TL1A antibody composition and method of use

Abstract

TL1A is elevated in individuals with inflammatory diseases, including Crohn's disease and ulcerative colitis. Therefore, TL1A, along with other members of the TNF superfamily, is being investigated as a therapeutic target to treat inflammatory diseases, including inflammatory bowel disease. Current biologics targeting TNF are associated with serious side effects, highlighting the need for improved treatments targeting TL1A. A variant TL1A antibody and its use for treating inflammatory diseases, including inflammatory bowel disease, are provided herein. The TL1A antibody also contains a modified Fc region for extended serum half-life.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 509,463, filed on June 21, 2023, the entire content of which is incorporated herein by reference.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy (creation date: June 12, 2024) is named PRG - 006WO_SL.xml and has a size of 416 kilobytes.

Background Art

Summary of the Invention

Means for Solving the Problems

[0004] Summary of the Disclosure In certain embodiments, TL1A-binding proteins are described herein that include a) a heavy chain variable region (VH) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 1 to 18, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 19 to 36, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 37 to 54; b) a light chain variable region (VL) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 55 to 72, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 73 to 90, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 91 to 108; and c) an Fc domain comprising amino acid modifications M252Y, S254T, and T256E(YTE), and / or M428L and N434S(LS). In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 1, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 19, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 37; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 55, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 73, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 91. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 2, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 20, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 38; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 56, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 74, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 92. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 3, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 21, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 39; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 57, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 75, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 93.In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 4, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 22, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 40; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 58, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 76, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 94. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 5, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 23, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 41; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 59, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 77, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 95. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 6, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 24, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 42; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 60, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 78, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 96. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 7, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 25, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 43; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 61, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 79, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 97.In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 8, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 26, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 44; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 62, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 80, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 98. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 9, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 27, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 45; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 63, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 81, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 99. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 10, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 28, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 46; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 64, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 82, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 100. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 11, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 29, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 47; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 65, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 83, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 101.In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 12, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 30, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 48; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 66, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 84, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 102. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 13, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 31, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 49; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 67, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 85, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 103. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 14, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 32, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 50; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 68, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 86, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 104. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 15, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 33, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 51; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 69, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 87, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 105.In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 16, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 34, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 52; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 70, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 88, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 106. In some embodiments, VH includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 17, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 35, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 53; VL includes (i) CDR1 having the amino acid sequence according to SEQ ID NO: 71, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 89, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 107. In some embodiments, VH includes (i) CDR1 having the amino acid sequence of SEQ ID NO: 18, (ii) CDR2 having the amino acid sequence of SEQ ID NO: 36, and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 54; VL includes (i) CDR1 having the amino acid sequence of SEQ ID NO: 72, (ii) CDR2 having the amino acid sequence of SEQ ID NO: 90, and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 108. In some embodiments, VH includes a sequence having at least 80% sequence identity with any one of the amino acid sequences of SEQ ID NOs. 325 to 342, and VL includes a sequence having at least 80% sequence identity with any one of the amino acid sequences of SEQ ID NOs. 343 to 360. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 344.In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334, and VL includes... , includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, VH includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342, and VL includes a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, Fc is an IgG1, IgG2, or IgG4 immunoglobulin Fc domain. In some embodiments, Fc is an IgG1 immunoglobulin domain. In some embodiments, Fc is the IgG2 immunoglobulin domain.In some embodiments, Fc is the IgG4 immunoglobulin domain.

[0005] In a particular embodiment, a TL1A-binding protein comprising a) a heavy chain variable region (VH) having (i) an amino acid sequence of any one of SEQ ID NOs: 1 to 18, (ii) a CDR2 having an amino acid sequence of any one of SEQ ID NOs: 19 to 36, and (iii) a CDR3 having an amino acid sequence of any one of SEQ ID NOs: 37 to 54; b) a light chain variable region (VL) having (i) a CDR1 having an amino acid sequence of any one of SEQ ID NOs: 55 to 72, (ii) a CDR2 having an amino acid sequence of any one of SEQ ID NOs: 73 to 90, and (iii) a CDR3 having an amino acid sequence of any one of SEQ ID NOs: 91 to 108; and c) a modified Fc which extends the half-life of the TL1A-binding protein compared to a TL1A-binding protein that does not contain the modified Fc, is described herein.

[0006] In some embodiments, TL1A-binding proteins are described herein, wherein the TL1A-binding protein specifically binds to the epitope of TL1A and comprises an Fc domain including amino acid modifications M252Y, S254T, and T256E(YTE), and / or M428L and N434S(LS).

[0007] In certain embodiments, a method for treating inflammatory bowel disease in a patient in need is described herein, the method comprising administering an effective amount of the TL1A-binding protein described herein subcutaneously or intravenously to the patient. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the administration of the TL1A-binding protein is subcutaneous. In some embodiments, the administration of the TL1A-binding protein is intravenous. [Modes for carrying out the invention]

[0008] Detailed explanation To facilitate understanding of this disclosure, many terms and phrases are defined below.

[0009] 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 (e.g., an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody)), or an antigen-binding fragment of an antibody containing an intact antibody (e.g., an antigen-binding fragment of a monoclonal antibody), an antigen-binding fragment, or an Fc fragment that has been modified, manipulated, or chemically conjugated. Generally, an antibody is a multimeric protein containing 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 linked by interchain disulfide bonds. The immunoglobulin heavy chains are linked by interchain disulfide bonds. The light chains consist 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 (CH1, CH2, and CH3). The variable region determines the antibody binding specificity. Each variable region contains three hypervariable regions known as complementarity-determining regions (CDRs), adjacent to four relatively conserved regions known as framework regions (FRs). The ranges of the FRs and CDRs are defined (Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US 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 antibody binding specificity. Naturally occurring antibodies are used as starting materials for engineered antibodies (e.g., 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 modified or manipulated antibodies include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is one in which the toxin portion is conjugated.

