Anti-TL1a antibodies for treating systemic inflammatory diseases and related methods

Abstract

Aspects of the disclosure relate to a method for treating a systemic inflammatory disease in a subject comprising administering an anti-TL1A antibody that is modified for half-life extension. In some embodiments, administration of the anti-TL1A antibody leads to improvement in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment. In some embodiments, the systemic inflammatory disease includes Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 mellitus, sarcoidosis. The anti-TL1A antibody treatment can be administered at disease onset or prior to full symptomology. The method is applicable to humans, non-human primates, and animal models of systemic inflammatory disease.

Description

Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 ANTI-TL1A ANTIBODIES FOR TREATING SYSTEMIC INFLAMMATORY DISEASES AND RELATED METHODS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Application No.63 / 744,328, filed on January 12. 2025 and U.S. Provisional Application No. 63 / 757,765. filed on February 12, 2025, the entire content of each of which are incorporated herein by reference.REFERENCE TO SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 8, 2026, is named 220703-011901_PCT_SL.xml and is 2,012,906 bytes in size.TECHNICAL FIELD

[0003] Aspects of the present disclosure relate to anti-TLl A antibodies for the treatment of systemic inflammatory diseases, and methods of treatment with such antibodies.BACKGROUND

[0004] Systemic inflammatory diseases, such as Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myogelosis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, and sarcoidosis, are chronic immune-mediated conditions characterized by dysregulated immune responses, in which the immune system mistakenly targets and damages the body’s own tissues. These diseases often result in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems. In particular, they can involve widespread inflammation in diverse systems, including the cardiovascular, pulmonary, integumentary (skin), musculoskeletal, gastrointestinal, nervous, endocrine, and reproductive systems. Type 1 diabetes mellitus and multiple sclerosis, in particular, are prevalent forms of systemic inflammatory diseases that affect millions of people worldwide, significantly impacting their quality of life. Current treatments may not be effective for all patients and can have significant side effects, highlighting the need for new therapeutic approaches.1 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0005] These systemic inflammatory diseases are typically managed with a combination of corticosteroids (e.g., prednisone), immunosuppressive therapies (e.g.. methotrexate, azathioprine, cyclophosphamide, my cophenolate mofetil), symptom management, and / or biologic therapies (e.g., TNF inhibitors, interleukin inhibitors, or B-cell depleting agents). The treatment regimen is highly individualized, depending on disease severity7, organ involvement, and patient’s response to therapy. Biologic therapies have become increasingly important, as they specifically target immune system pathways involved in the disease process, offering a more precise and effective approach to modulating inflammation, reducing disease activity7, and preventing further tissue damage. Biologies have advanced the treatment landscape for systemic inflammatory7diseases, by improving long-term outcomes, particularly for diseases with significant immune dysregulation and inflammation. Despite these advances, there remains substantial unmet need for therapies that provide better efficacy, safety7, and convenience for patients. The complexity of the immune system and the variability7in patient responses to existing treatments necessitate ongoing research and innovation. Current biologic treatments, such as infliximab can increase the risk of serious infection, require frequent drug administration and are ineffective in a subset of patients. Therefore, the development of additional biologic treatments against novel disease targets with favorable safety7and dosing profiles could improve patient care and open the door to combination therapies to treat patients with systemic inflammatory diseases.SUMMARY

[0006] Aspects of the disclosure relate to methods for treating systemic inflammation in a subject in need thereof by administering an inhibitor of TL1A binding to its receptor, hereinafter “a TL1A inhibitor,” such as an anti-TLIA antibody. In some embodiments, the method comprises treating a systemic inflammatory disease in a subject in need thereof by administering a TL1 A inhibitor, such as an anti-TLIA antibody. In a specific embodiment, the anti-TLIA antibody is modified in the Fc region to have an extended half-life compared to the unmodified form of the antibody. Exemplary modifications to increase antibody halflife include YTE and LS (as described in detail infra). Its administration may lead to improvements in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment.

[0007] In some embodiments, the administration of an effective amount of the TL1A inhibitor, such as an anti-TLIA antibody (e.g., an half-life extended anti-TLIA antibody), to the subject results in one or more of the following: changes in cytokine levels, particularly2 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 serum cytokine levels, reduction of serum antibodies, modified histopathology, e.g., of biopsy tissue from multiple sites, and / or altered RNA expression, e.g., in peripheral blood cells or tissue, cell or fluid from biopsy, compared to no treatment. The TL1 A inhibitor, such as an anti-TLl A antibody, may be at least as effective as standard of care for managing an inflammatory systemic disease. In another embodiment, the TL1A inhibitor, such as an anti-TLl A antibody, is more effective than standard of care for managing a systemic inflammatory disease.

[0008] In some embodiments, the anti-TLl A antibody, particularly an half-life extended anti-TLl A antibody, more effectively treats systemic inflammatory disease in a subject compared to TNF inhibitor treatment.

[0009] In a specific embodiment wherein the TL 1 A inhibitor is an anti-TLl A antibody, the anti-TLl A antibody binds TL1 A with a dissociation constant (Kn) less than about 0.5 nanomolar (nM), optionally less than about 0.4 nM, and optionally less than about 0.3 nM. In a specific embodiment, the anti-TLl A antibody binds TL1A with a KD of 0.22 nM. In a specific embodiment the anti-TLl A antibody binds TL1 A with a KD of 0.10 nM.

[0010] In some embodiments, the administration of an effective amount of the anti-TLl A antibody to the subject results in changes to the levels of serum cytokines, modified histopathology7, and / or altered RNA expression in peripheral blood cells or tissue, cell or fluid from biopsy, compared to no treatment. In some embodiments, administration of an effective amount of the anti-TLl A antibody to the subject results in modulation of fibroblast or fibroblast-like cells. In some embodiments, administration of an effective amount of the anti-TLl A antibody to the subject results in a decrease of the level of cytokines, such as, TNF, IL-1, IL-4, IL- 5, IL- 6, IL-13, IL-17, INFy. In some embodiments, administration of the anti-TL1A antibody to the subject results in a decrease of the level of TNF, IL-6, IL-17 or combination thereof.

[0011] The administration of the anti-TLl A antibody to the subject may result in reduction of systemic inflammation, tissue damage, and functional impairment across multiple organ systems, or combination thereof.

[0012] In some embodiments, the anti-TLIA antibody is a long acting anti-TLIA antibody. In methods of the disclosure, an anti-TLIA antibody can be modified to extend its half-life, to reduce Fc functionality7, or to provide Fab or Fab' fragments. In a specific embodiment, an anti-TLIA antibody Fc domain comprises amino acid modifications L234A / L235A (LALA)3 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 to reduce Fc functionality, and / or M252Y, S254T, and T256E (YTE) or M428L and N434S (LS) (according to EU numbering system) to increase half-life.

[0013] In some embodiments, the TL1 A binding antibody comprises a heavy chain variable region (VH) comprising (i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 A, TABLE 1.1 B, and TABLE 1.1 C, (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A. TABLE LI B. and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C. In some embodiments, the TL1A binding antibody comprises alight chain variable region (VL) comprising (i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE 1.1 B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C. In some embodiments, the TL1A binding antibody comprises a modified Fc domain that extends half-life of the TL1 A binding protein as compared to a TL1A binding protein that does not comprise the modified Fc domain.

[0014] In a specific embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from Lys243, Lys240, Thr239, Tyr238, Asp237, Val236, Leu235, Ser234, Ile233, Asp232, Metl58, Argl56, Trpll9, Hisl l8, Lyslll, Phel lO, Hisl09, Glnl08, Thrl07, Prol06, Thrl05, Glnl04, Argl03, Vall02, and VallOl of a TLIA polypeptide comprising SEQ ID NO: 2493. In another specific embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from Vai 101. Vai 102, Arg 103, Gin 104, Thr 105, Pro 106, Thr 107, Gin 108, His 109, Phe 110, Lys 111,4 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 His 118, Trp 119, Glu 120, Glu 122, Leu 123, Gly 124, Lys 137, Arg 156, Gly 157, Met 158, Ser 234, Tyr 238, and Thr 239 of SEQ ID NO: 2493. In another specific embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from Vai 102, Arg 103, Gin 104, Thr 105, Thr 107, Gin 108, His 118, Trp 119, Glu 120, Glu 122, Leu 123, Gly 124, Lys 137, Arg 156, Gly 157, Met 158, Ser 234, Tyr 238, and Thr 239 of SEQ ID NO: 2493. In another specific embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from Lys240, Thr239, Tyr238, Asp237, Val236, Leu235, Ser234, Glnl04, and Argl03 of SEQ ID NO: 2493. In some embodiments, the TL1A binding antibody specifically binds to the TL1A polypeptide comprising SEQ ID NO: 2493 at one or more of amino acid residues Vai 102, Arg 103, Gin 104, Glu 120, Glu 122, Leu 123. and Arg 156.

[0015] Exemplary anti-TLIA antibodies, CDRs, or both for use in the disclosure are described in PCT application No. PCT / US24 / 41774 entitled "TL1A BINDING PROTEINS AND METHODS OF USE," filed on August 9, 2024, PCT application No PCT / US24 / 34949 entitled "TL1A ANTIBODY COMPOSITIONS AND METHODS OF USE" filed on June 21, 2024, which are incorporated by reference herein in their entireties.

[0016] In accordance with aspects of the disclosure, a TL1A inhibitor, such as an anti-TLIA antibody, can be used in methods of treating a systemic inflammatory disease comprising administering an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, to a subject in need of such treatment, e.g.. diagnosed with a systemic inflammatory disease. In some embodiments, the method is as effective in treating a systemic inflammatory disease as administration of standard of care. In some embodiments, the method is more effective in treating a systemic inflammatory disease than administration of standard of care.

[0017] The products, compositions and methods of the disclosure for treating systemic inflammatory disease may lead to improvements in systemic inflammation, tissue damage, and functional impairment across multiple organ systems. The products, compositions and methods of the disclosure can also reduce or treat the widespread effects on other organs and systems in the body, as systemic inflammatory diseases impact the entire body and often involve widespread inflammation, immune dysregulation, or other systemic complications. Non-limiting examples of systemic inflammatory diseases that can be treated using the methods of the disclosure include but are not limited to Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves'5 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 disease, type 1 diabetes mellitus. sarcoidosis Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) Vasculitis, systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC). Systemic inflammatory diseases can be associated with or caused by an autoimmune response. In some embodiments, the products, compositions and methods of the disclosure reduce or treat the systemic inflammation associated with Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, Anti -Neutrophilic Cytoplasmic Autoantibody(ANCA) Vasculitis, Primary' biliary cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), systemic sclerosis, or Systemic Lupus Erythematosus.

[0018] In one embodiment, the TL1 A inhibitor, such as an anti-TLIA antibody, is administered to the subject at the onset of the disease. In another embodiment, the TL1 A inhibitor, such as an anti-TLIA antibody is administered to the subject in need thereof before the full symptoms of the disease appear. In another embodiment, the TL1A inhibitor, such as an anti-TLIA antibody is administered to the subject after the full symptoms of the disease appear. The TL1A inhibitor, such as an anti-TLIA antibody, can be administered intravenously or subcutaneously.

[0019] In some embodiments, the anti-TLIA antibody is a long-acting anti-TLIA antibody. In some embodiments, the anti-TLIA antibody is a YTE modified anti-TLIA antibody.

[0020] The subject receiving the treatment can be a primate. In some embodiments, the subject receiving the treatment is a human.

[0021] In some embodiments, as a result of the treatment, the subject achieves a clinical response and / or improvement in physical function. In some embodiments, the subject achieves slowing or reduction in systemic inflammation, tissue damage, and functional impairment across multiple organ systems. In some embodiments, laboratory tests may show lowered inflammatory markers (e.g., C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR)). In some embodiments, as a result of the treatment, key indicators include stabilization or improvement of organ function. In some embodiments, symptom relief further signifies disease control. In some embodiments, imaging studies may demonstrate stabilization or slowed progression. In some embodiments, disease improvement is indicated by better systemic function, symptom relief, and stabilization of disease markers, reflecting both a decrease in inflammation and slowed progression.6 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0022] A method for treating systemic inflammatory diseases in a subject may involve administering an anti-TLIA antibody, which can lead to improvements in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, or a combination thereof, compared to no treatment. In some embodiments, administration of the anti-TLIA antibody to the subject results in modulation of fibroblast-like cells. The anti-TLIA antibody may effectively treat systemic inflammatory diseases as well as or better than standard of care. In some embodiments, the anti-TLIA antibody is a long-acting anti-TLIA antibody. In some embodiments, the anti-TLIA antibody is administered intravenously or subcutaneously.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 provides a schematic for the Collagen Induced Arthritis (CIA) model in rats used in Example 1.

[0024] FIG. 2 shows the binding activity of anti-TLIA antibody AbX to rat TL1A as determined with surface plasmon resonance (SPR). Surface plasmon resonance (SPR) sensorgram showing the binding of rat TL1 A to AbX. AbX was immobilized to the sensor chip, and recombinant rat TL1 A binding was measured at concentrations of 200 nM (purple), 100 nM (brown), 50 nM (pink), 25 (green) or 12.5 nM (orange) nM. The binding affinity of AbX to rat TL1A was quantified based on a global curve fitting analysis.

