSA-0103, LD- 2020, leflunomide, lenabasum, leramistat, LEVL04, levilimab, LG-00034053, LG-283, LH-021, LipoCartigen, liraglutide, lisaftoclax, litifilimab, LLDT-8, LMY-920, LNA-043, LNK-01001, LNK-01004, LNP-1955, LOFC-00501, lorecivivint, low dose human recombinant interleukin-2, LP-168, LR-19024, LR-19025, LR-21004, LrS-235, LRX-712, LS-301, lumiracoxib, lumrotatug, LW-104, LY-3556050, LY-3857210, LY-3871801, lysophospholipase inhibitor, M-002, MaaT- 033, macitentan, MB-CART19.1, MBQ-167, MDI-2517, MEDI-0618, MEDL7352, meloxicam, mesenchymoangioblast-derived mesenchymal stem cell therapy , methotrexate, methylprednisolone, methylprednisolone hemi succinate, MGY-1838, MH-004, MHS-552, MHV- 370, MIC-Lx, MIL-62, misoprostol + diclofenac, MIV-711, mizoribine, MM-II, momelotinib, mometasone, mosunetuzumab, MP-2021, MPO-0144, mRNA encoding runt-related transcription factor-1, MRT-6160, MT-5562, MT-SYK-03, MTX-474, mufemilast, MY-004, mycophenolate mofetil, MYJ-1633, MYMD-1, N-65 lacritin, nabum etone, NAP- 1051, naproxen + esomeprazole, naproxen + esomeprazole strontium, narsoplimab, NCP-111, NCP-112, NCR-100, nemolizumab, NEO-TRA1, netakimab, NGRM-001, NIM-1324, NIP-046, NIP-322, nipocalimab, nitroglycerin, NKX-019, noscapine / noscapine analogs, NS-403, NT-0004, NT-0007, NT-0008, NTM-006, NTR-441, NTX-748, NX-5948, NYX-2925, OA-201, OA-SYS, OB-756, obecabtagene autoleucel, obefazimod, obexelimab, obinutuzumab, ocadusertib, ocaratuzumab, Octagam 10%, 67ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTOD-07656, olinciguat, olokizumab, OLP-1002, OM-OOl, OM-89, ON-104, opinercept, OpSCF, Oral IL- 17 receptor antagonist, ORBCEL-C, orelabrutinib, ORKA-002, Orthokine, Orynotide rhesus theta defensin-1, otenaproxesul, otilimab, oxaprozin, ozoralizumab, pafolacianine, Panzyga, pari diprubart, parsaclisib, PB (OA)-5010, PDX-02, PDX-06, peficitinib, pegylated antianji peptide, pelubiprofen, pentosan poly sulfate sodium, peptide therapy, peresolimab, PF- 06687234, PF-06835375, PG-201, PG-OA-IOCN, PH-00011, PHDC-02, PHP-1212, piclidenoson, pirfenidone, piroxicam, PIT-565, PK-101, PK101-002, PKC theta inhibitors, plexaris, plonmarlimab, polmacoxib, povetacicept, PPS, PPV-06, prednisone, Procell, Prosorba, Protego-PD, protein arginine deiminase IV inhibitor, protein kinase C-theta inhibitors, protein kinase inhibitors, PRV-3279, PSC-01, psilocybin, PT-101, PUR-0110, QRX-008, QUC-398, QX- 002-N, QX-006-N, QY-201, R-2487, R-851, rabeximod, rapcabtagene autoleucel, ravulizumab, RAY-121, RBM-010, RC-0165, rebamipide mofetil, recombinant human interleukin-1 receptor antagonist, recombinant human interleukin-2, recombinant human lubricin, recombinant human plasma gelsolin, redasemtide, regenerative cartilage therapy, ReJoin, relmacabtagene autoleucel, remibrutinib, renzapride, resiniferatoxin, resomelagon acetate, RG-6315, RgnA-09, RHE-70202, RHH-646, riociguat, risankizumab, ritlecitinib, rituximab, RMD-1101, RO-7507062, roconkibart, rofecoxib, rosnilimab, RP-3128, RP-901, RPH-104, RPI-78, RSLV-132, ruxolitinib, RYSW-01, S-151128, S1P1 receptor modulator, SAB-03, SAL-0119, salsalate, SAR-441566, sarilumab, SB- 061, SBI-3150, SBT-77-7101, SC-291, SCT-650-C, SDC-1801, secukinumab, selective JAKs inhibitor, selective MCT inhibitor, seletalisib, seliciclib, SER-101, SFX-01, SG-301, SHR-1654, SHR-2001, SHR-2173, si-544, SIG-001, SIG-002, SIM-0278, Sinbaro, SINE compounds, SIT- 047, sitaxentan, sitocabnagene loxiveluecel, SK-01, SK-1306X, SKCPT, SKLO-703, SM-06, SM-934, SMUP-IA-01, SN-1011, SNC-103, Sodium Hyaluronate, sodium thiosulfate, sofnobrutinib, Sofusa anti-TNF, SOL-116, sonelokimab, soquelitinib, sovleplenib, SP-16, SP5- M001, SP5M-002, sprifermin, SR-047, SR-878, SSS-07, STAT3 inhibitor, StemCART, Stemchymal, Stempeucel, STK-009 + SYNCAR-001, StroMel, suciraslimab, SuperMApo, Suplasyn, SYHX-1901, SYN-321, tacrolimus, tadekinig-alfa, tagraxofusp, TAS-5315, TBK1 exosite inhibitor, TCK-276, TDM-SLE01, technetium Tc 99m tilmanocept, technetium [99Tc] methylenediphosphonate, telazorlimab, telitacicept, TELOMIR-1, tenoxicam, teprotumumab, terguride, tibulizumab, tildrakizumab, timolumab, tipelukast, TISA-633, tivanisiran, TLC-599, TLL-018, TLY-012, TNF-2, TNX-1500, tocilizumab, tofacitinib, tofacitinib citrate, tofacitinib citrate extended-release tablet, TollB-001, tonogenchoncel-L, TOP-N44, TOP-N53, TPX-100, TQB-3702, TQH-3821, TQH-3910, trans-capsaicin, TRE-515, treprostinil, treprostinil diolamine, TreXTAM, triamcinolone acetonide, Trichomylin, Trichuris suis ova, TTAX-03, tulinercept, TXB-0063, TXR-711, UA-008, UA-021, UBG-T19, UBP-1213, UI-055, UI-056, umbilical cord 68ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT blood-derived stem cell therapy, umbilical cord-derived mesenchymal stem cells, UMC119-06, UMC1 19-06-05, umedaptanib pegol, upadacitinib, upadacitinib + elsubrutinib, ustekinumab, UTAA-09, valziflocept, vamorolone, VB-601, VC-005, VDJ-010, VDJ-142, VDJ-206, VEGFR targeted DK4 / 10, vemircopan, VENT-03, verdinexor, vilamakitug, vipoglanstat hydrogensulfate, vobarilizumab, voclosporin, vorbipiprant sodium, VRN-04, VTX-2735, VTX-958, vunakizumab, VX-150, VYN-202, WD-890, WF-10, WGc-043, Wharton jelly derived mesenchymal stem cells, Wnt pathway modulating antibody, WXFL-10203614, WXSH-0150, XG-004, XIN-5404, XIN- 5494, Xinbang Mesenchymal Stem Cell Injection, XSTEM-OA, XT-150, YC-002, YY-1201, YY- 3411, YY-3970, zanubrutinib, zasocitinib, ZB-002, zetomipzomib, zevaquenabant, ZGHUMSC- 001, zibotentan, zilucoplan, zirconium zr 89 crefmirlimab berdoxam, ZL-82, ZM-008, zoledronate disodium, zoledronic acid, zuberitamab, zucapsaicin, ZXBT-1158, ZYBK-2 and / or bi-specific antibodies targeting one or more targets referenced herein.