[0010] The terms "variable domain" and "variable region" refer to a portion of an antibody or immunoglobulin domain that is interchangeable, exhibits variability in its sequence, and is involved in determining the specificity and binding affinity of a particular antibody. Variability is not uniformly distributed throughout the antibody's variable domain; it is concentrated within the subdomains of the heavy and light chain variable regions. These subdomains are referred to as "hypervariable regions" or "complementarity-determining regions" (CDRs). The more conserved (i.e., non-hypervariable) portion of the variable domain is called the "framework" region (FRM or FR), which provides a scaffold for six CDRs in three-dimensional space, forming the antigen-binding surface.

[0011] As used herein, the “Fc polypeptide” of dimer Fc refers to one of the two polypeptides that form the dimer Fc domain (i.e., the polypeptide containing the C-terminal constant region of the immunoglobulin heavy chain and possessing the ability to stably self-associate). For example, the Fc polypeptide of dimer IgG Fc contains the IgG CH2 and IgG CH3 constant domain sequences. Fc can be of classes IgA, IgD, IgE, IgG, and IgM. These classes are also denoted as α, δ, ε, γ, and μ, respectively. Some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0012] The terms “Fc receptor” and “FcR” are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR can be a human FcR in its natural sequence. Generally, FcRs are those that bind to IgG antibodies (γ receptors) and include the FcγRI, FcγRII, and FcγRIII subclass receptors, which include allele variants and alternatively spliced ​​forms of these receptors. Examples of FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have different but similar amino acid sequences, primarily in their cytoplasmic domains. Other isotypes of immunoglobulins 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)). The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) within its cytoplasmic domain (reviewed in Daeron, Annu. 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" as used herein. The above terms also include FcRn, the fetal receptor responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0013] The terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably herein and, in some embodiments, refer to any mammalian subject, in particular human, for which diagnosis, treatment, or therapy is desired. “Mammal” for treatment purposes refers to any animal classified as a mammal (including humans, domesticated animals and livestock, as well as animals kept for laboratory, zoo, competition, or pet purposes (e.g., 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 a medical professional.

[0014] As used herein, the term “effective dose” means an amount of a compound (e.g., a compound of this disclosure) sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or applications and is not intended to be limited to any particular formulation or route of administration. As used herein, the term “to treat” includes any effect that results in improvement of a condition, disease, disorder, etc., such as reducing, mitigating, regulating, improving or eliminating, or improving the symptoms thereof.

[0015] As used herein, the term “pharmaceutical composition” refers to a combination of an active agent and a carrier, inactive or active substance, which makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0016] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutically acceptable carriers (e.g., phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents). The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA (1975).

[0017] The terms “a” and “an” as used herein mean “one or more,” and include the plural unless the context is appropriate.

[0018] As used herein, all numbers or numerical ranges include all integers within or encompassing such a range, and fractions of values ​​or integers within or encompassing such a range, unless the context otherwise clearly indicates otherwise. Thus, for example, a reference to the range 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. In another example, references to the range of 1 to 5,000 times include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, 2.1, 2.2, 2.3, 2.4, 2.5 times, etc.

[0019] As used herein, "approximately" a number means a range that includes that number and extends from 10% below that number to 10% above that value. "Approximately" a range means that extends from 10% below the lower limit of that range to 10% above the upper limit of that range.

[0020] "Percent (%) identity" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same position in their alignment. For example, "an amino acid sequence is X% identical to sequence number Y" refers to the % identity of the amino acid sequence to sequence number Y, and is further detailed as X% of the residues in that amino acid sequence being identical to the residues in the sequence disclosed in sequence number Y. Generally, computer programs are employed for such calculations. Exemplary programs for comparing and aligning 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).

[0021] Throughout this description, where a composition is described as having, including, or comprising, certain components, or where a process and method is described as having, including, or comprising, certain steps, it is intended that the compositions of the Disclosure are essentially or consist of the components described, and that the processes and methods relating to the Disclosure are essentially or consist of the processing steps described.

[0022] As a general rule, percentages of compositions are expressed in units of weight unless otherwise specified. Furthermore, if a variable is not given a definition, the previous definition of that variable takes precedence.

[0023] TL1A-binding protein TL1A-binding proteins comprising a modified Fc region are provided herein. In certain embodiments, a) a heavy chain variable region (VH) comprising: (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-18, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19-36, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37-54; b) a light chain variable region (VL) comprising: (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 91-108; and c) an Fc domain comprising the amino acid modifications M252Y, S254T, and T256E (YTE), and / or M428L and N434S (LS), are described herein.

[0024] In certain embodiments, a) a heavy chain variable region (VH) comprising: (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-18, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19-36, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37-54; b) a light chain variable region (VL) comprising: (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 91-108; and c) an Fc domain comprising a modified Fc that extends the half-life of the TL1A-binding protein as compared to a TL1A-binding protein that does not comprise the modified Fc, are further described herein.

[0025] In certain embodiments, a TL1A binding protein is provided, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain comprising the amino acid modifications M252Y, S254T, and T256E (YTE), and / or M428L and N434S (LS), and the TL1A binding protein is further described herein.

[0026] Exemplary amino acid sequences of CDRs of the TL1A binding protein are provided in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0027] In some embodiments, the TL1A binding protein comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 as set forth in Table 1. In some embodiments, the TL1A binding protein comprises a heavy chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-18, (b) CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19-36, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37-54.

[0028] In some embodiments, the TL1A-binding protein includes a light chain variable region comprising CDR1, CDR2, and CDR3 as described in Table 1. In some embodiments, the TL1A-binding protein includes a light chain variable region comprising (a) CDR1 having the amino acid sequence of any one of SEQ ID NOs. 55 to 72, (b) CDR2 having the amino acid sequence of any one of SEQ ID NOs. 73 to 90, and (c) CDR3 having the amino acid sequence of any one of SEQ ID NOs. 91 to 108.