[0025] FIG. 3 shows arthritis scores in the semi-established CIA model.

[0026] FIG. 4 shows arthritis scores in the therapeutic CIA model.

[0027] FIG. 5 shows effect of treatment on foot volume increase in the semi-established CIA model.

[0028] FIG. 6 shows effect of treatment on foot volume increase in the therapeutic CIA model.

[0029] FIG. 7 shows effect of treatment on hind paw x-ray score in the semi-established CIA model.

[0030] FIG. 8 shows effect of treatment on hind paw x-ray score in the therapeutic CIA model.

[0031] FIGS. 9A-9D show Histopathology scores (Infiltration of cells FIG. 9A, Pannus severity grade FIG. 9B, Cartilage lesion severity grade FIG. 9C, Bone resorption severity grade FIG. 9D) in the semi-established CIA model.

[0032] FIGS. 10A-10B show simulated PK in serum and tissue for Regimen 1 and Regimen 2. Regimen 1 includes administration of Antibody 63 at Weeks 0, 4 and 8, and extension7 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Weeks 12, 24 and 36. Regimen 2 includes administration of Antibody 63 at Weeks 0, and extension Weeks 12 and 36. FIG. 10A is a graph showing serum PK concentration (pg / mL) for Regimen 1 and Regimen 2. FIG. 10B is a graph showing tissue PK concentration (pg / mL) for Regimen 1 and Regimen 2. PK concentration data shows median (solid line) and 2.5 to 97.5 percentiles (shaded area). Tissue to serum partitioning coefficient is assumed to be 0.35.

[0033] FIGS. 11A-11B show simulated free sTLIA in serum and tissue for Regimen 1 and Regimen 2. Regimen 1 includes administration of Antibody 63 at Weeks 0, 4 and 8, and extension Weeks 12, 24 and 36. Regimen 2 includes administration of Antibody 63 at Weeks 0, and extension Weeks 12 and 36. FIG. 11A is a graph showing serum sTLIA concentration (% baseline) for Regimen 1 and Regimen 2. FIG. 11B is a graph showing tissue sTLIA concentration (% baseline) for Regimen 1 and Regimen 2. Baseline sTLIA assumed to be 500 pg / mL up to Week 12 and 100 pg / mL in extension in both serum and tissue. Tissue to serum partitioning coefficient is assumed to be 0.35. PD data shows median (solid line) and 5 to 95 percentiles (shaded area).DETAILED DESCRIPTION

[0034] It is to be understood that both the foregoing general description and the following detailed description are exemplary', and explanatory' only, and are not restrictive of the disclosure.

[0035] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0036] All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0037] Tumor Necrosis Factor-like protein 1A (TL1A) is a pro-inflammatory' cytokine that plays a key role in regulating immune responses, particularly in the context of autoimmune and inflammatory' diseases. It is primarily produced by immune cells such as dendritic cells, T cells, and macrophages, and it exerts its effects by interacting with its receptor Death Receptor 3 (DR3), which is found on various immune and fibroblast cell types. By binding to DR3, TL1A may' enhance the activation of T cells, leading to the release of inflammatory cytokines like IL-17, IL-4, IL-13, and IL-5. In this context, intervention by way of inhibiting the TL1 A pathway, particularly with novel anti-TLIA antibodies disclosed here, whether used alone or in combination with other interventions, represents a promising avenue for8 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 developing new treatments that offer improved outcomes for patients suffering from these debilitating systemic conditions.Definitions

[0038] Unless otherwise indicated, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless otherwise indicated or obvious from context, the following terms have the following meanings:

[0039] As used herein, unless otherwise indicated, the term “antibody” is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as a Fc fragment of an antibody (e.g, an Fc fragment of a monoclonal antibody), or an antigenbinding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.9 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0040] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These sub-domains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface.

[0041] An “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, e, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0042] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII. and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g. Janeway et al.. Immuno Biology, the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Amu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim etal., J. Immunol. 24:249 (1994)).10 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0043] The terms “recipient"’, “individual"’, “subject”, “host”, and “patient"’, are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory', zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0044] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0045] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0046] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0047] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0048] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2. 2.3, 2.4, 2.5, fold, etc., and so forth.11 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0049] “About” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0050] “Percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y. Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP.BLASTN, or GCG (Devereux et al., 1984). As used herein, the term “total TL1A” refers to both monomeric and trimeric TL1 A including soluble form thereof.

[0051] An improvement in disease or an alleviation of clinical sy mptoms can be characterized as a complete alleviation of one or more symptoms, where the subject has or displays no clinical symptoms of the disease, or a partial alleviation of symptoms, where the subject displays at least a 20% improvement in one or more of clinical symptoms of the disease.

[0052] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0053] As a general matter, compositions specifying a percentage are by weight unless otherw ise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0054] Tumor necrosis factor (TNF)-like cytokine 1A (TL1 A) is part of the TNF superfamily and is a transmembrane protein expressed by myeloid mononuclear cells and endothelial cells, as well as T cells and B cells. TL1 A interacts with its receptors, death receptor 3 (DR3) and decoy receptor 3 (DcR3), or TL1 A / tumor necrosis factor receptor 2, to trigger signaling. It is a pro-inflammatory cytokine that plays a key role in regulating immune responses, particularly in the context of autoimmune and inflammatory’ diseases. It is primarily produced by immune cells such as dendritic cells, T cells, and macrophages, and it exerts its effects by 12 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 interacting with its receptor Death Receptor 3 (DR3), which is found on various immune cells. TL1A interacts with its receptors, membrane-bound death receptor 3 (DR3) and soluble decoy receptor 3 (DcR3), or TL1 A / tumor necrosis factor receptor 2, to trigger signaling. TL1 A is elevated in individuals with inflammatory diseases, for example rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and ankylosing spondylitis, and DR3 expression is upregulated in inflamed tissue. By binding to DR3, TL1A may enhance the activation of T cells, leading to the release of inflammatory cytokines like IL-16, IL-17, IL-4, IL-13, and IL-5. Soluble TL1A exists in both monomeric and trimeric form in vivo and in vitro. Trimers dissociate naturally into monomers. TL1 A is active as a homotrimer. Trimeric TL1 A induces trimerization of DR3 receptors on the cell surface that is necessary for downstream signaling. In contrast, while the monomeric TL1A can bind DR3 receptors on T cells, it cannot induce trimerization of the DR3 receptors, and is, therefore, biologically inactive. Typical serum levels of soluble TL1A are about 100 pg / mL or below in humans. In contrast, patients with autoimmune diseases often exhibit elevated levels.

[0055] Current biologies targeting TNF are associated with serious side effects and infection, require frequent drug administration and are ineffective in a subset of patients highlighting the need for improved therapies targeting TL1 A.

[0056] Aspects of the disclosure provide a method for treating systemic inflammatory diseases, including but not limited to Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, ANC A Vasculitis, PBC, by administering a TL1A inhibitor, e.g., an anti-TLl A antibody. Other aspects of the disclosure provide a method for treating or ameliorating systemic inflammation associated with Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema. Graves' disease, type 1 diabetes mellitus, sarcoidosis, ANCA vasculitis, primary biliary7cholangitis (PBC), primary Sclerosing Cholangitis (PSC), systemic sclerosis and Systemic Lupus Erythematosus by administering a TL1 A inhibitor, e.g., an anti-TLl A antibody. In an embodiment, an anti-TLl A antibody is a fully human antibody, a humanized antibody, or a chimeric antibody. In an embodiment, the antibody is a fully human antibody. The anti-TLl A 13 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 antibody may be modified to extend its half-life. The anti-TLl A antibody may also be modified to reduce Fc functional activity. Administration of the TL1 A inhibitor, such as an anti-TLl A antibody, can result in improvement of one or more of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems. The treatment may be as effective as or even more effective than treatment with a TNF inhibitor. Treatment with the TL1A inhibitor, such as an anti-TLIA antibody, can begin prior to full symptom development, or after full symptom development. Treatment with the TL1A inhibitor, such as an anti-TLIA antibody, can begin at disease onset, or after disease onset. Treatment with the TL1 A inhibitor, such as an anti-TLIA antibody, can begin at disease onset or prior to full symptom development, or after disease onset and full symptom development.

[0057] In some embodiments, an anti-TLIA antibody, as described herein, can preferentially bind to soluble human TL1A (sTLIA) relative to any TL1 A-related TNFSF members. In some embodiments, an anti-TLIA antibody, as described herein, can have higher binding affinity for soluble human TL1A relative to any TLlA-related TNFSF members. In some embodiments, an anti-TLIA antibody, as described herein, may not bind to any TLlA-related TNFSF members.

[0058] In some embodiments, an anti-TLIA antibody, as described herein, can have a concentration-dependent inhibitory7effect on apoptosis induced by the combination of cycloheximide and TL1 A in TF-1 cells, a human erythroleukemia cell line that expresses high levels of endogenous DR3. In some embodiments, an anti-TLIA antibody, as described herein, can have a concentration-dependent inhibitory effect on binding of TL1 A to DcR3 receptors, DR3 receptors, or combinations thereof. In some embodiments, an anti-TLIA antibody, as described herein, can inhibit human TL1 A's ability to induce apoptosis and elicit IFNgamma secretion. In some embodiments, an anti-TLIA antibody, as described herein, shows enhanced binding (i. e. , lower KD) to human FcRn at pH 5.8 compared to a control antibody lacking a YTE modification. In some embodiments, an anti-TLIA antibody, as described herein, does not bind to human FcRn at pH 7.2. In some embodiments, an anti-TLIA antibody, as described herein, does not bind to activating Fc receptors CD 16a. CD 16b, CD32a, CD32b or CD64 or to complement component Clq.

[0059] In some embodiments, an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, is administered to the subject at the onset of the disease. In other embodiments, an effective amount of the TL1A inhibitor, such as an anti-TLIA antibody is administered to the subject in need thereof before the full symptoms of the systemic inflammatory disease appear. In other embodiments, an effective amount of the TL1 A14 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 inhibitor, such as an anti-TLIA antibody is administered to the subject after the full symptoms of the systemic inflammatory disease appears. The TL1 A inhibitor, such as an anti-TLIA antibody, can be administered intravenously or subcutaneously.

[0060] In some embodiments, the systemic inflammatory disease is characterized by systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems.

[0061] The TL1A inhibitor, such as an anti-TLIA antibody, may be administered to the subject, which may include primates such as humans and non-human primates, or a rat model, to treat systemic inflammatory diseases such as Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, ANCA Vasculitis, or PBC.

[0062] In some embodiments, administration of an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, results in improvement of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment. In some embodiments, administration of an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, results in reduction of the rate of progression of the disease. In an embodiment, the treatment the TL1 A inhibitor, such as an anti-TLIA antibody, is as effective as TNF inhibitor treatment for treating the systemic inflammatory disease. In an embodiment, the treatment the TL1 A inhibitor, such as an anti-TLIA antibody, is more effective than TNF inhibitor treatment for treating the systemic inflammatory’ disease.

[0063] In some embodiments, administration of an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, results in one or more of reducing systemic inflammation, reducing tissue damage, and / or reducing functional impairment affecting multiple organ systems. In some embodiments, the systemic inflammation, tissue damage, and / or functional impairment affecting multiple organ systems are reduced by at least about 10%, at least about 20%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, or by at least about 80%. In some embodiments, administration of an effective amount of the TL1A inhibitor, such as an anti-TLIA antibody, results in improvement of the disease treated as measured by erythrocyte sedimentation rate (ESR), levels of C-reactive protein, or combination thereof. In some embodiments, administration of the TL1A inhibitor, such as an anti-TLIA antibody, results in improvement of the disease treated as measured by erythrocyte sedimentation rate (ESR), levels of C-reactive protein,15 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 levels of anti-citrullinated protein / peptide antibodies or combination thereof by at least about 10%, at least about 20%. by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, or by at least about 80%.

[0064] In some embodiments, administration of an effective amount of the TL1 A inhibitor, such as an anti-TLIA antibody, results in improvement of the disease treated as measured by disease activity score, or the like.

[0065] In some embodiments, administration of an effective amount of the TL1A inhibitor, such as an anti-TLIA antibody, results in in one or more of the following: changes in cytokine levels, particularly serum cytokine levels, modified histopathology7, e.g., of systemic biopsy tissue, modulation of fibroblast or fibroblast-like cells and altered RNA expression, e.g., in peripheral blood cells and / or tissue, cells or fluid from biopsy, compared to no treatment.

[0066] In some embodiments, administration of an effective amount of the TL1A inhibitor, such as an anti-TLIA antibody, results in reduction of the levels of serum cytokines, modified histopathology, modulation of fibroblast and fibroblast-like cells, and altered RNA expression in peripheral blood cells and / or tissue, cells or fluid from biopsy, compared to no treatment. In some embodiments, administration of an effective amount of the anti-TLIA antibody to the subject results in a decrease of the level of cytokines, such as, TNF, TL1A, IL-1, IL-4, IL- 5. IL- 6, IL-13, IL-17, INFy. In some embodiments, administration of the anti-TLIA antibody to the subject results in a decrease of the level of TNF, IL-6, IL- 17 or combination thereof.