[0184] In some embodiments, the methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof further comprise administering one or more of the additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents is selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone.

[0185] In some embodiments, an anti-BTLA antibody of the disclosure, or a fragment thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of rheumatoid arthritis. Non-limiting examples of such agents include disease-modifying antirheumatic drugs (DMARDS), such as hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; TNF inhibitors (e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol), T cell69ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT costimulatory inhibitor, (e.g., abatacept), IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab), anti-CD20 antibody (e.g., rituximab); and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib); NSAIDs, such as ibuprofen, naproxen, and diclofenac; COX-2 inhibitor, such as celecoxib and etoricoxib; steroids and corticosteroids, such as prednisolone and cortisone; and biological agents known for treatment and / or prophylaxis of such conditions, including for example etanercept (e.g., ENBREL), infliximab (e.g., REMICADE), adalimumab (e.g., HUMIRA), anakinra (e.g., KINARET), abatacept (ORENCIA), rituximab (e.g., RITUXAN), certolizumab (e.g., CIMZIA), golimumab (e.g., SIMPONI), and tocilizumab (e.g., ACTEMRA). In some embodiments, a compound of the disclosure is administered with two additional therapeutic agents useful for the treatment and / or prophylaxis of a rheumatological condition. In some embodiments, agents useful for the treatment and / or prophylaxis of a rheumatological condition include a compound of the disclosure and two additional therapeutic agents, such as methotrexate and leflunomide, methotrexate and sulfasalazine, methotrexate and cyclosporine, methotrexate and hydroxychloroquine, and triple therapy treatments, such as hydroxychloroquine, sulfasalazine and methotrexate or hydroxychloroquine, sulfasalazine and leflunomide.

[0186] In some embodiments, the methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof further comprise administering one or more of the additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents is selected from hydroxychloroquine, steroids and corticosteroids, belimumab, azathioprine, methotrexate, cyclophosphamide, mycophenolate and mycophenolate mofetil, cyclosporine, leflunomide, voclosporin, abatacept, anifrolumab, rituximab, NSAIDS, antimalarial drugs, such as hydroxychloroquine, calcineurin inhibitors, and tacrolimus. In some embodiments, the steroid or corticosteroid is prednisone or methylprednisolone. In some embodiments, the NSAID is naproxen sodium or ibuprofen. In some embodiments, the antimalarial drug is selected from hydroxychloroquine, calcineurin inhibitors, and tacrolimus.

[0187] In some embodiments, an anti-BTLA antibody of the disclosure, or a fragment thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of systemic lupus erythematosus (SLE) or lupus nephritis (LN). Non-limiting examples of such agents include immunosuppressive drugs that inhibit activity of the immune system and agents approved for treatment of SLE, such as hydroxychloroquine, steroids and corticosteroids (e.g., prednisone, methylprednisolone), belimumab, azathioprine, methotrexate, cyclophosphamide, mycophenolate and mycophenolate mofetil, cyclosporine, leflunomide, voclosporin, abatacept, anifrolumab,70ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT rituximab, NSAIDS, such as naproxen sodium and ibuprofen, antimalarial drugs, such as hydroxychloroquine, calcineurin inhibitors, and tacrolimus.

[0188] In some embodiments, an anti-BTLA antibody of the disclosure, or a fragment thereof, is co-administered with two or more agents useful for the treatment of LN, such as prednisone and mycophenolic acid analogs, prednisone, mycophenolic acid sodium prednisone and cyclophosphamide, prednisone and tacrolimus, prednisone and voclosporin, prednisone, belimumab and mycophenolic acid analogs, prednisone, belimumab and cyclophosphamide, or prednisone and rituximab.