[0029] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1 to 18, (b) CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19 to 36, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37 to 54; and a light chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 55 to 72, (b) CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 73 to 90, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 91 to 108.

[0030] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of any one of SEQ ID NOs: 109-126, (b) CDR2 having the amino acid sequence of any one of SEQ ID NOs: 127-144, and (c) CDR3 having the amino acid sequence of any one of SEQ ID NOs: 145-162.

[0031] In some embodiments, the TL1A-binding protein includes a light chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 163-180, (b) CDR2 having an amino acid sequence according to DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS or KVS or SEQ ID NO: 198, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 199-216.

[0032] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 109-126, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 127-144, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 145-162; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 163-180, (b) a CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS or KVS or SEQ ID NO: 198, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 199-216.

[0033] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 217-234, (b) CDR2 having an amino acid sequence according to any one of SEQ ID NOs. 235-252, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 253-270.

[0034] In some embodiments, the TL1A-binding protein includes a light chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 271-288, (b) CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS, KVS, or DA, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 307-324.

[0035] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 217-234, (b) CDR2 having an amino acid sequence according to any one of SEQ ID NOs. 235-252, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 253-270; and a light chain variable region comprising (a) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 271-288, (b) CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS, KVS, or DA, and (c) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 307-324.

[0036] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 1, (b) CDR2 having the amino acid sequence of SEQ ID NO: 19, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 37; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 55, (b) CDR2 having the amino acid sequence of SEQ ID NO: 73, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 91.

[0037] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 2, (b) CDR2 having the amino acid sequence of SEQ ID NO: 20, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 38; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 56, (b) CDR2 having the amino acid sequence of SEQ ID NO: 74, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 92.

[0038] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) CDR2 having the amino acid sequence of SEQ ID NO: 21, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 39; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 57, (b) CDR2 having the amino acid sequence of SEQ ID NO: 75, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 93.

[0039] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 4, (b) CDR2 having the amino acid sequence of SEQ ID NO: 22, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 40; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 58, (b) CDR2 having the amino acid sequence of SEQ ID NO: 76, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 94.

[0040] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 5, (b) CDR2 having the amino acid sequence of SEQ ID NO: 23, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 41; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 59, (b) CDR2 having the amino acid sequence of SEQ ID NO: 77, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 95.

[0041] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) CDR2 having the amino acid sequence of SEQ ID NO: 24, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 42; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 60, (b) CDR2 having the amino acid sequence of SEQ ID NO: 78, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 96.

[0042] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 7, (b) CDR2 having the amino acid sequence of SEQ ID NO: 25, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 43; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 61, (b) CDR2 having the amino acid sequence of SEQ ID NO: 79, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 97.

[0043] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 8, (b) CDR2 having the amino acid sequence of SEQ ID NO: 26, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 44; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 62, (b) CDR2 having the amino acid sequence of SEQ ID NO: 80, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 98.

[0044] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 9, (b) CDR2 having the amino acid sequence of SEQ ID NO: 27, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 45; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 63, (b) CDR2 having the amino acid sequence of SEQ ID NO: 81, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 99.

[0045] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 10, (b) CDR2 having the amino acid sequence of SEQ ID NO: 28, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 46; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 64, (b) CDR2 having the amino acid sequence of SEQ ID NO: 82, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 100.

[0046] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 11, (b) CDR2 having the amino acid sequence of SEQ ID NO: 29, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 47; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 65, (b) CDR2 having the amino acid sequence of SEQ ID NO: 83, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 101.

[0047] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 12, (b) CDR2 having the amino acid sequence of SEQ ID NO: 30, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 48; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 66, (b) CDR2 having the amino acid sequence of SEQ ID NO: 84, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 102.

[0048] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 13, (b) CDR2 having the amino acid sequence of SEQ ID NO: 31, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 67, (b) CDR2 having the amino acid sequence of SEQ ID NO: 85, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 103.

[0049] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 14, (b) CDR2 having the amino acid sequence of SEQ ID NO: 32, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 50; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 68, (b) CDR2 having the amino acid sequence of SEQ ID NO: 86, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 104.

[0050] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 15, (b) CDR2 having the amino acid sequence of SEQ ID NO: 33, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 51; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 69, (b) CDR2 having the amino acid sequence of SEQ ID NO: 87, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 105.

[0051] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 16, (b) CDR2 having the amino acid sequence of SEQ ID NO: 34, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 52; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 70, (b) CDR2 having the amino acid sequence of SEQ ID NO: 88, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 106.

[0052] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 17, (b) CDR2 having the amino acid sequence of SEQ ID NO: 35, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 53; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 71, (b) CDR2 having the amino acid sequence of SEQ ID NO: 89, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 107.

[0053] In some embodiments, the TL1A-binding protein includes a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 18, (b) CDR2 having the amino acid sequence of SEQ ID NO: 36, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 54; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 72, (b) CDR2 having the amino acid sequence of SEQ ID NO: 90, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 108.

[0054] Exemplary amino acid sequences of the heavy chain variable region (VH) and light chain variable region (VL) of TL1A-binding proteins are provided in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0055] In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence of any one of SEQ ID NOs. 325-342.

[0056] In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein antibody includes a light chain variable region (VL) containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a light chain variable region (VL) containing an amino acid sequence of any one of SEQ ID NOs. 343-360.

[0057] In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) the same amino acid sequence as the heavy chain variable region (VH) of the TL1A-binding protein disclosed in Table 2, and a light chain variable region (VL) containing at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) the same amino acid sequence as the light chain variable region (VL) of the same TL1A-binding protein disclosed in Table 2.