[0067] In some embodiments, the TL1A inhibitor, such as an anti-TLIA antibody, may be at least as effective as TNF inhibitor for managing a systemic inflammatory disease. In another embodiment, the TL1 A inhibitor, such as an anti-TLIA antibody, is more effective than a TNF inhibitor for managing a systemic inflammatory disease.

[0068] Described herein, in certain embodiments, are methods of treating a systemic inflammatory' disease in a patient in need thereof, the method comprising subcutaneously or intravenously’ administering to the patient an effective amount of an anti-TLIA antibody disclosed herein. In some embodiments, the method comprises administering one or more effective amounts of the anti-TLIA antibody subcutaneously or intravenously. In some embodiments, the anti-TLIA antibody is a long acting anti-TLIA antibody. In some embodiments, the long acting anti-TLIA antibody is administered subcutaneously or intravenously. In some embodiments, methods of treatment described herein comprise16 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 administering an effective amount of a TL1A inhibitor (e.g., an anti-TLIA antibody), to a subject (e.g, a human) in need of treatment. In some embodiments, the effective amount of the anti-TLIA antibody is at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, or at least 1500 mg. In some embodiments, the effective amount of the anti-TLIA antibody is in a range of from about 200 mg to about 2000 mg, from about 300 mg to about 2000 mg, from about 400 mg to about 2000 mg, from about 500 mg to about 2000 mg, from about 800 mg to about 2000 mg, from about 1000 mg to about 2000 mg, from about 1200 mg to about 2000 mg, from about 1500 mg to about 2000 mg, from about 1800 mg to about 2000 mg, from about 200 mg to about 1800 mg, from about 300 mg to about 1800 mg. from about 400 mg to about 1800 mg. from about 500 mg to about 1800 mg, from about 800 mg to about 1800 mg, from about 1000 mg to about 1800 mg, from about 1200 mg to about 1800 mg, from about 1500 mg to about 1800 mg, from about 200 mg to about 1500 mg, from about 300 mg to about 1500 mg, from about 400 mg to about 1500 mg, from about 500 mg to about 1500 mg, from about 800 mg to about 1500 mg, from about 1000 mg to about 1500 mg, from about 1200 mg to about 1500 mg, from about 200 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 400 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 800 mg to about 1200 mg, from about 1000 mg to about 1200 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 1000 mg. from about 400 mg to about 1000 mg. from about 500 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, from about 200 mg to about 400 mg, from about 300 mg to about 400 mg, or from about 200 mg to about 300 mg. In some embodiments, the effective amount of the anti-TLIA antibody is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg. about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg or about 2000 mg. In some embodiments, the administering of the effective dose of the anti-TLIA antibody in the subject reduces soluble TL1 A levels from baseline (e.g., about 90% suppression of free serum sTLAl). Alternatively, the administering of the effective dose of the anti-TLIA antibody in the subject reduces soluble TL1 A levels from about 500 pg / mL in serum (baseline) to about 100 pg / mL in serum. In some embodiments, the anti-TLIA antibody is 17 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 administered subcutaneously or intravenously in an induction phase, and subcutaneously in a maintenance phase. In a specific embodiment, the anti-TLIA antibody is an extended halflife anti-TLl A antibody. In some embodiments, methods of treatment described herein comprise administering of the extended half-life anti-TLIA antibody. In some embodiments, the extended half-life anti-TLIA antibody is administered Q24W or Q6M. In specific embodiments, a maintenance dose of the extended half-life anti-TLIA antibody is administered Q12W / Q3M or Q24W / Q6M subcutaneously. In another embodiment, a maintenance dose of the extended half-life anti-TLIA antibody is administered Q52W subcutaneously. In another embodiment, a maintenance dose of the extended half-life anti-TLIA antibody is administered Q104W subcutaneously. In some embodiments, the maintenance dose of the extended half-life anti-TLIA antibody described herein is administered subcutaneously from Q12W to Q104W. In each of the foregoing therapeutic regimen, subcutaneous administration can be by autoinjector.

[0069] In some embodiments, the systemic inflammatory disease is ANCA Vasculitis. Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, which is a common primary systemic vasculitis, defined by inflammation of the blood-vessel wall, includes microscopic polyangiitis, Wegener's granulomatosis, Churg-Strauss syndrome, renal-limited vasculitis. Most patients have a prodromal flu-like onset consisting of malaise, myalgias, arthralgias, fever, and weight loss. Treatment includes prednisone therapy. TNF-alpha blockade with infliximab is a potential therapy for ANCA- associated vasculitis, both for initial therapy and in the management of refractory disease.

[0070] In some embodiments, the systemic inflammatory disease is primary biliary cholangitis (PBC). PBC affects mainly adult women. It is characterized by histopathological lesion in primary biliary cholangitis, leading to bile duct destruction. Patients suffer from numerous symptoms, including fatigue, pruritus, and cognitive symptoms.

[0071] In some embodiments, the systemic inflammatory disease is systemic sclerosis or scleroderma. Scleroderma is a disease involving buildup of collagen in the skin and elsewhere in the body, such as in the arteries, Treatment includes administration of corticosteroids, mycophenolate, cyclophosphamide, cyclosponne or methotrexate and / or hydroxychloroquine.

[0072] In some embodiments, the systemic inflammatory disease is Addison's disease, which is a rare but serious endocrine disorder resulting from the insufficient production of cortisol and aldosterone by the adrenal glands. This condition is most often caused by autoimmune destruction of the adrenal cortex, but it can also be due to infections, tumors, or genetic 18 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 conditions. Clinical manifestations ty pically include symptoms such as chronic fatigue, unexplained weight loss, hypotension, hyperpigmentation, and salt cravings due to low aldosterone. Patients may also present with nausea, vomiting, and muscle weakness.Diagnosis is confirmed through blood tests that show low cortisol levels, elevated adrenocorticotropic hormone (ACTH), and a poor response to an ACTH stimulation test. Additional tests may show hyponatremia, hyperkalemia, and hypoglycemia, reflecting adrenal insufficiency. Imaging studies such as CT scans can be performed to assess adrenal gland size and detect possible lesions or adrenal atrophy. Treatment is centered around lifelong hormone replacement therapy to restore normal cortisol and aldosterone levels. The primary' agents used are glucocorticoids (e.g., hydrocortisone or prednisone) and mineralocorticoids (e.g., fludrocortisone) to replace cortisol and aldosterone, respectively.

[0073] In some embodiments, the systemic inflammatory disease is autoimmune hemolytic anemia (AIHA), which is a rare condition in which the body’s immune system produces antibodies that attack and destroy its own red blood cells, resulting in anemia. AIHA can be divided into warm autoimmune hemolytic anemia (WAIHA) and cold agglutinin disease, depending on the temperature at which the antibodies cause red blood cell destruction.Diagnosis is made through the direct antiglobulin test (DAT), which detects antibodies attached to red blood cells. Treatment options include corticosteroids (e.g., prednisone) as first-line therapy, immunosuppressive drugs (e.g., azathioprine, cyclophosphamide) for refractory cases, and anti-CD20 antibody (e.g., rituximab) biologic treatment in cases that do not respond to conventional treatments. If necessary', splenectomy can be performed in patients who do not respond to medical therapy.

[0074] In some embodiments, the sy stemic inflammatory disease is chronic active hepatitis, which is a long-standing liver inflammation, often caused by chronic infections such as hepatitis B or C, or by autoimmune processes. Patients with chronic active hepatitis may present with fatiguejaundice, and abdominal pain, with complications such as cirrhosis or liver failure. Diagnosis is based on elevated liver enzymes, specific antibodies (e.g., antinuclear antibodies, anti-smooth muscle antibodies), and liver biopsy. Treatment varies based on the underlying cause: antiviral medications (e.g., interferon, direct-acting antivirals for hepatitis C), or immunosuppressive therapies (e.g., azathioprine or prednisone for autoimmune hepatitis). In advanced cases, liver transplantation may be considered for endstage liver disease.

[0075] In some embodiments, the systemic inflammatory disease is Goodpasture's syndrome, which is a rare autoimmune disorder where antibodies target the glomerular basement 19 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 membrane of the kidneys and the lungs, leading to kidney failure and pulmonary hemorrhage. Diagnosis is confirmed through the detection of anti-glomerular basement membrane antibodies in the blood. Treatment typically includes plasmapheresis to remove the circulating antibodies, combined with immunosuppressive therapy (e.g., cyclophosphamide, corticosteroids) to suppress the immune response. If kidney failure develops, dialysis may be required, and renal transplantation may be an option for end-stage renal disease. Timely intervention is critical to prevent irreversible organ damage.

[0076] In some embodiments, the systemic inflammatory disease is graft-versus-host disease (GVHD), which is an immunologic complication that occurs after allogeneic hematopoietic stem cell or bone marrow transplants, where the donor’s immune cells attack the recipient's tissues. It occurs in 30-50% of patients undergoing allogeneic transplants and can involve the skin, liver, and gastrointestinal tract. Diagnosis is based on clinical signs and symptoms, such as skin rashes, jaundice, and diarrhea, along with histopathological findings. GVHD is categorized into acute and chronic forms, with the acute form often presenting within 100 days of transplant. Treatment includes immunosuppressive therapy, such as calcineurin inhibitors (e.g.. cyclosporine), methotrexate, and corticosteroids to suppress the immune response and prevent organ damage. For chronic GVHD, rituximab and extracorporeal photopheresis may be considered.

[0077] In some embodiments, the systemic inflammatory disease is Hashimoto’s thyroiditis, which is the most common cause of hypothyroidism, particularly in women over 40 years of age. The condition is characterized by the autoimmune destruction of the thyroid gland, leading to insufficient production of thyroid hormones. It affects about 1 in 1,000 individuals, with a higher prevalence in women. Diagnosis is made by detecting anti-thyroid peroxidase (TPO) antibodies and measuring serum TSH and free T4 levels. Treatment involves levothyroxine replacement therapy to normalize thyroid hormone levels, which is typically lifelong. Patients require regular monitoring to adjust doses as needed, particularly during pregnancy or times of stress.

[0078] In some embodiments, the systemic inflammatory disease is immune thrombocytopenia (ITP), which is an autoimmune disorder where the immune system destroys platelets, leading to an increased risk of bleeding and bruising. Diagnosis is based on exclusion, with low platelet counts and normal bone marrow. First-line treatment includes corticosteroids (e.g., prednisone), intravenous immunoglobulin (IVIG), and platelet transfusions in severe cases. For refractory cases, rituximab, splenectomy, or other immunosuppressive therapies (e.g., azathioprine) may be considered.20 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0079] In some embodiments, the systemic inflammatory disease is leprosy, caused by Mycobacterium leprae, is a chronic infectious disease that primarily affects the skin, peripheral nerves, and mucosal tissues. It is now rare in developed countries, with around 200,000 new cases globally each year. The prevalence is significantly higher in tropical regions of Asia, Africa, and South America. Diagnosis is based on clinical features, skin biopsy, and detection of acid-fast bacilli. Treatment consists of a multi-drug regimen with dapsone, rifampicin, and clofazimine over 6-12 months, with longer courses for more severe forms. Early diagnosis and treatment prevent nerve damage and deformities, significantly improving outcomes.

[0080] In some embodiments, the systemic inflammatory disease is lupus nephritis, which is a serious complication of lupus that involves inflammation of the kidneys, leading to proteinuria and potential kidney failure. It occurs in 30-60% of patients with systemic lupus erythematosus (SLE). Diagnosis is confirmed through urine tests (e.g., proteinuria), kidney biopsy, and serologic testing. Treatment includes immunosuppressive therapies such as cyclophosphamide, mycophenolate mofetil, and corticosteroids to control inflammation and prevent progression to end-stage kidney disease. Biologic agents like belimumab may be added in cases that are resistant to conventional therapies. Timely and aggressive treatment is essential to preserve kidney function.

[0081] In other embodiments, the systemic inflammatory disease is systemic lupus erythematosus. Systemic lupus erythematosus (lupus. SLE) is a chronic autoimmune disease that can affect skin, joints, heart, lung, kidneys, circulating blood cells, and brain. Common symptoms include fatigue, joint pain and swelling, skin rash and sensitivity to light. Joint symptoms occur in 90% of the patient having SLE. Commonly affected joints in lupus are those in the hands, wrists, and knees. Patients with SLE may have high levels of antinuclear antibodies.

[0082] In some embodiments, the systemic inflammatory disease is multiple sclerosis (MS), which is a chronic autoimmune disease of the central nervous system (CNS), characterized by the demyelination of nerve fibers, leading to motor and sensory deficits. The prevalence is approximately 1 in 1,000, with higher rates in women and individuals of Northern European descent. The disease course can be relapsing-remitting, secondary progressive, or primary progressive. Diagnosis is made through MRI showing characteristic plaques in the CNS and lumbar puncture for oligoclonal bands. Treatment involves disease-modifying therapies (e g., interferons, glatiramer acetate), steroids for relapses, and symptom management strategies.21 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Corticosteroids are used to manage acute relapses, while symptom management (e.g., muscle relaxants, antispasticity agents) are used for improving daily life.