[0189] In further embodiments, an anti-BTLA antibody of the disclosure, or a fragment thereof, is co-administered with two or more agents useful for the treatment of LN, such as prednisone and mycophenolic acid analogs, prednisone and mycophenolic acid sodium, prednisone and azathioprine, prednisone and tacrolimus, prednisone and cyclosporine, or prednisone and mizoribine.

[0190] In some embodiments, an anti-BTLA antibody of the disclosure, or a fragment thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of osteoarthritis (OA). Non-limiting examples of such agents include nonsteroidal anti-inflammatory drugs (NSAIDs), topical capsaicin, intraarticular glucocorticoid injections, acetaminophen, duloxetine, tramadol, and injectable corticosteroids such as methylprednisolone acetate, triamcinolone acetate, betamethasone acetate and betamethasone sodium phosphate, triamcinolone hexacetonide, and dexamethasone.V. Pharmaceutical Compositions

[0191] Provided herein are pharmaceutical compositions for use in the treatment or prevention of autoimmune diseases. The pharmaceutical compositions comprise an agonistic anti-BTLA antibody (e.g., anti-BTLA antibody of Section III) with a reduced capacity to bind FcyRs or an inability to bind FcyRs, particularly activating FcyRs.

[0192] Pharmaceutical compositions of an anti-BTLA antibody (or a fragment or variant thereof or an equivalent thereof) of the present disclosure can be prepared as formulations (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). The pharmaceutical compositions generally comprise a carrier and / or additive in addition to the antibody. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (for example, PEG and Tween), excipients, antioxidants (for example, ascorbic71ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT acid), coloring agents, flavoring agents, preservatives, stabilizers, buffering agents (for example, phosphoric acid, citric acid, and other organic acids), chelating agents (for example, EDTA, pentetic acid), suspending agents, isotonizing agents, binders, disintegrators, lubricants, fluidity promoters, corrigents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmelose calcium, carmelose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylacetaldiethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, com starch, and inorganic salt. In some embodiments, the pharmaceutical composition comprises one or more other low-molecular-weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulin. In some embodiments, the pharmaceutical composition comprises one or more amino acids such as glycine, glutamine, histidine, asparagine, arginine, and lysine.

[0193] An anti-BTLA antibody (e.g., an anti-BTLA antibody of Section III or a fragment or variant thereof) may be prepared as an aqueous solution for injection, in which the anti-BTLA antibody (e.g., an anti-BTLA antibody of Section III or a fragment or variant thereof) may be dissolved in an isotonic solution containing, for example, physiological saline, dextrose, or other excipients or tonifiers (i.e., tonicity agents). The tonifier may include, for example, D-sorbitol, D- mannose, D-mannitol, trehalose, sodium chloride, or combinations thereof. In addition, appropriate buffers (Tris / Tris-HCl, histidine / histidine HCL, etc.), chelators (e.g., EDTA, pentetic acid, etc.), preservatives, and solubilizing agents, for example, alcohols (for example, ethanol), polyalcohols (for example, propylene glycols, PEGs, etc.), non-ionic detergents (polysorbate 80, HCO-50, etc.) may be used concomitantly.

[0194] The pharmaceutical compositions of the present disclosure can be administered either orally, intramuscularly, intravenously, subcutaneously, or parenterally. Specifically, the pharmaceutical compositions are administered to patients by injection or percutaneous administration. Injections include, for example, intravenous injections, intravenous infusions, intramuscular injections, and subcutaneous injections, for systemic or local administration. For the purposes of this disclosure, injectable pharmaceutical compositions can include undiluted formulations (e.g., formulations to be used “as-is”) or formulations that are to be diluted with a physiological solution, such as saline (0.9% sodium chloride), dextrose in water (e.g., 5% dextrose) prior to administration, and the like.