[0058] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 343-360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence of any one of SEQ ID NOs. 325-342; and a light chain variable region containing an amino acid sequence of any one of SEQ ID NOs. 343-360.

[0059] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 343.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 343.

[0060] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 344.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 344.

[0061] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 345.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 345.

[0062] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 346.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 346.

[0063] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 347.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 347.

[0064] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 348.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 348.

[0065] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 349.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 349.

[0066] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 350.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 350.

[0067] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 351.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 351.

[0068] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 352.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 352.

[0069] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 353.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 353.

[0070] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 354.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 354.

[0071] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 355.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 355.

[0072] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 356.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 356.

[0073] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 357.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 357.

[0074] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 358.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 358.

[0075] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 359.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 359.

[0076] In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 360.In some embodiments, the TL1A-binding protein includes a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 360.

[0077] FC modification TL1A-binding proteins containing a modified Fc region are described herein. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition. Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0078] In some embodiments, the TL1A-binding protein contains a modified Fc comprising one or more modifications. In some embodiments, one or more modifications are located in an Fc derived from IgG1 (e.g., human IgG1 (hIgG1)). In some embodiments, one or more modifications are located in an Fc derived from IgG4 (e.g., human IgG4 (hIgG4)). In some embodiments, one or more modifications are located in an Fc derived from IgG2. In some embodiments, one or more modifications promote selective binding of the Fc-γ receptor.

[0079] An example amino acid sequence of an Fc sequence is provided in Table 3. [Table 3-1] Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21

[0080] In some embodiments, the TL1A-binding protein includes an Fc containing one or more modifications of SEQ ID NO: 361. In some embodiments, the TL1A-binding protein includes an Fc containing one or more modifications of SEQ ID NO: 362. In some embodiments, the TL1A-binding protein includes an Fc containing one or more modifications of SEQ ID NO: 363. In some embodiments, the Fc includes an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 361-363. In some embodiments, the Fc includes an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 361-363. In some embodiments, the Fc includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 361-363. In some embodiments, the Fc includes an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 361-363. In some embodiments, Fc includes an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of sequence numbers 361 to 363. In some embodiments, Fc includes an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of sequence numbers 361 to 363. In some embodiments, Fc includes an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of sequence numbers 361 to 363. In some embodiments, Fc includes an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of sequence numbers 361 to 363. In some embodiments, Fc includes an amino acid sequence of any one of sequence numbers 361 to 363.

[0081] In some embodiments, one or more modifications in the modified Fc are 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 are 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.

[0082] In some embodiments, the modified Fc includes specific combinations of amino acid substitutions selected from the group consisting of L234A / L235A, V234A / G237A, L235A / G237A / E318A, S228P / L236E, H268Q / V309L / A330S / A331S, 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.

[0083] 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), 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, LA LA / 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、LA LAGA / LA、LALAPG / LA、N297A / N434A、D265A / N434A、LALA / N434A、LAGA / N4 34A、LALAGA / N434A、LALAPG / N434A、N297A / N434W、D265A / N434W、LALA / N4 34W、LAGA / N434W、LALAGA / N434W、LALAPG / N434W、N297A / DQ、D265A / DQ、L ALA / DQ、LAGA / DQ、LALAGA / DQ、LALAPG / DQ、N297A / DW、D265A / DW、LALA / DW 、LAGA / DW、LALAGA / DW、LALAPG / DW、N297A / YD、D265A / YD、LALA / YD、LAGA / YD、LALAGA / YD、LALAPG / YD、N297A / QVV、D265A / QVV、LALA / QVV、LAGA / QVV,This includes specific combinations of amino acid substitutions selected from the group consisting of 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 includes specific combinations of amino acid substitutions selected from the group consisting of M428L / N434S(LS) and M252Y / S254T / T256E(YTE). In some embodiments, the modified Fc includes modifications of M428L / N434S(LS) (e.g., SEQ ID NO: 379, SEQ ID NO: 396, SEQ ID NO: 403). In some embodiments, the modified Fc includes modifications of M252Y / S254T / T256E(YTE) (e.g., SEQ ID NO: 372, SEQ ID NO: 393, SEQ ID NO: 402).

[0084] In some embodiments, the TL1A-binding proteins described herein include modifications to improve their ability to mediate effector function. Such modifications are known in the art and include defucosylation or manipulation of the affinity of Fc to activating receptors (primarily FCGR3a for antibody-dependent cell-mediated cytotoxicity (ADCC)) and to C1q for complement-dependent cell-mediated cytotoxicity (CDC).

[0085] In some embodiments, the antibodies provided herein contain an Fc domain (e.g., IgG1) having a reduced fucose content at position Asn 297 (EU numbering) compared to naturally occurring Fc domains. Such Fc domains are known to have improved ADCC. In some embodiments, such antibodies contain no fucose at position Asn 297.

[0086] In some embodiments, the TL1A-binding proteins described herein include an Fc region having one or more amino acid substitutions that improve ADCC (e.g., substitutions at one or more positions among positions 298, 333, and 334 of the Fc region). In some embodiments, the antibodies provided herein include an Fc region having one or more amino acid substitutions at positions 239, 332, and 330.

[0087] In some embodiments, Fc includes an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NOs. 364-472. In some embodiments, Fc includes an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of sequence numbers 364 to 472. In some embodiments, Fc includes an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of sequence numbers 364 to 472. In some embodiments, Fc includes an amino acid sequence of any one of sequence numbers 364 to 472.