[0083] In some embodiments, the systemic inflammatory disease is myasthenia gravis (MG), which is a rare autoimmune neuromuscular disorder characterized by muscle weakness, particularly affecting the ocular, bulbar, and proximal limb muscles. The condition arises from the production of autoantibodies targeting acetylcholine receptors (AChRs) at the neuromuscular junction, impairing neuromuscular transmission. Symptoms include ptosis, diplopia, dysphagia, dysarthria, and, in severe cases, respiratory failure due to involvement of respiratory muscles. MG predominantly affects women in their 20s to 30s and men in their 50s to 60s, with an estimated prevalence of 14 to 20 cases per 100,000 people. Treatment strategies include acetylcholinesterase inhibitors like pyridostigmine to improve neuromuscular transmission, immunosuppressive therapies (e.g., prednisone, azathioprine) to reduce autoantibody production, and plasma exchange or IVIG for acute exacerbations or myasthenic crises. In refractory cases, thymectomy may provide long-term symptomatic relief, as well as biologic agents such as rituximab and eculizumab.

[0084] In some embodiments, the systemic inflammatory disease is myositis, which is used to describe a group of inflammatory muscle diseases characterized by inflammation and weakness, affecting multiple muscle groups. Myositis can be classified into different types, including polymyositis, dermatomyositis, and inclusion body myositis. The condition is associated with autoimmune dysfunction, where the body’s immune system mistakenly attacks its own muscle tissues. Diagnosis is typically confirmed through a combination of clinical assessment, elevated creatine kinase (CK) levels, electromyography (EMG), and muscle biopsy. Primary treatment involves immunosuppressive therapies, such as corticosteroids (e.g., prednisone) and methotrexate, which help to reduce inflammation. In more severe cases, additional immunosuppressants, including azathioprine or mycophenolate mofetil, may be prescribed. For dermatomyositis, intravenous immunoglobulin (IVIG) and plasmapheresis can be utilized during acute flare-ups. A potential complication of myositis is the development of interstitial lung disease.

[0085] In some embodiments, the systemic inflammatory disease is pernicious anemia, which is a type of megaloblastic anemia caused by an autoimmune attack on the gastric parietal cells, leading to deficiency of intrinsic factor (IF), a protein essential for the absorption of vitamin B12 in the small intestine. This deficiency results in impaired ery thropoiesis and reduced production of red blood cells, leading to symptoms such as fatigue, pallor, shortness of breath, and neurological issues like numbness, tingling, and cognitive disturbances. The 22 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 diagnosis is confirmed through serum vitamin B12 levels, antibodies to intrinsic factor, and Schilling test. Current treatment for pernicious anemia consists of lifelong vitamin B12 supplementation, either through intramuscular injections or high-dose oral vitamin B12. Regular monitoring of vitamin B12 levels is essential to prevent recurrence of symptoms and to manage potential complications, such as peripheral neuropathy.

[0086] In some embodiments, the systemic inflammatory disease is primary myxedema, also known as severe hypothyroidism, which is a condition resulting from insufficient thyroid hormone production by the thyroid gland, often due to autoimmune thyroiditis (e.g., Hashimoto's thyroiditis), iodine deficiency, or surgical removal of the thyroid. It primarily affects the metabolic function of various organs, leading to symptoms such as fatigue, weight gain, cold intolerance, constipation, dry skin, and myxedema (a non-pitting edema, often seen around the eyes and lower legs). In severe cases, untreated primary myxedema can lead to myxedema coma, a life-threatening condition characterized by hypothermia, hypoventilation, and mental status changes. The prevalence of primary myxedema varies but is estimated to affect approximately 0.3% to 1% of the population, with a higher incidence in older women. Diagnosis is confirmed through elevated thyroid-stimulating hormone (TSH) and low free thyroxine (T4) levels in blood tests. The mainstay of treatment for primary myxedema is lifelong thyroid hormone replacement therapy, ty pically with levothyroxine to normalize thyroid hormone levels and alleviate symptoms. Dosing is adjusted based on clinical response and periodic monitoring of thyroid function tests. Prompt treatment is critical to prevent complications such as cardiovascular issues and myxedema coma.

[0087] In some embodiments, the systemic inflammatory7disease is Graves' disease, which is an autoimmune disorder that leads to hyperthyroidism, characterized by the overproduction of thyroid hormones due to the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR). This results in excessive thyroid hormone production and an acceleration of metabolic processes, leading to symptoms such as weight loss, tachycardia, palpitations, heat intolerance, tremors, nervousness, fatigue, and exophthalmos, along with goiter. Graves' disease is the most common cause of hyperthyroidism, affecting approximately 0.5% to 2% of the population, with a higher prevalence in women aged 20 to 40 years. The disease is often diagnosed through elevated thyroid hormone levels (T3 and T4) and suppressed TSH levels, along with detection of thyroid-stimulating immunoglobulins (TSI) in the blood. Treatment for Graves' disease includes antithyroid medications, such as methimazole or propylthiouracil (PTU). to inhibit thyroid hormone synthesis.23 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0088] In some embodiments, the systemic inflammatory disease is ty pe 1 diabetes mellitus (T1DM), a metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion, action, or both. T1DM is an autoimmune disease where the body’s immune system attacks and destroys insulin-producing beta cells in the pancreas, leading to absolute insulin deficiency. This condition ty pically manifests in childhood or adolescence, and while it is less prevalent, it affects about 5-10 % of all diabetes cases. In contrast, type 2 diabetes mellitus (T2DM) is primarily caused by insulin resistance, where the body’s cells become less responsive to insulin, followed by eventual pancreatic beta-cell dysfunction. T2DM is much more common, accounting for about 90-95 % of all diabetes cases, with higher prevalence in adults over 40 years, though it is increasingly diagnosed in younger populations. Both types of diabetes impact various organs and systems, including the cardiovascular, renal, nervous, and ocular systems, leading to complications such as nephropathy, retinopathy, neuropathy, atherosclerosis, and increased risk of infections. The primary' treatment for T1DM involves insulin replacement therapy, typically through multiple daily injections or insulin pumps to maintain glucose control, along with continuous glucose monitoring. T2DM management initially focuses on lifestyle modifications, such as diet and exercise, followed by oral medications (e g., metformin, sulfonylureas, GLP-1 agonists) to improve insulin sensitivity' or increase insulin secretion. In more advanced cases of T2DM, insulin therapy may be required. Both types of diabetes necessitate regular monitoring of blood glucose levels to achieve optimal management and prevent long-term complications.

[0089] In some embodiments, the systemic inflammatory disease is sarcoidosis, which is characterized by the formation of granulomas, which are clusters of immune cells, in various organs, most commonly the lungs, lymph nodes, skin, eyes, and heart. The exact cause of sarcoidosis remains unclear, but it is believed to result from an abnormal immune response to an environmental trigger in genetically predisposed individuals. It affects approximately 10-20 per 100,000 people annually, with a higher prevalence in African American populations and ty pically presents between the ages of 20 and 40 years. In the lungs, sarcoidosis can lead to symptoms such as cough, dyspnea, chest pain, and fatigue, while skin involvement may cause erythema nodosum or other lesions. Diagnosis is based on clinical findings, elevated levels of serum angiotensin-converting enzyme (ACE), radiographic evidence (often a chest X-ray showing bilateral hilar lymphadenopathy), and biopsy of affected tissues revealing granulomas. While the disease can resolve spontaneously in many cases, treatment is often necessary’ for moderate to severe disease or when significant organ function is at risk. The mainstay of therapy involves corticosteroids (e.g., prednisone) to reduce inflammation and 24 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 control granuloma formation. In cases where corticosteroids are ineffective or poorly tolerated, immunosuppressive agents such as methotrexate, azathioprine, or mycophenolate mofetil may be used. For refractory sarcoidosis, biologic therapies, such as TNF-alpha inhibitors (e.g., infliximab) are considered. Management focuses on controlling symptoms and preventing organ damage, especially in the lungs and heart, which are most commonly affected by the disease.TL1A inhibitors

[0090] Death-domain receptor 3 (DR3) is a tumor necrosis factor receptor family member expressed specifically on T cells, natural killer (NK) cells, natural killer T (NKT), some dendritic cell ty pes, and some fibroblast cell ty pes. The ligand for DR3 is TL1A, a TNF family member protein reported to be expressed by myeloid mononuclear cells, endothelial cells, and B and T lymphocytes endothelial cells.

[0091] The interaction between DR3 and TLIA can be blocked using inhibitors that directly interfere with the interaction between DR3 and TLIA, for example, by an inhibitor that binds to DR3 at its binding site for TLIA or an inhibitor that binds to TLIA at its binding site for DR3.

[0092] The interaction between DR3 and TLIA can be blocked by administration of an anti-TL1A antibody. In some embodiments, administration of the anti-TLIA antibody reduces an amount of free soluble TLIA (sTLl A) in the subject compared to no treatment. In one embodiment, such an antibody has the heavy and light chain sequences, or the heavy chain variable region and light chain variable region sequences, or the heavy chain CDR sequences as set out in PCT application No. PCT / US24 / 41774 entitled "TLIA BINDING PROTEINS AND METHODS OF USE," or PCT application No PCT / US24 / 34949 entitled "TLIA ANTIBODY COMPOSITIONS AND METHODS OF USE", as set forth above, which are incorporated by reference in their entireties.

[0093] The method comprises treating a systemic inflammatory disease in a subject in need thereof by administering an inhibitor of TLIA binding to TLIA receptor, hereinafter a “TLIA inhibitor.”

[0094] Provided herein are compositions, systems, and methods comprising a TLIA inhibitor. In some embodiments, the TLIA inhibitor is a small molecule TLIA inhibitor. In some embodiments, the TLIA inhibitor is a TLIA small molecule allosteric inhibitor. In some embodiments, the TLIA inhibitor is a TLIA binding protein. In some embodiments, the TLIA inhibitor is an anti-TLIA antibody or binding fragment thereof.25 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0095] In some embodiments, the compositions are injectable liquid compositions. In some embodiments, the compositions are injectable liquid composition for intravenous administration. In some embodiments, the compositions are injectable liquid composition for subcutaneous administration.

[0096] The TL1 A binding proteins described herein can bind to TL1A monomers and / or TL1 A trimers. In some embodiments, the TL1A binding protein is an anti-TLl A antibody having picomolar potency against TL1A monomers, TL1A trimers, or both.

[0097] In some embodiments, the anti-TLl A antibody, as described herein, binds to monomeric TL1 A, trimeric TL1 A, or monomeric and trimeric TL1A. In some embodiments, the anti-TLl A antibody binds to monomeric TL1A. In some embodiments, the anti-TLIA antibody binds to monomeric TL1A and trimeric TL1A. In some embodiments, the anti-TLIA antibody neutralizes the monomeric TL1A, trimeric TL1 A, or both monomeric and trimeric TL1A. In some embodiments, the anti-TLIA antibody neutralizes the monomeric TL1A, trimeric TL1A, or both monomeric and trimeric TL1A by from about 50% to about 99% or more (e.g. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%. 87%. 88%. 89%. 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%. 98%. or 99% of the monomeric TL1A, trimeric TL1 A, or both monomeric and trimeric TL1A. For example, the anti-TLIA antibody can neutralize both the monomeric and trimeric TL1A. In some embodiments, the anti-TLIA antibody blocks binding of TL1A to DR3 receptors, DcR3 receptors or DR3 receptors and DcR3 receptors. In some embodiments, the anti-TLIA antibody reduces TL1 A concentration in a diseased tissue.

[0098] In some embodiments, the anti-TLIA antibody, as described herein, binds to TL1A trimer (homo trimers) only. In some embodiments, binding to the TL1 A trimer stabilizes the timer. In some embodiments, binding of the antibody to the TL1A trimer makes the TL1 A trimer inactive, whether or not it stabilizes the trimer configuration. In some embodiments such a trimer-binding antibody does not bind to the TL1 A monomer. In some embodiments, such a trimer-binding antibody can bind to more than one trimer. In some embodiments, each trimer-binding antibody can bind up to two TL1A trimers. In some embodiments, each TL1A trimer can bind up to three trimer-binding antibodies. In some embodiments, an effective amount of a trimer-binding antibody is administered in a subject in need thereof for treating systemic inflammatory' conditions. In some embodiments, clearance of trimer-binding antibodies may involve unbound trimer-binding antibodies and antibody-TLIA complexes, wherein the antibody-TLIA complexes can comprise one or more TL1A trimers bound to one or more antibodies. In some embodiments, an antibody-TLIA complex formed by anti- 26 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 TL1A antibody and TL1A trimer at a ratio of 3: 1 exhibits faster clearance relative to an antibody-TLIA complex that comprises less than 3:1 ratio of the anti-TLIA antibody and TL1A trimer. For example, in some embodiments, a TL1A trimer bound to three antibodies exhibit faster clearance relative to a TL1A trimer bound to less than three antibodies (e.g., two or one). In some embodiments, treatment with the trimer-binding antibody does not affect the rate of synthesis of TL1A monomer. In some embodiments, treatment with the trimer-binding antibody does not affect the rate of saturation / equilibration of PD. Nonlimiting exemplary trimer-binding anti-TLIA antibodies include Antibody 10, Antibody 47, Antibody 49, Antibody 69, Antibody 71 and Antibody 92.