[0195] The administration methods can be properly selected according to the patient’s age, weight, and condition. The single-administration dose can be selected, for example, from within the range of 0.0001 to 1000 mg of an anti-BTLA antibody of Section III or a fragment or variant 72ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.0001 to 900 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.0001 to 800 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.0001 to 700 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.0001 to 600 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.001 to 500 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 1000 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 900 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 800 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 700 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 600 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.01 to 500 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 1000 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 900 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 800 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 700 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 600 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 0.1 to 500 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, 73ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT from within the range of 1 to 1000 mg of an anti -B TLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 1 to 900 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 1 to 800 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 1 to 700 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 1 to 600 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 1 to 500 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 1000 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 900 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 800 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 700 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 600 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 500 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 400 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 300 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. The single-administration dose can be selected, for example, from within the range of 10 to 200 mg of an anti-BTLA antibody of Section III or a fragment or variant thereof per kg body weight. For example, when the anti-BTLA antibody of Section III or a fragment or variant thereof is administered to human patients intravenously, the dose of the anti- BTLA antibody of Section III or a fragment or variant thereof can be selected from within the range of 0.01 to 100 mg / kg body weight, preferably 0.05 to 100 mg / kg body weight, or more preferably 0.1 to 100 mg / kg. In some embodiments, the antibody is administered at a dose of, for example, about 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to 74ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT about 100 mg / kg, 0.01 to about 50 mg / kg, about 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg, 0.05 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 200 mg / kg, 0.1 mg / kg to about 150 mg / kg, 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 200 mg / kg, 0.3 mg / kg to about 150 mg / kg, 0.3 mg / kg to about 100 mg / kg, about 0.3 mg / kg to 50 mg / kg, about 0.3 mg / kg to about 40 mg / kg, about 0.3 mg / kg to 30 mg / kg, about 0.3 mg / kg to about 20 mg / kg, about 0.4 mg / kg to about 200 mg / kg, 0.4 mg / kg to about 150 mg / kg, 0.4 mg / kg to about 100 mg / kg, about 0.4 mg / kg to 50 mg / kg, about 0.4 mg / kg to about 40 mg / kg, about 0.4 mg / kg to 30 mg / kg, about 0.4 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, about 0.5 mg / kg to 50 mg / kg, about 0.5 mg / kg to about 40 mg / kg, about 0.5 mg / kg to 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, about 1 mg / kg to 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 200 mg / kg, 5 mg / kg to about 150 mg / kg, 5 mg / kg to about 100 mg / kg, about 5 mg / kg to 50 mg / kg, about 5 mg / kg to about 40 mg / kg, about 5 mg / kg to 30 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 200 mg / kg, 10 mg / kg to about 150 mg / kg, 10 mg / kg to about 100 mg / kg, about 10 mg / kg to 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 10 mg / kg to 30 mg / kg, about 10 mg / kg to about 20 mg / kg, body weight of an antibody (e.g., anti-BTLA antibody clone 1, or another antibody described herein). In preferred embodiments, the anti-BTLA antibody of Section III or a fragment or variant thereof may be administered at a dose in the range of 0.1 mg / kg to 30 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 10 mg / kg, 1.0 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 10 mg / kg to 10 mg / kg, 10 mg / kg to 30 mg / kg, 10 mg / kg to 40 mg / kg, 10 mg / kg to 50 mg / kg, 10 mg / kg to 75 mg / kg, 10 mg / kg to 100 mg / kg, 10 mg / kg to 120 mg / kg, 10 mg / kg to 140 mg / kg, 10 mg / kg to 160 mg / kg, 10 mg / kg to 180 mg / kg, 10 mg / kg to 200 mg / kg, 15 mg / kg to 20 mg / kg, 15 mg / kg to 30 mg / kg, 15 mg / kg to 40 mg / kg, 15 mg / kg to 50 mg / kg, 15 mg / kg to 75 mg / kg, 15 mg / kg to 100 mg / kg, 15 mg / kg to 120 mg / kg, 15 mg / kg to 140 mg / kg, 15 mg / kg to 160 mg / kg, 15 mg / kg to 180 mg / kg, 15 mg / kg to 200 mg / kg. Accordingly, the administered dose may be 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / lg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, or any dose in between the foregoing doses. In particular embodiments, the effective 75ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT amount of the anti-BTLA antibody or a fragment or variant thereof is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, about 10.0 mg / kg, about 15.0 mg / kg, or about 20.0 mg / kg. For the purposes of the forgoing doses, these amounts may be administered as appropriate, such as weekly, once every other week (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, for example, the anti-BTLA antibody of Section III or a fragment or variant thereof may be administered at a dose of 10 mg / kg Q2W, Q3W, or Q4W. In some embodiments, the antibody may be administered at a dose of 15 mg / kg Q2W, Q3W, or Q4W. In some embodiments, the anti-BTLA antibody of Section III or a fragment or variant thereof may be administered at a dose of 20 mg / kg Q2W, Q3W, or Q4W.

[0196] In some embodiments, a dose of the anti-BTLA antibody of Section III or a fragment or variant thereof can be selected irrespective of a subject’s body weight. For example, in some embodiments, a dose of the anti-BTLA antibody of Section III or a fragment or variant thereof can be selected from within the range of between about 1 mg to about 2000 mg, between about 1 mg to about 1500 mg, between about 1 mg to about 1000 mg, between about 1 mg to about 900 mg, between about 1 mg to about 800 mg, between about 1 mg to about 700 mg, between about 1 mg to about 600 mg, between about 1 mg to about 500 mg, between about 1 mg to about 450 mg, between about 1 mg to about 400 mg, between about 1 mg to about 300 mg, between about 1 mg to about 200 mg, between about 1 mg to about 150 mg, between about 1 mg to about 500 mg, between about 1 mg to about 450 mg, between about 1 mg to about 400 mg, between about 1 mg to about 300 mg, between about 1 mg to about 200 mg, or between about 1 mg to about 150 mg. In some embodiments, a dose of the anti-BTLA antibody of Section III or a fragment or variant thereof is at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 5500 mg, or about 600 mg. In some embodiments, a dose of the anti-BTLA antibody of Section III or a fragment or variant thereof less than about 1500 mg, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 450 mg, about 400 mg, about 300 mg, about 200 mg, about 150 mg, or about 100 mg.VI. Treatment and Prevention of Autoimmune Diseases

[0197] The present disclosure provides treatments and preventions for autoimmune disease using agonistic anti-BTLA antibodies with reduced or absent Fc effector function (e.g., an anti-BTLA 76ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT antibody of Section III or a fragment or variant thereof). The methods are characterized by the unexpected advantages described herein. In some embodiments, the improved safety allows for patient selection, dosing and combination regimens. The disclosed agonistic anti-BTLA antibodies with reduced or absent Fc effector function (e.g., an anti-BTLA antibody of Section III or a fragment or variant thereof) and compositions comprising the same can be used alone or in combination with one or more additional therapy to treat or prevent an autoimmune disease or inflammatory disease and achieve certain biological endpoints as explained in more detail herein.