[0088] In some embodiments, the Fc of the TL1A-binding protein includes an amino acid sequence having one or more amino acid modifications (e.g., substitutions, additions, deletions, etc., compared to one of the sequences indicated by sequence numbers 364-472) as shown by any one of sequence numbers 364-472. In some embodiments, one or more amino acid modifications include the deletion of a C-terminal lysine. In some embodiments, one or more amino acid modifications include the addition of a C-terminal lysine. For example, the Fc of the TL1A-binding protein provided herein may include the amino acid sequence shown by sequence number 376, but with a C-terminal lysine added such that the amino acid sequence ends with "K" instead of "G".

[0089] In some embodiments, any of the SEQ ID NOs. 346-472 containing C-terminal lysine may have its C-terminal lysine deleted or substituted. In some embodiments, any of the SEQ ID NOs. 346-472 not containing C-terminal lysine may have C-terminal lysine added. In certain embodiments, any one of the SEQ ID NOs. 346-472 not containing C-terminal lysine itself may have its C-terminal amino acid substituted with lysine (for example, from another amino acid).

[0090] In some embodiments, the TL1A-binding proteins described herein include an Fc region having at least one galactose residue within an oligosaccharide bound to the Fc region. Such antibody variants may have improved CDC function.

[0091] In some embodiments, the TL1A-binding proteins described herein include one or more modifications that improve or reduce C1q binding and / or CDC.

[0092] In certain embodiments, the Fc region comprises one or more amino acid substitutions, where one or more substitutions result in an increase in one or more of the following compared to an Fc region without one or more substitutions: antibody half-life, ADCC activity, ADCP activity, or CDC activity. In certain embodiments, one or more amino acid substitutions result in an increased antibody half-life at pH 6.0 compared to an antibody containing a wild-type Fc region. In a particular embodiment, the antibody has an increased half-life that is longer by approximately 10,000 times, 1,000 times, 500 times, 100 times, 50 times, 20 times, 10 times, 9 times, 8 times, 7 times, 6 times, 5 times, 4.5 times, 4 times, 3.5 times, 3 times, 2.5 times, 2 times, 1.95 times, 1.9 times, 1.85 times, 1.8 times, 1.75 times, 1.7 times, 1.65 times, 1.6 times, 1.55 times, 1.50 times, 1.45 times, 1.4 times, 1.35 times, 1.3 times, 1.25 times, 1.2 times, 1.15 times, 1.1 times, or 1.05 times compared to an antibody containing a wild-type Fc region.

[0093] In a particular embodiment, the Fc region comprises one or more amino acid substitutions, where one or more substitutions result in a decrease in one or more of the ADCC activity, ADCP activity, or CDC activity compared to an Fc without one or more substitutions.

[0094] In a particular embodiment, the Fc region binds to an Fcγ receptor selected from the group consisting of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In a particular embodiment, the Fc region binds to the Fcγ receptor with higher affinity at pH 6.0 compared to an antibody containing a wild-type Fc region.

[0095] In some embodiments, the TL1A-binding proteins described herein include a long half-life (i.e., serum half-life). In some embodiments, the TL1A-binding proteins described herein include a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 weeks. In some embodiments, the TL1A-binding proteins described herein include half-lives in the range of about 14 to about 96 days, about 14 to about 84 days, about 14 to about 70 days, about 14 to about 56 days, about 14 to about 42 days, about 14 to about 28 days, about 28 to about 96 days, about 28 to about 84 days, about 28 to about 70 days, about 28 to about 56 days, about 28 to about 42 days, about 42 to about 96 days, about 42 to about 84 days, about 42 to about 70 days, or about 42 to about 56 days. In some embodiments, the TL1A-binding proteins described herein include half-lives in the range of about 42 to about 56 days. In some embodiments, the TL1A-binding proteins described herein include half-lives in the range of about 42 to about 56 days. In some embodiments, the TL1A-binding proteins described herein have a half-life of about 50 days. Methods for measuring half-life are known in the art. In some embodiments, the half-life is measured in non-human primates. In some embodiments, the half-life is measured in humans. In some embodiments, the half-life is measured after intravenous administration. In some embodiments, the half-life is measured after subcutaneous administration.

[0096] In some embodiments, the TL1A-binding protein described herein has a half-life at least 20% longer than that of the comparative antibody. In some embodiments, the comparative antibody contains the same complementarity-determining region and variable region, but contains a different Fc region. In some embodiments, the half-life of the TL1A-binding protein 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 that of the comparative antibody. In some embodiments, the half-life of the TL1A-binding protein described herein is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times longer than that of the comparative antibody.

[0097] Treatment method In a particular embodiment, a method for treating inflammatory bowel disease in a patient in need, the method comprising administering to the patient subcutaneously or intravenously an effective amount of a TL1A-binding protein containing a modified Fc region, is described herein. In a particular embodiment, a method for treating inflammatory bowel disease in a patient in need, the method comprising a) a heavy chain variable region (VH) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 1 to 18, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 19 to 36, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 37 to 54; b) a light chain variable region (VL) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 55 to 72, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 73 to 90, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 91 to 108; and c) subcutaneous or intravenous administration to the patient an effective amount of TL1A-binding protein comprising an Fc domain comprising amino acid modifications M252Y, S254T, and T256E(YTE), and / or M428L and N434S(LS).

[0098] In a particular embodiment, a method for treating inflammatory bowel disease in a patient in need, the method further described herein includes: a) a heavy chain variable region (VH) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 1 to 18, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 19 to 36, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 37 to 54; b) a light chain variable region (VL) comprising (i) a CDR1 having the amino acid sequence of any one of SEQ ID NOs: 55 to 72, (ii) a CDR2 having the amino acid sequence of any one of SEQ ID NOs: 73 to 90, and (iii) a CDR3 having the amino acid sequence of any one of SEQ ID NOs: 91 to 108; and c) subcutaneous or intravenous administration to the patient an effective amount of TL1A-binding protein containing a modified Fc that extends the half-life of the TL1A-binding protein compared to a TL1A-binding protein without the modified Fc.