[0099] In other embodiments, the anti-TLIA antibody, as described herein, is a disruptor that binds monomer and trimer. In some embodiments, the disruptor promotes dissociation of homotrimers into TL1A monomers. In some embodiments, the disruptor can bind to more than one TL1 A monomer. For example, in some embodiments, each disruptor can bind up to two TL1 A monomers. In some embodiments, an effective amount of a disruptor is administered in a subject in need thereof for treating inflammatory conditions. In some embodiments, clearance of disruptors may contain unbound disruptors and antibody-TLIA complex complexes, wherein the antibody-TLIA complex complexes can comprise disruptors bound to TL1A trimers and / or TL1 A monomer(s). In some embodiments, treatment with the disruptors does not affect the rate of synthesis of TL1A monomers. In some embodiments, treatment with the disruptors does not affect the rate of saturation / equilibration of PD. Non-limiting exemplary disruptors include Antibody 19, Antibody 63, Antibody 86 and Antibody 98.

[0100] In some embodiments, the anti-TLIA antibody, as described herein, binds monomer and trimer, wherein the anti-TLIA antibody does not promote dissociation of homotrimers into TL1A monomer(s). In some embodiments, the anti-TLIA antibody, upon contacting a TL1 A trimer, modifies a rate of dissociation of the TL1 A trimer into TL1 A monomer less than 5%, less than 3%, less than 2%, less than 1%, or lesser compared to the rate of dissociation of the TL1A trimer prior to the contacting. In some embodiments, the anti-TLIA antibody, as described herein, selectively binds monomer(s) and does not bind trimers.

[0101] Disclosed herein are anti-TLIA antibodies, excluding RVT-3101, MK-7240 and / or TEV-48574, that (1) bind TL1 A trimer and optionally stabilize TL1 A trimer and do not bind TL1 A monomer; (2) bind TL1A trimer and TL1A monomer, and on binding TL1 A trimer disrupts TL1A trimer into TL1A monomer(s); (3) bind TL1A trimer and TL1A monomer; or27 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (4) selectively bind TL1A monomer, wherein the anti-TLIA antibodies do not bind TL1A trimer and do not disrupt TL1 A trimer into TL1A monomer(s).

[0102] In some embodiments, an antibody-TLIA complex of an anti-TLIA antibody and a TL1 A trimer, when comprising a 3: 1 ratio of the anti-TLIA antibody to the TL1 A trimer, exhibits at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100% or more faster rate of clearance relative to an antibody-TLIA complex comprising less than 3: 1 ratio of the anti-TLIA antibody to the TL1A trimer. In some embodiments, the trimer-binding anti-TLIA antibody (stabilizer), upon selectively binding to a TL1 A trimer, decreases rate of dissociation of the TL1 A trimer into TL1 A monomer by at least 10%, at least 20%, at least 50%, at least 80%, at least 100%, or more compared to no treatment. In some embodiments, the anti-TLIA antibody (stabilizer), upon contacting a TL1 A trimer, decreases a rate of dissociation of the TL1 A trimer into TL1 A monomer by at least 10%, at least 20%, at least 50%, at least 80%, at least 100%, or more compared to the rate of dissociation of the TL1 A trimer prior to the contacting. In some embodiments, the anti-TLIA antibody (disruptor), upon binding to TL1A trimer, increases rate of dissociation of the TL1A trimer into TL1A monomer by at least 10%, at least 20%, at least 50%, or more, compared to no treatment. In some embodiments, the anti-TLIA antibody (disruptor), upon contacting a TL1 A trimer, increases a rate of dissociation of the TL1A trimer into TL1A monomer by at least 10%, at least 20%, at least 50%, or more, compared to the rate of dissociation of the TL1 A trimer prior to the contacting.

[0103] In some embodiments, the anti-TLIA antibody is a fully human IgGl monoclonal anti-TLIA antibody or IgGl -humanized monoclonal antibody (e.g. RVT-3101, MK-7240, TEV-48574).

[0104] In some embodiments, the anti-TLIA antibody has an extended half-life (e.g., as compared to known TL1 A directed antibodies). In some embodiments, the anti-TLIA antibodies described herein allow for subcutaneous administration. In some embodiments, the anti-TLIA antibodies described herein allow for less frequent dosing than known TL1 A-directed antibodies, e.g., every 8 weeks or every 12-13 weeks (or 3 months), or every’ 24-26 weeks (or 6 months), or every 52 weeks (or 12 months or a year), or every 104 weeks (24 months or 2 years), etc. Anti-TLIA antibodies described herein may also have improved specificity. Anti-TLIA antibodies described herein may have specificity for monomeric and trimeric TL1A and not to related TNF super family proteins TNF, FasL, TRAIL, or LIGHT.

[0105] Binding kinetics of an antibody can be determined by SPR on aBIAcore instrument. In some embodiments, an anti-TLIA antibody has ka(NT's-1) of 2.0xl06. In some28 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 embodiments, an anti-TLIA antibody has kd (s'1) of 5.8xl0'5. In some embodiments, an anti-TL1 A antibody binds TL1 A with a dissociation constant (KD) less than about 0.5 nanomolar (nM), optionally less than about 0.4 nM, and optionally less than about 0.3 nM. In a specific embodiment, the anti-TLIA antibody binds TL1 A with a KD of 0.22 nM. In a specific embodiment the anti-TLIA antibody binds TL1A with a KD of 0.10 nM. In some embodiments, an anti-TLIA antibody binds TL1 A with a KD (M) of 3. IxlO'11. In some embodiments, an anti-TLIA antibody binds TL1A with a KD of about 0.24 nM. In some embodiments, an anti-TLIA antibody, as described herein, does not bind to related TNFSF members TNFa, FasL, TRAIL, or LIGHT.

[0106] In some embodiments, the TL1A binding antibody comprises a heavy chain variable region (VH) comprising (i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C. In some embodiments, the TL1 A binding antibody comprises a light chain variable region (VL) comprising (i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE 1.1 B, and TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C. In some embodiments, the TL1A binding antibody comprises a modified Fc domain that extends half-life of the TL1A binding protein as compared to a TL1A binding protein that does not comprise the modified Fc domain.29 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0107] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C. and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C.

[0108] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.1 A. TABLE LI B, and TABLE 1.1 C. (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.1 A. TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; and c) a modified Fc domain that extends half-life of the TL1 A binding protein as compared to a TL1 A binding protein that does not comprise the modified Fc domain.

[0109] In some embodiments, the TL1A binding antibody comprises a heavy chain variable region (VH) comprising (i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises I to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, and (iii) a 30 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C. In some embodiments, the TL1A binding antibody comprises alight chain variable region (VL) comprising (i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, (ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.2 A. TABLE 1.2 B, and TABLE 1.2 C. and (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C. In some embodiments, the TL1A binding antibody comprises a modified Fc domain that extends half-life of the TL1 A binding protein as compared to a TL1A binding protein that does not comprise the modified Fc domain.

[0110] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.2 A. TABLE 1.2 B. and TABLE 1.2 C. (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C: and b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C.[OlH] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, and (iii) a CDR3 having an amino acid 31 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 sequence according to any one of CDRH3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C: b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.2 A, TABLE 1.2 B, and TABLE 1.2 C; and c) a modified Fc domain that extends half-life of the TL1A binding protein as compared to a TL1 A binding protein that does not comprise the modified Fc domain.

[0112] In some embodiments, the TL1A binding antibody comprises a heavy chain variable region (VH) comprising (i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, and (iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C. In some embodiments, the TL1 A binding antibody comprises a light chain variable region (VL) comprising (i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, (ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, and (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C. In some embodiments, the TL1A binding antibody comprises a modified Fc domain that extends half-life of the TL1A binding protein as compared to a TL1A binding protein that does not comprise the modified Fc domain.32 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0113] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C; and b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C. and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C.

[0114] In some embodiments, the TL1A binding antibody comprises: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.3 A. TABLE 1.3 B, and TABLE 1.3 C. (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.3 A. TABLE 1.3 B, and TABLE 1.3 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.3 A, TABLE 1.3 B, and TABLE 1.3 C; and c) a modified Fc domain that extends half-life of the TL1 A binding protein as compared to a TL1 A binding protein that does not comprise the modified Fc domain.

[0115] In some embodiments, the TL1 A binding antibodies comprise a VH comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to the ammo acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding antibodies comprises a VL comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2.33 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0116] In some embodiments, the TL1 A binding antibodies comprise a VH comprising a sequence having at least 80% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 80% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a VH comprising a sequence having at least 85% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL compnsing a sequence having at least 85% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1A binding protein comprises a VH comprising a sequence having at least 90% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 90% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a VH comprising a sequence having at least 95% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 95% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1A binding protein comprises a VH comprising a sequence having at least 96% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 96% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1A binding protein comprises a VH comprising a sequence having at least 97% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 97% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1A binding protein comprises a VH comprising a sequence having at least 98% sequence identity' to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 98% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a VH comprising a sequence having at least 99% sequence identity to the amino acid sequence of any one of VH sequences listed in TABLE 2.1 and TABLE 2.2, and a VL comprising a sequence having at least 99% sequence identity to the amino acid sequence of any one of VL sequences listed in TABLE 2.1 and TABLE 2.2. In 34 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 some embodiments, the TL1A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2 (SEQ ID NOs: 181-190 and 2275-2383). In some embodiments, the TL1A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 97% sequence identity' with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 98% sequence identity' with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2. In some embodiments, the TL1 A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence according to any one of VH sequences listed in TABLE 2.1 and TABLE 2.2.35 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0117] Table 1. TL1 A Sequences

[0118] Table 1.1 A. amino acid Sequences of exemplary CDRs of Antibody 1-436 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0119] Table 1.2 A. amino acid Sequences of exemplary CDRs of Antibody 1-437 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0120] Table 1.3 A. amino acid Sequences of exemplary CDRs of Antibody 1-4

[0121] Table 1.1 B. amino acid Sequences of exemplary CDRs of Antibody 5-1038 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202639 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0122] Table 1.2 B. amino acid Sequences of exemplary CDRs of Antibody 5-1040 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0123] Table 1.3 B. amino acid Sequences of exemplary CDRs of Antibody 5-1041 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0124] Table 1.1 C. amino acid Sequences of exemplary CDRs of Antibody 11-11942 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202643 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202644 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202645 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202646 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202647 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202648 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202649 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202650 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202651 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202652 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202653 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202654 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202655 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202656 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202657 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202658 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202659 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202660 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0125] Table 1.2 C. amino acid Sequences of exemplary CDRs of Antibody 11-11961 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202662 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202663 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202664 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202665 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202666 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202667 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202668 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202669 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202670 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202671 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0126] Table 1.3 C. amino acid Sequences of exemplary CDRs of Antibody 11-11972 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202673 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202674 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202675 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202676 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202677 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202678 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202679 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202680 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202681 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202682 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0127] TABLE 2.1. SEQUENCES OF HEAVY CHAIN VARIABLE REGIONS (VH) AND LIGHT CHAIN VARIABLE REGIONS (VL) OF TL1A BINDING PROTEINS (ANTIBODY 5-10)83 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202684 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0128] Table 2.2. Sequences of heavy chain variable regions (VH) and light chain variable regions (VL) of TL1 A binding proteins (Antibody 1-4, 11-119)85 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202686 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202687 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202688 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202689 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202690 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202691 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202692 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202693 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202694 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202695 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202696 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202697 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202698 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202699 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026100 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026101 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026102 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026103 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026104 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026105 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026106 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026107 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026108 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026109 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026110 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026111 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026112 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026113 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026114 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0129] In some embodiments, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25) amino acid residues selected from Lys243, Lys240, Thr239, Tyr238, Asp237, Val236, Leu235, Ser234, Ue233, Asp232, Metl58, Argl56, Trpll9, Hisll8, Lyslll, PhellO, Hisl09, Glnl08, Thrl07, Prol06, Thrl05, Glnl04, Argl03, Vall02, and VallOl of a TL1A polypeptide comprising SEQ ID NO: 2493. In another embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acid residues selected from Vai 101, Vai 102, Arg 103, Gin 104, Thr 105, Pro 106, Thr 107, Gin 108, His 109, Phe 110, Lys 111, His 118, Trp 119, Glu 120, Glu 122, Leu 123, Gly 124, Lys 137, Arg 156, Gly 157, Met 158, Ser 234, Tyr 238, and Thr 239 of SEQ ID NO: 2493. In another embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19) amino acid residues selected from Vai 102, Arg 103, Gin 104, Thr 105, Thr 107, Gin 108, His 118, Trp 119, Glu 120, Glu 122, Leu 123, Gly 124, Lys 137, Arg 156, Gly 157, Met 158, Ser 234, Tyr 238, and Thr 239 of SEQ ID NO: 2493. In another embodiment, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, or 9) amino acid residues selected from Lys240, Thr239, Tyr238, Asp237, Val236, Leu235, Ser234, Glnl04, and Argl03 of SEQ ID NO: 2493. In some embodiments, the TL1A binding antibody specifically binds to the TL1A polypeptide comprising SEQ ID NO: 2493 at one or more of amino acid residues Vai 102, Arg 103, Gin 104, Glu 120, Glu 122, Leu 123, and Arg 156.