[0198] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), Sjogren’s syndrome, systemic sclerosis (SSc), ankylosing spondylitis (AS), dermatomyositis, psoriatic arthritis (PsA), ANCA vasculitis, IgG4- related disease, non-radiographic axial spondyloarthritis (nr-AxSpA), polymyositis, Takayasu arteritis, cutaneous lupus erythematosus (CLE) types: chronic CLE (including discoid), subacute CLE, acute CLE, seropositive RA, seronegative RA, juvenile idiopathic arthritis (JIA), primary OA, secondary OA, cervical and lumbar spinal OA, hip OA, knee OA, erosive OA, ulcerative colitis (UC), Crohn’s disease (CD), and graft vs. host disease (GVHD). In some embodiments, the autoimmune disease or inflammatory disease is RA. In some embodiments, the autoimmune disease or inflammatory disease is SLE. In some embodiments, the autoimmune disease or inflammatory disease is UC. In some embodiments, the autoimmune disease or inflammatory disease is CD. In some embodiments, the autoimmune disease or inflammatory disease is GVHD. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino77ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K).In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some 78ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence comprising SEQ ID NO: 20. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl . In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from 79ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTP238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

[0199] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11 or 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementaritydetermining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5 or 16; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), Sjogren’s syndrome, systemic sclerosis (SSc), ankylosing spondylitis (AS), dermatomyositis, psoriatic arthritis (PsA), ANCA vasculitis, IgG4-related disease, non-radiographic axial spondyloarthritis (nr-AxSpA), polymyositis, Takayasu arteritis, cutaneous lupus erythematosus (CLE) types: chronic CLE (including discoid), subacute CLE, acute CLE, seropositive RA, seronegative RA, juvenile idiopathic arthritis (JIA), primary OA, secondary OA, cervical and lumbar spinal OA, hip OA,80ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT knee OA, erosive OA, ulcerative colitis (UC), Crohn’s disease (CD), and graft vs. host disease (GVHD). In some embodiments, the autoimmune disease or inflammatory disease is RA. In some embodiments, the autoimmune disease or inflammatory disease is SLE. In some embodiments, the autoimmune disease or inflammatory disease is UC. In some embodiments, the autoimmune disease or inflammatory disease is CD. In some embodiments, the autoimmune disease or inflammatory disease is GVHD. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 11 and LCDR2 of SEQ ID NO: 5. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 15 and LCDR2 of SEQ ID NO: 16. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12 In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the light chain of the anti- BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA 81ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full- length heavy chain sequence comprising SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 82ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence comprising SEQ ID NO: 20. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl. In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti- BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and 83ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTN297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

[0200] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7 In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy84ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K). In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl . In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some 85ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic 86ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subject is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL- 6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks for a period of at least about 12 weeks.

[0201] Further disclosed herein are methods of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis (RA) in a subject in87ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT need thereof. In some embodiments, the method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an RA in a subject in need thereof comprises administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementaritydetermining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11 or 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5 or 16; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 11 and LCDR2 of SEQ ID NO: 5. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 15 and LCDR2 of SEQ ID NO: 16. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12 In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti- BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 25. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino 88ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT acid sequence of SEQ ID NO: 25. In some embodiments, the light chain of the anti -B TLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti- BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant 89ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT domain sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the light chain of the anti -B TLA antibody comprises a light chain constant domain sequence comprising SEQ ID NO: 20. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl . In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, 90ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A33 OR, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subject is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL- 6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from 91ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 500 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 700 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 500 mg every two weeks for a period of at least about 12 92ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 700 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks for a period of at least about 12 weeks.

[0202] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 2; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7 In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length93ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the X of SEQ ID NO: 9 is absent. In some embodiments, the X of SEQ ID NO: 9 is lysine (K). In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti- BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full- length light chain sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy 94ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT chain comprises IgGl . In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, 95ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTMTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subj ect is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib. In some embodiments, the steroid or corticosteroids is prednisolone or cortisone. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered 96ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT subcutaneously at a dose of up to about 500 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 700 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 500 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 700 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks for a period of at least about 12 weeks.

[0203] In some embodiments, a method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount97ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises: (A) a heavy chain comprising: (I) a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1; (II) a HCDR2 comprising SEQ ID NO: 11 or 15; and (III) a HCDR3 comprising SEQ ID NO: 3; and (B) a light chain comprising: (I) a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4; (II) a LCDR2 comprising SEQ ID NO: 5 or 16; and (III) a LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 11 and LCDR2 of SEQ ID NO: 5. In some embodiments, the anti-BTLA antibody comprises the HCDR2 of SEQ ID NO: 15 and LCDR2 of SEQ ID NO: 16. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12 In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 25. In some embodiments, the heavy chain of the anti- BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10. In some embodiments, the light chain 98ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 97% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 98% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 99% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 23. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 24. In some embodiments, the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence comprising SEQ ID NO: 19. In some embodiments, the heavy chain of the anti-BTLA antibody comprises a heavy chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 99ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence comprising SEQ ID NO: 20. In some embodiments, the light chain of the anti-BTLA antibody comprises a light chain constant domain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody. In some embodiments, the anti-BTLA antibody is a humanized antibody. In some embodiments, the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M). In some embodiments, the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain. In some embodiments, the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the IgG heavy chain comprises IgGl. In some embodiments, the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the IgG heavy chain comprises IgG4. In some embodiments, the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region. In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the heavy chain of the anti-BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, 100ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTD265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index). In some embodiments, the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index). In some embodiments, the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody. In some embodiments, the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, or leflunomide and sulfasalazine. In some embodiments, the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody. In some embodiments, the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra. In some embodiments, the subj ect is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. In some embodiments, the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib. In some embodiments, the method further comprises co-administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids. In some embodiments, the csDMARDs is selected from hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. In some embodiments, the TNF inhibitor is selected from etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. In some embodiments, the T cell costimulatory inhibitor is abatacept. In some embodiments, the IL-6 receptor inhibitor is tocilizumab or sarilumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, and upadacitinib. In some embodiments, the NSAID is selected from ibuprofen, naproxen, and diclofenac. In some embodiments, the COX-2 inhibitor is selected from celecoxib and etoricoxib.101ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCTIn some embodiments, the steroid or corticosteroids is prednisolone or cortisone. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 500 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 700 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of at least about 50 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 100 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 200 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 300 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 400 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 450 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 500 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti- BTLA antibody is administered subcutaneously at a dose of up to about 600 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is 102ACTIVE 714274499v 1Attorney Docket No: 210196-224003 / PCT administered subcutaneously at a dose of up to about 700 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 800 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 900 mg every two weeks for a period of at least about 12 weeks. In some embodiments, the anti-BTLA antibody is administered subcutaneously at a dose of up to about 1000 mg every two weeks for a period of at least about 12 weeks...