[0099] In a particular embodiment, a method for treating inflammatory bowel disease in a patient in need, the method comprising administering an effective amount of TL1A-binding protein to the patient subcutaneously or intravenously, wherein the TL1A-binding protein specifically binds to an epitope of TL1A and comprises an Fc domain including amino acid modifications M252Y, S254T, and T256E(YTE), and / or M428L and N434S(LS), as further described herein.

[0100] In some embodiments, inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0101] In some embodiments, the TL1A-binding protein is administered in doses of approximately 75 mg to approximately 150 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 250 mg to approximately 750 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 700 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 600 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 500 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 400 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 400 mg to approximately 700 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 400 mg to approximately 600 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 500 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 500 mg to approximately 700 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 500 mg to approximately 600 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 600 mg to approximately 700 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, or approximately 700 mg.

[0102] In some embodiments, TL1A-binding protein is administered intravenously, intratumorally, intramuscularly, subcutaneously, intralesionally, intraintestinally, intracolonally, intrarectally, in a pouch, or intraperitoneally. In some embodiments, TL1A-binding protein is administered via parenteral routes (e.g., intravenously, intramuscularly, subcutaneously, intra-arterially, or intraperitoneally). In some embodiments, TL1A-binding protein is administered intravenously or subcutaneously. In some embodiments, TL1A-binding protein is administered intravenously. In some embodiments, TL1A-binding protein is administered subcutaneously.

[0103] Administration of TL1A-binding protein can occur at various intervals. In some embodiments, TL1A-binding protein is administered to the patient at least once at intervals longer than 8 weeks. In some embodiments, the interval is about 12 weeks to about 26 weeks. In some embodiments, the interval for TL1A-binding protein is about 12 weeks to about 22 weeks. In some embodiments, the interval is about 12 weeks to about 18 weeks. In some embodiments, the interval is about 12 weeks to about 14 weeks. In some embodiments, the interval is about 16 weeks to about 26 weeks. In some embodiments, the interval is about 16 weeks to about 22 weeks. In some embodiments, the interval is about 16 weeks to about 18 weeks. In some embodiments, the interval is about 20 weeks to about 26 weeks. In some embodiments, the interval is about 20 weeks to about 22 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 16 weeks. In some embodiments, the interval is about 26 weeks.

[0104] Pharmaceutical composition This disclosure also features a pharmaceutical composition comprising a therapeutically effective amount of the TL1A-binding protein described herein. The composition may be formulated for use in various drug delivery systems. One or more physiologically acceptable excipients or carriers may also be included in the composition for appropriate formulation. Formulations suitable for use in this disclosure can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th edition, 1985. For a brief review of methods for drug delivery, see, for example, Langer (Science 249:1527-1533, 1990).

[0105] In some embodiments, the pharmaceutical composition may include, for example, formulation materials for modifying, maintaining, or preserving the pH, volume osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or osmosis of the composition.In such embodiments, suitable formulation materials include, but are not limited to, the following: amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids); fillers (e.g., mannitol or glycine); chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); complexing agents (e.g., caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (e.g., glucose, mannose, or dextrin); proteins (e.g., serum albumin, gelatin, or immunoglobulin); colorants, flavoring agents, and diluents; emulsifiers; hydrophilic polymers (e.g., polyvinylpyrrolidone); and low molecular weight polypeptides. Hydrogenated ions; salt-forming counterions (e.g., sodium); preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (e.g., glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., Pluronic®, PEG, sorbitan esters, polysorbate (e.g., polysorbate 20), polysorbate, triton®, tromethamine, lecithin, cholesterol, tyroxapole); stability enhancers (e.g., sucrose or sorbitol); tonicity enhancers (e.g., alkali metal halides (preferably sodium chloride or potassium chloride), mannitol, sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (Remington's See Pharmaceutical Sciences, 18th edition (Mack Publishing Company, 1990).

[0106] In some embodiments, the pharmaceutical composition is citric acid-free.

[0107] In some embodiments, the pharmaceutical composition may include nanoparticles, such as polymer nanoparticles, liposomes, or micelles.

[0108] In some embodiments, the pharmaceutical composition may include sustained-release or controlled-release formulations. Techniques for formulating sustained-release or controlled-release means (e.g., liposome carriers, biodegradable microparticles or porous beads and depot injections) are also known to those skilled in the art. Sustained-release preparations may include, for example, porous polymer microparticles or semipermeable polymer matrices in the form of molded articles (e.g., films) or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl-inethacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. The sustained-release composition may also include liposomes, which can be prepared by any of several methods known in the art.

[0109] The pharmaceutical compositions comprising the TL1A-binding protein disclosed herein may be presented in dosage unit form and may be prepared by any suitable method. The pharmaceutical compositions should be formulated to be compatible with their intended route of administration. Examples of routes of administration include intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal, and rectal administration. In some embodiments, the TL1A-binding protein disclosed herein is administered intravenously or subcutaneously. In some embodiments, the TL1A-binding protein disclosed herein is administered intravenously. In some embodiments, the TL1A-binding protein disclosed herein is administered subcutaneously.

[0110] Useful formulations can be prepared by methods known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, 1990). Suitable formulation components for parenteral administration include sterile diluents (e.g., water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents); antimicrobial agents (e.g., benzyl alcohol or methylparaben); antioxidants (e.g., ascorbic acid or sodium sulfite); chelating agents (e.g., EDTA); buffers (e.g., acetates, citrates, or phosphates); and agents for tonic adjustment (e.g., sodium chloride or dextrose). In some embodiments, formulations for parenteral administration are citrate-free.

[0111] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered physiological saline (PBS). The carrier should be stable under manufacturing and storage conditions and should be protected from microorganisms. The carrier may be a solvent or dispersion medium (e.g., water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof).