[0130] In some embodiments, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) amino acid residues selected from Argl03,115 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 ThrlO5, Prol06, Thrl07, Glnl08, Hisl09, Argl56, Asp232, Ile233, Ser234, Leu235. Asp237, Tyr238, Thr239, Lys240, and Glu241 of a TL1A polypeptide comprising SEQ ID NO: 2493. In some embodiments, the anti-TLl A antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, or 12) amino acid residues selected from Argl03, Thrl07, Glnl08, Hisl09, Argl56, Ser231, Ile233, Ser234, Asp237, Tyr238, Thr239, and Glu241 of a TL1A polypeptide comprising SEQ ID NO: 2493. In some embodiments, the anti-TLl A antibody is a TL1A trimer disruptor. In some embodiments, the anti-TLl A antibody, upon binding to TL1A trimer, increases rate of dissociation of the TL1A trimer into TL1A monomer by at least 10%, at least 20%, at least 50%, or more, compared to no treatment. Non-limiting exemplary disruptors include Antibody 19, Antibody 63, Antibody 86 and Antibody 98.

[0131] In some embodiments, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid residues selected from VallOl, Argl03, Glnl04, Thrl05, Thrl07, Hisll8, Glul20, Hisl21, Glul22, Leul23, Argl56, Metl58, Ser234, Tyr238, and Thr239 of a TL1A polypeptide comprising SEQ ID NO: 2493. In some embodiments, the anti-TLIA antibody binds an epitope that includes at least 5 (e.g. 5 or 6) amino acid residues selected from Argl03, Thrl07, Hisl 18, Glul20, Argl56, and Tyr238 of a TL1A polypeptide comprising SEQ ID NO: 2493. In some embodiments, the anti-TLIA antibody is a TL1A trimer stabilizer. In some embodiments, the anti-TLIA antibody, upon selectively binding to a TL1A trimer, decreases rate of dissociation of the TL1A trimer into TL1 A monomer by at least 10%, at least 20%, at least 50%, at least 80%, or more compared to no treatment. Non-limiting exemplary trimer-binding anti-TLIA antibodies include Antibody 10, Antibody 47, Antibody 49, Antibody 69, Antibody 71 and Antibody 92.

[0132] In some embodiments, the TL1 A binding antibody is a TL1A binding antibody disclosed in PCT application No. PCT / US24 / 41774 entitled "TL1A BINDING PROTEINS AND METHODS OF USE," filed on August 9, 2024, which is incorporated by reference herein in its entirety. In some embodiments, the TL1A binding antibody is a TL1A binding antibody disclosed in PCT application No PCT / US24 / 34949 entitled "TL1A ANTIBODY COMPOSITIONS AND METHODS OF USE" filed on June 21, 2024, which is incorporated by reference herein in its entirety.116 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Fc Modifications

[0133] The TL1 A binding protein may comprise a modified Fc region. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0134] In some embodiments, the TL1 A binding protein comprises a modified Fc domain comprising one or more modifications. In some embodiments, the one or more modifications are located in a Fc from IgGl (e.g., human IgGl (hlgGl)). In some embodiments, the one or more modifications are located in a Fc from IgG4 (e.g., human IgG4 (hIgG4)). In some embodiments, the one or more modifications are located in a Fc from IgG2. In some embodiments, the one or more modifications promote selective binding of Fc-gamma receptors.

[0135] In some embodiments, one or more modifications in the modified Fc is selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications in the modified Fc is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0136] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A; V234A / G237A;L235A / G237AZE318A; S228P / L236E; H268Q / V309L / A330S / A33 IS;C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; and L234A / L235A / P329G.

[0137] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA);117 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA);L234A / L235A / P329G (LALAPG); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE;LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS;LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A;D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A;N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W;LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ;LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW; LALAGA / DW;LALAPG / DW; N297A / YD; D265 A / YD; LALA / YD; LAGA / YD; LALAGA / YD;LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV;LALAPG / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV;LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L; SPLE / Q311R / M428L;N297A / Q311R / M428L; D265A / Q311R / M428L; LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L; and LALAPG / Q311R / M428L. In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of L234A / L235A and P329G (PG). In some embodiments, the modified Fc comprises L234A / L235A modifications. In some embodiments, the modified Fc comprises P329G (PG) modifications.

[0138] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in antibody half-life, and / or in a reduction of Fc functionality compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region.118 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0139] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0140] In some embodiments, the binding proteins described herein include posttranslational modifications to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGRIIIa for antibody-dependent cellular cytotoxicity (ADCC), and / or towards Clq for complement-dependent cytotoxicity (CDC).

[0141] In some embodiments, an antibody provided herein comprises a Fc domain (e.g., IgGl) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc domain. Such Fc domains are known to have increased ADCC. In some aspects, such antibodies do not comprise any fucose at position Asn 297.

[0142] In some embodiments, the binding proteins described herein comprise an Fc region with one or more amino acid substitutions which increase ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0143] In some embodiments, the binding proteins described herein comprise an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0144] In some embodiments, the binding proteins described herein comprise one or more alterations that improve or diminish Clq binding and / or CDC.

[0145] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0146] In some embodiments, the TL1A binding proteins described herein (e.g. anti-TLIA antibodies) comprise an extended half-life (i.e., serum half-life) and are also referred herein as long acting TL1 A binding proteins. In some embodiments, the TL1 A binding proteins described herein comprise a half-life of at least about 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 42, 56, 70, 84, 96, or more than 96 days. In some embodiments, the TL1 A binding proteins described herein119 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 comprise a half-life in a range of about 10 to about 20 days, about 10 to about 30 days, about 18 days to about 30 days, about 14 days to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, of about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the TL1 A binding proteins described herein comprise a half-life in a range of about 42 days to about 56 days. In some embodiments, the TL1 A binding proteins described herein comprise a half-life in a range of about 42 days to about 60 days. In a specific embodiment, an anti-TLIA binding protein is an antibody with a popPK half-life of 75 days. In some embodiments, the TL1 A binding proteins described herein comprise a half-life of at least about 18 days. In some embodiments, the TL1A binding proteins described herein comprise a half-life of about 18 days. In some embodiments, the TL1A binding proteins described herein comprise a half-life of at least about 50 days. In some embodiments, the TL1 A binding proteins described herein comprise a half-life of about 50 days. Methods of measuring half-life are known in the art. In some embodiments, the half-life is measured in a rodent model, such as Tg276 mice. In some embodiments, the half-life is measured in a nonhuman primate. In some embodiments, the half-life is measured in a human. In some embodiments, the half-life is measured following intravenous administration. In some embodiments, the half-life is measured following subcutaneous administration.

[0147] In some embodiments, the TL1 A binding proteins described herein have a half-life that is at least 20% longer than a comparator antibody. In some embodiments, the comparator antibody comprises the same complementarity determining regions and variable regions but different Fc regions. In some embodiments, the half-life of the TL1 A binding proteins described herein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than the half-life of the comparator antibody. In some embodiments, the half-life of the TL1A binding proteins described herein is longer than the half-life of the comparator antibody by at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, or at least 10 fold.120 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Combination Products and Methods

[0148] The present disclosure includes combination products, compositions and methods of treatment with combinations of the TL1A inhibitors, e.g., anti-TLIA antibodies, with other immunomodulatory drugs. In a specific embodiment, treatment of a systemic inflammatory disease includes co-administration of a TL1A inhibitor, such as an anti-TLIA antibody, and a corticosteroid, an immunosuppressive drug (e.g., methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide), which aim to reduce inflammation and slow disease progression. Steroids are often indicated for the treatment of inflammatory conditions and may be used in combination with a TL1 A inhibitor, such as an anti-TLIA antibody, at least transiently. In some embodiments, treatment of inflammatory pulmonary diseases includes coadministration of a TL1A inhibitor, such as an anti-TLIA antibody, and at least an IL-23 inhibitor, an IL- 17 inhibitor, an IL- 12 inhibitor, an IL-6 inhibitor, IL-1 inhibitor. In some embodiments, the IL -23 inhibitor is an anti-IL-23 antibody. In some embodiments, the anti-IL-23 antibody is guselkumab, risankizumab, tildrakizumabor mirikizumab, brazikumab or ustekinumab. In some embodiments, the anti-IL-23 antibody is modified to have an extended half-life, e.g., as described in PCT Publication W02024 / 263900. In some embodiments, the IL-17 inhibitor is an anti-IL-17 antibody. The anti-IL-17 antibody can bind IL-17A, IL-17F, or IL17A / F. In some embodiments, the anti-IL-17 antibody is secukinumab, ixekizumab, brodalumab or bimekizumab. In some embodiments, the anti-IL-17 antibody is modified to have an extended half-life as described in PCT Publication WO2024 / 263945. In some embodiments, the IL-12 inhibitor is an anti-IL-12 antibody. The anti-IL-12 antibody can bind IL-12 and / or IL-23. In some embodiments, the anti-IL-12 antibody is ustekinumab. In some embodiments, the IL-6 inhibitor is an anti-IL-6 antibody. In some embodiments, the anti-IL-6 antibody is siltuximab, olokizumab, clazakizumab, sirukumab, or vobarilizumab. In some embodiments, the IL-1 inhibitor is an anti-IL-1 antibody. In some embodiments, the anti-IL-1 antibody is canakinumab.

[0149] In a specific embodiment, treatment of a systemic inflammatory disease includes coadministration of a TL1A inhibitor, such as an anti-TLIA antibody, and another active, a TNF inhibitor (e.g., infliximab) which targets Tumor Necrosis Factor (TNF); an anti-CD20 antibody (e.g., rituximab); and B-cell Activating Factor (BAFF) inhibitor (e.g., belimumab).121 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0150] In a specific embodiment, the anti-IL-23 antibody is an antibody as described in PCT International Application No. PCT / US25 / 14593 filed on February 5, 2025, entitled "IL-23 BINDING PROTEIN COMPOSITIONS AND METHODS OF USE."

[0151] In some embodiments, the anti-IL-23 antibody comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from Table 3A. In some embodiments, anti-IL-23 antibody comprises further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in the same table of Table 3 A. In some embodiments, anti-IL-23 comprises a heavy chain as shown in Table 3.1 A and a light chain as shown in Table 3.1A. In some embodiments, an IL-23 binding protein is means for binding IL-23 with a Fc portion modified to increase half-life in humans compared to that antibody without such modification, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), for example an increase by a factor of at least two, or at least three, or at least four. In some embodiments the half-life extension modification is the YTE modification. In some embodiments the half-life extension modification is the LS modification.

[0152] Table 3A. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of anti-IL-23 antibody122 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0153] Table 3.1 A. Exemplary heavy and light chain amino acid sequences of anti- IL-23 antibody123 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0154] In some embodiments, anti-IL-23 antibody comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from Table 3B. In some embodiments, anti-IL-23 antibody comprises further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in the same table of Table 3B. In some embodiments, anti -IL-23 antibody comprises a heavy chain as shown in Table 3. IB and a light chain as shown in Table 3. IB. In some embodiments, an IL-23 binding protein is means for binding IL -23 with a Fc portion modified to increase half-life in humans compared to that antibody without such modification, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), for example an increase by a factor of at least two, or at least three, or at least four. In some embodiments the half-life extension modification is the YTE modification. In some embodiments the half-life extension modification is the LS modification.

[0155] Table 3B. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of anti-IL-23 antibody124 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0156] Table 3.1 B. Exemplary heavy and light chain amino acid sequences of anti-IL-23 antibody proteins125 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: lanuary 11, 2026

[0157] In some embodiments, anti-IL-23 antibody comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from Table 3C. In some embodiments, anti-IL-23 antibody comprises further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in the same table of Table 3C. In some embodiments, anti-IL-23 antibody comprises a heavy chain as shown in Table 3.1C and a light chain as shown in Table 3.1C. In some embodiments, an IL-23 binding protein is means for binding IL-23 with a Fc portion modified to increase half-life in humans compared to that antibody without such modification, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), for example an increase by a factor of at least two, or at least three, or at least four. In some embodiments the half-life extension modification is the YTE modification. In some embodiments the half-life extension modification is the LS modification.

[0158] Table 3C. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of anti-IL-23 antibody126 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026127 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0159] Table 3.1 C. Exemplary heavy and light chain amino acid sequences of anti-TL-23 antibody

[0160] In some embodiments, anti-IL-23 antibody comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from Table 3D. In some embodiments, anti-IL-23 antibody comprises further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in the same table of Table 3D. In some embodiments, anti-IL-23 antibody comprises a heavy chain as shown in Table 3. ID and a light chain as shown in Table 3. ID. In some embodiments, an IL-23 binding protein is means for binding IL-23 with a Fc portion modified to increase half-life in humans compared to that antibody without such modification, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), for example an increase by a factor of at least two, or at least three, or at least four. In some embodiments the half-life extension modification is the YTE modification. In some embodiments the half-life extension modification is the LS modification.128 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0161] Table 3D. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of anti-IL-23 antibody129 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0162] Table 3.1 D. Exemplary heavy and light chain amino acid sequences of anti-IL-23 antibodyEXEMPLARY EMBODIMENTS

[0163] Embodiment 1. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising: administering to the subject an effective amount of a TL1A inhibitor, wherein administration of the effective amount of the TL1A inhibitor results in improvement in one or more of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment.