Claims

1. Attorney Docket No: 210196-224003 / PCTWhat is claimed is:

1. A method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of an autoimmune disease and / or an inflammatory disease in a subject in need thereof, comprising administering to the subject one or more doses of an anti -B TLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15; andIII. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

2. A method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15; andIII. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

3. A method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises:199Attorney Docket No: 210196-224003 / PCT(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15; andIII. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

4. Use of an anti-BTLA antibody for the manufacture of a medicament for treatment of rheumatoid arthritis, wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15;III. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

5. A method of treating, modulating, preventing, reducing the severity of, or ameliorating one or more symptoms of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody, wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15; andIII. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; and200Attorney Docket No: 210196-224003 / PCTIII. a LCDR3 comprising SEQ ID NO: 6.

6. A method of systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject one or more doses of an anti-BTLA antibody in an amount of between about 1 mg to about 2000 mg, wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15; andIII. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

7. Use of an anti-BTLA antibody for the manufacture of a medicament for treatment of systemic lupus erythematosus (SLE), wherein the anti-BTLA antibody comprises:(a) a heavy chain comprising:I. a heavy chain complementarity-determining region (HCDR) 1 comprising SEQ ID NO: 1;II. a HCDR2 comprising SEQ ID NO: 2, 11, or 15;III. a HCDR3 comprising SEQ ID NO: 3; and(b) a light chain comprising:I. a light chain complementarity-determining region (LCDR) 2 comprising SEQ ID NO: 4;II. a LCDR2 comprising SEQ ID NO: 5 or 16; andIII. a LCDR3 comprising SEQ ID NO: 6.

8. The method of claim 1, wherein the autoimmune disease or inflammatory is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), Sjogren’s syndrome, systemic sclerosis (SSc), ankylosing spondylitis (AS), dermatomyositis, psoriatic arthritis (PsA), ANCA vasculitis, IgG4- related disease, non-radiographic axial spondyloarthritis (nr-AxSpA), polymyositis, Takayasu arteritis, cutaneous lupus erythematosus (CLE) types: chronic CLE (including discoid), subacute CLE, acute CLE, seropositive RA, seronegative RA, juvenile idiopathic arthritis (JIA), primary OA, secondary OA, cervical and lumbar spinal OA,201Attorney Docket No: 210196-224003 / PCT hip OA, knee OA, erosive OA, ulcerative colitis (UC), Crohn’s disease (CD), and graft vs. host disease (GVHD).

9. The method or of claim 2 or 3 or the use of claim 4, wherein the subject is diagnosed with RA for at least 3 months prior to administering the anti-BTLA antibody.

10. The method or use of any one of claims 1 to 3 and 9, further comprising coadministering one or more additional therapeutic agents.

11. The method or use of claim 10, wherein the one or more additional therapeutic agents are selected from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), TNF inhibitors, T cell costimulatory inhibitor, IL-6 receptor inhibitors, anti-CD20 antibody, JAK inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, steroids and corticosteroids.

12. The method or use of any one of claims 2, 3, 4, and 7 to 11, wherein the subject is treated with 1 or 2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for at least 12 weeks prior to administering the first dose of the anti-BTLA antibody.

13. The method or use of claim 12, wherein the 1 or 2 csDMARDs are selected from methotrexate (MTX), antimalarial, sulfasalazine, leflunomide, MTX and antimalarial, MTX and sulfasalazine, leflunomide and antimalarial, leflunomide and sulfasalazine, hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide.

14. The method or use of any one of claims 2, 3, 4, and 7 to 13, wherein the subject is not simultaneously treated with a biologic or targeted synthetic disease-modifying antirheumatic drugs (b / tsDMARDs) on the first day of administering the anti-BTLA antibody.

15. The method of any one of claims 2, 3, 4, and 7 to 12, wherein the subject has not been treated with a b / tsDMARD for at least 4 weeks prior to administering the first dose of the anti-BTLA antibody.

16. The method of claim 14 or 15, wherein the b / tsDMARD is selected from a tumor necrosis factor (TNF) inhibitor, kinase inhibitor, abatacept, rituximab, tocilizumab, sarilumab, and anakinra.

17. The method of claim 16, wherein the subject is not administered rituximab for at least 16 weeks prior to administering the first dose of the anti-BTLA antibody.

18. The method of claim 16, wherein:(a) the TNF inhibitor is selected from etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab; or(b) the kinase inhibitor is selected from tofacitinib, baricitinib, upadacitinib, and filgotinib.202Attorney Docket No: 210196-224003 / PCT19. The method of claim 11, wherein:(a) the T cell costimulatory inhibitor is abatacept;(b) the IL-6 receptor inhibitor is tocilizumab or sarilumab;(c) the anti-CD20 antibody is rituximab;(d) the JAK inhibitor is selected from tofacitinib, baricitinib, and Upadacitinib;(e) the NSAID is selected from ibuprofen, naproxen, and diclofenac;(f) the COX-2 inhibitor is selected from celecoxib and etoricoxib; or(g) the steroid or corticosteroids is prednisolone or cortisone.

20. The method of claim 5 or 6 or the use of claim 7, wherein the subject fulfills EULAR / ACR 2019 classification criteria for SLE at least 24 weeks prior to administering the first dose of the anti-BTLA antibody.