[0112] Intravenous or subcutaneous drug delivery formulations may be contained in syringes, pens, or bags. In some embodiments, the bag may be connected to a channel including a tube and / or needle. In some embodiments, the formulation may be a lyophilized formulation or a liquid formulation.

[0113] These compositions may be sterilized by conventional sterilization techniques or by sterile filtration. The resulting aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier before administration.

[0114] Polyols (which can act as isotonic agents and stabilize the TL1A-binding protein) may also be included in the formulation. The polyol is added to the formulation in amounts that may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be varied in relation to the molecular weight of the polyol. For example, a small amount of monosaccharide (e.g., mannitol) may be added compared to a disaccharide (e.g., trehalose). In some embodiments, the polyol used in the formulation as a tonicity agent is mannitol.

[0115] Detergents or surfactants may also be added to the formulation. Exemplary detergents include nonionic detergents (e.g., polysorbates (e.g., polysorbate 20, 80, etc.) or poloxamers (e.g., poloxamer 188)). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulate matter in the formulation and / or reduces adsorption. In some embodiments, the formulation may contain a surfactant, which is a polysorbate. In some embodiments, the formulation may contain a detergent, polysorbate 80, or Tween® 80. Tween® 80 is a term used to describe polyoxyethylene (20) sorbitan monooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edition, 1996).

[0116] In some embodiments, the protein products of the present disclosure are formulated as liquid formulations. In some embodiments, the liquid formulations are prepared in combination with a sugar at a stabilizing level. In some embodiments, the liquid formulations are prepared in an aqueous carrier. In some embodiments, the stabilizer is added in an amount less than or equal to the amount that would result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is a disaccharide, such as sucrose. In some embodiments, the liquid formulations may also contain one or more of buffers, surfactants, and preservatives.

[0117] In some embodiments, the pH of the liquid formulation is set by the addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0118] In this specification, the aqueous carrier of interest is pharmaceutically acceptable (safe and non-toxic for administration to humans) and useful for the preparation of liquid formulations. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), pH-buffered solutions (e.g., phosphate-buffered saline), sterile saline, Ringer's solution, or dextrose solution.

[0119] Preservatives may be added to the formulations herein as needed to reduce bacterial activity. The addition of preservatives may facilitate, for example, the production of multi-dose formulations.

[0120] TL1A-binding proteins can be lyophilized to produce a lyophilized formulation containing the protein and a lyophilized protective agent. The lyophilized protective agent may be a sugar, for example, a disaccharide. In some embodiments, the lyophilized protective agent is sucrose or maltose. The lyophilized formulation may also contain one or more of the following: buffering agents, surfactants, fillers, and / or preservatives.

[0121] The amount of sucrose or maltose useful for stabilizing lyophilized drug products can be at least 1:2 protein to sucrose or maltose by weight ratio. In some embodiments, the protein to sucrose or maltose weight ratio is 1:2 to 1:5. In some embodiments, the pH of the formulation is set by adding a pharmaceutically acceptable acid and / or base before lyophilization. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0122] In some embodiments, the TL1A-binding protein is administered in doses of approximately 75 mg to approximately 150 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 250 mg to approximately 750 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 700 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 600 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 500 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 400 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 400 mg to approximately 700 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 400 mg to approximately 600 mg. In some embodiments, the TL1A-binding protein is administered in doses of approximately 300 mg to approximately 500 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 500 mg to approximately 700 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 500 mg to approximately 600 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 600 mg to approximately 700 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, or approximately 700 mg. In some embodiments, TL1A-binding protein is administered in doses of approximately 300 mg. The actual dose levels of the active ingredient in the pharmaceutical compositions of this disclosure may be about 250 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg, to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0123] The specific dose may be a uniform dose of approximately 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of protein per patient. Alternatively, the patient's dose may be adjusted to the patient's approximate body weight or surface area. Other factors in determining the appropriate dose may include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the patient's age, sex, and medical condition. Further refinements of the calculations required to determine the appropriate dose for treatment are customarily made by those skilled in the art, particularly in light of the dose information and assays disclosed herein. The dose may also be determined through the use of known assays for dose determination, used in conjunction with appropriate dose-response data. The dose for individual patients may be adjusted while monitoring the progression of the disease. Blood levels of the targetable construct or complex in the patient may be measured to determine whether the dose needs to be adjusted to achieve or maintain an effective concentration. Pharmacogenomics can be used to determine which targetable constructs and / or complexes, as well as their dosages, are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta 308: 33-41, 2001).

[0124] Preparation method The TL1A-binding proteins described above can be prepared using recombinant DNA techniques well known to those skilled in the art. For example, one or more isolated polynucleotides encoding a TL1A-binding protein can be ligated to other suitable nucleotide sequences (including, for example, constant region coding sequences and expression regulatory sequences) to produce a conventional gene expression construct (i.e., an expression vector) encoding a desired TL1A-binding protein. The production of the defined gene construct is within the scope of the conventional art in this field.

[0125] The nucleic acid encoding the desired TL1A-binding protein can be incorporated (ligated) into an expression vector (which can be introduced into host cells via conventional transfection or transformation techniques). Exemplary host cells include Escherichia coli (E. coli) cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and melanoma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that allow the host cell to express the gene encoding the TL1A-binding protein.

[0126] Specific expression and purification conditions vary depending on the expression system employed. For example, if the gene is to be expressed in E. coli, it is first cloned into an expression vector by positioning the engineered gene downstream from a suitable bacterial promoter (e.g., Trp or Tac) and a prokaryotic signaling sequence. The expressed protein may be secreted. The expressed protein may accumulate in a refractive body or inclusion body, which can be collected after the cells are disrupted by French press or sonication. The refractive body is then solubilized, and its protein can be refolded and / or cleaved by methods known in the art.