[0164] Embodiment 2. A method for treating or reducing systemic inflammation in a subject in need thereof, comprising: administering to the subject an effective amount of a TL1A inhibitor, wherein administration of the effective amount of the TL1 A inhibitor results in reducing systemic inflammation associated with a disease.

[0165] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the TL1A inhibitor is an anti-TLIA antibody.130 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0166] Embodiment 4. The method of embodiment 3, wherein the anti-TLIA antibody is modified to be half-life extended.

[0167] Embodiment 5. The method of embodiment 3 or embodiment 4, wherein the anti-TLl A antibody comprises a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; and c) a modified Fc that extends half-life of the anti-TLl A antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc.

[0168] Embodiment 6. The method of embodiment 5, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE).

[0169] Embodiment 7. The method of any one of embodiments 3-6, wherein the anti-TLIA antibody binds TL1A with a dissociation constant (KD) less than about 0.5 nanomolar (nM).

[0170] Embodiment 8. The method of any one of embodiments 3-6, wherein the anti-TLIA antibody binds TL1A with a dissociation constant (KD) less than about 0.4 nanomolar (nM).

[0171] Embodiment 9. The method of any one of embodiments 1-8, wherein the effective amount of the TL1A inhibitor is administered to the subject at disease onset.

[0172] Embodiment 10. The method of any one of embodiments 1-8, wherein the effective amount of the TL1 A inhibitor is administered after onset of symptoms of the systemic inflammatory disease.

[0173] Embodiment 11. The method of any one of embodiments 1-10, wherein the subject is a human.

[0174] Embodiment 12. The method of any one of embodiments 1-11, wherein the systemic inflammatory disease is selected from the group consisting of Addison's disease, autoimmune131 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) Vasculitis, and primary biliary cholangitis (PBC).

[0175] Embodiment 14. The method of any one of embodiments 1-11, wherein administration of the effective amount of the TL1A inhibitor results in improvement of systemic inflammation associated with Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) Vasculitis, primary biliary cholangitis (PBC), primary Sclerosing Cholangitis (PSC), systemic sclerosis, or Systemic Lupus Erythematosus.

[0176] Embodiment 15. The method of embodiments 3-14, wherein administration of the effective amount of the anti-TLIA antibody to the subject results in changes of serum cytokines, modulation of fibroblast and fibroblast-like cells, modified histopathology, and / or altered RNA expression in peripheral blood cells and / or tissue, cells or fluid from biopsy, compared to no treatment.

[0177] Embodiment 16. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody.

[0178] Embodiment 17. A method for treating or reducing systemic inflammation in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody.

[0179] Embodiment 18. The method of embodiment 16 or embodiment 17, wherein administration of the effective amount of the anti-TLIA antibody results in improvement in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems.

[0180] Embodiment 19. The method of any one of embodiments 16-18, wherein the anti-TLIA antibody is modified to be a half-life extended antibody.132 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0181] Embodiment 20. The method of embodiment 19, wherein the anti-TLl A antibody comprises a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRH1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRH2 sequences listed in TABLE 1.1 A, TABLE 1.1 B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRH3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of CDRL1 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, (ii) a CDR2 having an amino acid sequence according to any one of CDRL2 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C, and (iii) a CDR3 having an amino acid sequence according to any one of CDRL3 sequences listed in TABLE 1.1 A, TABLE LI B, and TABLE 1.1 C; and c) a modified Fc that extends half-life of the anti-TL1A antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc.

[0182] Embodiment 21. The method of embodiment 20, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) according to EU numbering system.

[0183] Embodiment 22. The method of any one of embodiments 16-21, wherein the subject is a human.

[0184] Embodiment 23. The method of any one of embodiments 16-22, wherein administration of the effective amount of the anti-TLIA antibody to the subject results in changes of serum cytokines, modulation of fibroblast and fibroblast-like cells, modified histopathology, and / or altered RNA expression in peripheral blood cells and / or tissue, cells or fluid from biopsy, compared to no treatment.

[0185] Embodiment 24. The method of any one of embodiments 16-23, wherein the effective amount of the anti-TLIA antibody is administered to the subject at disease onset or after onset of symptoms of a systemic inflammatory disease.

[0186] Embodiment 25. The method of any one of embodiments 16-24, wherein administration of the effective amount of the anti-TLIA antibody to the subject results in reduction of TNF alpha, TL1A, IL-1, IL-4, IL- 5, IL- 6, IL-13, IL- 17, and / or INFgamma.

[0187] Embodiment 26. The method of any one of embodiments 3-25, wherein the effective amount of the anti-TLIA antibody is administered intravenously.133 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0188] Embodiment 27. The method of any one of embodiments 3-25, wherein the effective amount of the anti-TLIA antibody is administered subcutaneously.

[0189] Embodiment 28. A method of treating a systemic inflammatory disease in a subject in need thereof, the method comprising administering subcutaneously an effective amount of a long acting anti-TLIA antibody, wherein subcutaneous administration of the effective amount of the long acting anti-TLIA antibody results in improvements in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, or a combination thereof.

[0190] Embodiment 29. The method of embodiment 28, wherein the systemic inflammatory disease is selected from the group consisting of Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, ANCA vasculitis, and PBC.

[0191] Embodiment 30. The method of any one of embodiments 3-29, wherein the anti-TLIA antibody comprises a heavy chain variable region (VH) having an amino acid sequence according to Table 2.1 and a light chain variable region (VL) according to Table2.1. Embodiment 31. The method of any one of embodiments 3-29, wherein the anti-TLIA antibody comprises a heavy chain variable region (VH) having an amino acid sequence according to Table 2.2 and a light chain variable region (VL) according to Table 2.2.

[0192] Embodiment 32: A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody that binds to a TL1A trimer to form an antibody-TLIA complex, wherein the antibody -TL1A complex, when comprises 3:1 ratio of the anti-TLIA antibody to the TL1A trimer, exhibits at least 10% faster rate of clearance relative to an antibody-TLIA complex comprising less than 3 : 1 ratio of the anti-TLIA antibody to the TL1 A trimer.

[0193] Embodiment 33: The method of embodiment 32, wherein the anti-TLIA antibody, upon selectively binding to a TL1A trimer, decreases rate of dissociation of the TL1A trimer into TL1 A monomer by at least 10% compared to no treatment.

[0194] Embodiment 34: The method of embodiment 33, wherein the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from VallOl, Argl03, Glnl04,134 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 ThrlO5, Thrl07, Hisl 18, Glul20, Hisl21, Glul22, Leul23, Argl56, Met158, Ser234, Tyr238, and Thr239 of a TL1A polypeptide comprising SEQ ID NO: 2493.

[0195] Embodiment 35: The method of embodiment 32, wherein the anti-TLIA antibody, upon binding to TL1 A trimer, increases rate of dissociation of the TL1A trimer into TL1A monomer by at least 10% compared to no treatment.

[0196] Embodiment 36: The method of embodiment 35 wherein the anti-TLIA antibody binds an epitope that includes at least 5 amino acid residues selected from Argl03, Thrl05, Prol06, Thrl07, Glnl08, Hisl09, Argl56, Asp232, Ile233, Ser234, Leu235. Asp237, Tyr238, Thr239, Lys240, and Glu241 of a TL1A polypeptide comprising SEQ ID NO: 2493.

[0197] Embodiment 37. Use of a half-life extended anti-TLIA antibody for treating a systemic inflammatory disease in a subject in need thereof, comprising administering subcutaneously an effective amount of the half-life extended anti-TLIA antibody, wherein subcutaneous administration of the effective amount of the half-life extended anti-TLIA antibody results in improvement in one or more of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment.

[0198] Embodiment 38. Use of a half-life extended anti-TLIA antibody for treating a systemic inflammatory disease in a subject in need thereof, comprising administering an effective amount of the half-life extended anti-TLIA antibody, wherein administration of the effective amount of the half-life extended anti-TLIA antibody results in improvement in one or more of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment.

[0199] Embodiment 39. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.1, and wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLl A) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0200] Embodiment 40. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA135 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.2, and wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0201] Embodiment 41. A method of treating a systemic inflammatory disease in a subject in need thereof, the method comprising administering subcutaneously an effective amount of a half-life extended anti-TLIA antibody, wherein subcutaneous administration of the effective amount of the half-life extended anti-TLIA antibody results in improvements in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, or a combination thereof compared to no treatment.

[0202] Embodiment 42. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.1, and wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0203] Embodiment 43. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.2, and wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0204] Embodiment 44. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody, comprising:136 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0205] Embodiment 45. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising: administering to the subject an effective amount of an anti- TLIA antibody, comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE LI B;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE LI B; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.137 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0206] Embodiment 46. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising: administering to the subject an effective amount of an anti- TL1A antibody, comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 C;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 C; and(c) a modified Fc domain that extends half-life of the anti-TLl A antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0207] Embodiment 47. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti- TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 A;(b) a light chain variable region (VL) comprising:138 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 A; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0208] Embodiment 48. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti- TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE LI B;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE LI B,139 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE LI B; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

[0209] Embodiment 49. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti- TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 C;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 C, and140 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 C; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.EXAMPLES

[0210] The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and is not intended to limit the disclosure.EXAMPLE 1. Rat Collagen Induced Arthritis (CIA) Model to Compare Anti-TLIA Antibody AbX to TNF Inhibitor Positive Control

[0211] Rat CIA models have been widely used as a model of human rheumatoid arthritis (RA) and psoriatic arthritis (PsA), as they share joint pathological features of similar to that of RA and PsA. These models are also relevant for systemic inflammatory disease.

[0212] The in vivo biological activity of anti-TLIA antibody AbX, a fully human anti-TLIA antibody with LALA and YTE modifications of the Fc region, was evaluated in two versions of a collagen-induced arthritis (CIA) model in rats: the semi-established model and the therapeutic model (FIG. 1). In order to induce arthritis, 6-8 week old female Wistar rats were subcutaneously injected in the tail with 200 pL of a bovine type II collagen emulsion in Freund’s incomplete adjuvant (IF A) on study days 0 and 7. The collagen-IFA emulsion was prepared by dissolving bovine type II collagen in 100 mM acetic acid at 4 mg / mL, mixing with IFA in a 1:1 (vol / vol) ratio and homogenizing the mixture for 1 hour on ice.

[0213] Binding of AbX to rat TL1A was evaluated to ensure appropriateness of the rat CIA model. Using surface plasmon resonance (SPR), the following binding values were determined: ka(M^s'1) of 1.38xl05; kd (s'1) of 5.87xl0'4; and KD (M) of 4.27xl0'9(FIG. 2). Enteracept has previously been shown to be active in rats as an anti -arthritic agent in the collagen-induced model (Lon, et al., Pharm Res 28:1622-1630 [20-11] doi 10.1007 / sl 1095-011-0396-7).141 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0214] In the semi-established CIA model, dosing of test articles was started on study day 6 prior to the second injection of collagen and before the beginning of observable symptoms. Anti-TL1 A antibody AbX was diluted into phosphate-buffered saline (PBS) and dosed intravenously on study days 6, 13 and 20. The comparator TNF inhibitor, Etanercept, was diluted into PBS and dosed intraperitoneally every three days starting on day 6 until the end of the study (day 25). Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgGl.

[0215] In the therapeutic CIA model, dosing of the test articles was started on study day 13 after the rats started showing symptoms of arthritis. Anti-TLl A antibody AbX was diluted into PBS and dosed intravenously on study days 13 and 20. Etanercept was diluted into PBS and dosed intraperitoneally every three days starting on day 13 until the end of the study (day 25).

[0216] Control populations including healthy untreated animals, animals treated with vehicle but no active, and animals treated with an isotype-matched (IgGl) nonspecific antibody (RecombiMAb human IgGl isotype control, anti-hen egg lysozyme (BioXCell)) as the same dosing schedules as the test articles.