21. The method or use of any one of claims 5, 6, 7, or 20, wherein the subject does not have highly active SLE.

22. The method of claim 21, wherein highly active SLE is selected from lupus nephritis, neuropsychiatric SLE, or vasculitis.

23. The method of any one of claims 5, 6, 7, and 20 to 22, wherein the subject is not exposed to cyclophosphamide or any biologic lupus therapy within 8 weeks prior to administering the first dose of the anti-BTLA antibody.

24. The method of any one of claims 1, 5, 6, 7, and 20 to 23, further comprising coadministering one or more additional therapeutic agents.

25. The method of claim 24, wherein the one or more additional therapeutic agents are selected from hydroxychloroquine, steroids and corticosteroids, belimumab, azathioprine, methotrexate, cyclophosphamide, mycophenolate and mycophenolate mofetil, cyclosporine, leflunomide, voclosporin, abatacept, anifrolumab, rituximab, NS AIDs, antimalarial drugs, such as hydroxychloroquine, calcineurin inhibitors, and tacrolimus.

26. The method of claim 25, wherein:(a) the steroid or corticosteroid is prednisone or methylprednisolone;(b) the NSAID is naproxen sodium or ibuprofen; or(c) the antimalarial drug is selected from hydroxychloroquine, calcineurin inhibitors, and tacrolimus.

27. The method or use of any one of claims 1 to 26, wherein the amount of the anti-BTLA antibody is:(a) between about 1 mg to about 1500 mg;(b) between about 1 mg to about 1000 mg;203Attorney Docket No: 210196-224003 / PCT(c) between about 1 mg to about 900 mg;(d) between about 1 mg to about 800 mg;(e) between about 1 mg to about 500 mg;(f) between about 1 mg to about 450 mg;(g) between about 1 mg to about 400 mg;(h) between about 1 mg to about 300 mg;(i) between about 1 mg to about 200 mg;(j) between about 1 mg to about 150 mg;(k) between about 1 mg to about 500 mg;(l) between about 1 mg to about 450 mg;(m)between about 1 mg to about 400 mg;(n) between about 1 mg to about 300 mg;(o) between about 1 mg to about 200 mg; or(p) between about 1 mg to about 150 mg.

28. The method or use of any one of claims 1 to 27, wherein the amount of the anti -B TLA antibody is:(a) at least about 1 mg;(b) at least about 2 mg;(c) at least about 3 mg;(d) at least about 4 mg;(e) at least about 5 mg;(f) at least about 10 mg;(g) at least about 15 mg;(h) at least about 20 mg;(i) at least about 25 mg;(j) at least about 30 mg;(k) at least about 35 mg;(l) at least about 40 mg; or(m)is at least about 50 mg.

29. The method or use of any one of claims 1 to 28, wherein the amount of the anti-BTLA antibody is:(a) less than about 1000 mg;(b) less than about 900 mg;(c) less than about 800 mg;(d) less than about 700 mg;204Attorney Docket No: 210196-224003 / PCT(e) less than about 600 mg;(f) less than about 500 mg;(g) less than about 450 mg;(h) less than about 400 mg;(i) less than about 300 mg;(j) less than about 200 mg;(k) less than about 150 mg; or(l) less than about 100 mg.

30. The method or use of any one of claims 1 to 29, wherein the anti-BTLA antibody is administered by one or more routes of administration selected from oral, parenteral, topical, or by inhalation.

31. The method or use of claim 30, wherein parenteral administration comprises intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration.

32. The method or use of any one of claims 1 to 31, wherein the anti-BTLA antibody is administered by subcutaneous administration.

33. The method or use of any one of claims 1 to 32, wherein two or more doses of the anti- BTLA antibody are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 or more days apart.

34. The method or use of any one of claims 1 to 32, wherein two or more doses of the anti- BTLA antibody are administered at least about 7 days apart, at least about 14 days apart, at least about 21 days apart, or at least about 30 days apart.

35. The method or use of any one of claims 1 to 32, wherein the anti-BTLA antibody is administered at least every week, at least every 2 weeks, at least every 3 weeks, at least every 4 weeks, at least every 5 weeks, or at least every 6 weeks.

36. The method or use of any one of claims 1 to 35, wherein the anti-BTLA antibody is administered for a period of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or more weeks.

37. The method or use of any one of claims 1 to 35, wherein the anti-BTLA antibody is administered for a period of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or more months.

38. The method or use of any one of claims 1 to 35, wherein the anti-BTLA antibody is administered for a period of at least about 4 weeks, at least about 8 weeks, at least about205Attorney Docket No: 210196-224003 / PCT12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 50 mg every two weeks.

39. The method or use of any one of claims 1 to 38, wherein the anti-BTLA antibody is administered subcutaneously at a dose of up to about 150 mg every two weeks, up to about 450 mg every two weeks, up to about 600 mg every two weeks, up to about 700 mg every two weeks, up to about 800 mg every two weeks, or up to about 1000 mg every two weeks.

40. The method or use of any one of claims 1 to 39, wherein the anti-BTLA antibody is administered subcutaneously at a dose of:(a) at least about 50 mg every two weeks for a period of at least about 12 weeks;(b) up to about 150 mg every two weeks for a period of at least about 12 weeks;(c) up to about 450 mg every two weeks for a period of at least about 12 weeks;(d) up to about 600 mg every two weeks for a period of at least about 12 weeks;(e) up to about 700 mg every two weeks for a period of at least about 12 weeks;(f) up to about 800 mg every two weeks for a period of at least about 12 weeks; or(g) up to about 1000 mg every two weeks for a period of at least about 12 weeks.

41. The method or use of any one of claims 1 to 40, wherein the heavy chain of the anti- BTLA antibody comprises the HCDR2 of SEQ ID NO: 2.