[0127] If the manipulated gene is to be expressed in a eukaryotic host cell (e.g., a CHO cell), it is first inserted into an expression vector containing a suitable eukaryotic promoter, secretory signal, poly(A) sequence, and stop codon. Optionally, the vector or gene construct may include enhancers and introns. In embodiments involving a fusion protein containing a TL1A-binding protein or a portion thereof, the expression vector may optionally include a sequence encoding all or part of the constant region, allowing for the expression of the entire heavy chain or light chain or a portion thereof. The gene construct can be introduced into a eukaryotic host cell using conventional techniques.

[0128] In some embodiments, an N-terminal signal sequence is included in the protein construct to express the TL1A-binding protein. Exemplary N-terminal signal sequences include those derived from interleukin-2, CD-5, IgG κ light chain, trypsinogen, serum albumin, and prolactin.

[0129] Following transfection, a single clone can be isolated for cell banking using methods known in the art (e.g., limiting dilution, ELISA, FACS, microscopy, or Clonepix). The clone can be cultured under conditions suitable for bioreactor scale-up, and TL1A-binding protein expression can be maintained.

[0130] TL1A-binding proteins can be isolated and purified using methods known in the art, including centrifugation, deep filtration, cell lysis, homogenization, freeze-thaw cycles, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.

[0131] Supporting display All publications and patents cited throughout this specification (including all patents, patent applications, scientific publications, manufacturer specifications, instructions, etc.), whether cited prior or subsequent, are incorporated herein by reference in their entirety for all purposes. To the extent that any material incorporated by reference is inconsistent with or contradicts this specification, this specification takes precedence over any such material.

[0132] Equal parts This disclosure can be embodied in other specific forms without departing from its intent or essential features. Accordingly, the embodiments described herein should be considered illustrative in all respects, and not limiting the disclosure described herein. The scope of this disclosure is therefore indicated by the appended claims rather than by the foregoing description, and all modifications that fall within the meaning and scope of the claims are intended to be encompassed therein.

Claims

1. a) A heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1 to 18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19 to 36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37 to 54; b) A light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 55 to 72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NOs. 73 to 90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 91 to 108; and c) Fc domains comprising amino acid modifications M252Y, S254T, and T256E (YTE), and / or M428L and N434S (LS), TL1A-binding protein containing this protein.

2. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 1, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 19, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 37; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 55, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 73, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

91.

3. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 2, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 20, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 38; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 56, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 74, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

92.

4. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 3, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 21, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 39; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 57, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 75, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

93.

5. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 4, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 22, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 40; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 58, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 76, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

94.

6. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 5, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 23, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 41; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 59, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 77, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

95.

7. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 6, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 24, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 42; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 60, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 78, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

96.

8. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 7, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 25, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 43; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 61, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 79, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

97.

9. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 8, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 26, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 44; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 62, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 80, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

98.

10. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 9, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 27, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 45; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 63, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 81, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

99.

11. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 10, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 28, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 46; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 64, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 82, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

100.

12. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 11, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 29, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 47; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 65, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 83, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

101.

13. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 12, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 30, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 48; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 66, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 84, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

102.

14. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 13, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 31, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 49; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 67, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 85, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

103.

15. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 14, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 32, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 50; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 68, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 86, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

104.

16. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 15, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 33, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 51; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 69, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 87, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

105.

17. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 16, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 34, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 52; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 70, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 88, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

106.

18. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 17, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 35, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 53; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 71, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 89, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

107.

19. The TL1A binding protein according to claim 1, wherein the VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 18, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 36, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 54; and the VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 72, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 90, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO:

108.

20. The TL1A binding protein according to any one of claims 1 to 19, wherein the VH comprises a sequence having at least 80% sequence identity with any one amino acid sequence from sequence numbers 325 to 342, and the VL comprises a sequence having at least 80% sequence identity with any one amino acid sequence from sequence numbers 343 to 360.

21. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

343.

22. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

344.

23. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

345.

24. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

346.

25. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

347.

26. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

348.

27. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

349.

28. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

350.

29. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

351.

30. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

352.

31. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

353.

32. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

354.

33. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

355.

34. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

356.

35. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

357.

36. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

358.

37. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

359.

38. The TL1A binding protein according to claim 20, wherein VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

360.

39. The TL1A-binding protein according to any one of claims 1 to 38, wherein the Fc is an IgG1, IgG2, or IgG4 immunoglobulin Fc domain.

40. The TL1A binding protein according to claim 39, wherein Fc is an IgG1 immunoglobulin domain.

41. The TL1A-binding protein according to claim 39, wherein Fc is an IgG2 immunoglobulin domain.

42. The TL1A-binding protein according to claim 39, wherein Fc is an IgG4 immunoglobulin domain.

43. a) A heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1 to 18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 19 to 36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 37 to 54; b) A light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NOs. 55 to 72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NOs. 73 to 90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NOs. 91 to 108; and c) A modified Fc which extends the half-life of the TL1A-binding protein compared to a TL1A-binding protein that does not contain the modified Fc, TL1A-binding protein containing this protein.

44. A TL1A-binding protein, wherein the TL1A-binding protein specifically binds to the epitope of TL1A and comprises an Fc domain including amino acid modifications M252Y, S254T, and T256E (YTE), and / or M428L and N434S (LS).

45. A method for treating inflammatory bowel disease in a patient requiring treatment for inflammatory bowel disease, the method comprising administering to the patient subcutaneously or intravenously an effective amount of the TL1A binding protein described in any one of claims 1 to 44.

46. The method according to claim 45, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

47. The method according to claim 46, wherein the inflammatory bowel disease is ulcerative colitis.

48. The method according to any one of claims 45 to 47, wherein the administration of the TL1A-binding protein is subcutaneous.

49. The method according to any one of claims 45 to 47, wherein the administration of the TL1A-binding protein is intravenous.

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