[0217] The volumes of both hind paws were measured twice per week using plethysmography. Each rat paw was evaluated for disease severity twice per week and was given a score based upon the following observations: score 0 - no arthritis, score 1 - swelling and / or redness of one to two interphalangeal (IP) joints, score 2 - involvement to three to four IP joints or one large joint, score 3 - more than four joints red or swollen, score 4 - severe arthritis of entire paw. The arthritis score is the sum of the scores for all four paws. In the semi-established model, AbX reduced arthritis score better than etanercept (FIG.3). Both actives showed significant improvement compared to controls (FIG. 3). AbX and etanercept both reduced the arthritis score relative to the vehicle and isotype controls in the therapeutic model, with no difference in arthritis score comparing etanercept monotherapy with AbX monotherapy (FIG. 4). Both AbX and enteracept reduced the increase in foot volume relative to vehicle and isotype controls in both models. AbX reduced the increase in foot volume compared to etanercept in the semiestablished model (FIG. 5), and there was no difference in foot volume measurement comparing etanercept with AbX in the therapeutic model (FIG. 6).142 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026

[0218] Both AbX and etanercept significantly reduced the hind paw x-ray score relative to vehicle and isotype controls in both then semi-established CIA model and the therapeutic CIA model (FIG. 7 and FIG. 8). AbX reduced more the hind paw x-ray score compared to etanercept in the semi-established model (FIG. 7), and there was no significant difference in hind paw x-ray score comparing etanercept with AbX in the therapeutic model (FIG. 8). AbX significantly reduced the histopathological scores (infiltration of cells (FIG. 9A), pannus severity grade (FIG.9B), cartilage lesion severity grade (FIG. 9C), bone resorption severity grade (FIG. 9D)) relative to the vehicle in the semi-established CIA model. There was not statistical difference in histopathological scores comparing etanercept relative to the vehicle or to the isotype control in the semi-established CIA model. (FIGs. 9A-9D)

[0219] In sum, the data show that anti-TLIA antibody AbX, a fully human anti-TLIA antibody with LALA and YTE modifications of the Fc region, was effective in treating rheumatic disease as demonstrated in two versions of a collagen-induced arthritis (CIA) model in rats: the semiestablished model and the therapeutic model. In some instances, AbX was more effective than etanercept. These data show the potential of anti-TLIA antibody, particularly a half-life extended anti-TLIA antibody, in treating a systemic inflammatory disease.EXAMPLE 2: Modelling for dose selection of anti-TLIA antibody for treating systemic inflammatory disease

[0220] PK simulations for three regimens were generated for treating i systemic inflammatory disease using the anti-TLIA antibody. The three regimens are summarized in Table 4.Table 4. Proposed regimens for treating systemic inflammatory disease using the anti- TLIA antibody

[0221] The results were generated for reducing soluble TL1A level from 500 pg / mL in serum (baseline) to 100 pg / mL after week 12. The projected PK parameters are summarized in Table 5.143 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Table 5. Pop PK Pop PK-PD Projected in systemic inflammatory disease treatment

[0222] Projected Ctrough values for regimen 1, 2 and 3 at week 12 are expected to be 118, 25.1 and 73.3, respectively. Likewise, projected Ctrough values for regimen 1, 2 and 3 at week 36 are expected to be 7.6, 3.9 and 6.3, respectively.

[0223] Based on the analysis it was projected that Regimen 1 can achieve >90% target suppression in serum and in tissue in nearly all subjects during induction phase and in ~ 90% of subject during maintenance phase. The safety margin was projected to be about 1 for AUCo-i2w. Likewise, Regimen 2 can achieve >90% target suppression in serum and in tissue in nearly all subjects during induction phase and in at least 70% of subject during maintenance phase. The safety margin was projected to be about 2.4 for AUCo-nw.EXAMPLE 3. PK Modelling for anti-TLIA antibody for treating systemic inflammatory disease

[0224] To estimate human exposures to Antibody 63, a population PK model using Antibody 63 was developed based on interim data. The final model was a 2-compartment model with first-order absorption from the SC injection site and a first-order elimination from the central compartment. For a typical participant, the estimated CL with Antibody 63 was 70.4 mL / d (3 to 4-fold lower than the typical therapeutic IgG, half-life was -45.5 days [individual participant range 31.5 to 64.5 days], which is -2 -fold longer than the typical therapeutic IgG) and F was -60.2% (individual participant range 44.8% to 80.1%). Population Pharmacokinetics-Predicted Exposures in Humans (Median and 2.5-97.5th Percentile) are summarized in Table 6.144 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Table 6. Estimated human exposures at the proposed dose regimensAUC=area under the concentration-time curve from 0 to 12 or 16 weeks (AUC12 and AUC16); Cmax=maximum observed concentration; Ctrough=concentration trough (pre-dose); NC=not calculated; W=weekNote: Simulations were conducted for 1000 healthy participants and 2000 patients per regimen. Note: Assumed that clearance was 15% higher for participants compared to healthy participants Note: Week 0=Day 1, Baseline (first dose of investigational product)EXAMPLE 4. Population PK-PD Modeling and Simulations

[0225] To support dosing of Antibody 63, a population PK-PD model was built using PK and PD data from the interim analysis. The sequential fitting method was used, with population PK parameters estimated as described in Example 2.

[0226] A population PK-PD antibody-antigen binding model was developed to describe the increase of serum total sTLIA following Antibody 63 administration. The Ab-Ag binding parameters were fixed based on measured value as described in Table 7.145 ACTIVE 717944513v1Attorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 Table 7. Antibody 63 Binding Kinetics and Affinity to Human TL1AAbbreviations: constant; kd=dissociation constant; KD= equilibrium dissociation constant between the antibody and its antigen

[0227] All other PD parameters were estimated. The population PK-PD model adequately captured the observed total sTLIA profiles in healthy participants and supported the notion that an increase in total soluble TL1 A is attributed to longer apparent half-life of Ab-Ag complexes (11 days for a typical patient) compared to free sTLIA (~1 hour).

[0228] The population PK-PD model was used to predict the systemic and tissue exposure and free sTLIA. Specifically, for each dosing regimen, PK and PD endpoints were simulated for 2000 virtual subjects. The baseline sTLIA in serum and tissue of patients were assumed to be -500 pg / mL during induction and -100 pg / mL during the Extension Period (i.e., the rate of sTLIA production was assumed to be 5-fold lower compared to induction and equivalent to that in healthy levels, as measured with total sTLAl assay in placebo participants (Table provided in Example 3). The serum to synovial fluid partition coefficient for the antibody was assumed to be 0.35 The clearance of Antibody 63 was assumed to be 15% higher compared to healthy participants, as reported for mAbs in autoimmune conditions. The model-based predictions are shown in FIGS. 10A, 10B, 11A and 11B

[0229] Based on these simulations, Dosing Regimen 1 is projected to achieve >90% target suppression in serum and tissue in most participants at the primary efficacy endpoint (Week 12) and in -70 to 90% of participants during the Extension Period. Nearly all participants are projected to achieve 80% target suppression throughout the Extension Period.

[0230] Based on these simulations, Dosing Regimen 2 is projected to achieve >80% target suppression in serum and tissue in -70 to 90% of the participants at the primary efficacy endpoint (Week 12) and throughout the Extension Period.146 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 INCORPORATION BY REFERENCE

[0231] All publications and patents cited throughout the text of this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety for all purposes. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.EQUIVALENTS

[0232] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.147 ACTIVE 717944513v1

Claims

Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 CLAIMSWhat is claimed is:

1. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody, comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

2. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody, comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 B,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 B, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 B;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 B,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 B, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 B; and148 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (c) a modified Fc domain that extends half-life of the anti-TLl A antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

3. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody, comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 C;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 C; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

4. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 A,149 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 A;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 A; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

5. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE LI B,150 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE LI B;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE LI B; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

6. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-TLIA antibody comprising:(a) a heavy chain variable region (VH) comprising:(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 C,151 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 C;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 C; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLl A antibody that does not comprise the modified Fc domain,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

7. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.1,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.152 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 20268. A method for treating a systemic inflammatory disease in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLl A antibody comprising a heavy chain variable region (VH) sequence and a light chain variable region (VL), wherein the VH sequence has at least 95% sequence identity with an amino acid sequence according to any one of the amino acid sequences listed in Table 2.2,wherein administration of the effective amount of the anti-TLIA antibody reduces an amount of free soluble TL1 A (sTLIA) in the subject compared to no treatment, thereby treating the systemic inflammatory disease.

9. The method of any one of claims 1-8, wherein administration of the effective amount of the anti-TLIA antibody results in improvement in one or more of systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, compared to no treatment.

10. A method for treating or reducing systemic inflammation in a subject in need thereof, comprising:administering to the subject an effective amount of a half-life extended anti-TLIA antibody, wherein administration of the effective amount of the half-life extended anti-TLIA antibody results in reducing systemic inflammation associated with a systemic inflammatory disease compared to no treatment.

11. A method for treating or reducing systemic inflammation in a subject in need thereof, comprising:administering to the subject an effective amount of an anti-TLIA antibody, wherein administration of the effective amount of the anti-TLIA antibody results in reducing systemic inflammation associated with a systemic inflammatory disease compared to no treatment.

12. The method of any one of claims 1-11, wherein the effective amount of the anti-TLIA antibody is administered intravenously.153 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 13. The method of any one of claims 1-11, wherein the effective amount of the anti-TLl A antibody is administered subcutaneously.

14. A method of treating a systemic inflammatory disease in a subject in need thereof, the method comprising administering subcutaneously an effective amount of a half-life extended anti-TLIA antibody, wherein subcutaneous administration of the effective amount of the half-life extended anti-TLIA antibody results in improvement in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, or a combination thereof compared to no treatment.

15. The method of any one of claims 1-14, wherein the effective amount of the anti-TLIA antibody is administered to the subject every 3 months (Q3M) or every 6 months (Q6M).

16. The method of any one of claims 10-15, wherein the anti-TLIA antibody comprises:(a) a heavy chain variable region (VH) comprising(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 A, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 A;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 A,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 A, and154 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 A, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 A; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain.

17. The method of any one of claims 10-15, wherein the anti-TLIA antibody comprises:(a) a heavy chain variable region (VH) comprising(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE LI B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE LI B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE LI B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE LI B;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE LI B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE LI B,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE LI B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE LI B, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 B, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE LI B; and(c) a modified Fc domain that extends half-life of the anti-TLIA antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain.

18. The method of any one of claims 10-15, wherein the anti-TLIA antibody comprises:155 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 (a) a heavy chain variable region (VH) comprising(i) a CDR1 comprising any one of CDRH1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRH2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRH3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRH3 sequences listed in TABLE 1.1 C;(b) a light chain variable region (VL) comprising:(i) a CDR1 comprising any one of CDRL1 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL1 sequences listed in TABLE 1.1 C,(ii) a CDR2 comprising any one of CDRL2 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL2 sequences listed in TABLE 1.1 C, and(iii) a CDR3 comprising any one of CDRL3 sequences listed in TABLE 1.1 C, or a variant thereof that comprises 1 to 2 amino acid modifications as compared to a corresponding CDRL3 sequences listed in TABLE 1.1 C; and(c) a modified Fc domain that extends half-life of the anti-TLl A antibody as compared to an anti-TLIA antibody that does not comprise the modified Fc domain.

19. The method of any one of claims 1-6 and 16-18, wherein the modified Fc domain comprises M252Y, S254T, and T256E (YTE) according to EU numbering system.

20. The method of any one of claims 1-19, wherein the anti-TLIA antibody binds TL1A with a dissociation constant (KD) less than about 0.5 nanomolar (nM).

21. The method of any one of claims 1-19, wherein the anti-TLIA antibody binds TL1A with a dissociation constant (KD) less than about 0.4 nanomolar (nM).156 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 202622. The method of any one of claims 1-21, wherein the effective amount of the anti-TLIA antibody is administered to the subject at disease onset.

23. The method of any one of claims 1-21, wherein the effective amount of the anti-TLIA antibody is administered after onset of symptoms of the systemic inflammatory disease.

24. The method of any one of claims 1-23, wherein the subject is a human.

25. The method of any one of claims 1-24, wherein the systemic inflammatory disease is selected from the group consisting of Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) Vasculitis, and primary biliary cholangitis (PBC).

26. The method of any one of claims 1-25, wherein administration of the effective amount of the anti-TLIA antibody results in improvement of systemic inflammation associated with Addison's disease, autoimmune hemolytic anemia, chronic active hepatitis, Goodpasture syndrome, graft-versus-host disease, Hashimoto's thyroiditis, immune thrombocytopenia, leprosy, lupus nephritis, multiple sclerosis, myasthenia gravis, myositis, pernicious anemia, primary myxedema, Graves' disease, type 1 diabetes mellitus, sarcoidosis, Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) Vasculitis, primary biliary cholangitis (PBC), primary Sclerosing Cholangitis (PSC), systemic sclerosis, or Systemic Lupus Erythematosus.

27. The method of any one of claims 1-26, wherein administration of the effective amount of the anti-TLIA antibody to the subject results in changes of serum cytokines, modulation of fibroblast and fibroblast-like cells, modified histopathology, and / or altered RNA expression in peripheral blood cells and / or tissue, cells or fluid from biopsy, compared to no treatment.157 ACTIVE 717944513v1Atorney Docket No. 220703-011901 / PCT Electronically Filed: January 11, 2026 28. The method of any one of claims 1-27, wherein administration of the effective amount of the anti-TLIA antibody to the subject results in reduction of TNFoc, TL1A, IL-1, IL-4, IL-5, IL-6, IL- 13, IL- 17, and / or INFy29. Use of a half-life extended anti-TLIA antibody for treating a systemic inflammatory disease in a subject in need thereof, comprising administering an effective amount of the half-life extended anti-TLIA antibody, wherein administration of the effective amount of the half-life extended anti-TLIA antibody results in improvement in systemic inflammation, tissue damage, and functional impairment affecting multiple organ systems, or a combination thereof compared to no treatment.158 ACTIVE 717944513v1

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