42. The method or use of any one of claims 1 to 41, wherein the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 7.

43. The method or use of any one of claims 1 to 41, wherein the heavy chain of the anti- BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7.

44. The method or use of any one of claims 1 to 43, wherein the heavy chain of the anti- BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 9.

45. The method or use of any one of claims 1 to 43, wherein the heavy chain of the anti- BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9.

46. The method or use of any one of claims 1 to 40, wherein the heavy chain of the anti- BTLA antibody comprises the HCDR2 of SEQ ID NO: 11.206Attorney Docket No: 210196-224003 / PCT47. The method or use of any one of claims 1 to 40 and 46, wherein the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 12.

48. The method or use of any one of claims 1 to 40 and 46, wherein the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12.

49. The method or use of any one of claims 1 to 40 and 46 to 48, wherein the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 25.

50. The method or use of any one of claims 1 to 40 and 46 to 48, wherein the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25.

51. The method or use of any one of claims 1 to 50, wherein the light chain of the anti- BTLA antibody comprises the LCDR2 of SEQ ID NO: 5.

52. The method or use of any one of claims 1 to 51, wherein the light chain of the anti- BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 8.

53. The method or use of any one of claims 1 to 51, wherein the light chain of the anti- BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8.

54. The method or use of any one of claims 1 to 53, wherein the light chain of the anti- BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 10.

55. The method or use of any one of claims 1 to 53, wherein the light chain of the anti- BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10.

56. The method or use of any one of claims 1 to 40, wherein the heavy chain of the anti- BTLA antibody comprises the HCDR2 of SEQ ID NO: 15.

57. The method or use of any one of claims 1 to 40 and 56, wherein the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region (HCVR) sequence comprising SEQ ID NO: 13.207Attorney Docket No: 210196-224003 / PCT58. The method or use of any one of claims 1 to 40 and 56, wherein the heavy chain of the anti-BTLA antibody comprises a heavy chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13.

59. The method or use of any one of claims 1 to 40 and 56 to 59, wherein the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence comprising SEQ ID NO: 23.

60. The method or use of any one of claims 1 to 40 and 56 to 59, wherein the heavy chain of the anti-BTLA antibody comprises a full-length heavy chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23.

61. The method or use of any one of claims 1 to 40 and 56 to 60, wherein the light chain of the anti-BTLA antibody comprises the LCDR2 of SEQ ID NO: 16.

62. The method or use of any one of claims 1 to 40 and 56 to 61, wherein the light chain of the anti-BTLA antibody comprises a light chain variable region sequence comprising SEQ ID NO: 14.

63. The method or use of any one of claims 1 to 40 and 56 to 61, wherein the light chain of the anti-BTLA antibody comprises a light chain variable region sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14.

64. The method or use of any one of claims 1 to 40 and 56 to 63, wherein the light chain of the anti-BTLA antibody comprises a full-length light chain sequence comprising SEQ ID NO: 24.

65. The method or use of any one of claims 1 to 40 and 56 to 63, wherein the light chain of the anti-BTLA antibody comprises a full-length light chain sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24.

66. The method or use of any one of claims 1 to 65, wherein the anti-BTLA antibody is a chimeric, humanized, veneered, or human antibody.

67. The method or use of any one of claims 1 to 65, wherein the anti-BTLA antibody is a humanized antibody.

68. The method or use of any one of claims 1 to 67, wherein the anti-BTLA antibody comprises an immunoglobulin (Ig) heavy chain selected from gamma (G), alpha (A), delta (D), epsilon (E), or mu (M).208Attorney Docket No: 210196-224003 / PCT69. The method or use of claim 68, wherein the Ig heavy chain comprises an immunoglobulin gamma (IgG) heavy chain.

70. The method or use of claim 69, wherein the IgG heavy chain is selected from IgGl, IgG2, IgG3, or IgG4.

71. The method or use of claim 70, wherein the IgG heavy chain comprises IgGl.

72. The method or use of claim 71, wherein the IgG heavy chain comprises an IgGl heavy chain that has up to 10 amino acid substitutions in the constant region.

73. The method or use of claim 70, wherein the IgG heavy chain comprises IgG4.

74. The method or use of claim 73, wherein the IgG heavy chain comprises an IgG4 heavy chain that has up to 10 amino acid substitutions in the constant region.

75. The method or use of any one of claims 1 to 74, wherein the heavy chain of the anti- BTLA antibody comprises an Fc region that comprises one or more of the following amino acids: alanine (A) at position 234, alanine (A) at position 235, aspartic acid (D) at position 236, aspartic acid (D) at position 237, aspartic acid (D) at position 238, alanine (A) at position 265, glutamic acid (E) at position 267, glycine (G) at position 271, arginine (R) at position 330, alanine (A) at position 332, or alanine (A) at position 297 (all numbering according to EU Index).

76. The method or use of any one of claims 1 to 72 and 75, wherein the anti-BTLA antibody comprises a human IgGl antibody having one or more substitutions selected from G236D, G237D, P238D, D265A, S267E, P271G, A330R, K322A, and N297A (all numbering according to EU Index).

77. The method or use of claim 78, wherein the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

78. The method or use of any one of claims 1 to 70, and 73 to 75, wherein the anti-BTLA antibody comprises a human IgG4 antibody having one or more substitutions selected from P238D, G237D, P271G, S330R, F234A and L235A (all numbering according to EU Index).

79. The method or use of claim 78, wherein the anti-BTLA antibody comprises a P238D substitution (numbering according to EU index).

80. The method or use of claim 44 or 45, wherein the X of SEQ ID NO: 9 is absent.

81. The method or use of claim 44 or 45, wherein the X of SEQ ID NO: 9 is lysine.209

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