Anti-TNFR2 antibodies

Abstract

The present invention relates to antibodies and antigen-binding fragments thereof that specifically bind to tumor necrosis factor (TNF) receptor 2 (TNFR2). The present invention also provides compositions and pharmaceutical compositions comprising the same, as well as methods of treatment and various other aspects.

Description

[0001] ANTI-TNFR2 ANTIBODIES

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] [1] The present invention relates to antibodies and antigen-binding fragments thereofthat specifically bind to tumor necrosis factor (TNF) receptor 2 (TNFR2). The present invention also provides compositions and pharmaceutical compositions comprising the same, as well as methods of treatment and various other aspects.

[0004] BACKGROUND

[0005] [2] Tregs are a heterogeneous subset ofT cells that regulate immune responses and promote tissue repair through a variety of mechanisms, including production of anti-inflammatory cytokines, expression of co-inhibitory molecules, cytotoxicity towards effector T cells (Teff), modulation of antigen-presenting cell (APC) maturation and function, and expression of the ectonucleotidases, CD39 and CD37, that generate anti-inflammatory adenosine. The expression of murine and human transcription factor Forkhead Box P3 (Foxp3) is enriched within cluster of differentiation (CD)4+ CD25+ T cells in both mice and humans and is now used to define “Treg” populations (Fontenot JD et al. Nature immunology. 2003;4(4):330-6; Khattri R et al. Nature immunology. 2003;4(4):337-42; Hori S et al. Science. 2003;299(5609):1057-61). A reduction in Treg number and / or function contributes to the loss of tolerance in many human autoimmune diseases (Grant CR, et al. Autoimmunity reviews. 2015; 14(2):105-16). Thus, understanding the biological pathways that modulate Tregs has opened avenues for therapeutic intervention to restore immune homeostasis in patients with autoimmune diseases.

[0006] [3] Therapeutics that expand Tregs, namely the IL-2 class, have shown clinical benefit in rheumatology and dermatology diseases including AD, RA, lupus, and Sjogren’s disease. TNFR2 is highly expressed on Tregs and has a more restricted expression pattern on immune cells as compared to the IL- 2 receptor. The TNFa / TNFR1 / TNFR2 axis plays a crucial role in the function, fate, and balance of Teff and Tregs. TNFa is a pleiotropic cytokine with both proinflammatory and regulatory roles, thought to be mediated by distinct signaling pathways triggered by its receptors, TNFR1 and TNFR2, respectively. In terms of function, TNFR1 has a death domain in its cytoplasmic portion (Tartaglia LA, et al. Cell. 1993;74(5):845-53) and activates proinflammatory pathways and cytotoxic signaling. In contrast, TNFR2 lacks a death domain and instead involves the TNFR-associated factor-2 (TRAF2) adapter protein (Rothe M et al. Science. 1995;269(5229):1424-7) to initiate an anti-inflammatory cascade. When TNFa binds to TNFR2, its intracellular domains recruit TRAF2, cellular inhibitor of apoptosis protein (clAP) 1 , and clAP2 to form complexes (Rothe M, et al. Cell. 1994;78(4):681-92). These proteins activate several othersignaling proteins and can result in the initiation of both canonical and non-canonical nuclear factor kappa-light-chain- enhancer of activated B cells (NF-KB) activation (Gough P, and Myles IA. Frontiers in immunology. 2020;11 (585880)). In addition, TNF-TNFR2 interaction can also activate the reciprocal phosphoinositide 3- kinase (PI3K) / protein kinase B (Akt) pathway. These pathways impact various cellular processes such as proliferation, survival, migration, and cell adhesion and drive immune-modulatory responses and tissue regeneration (Yang S, et al. Frontiers in immunology. 2018;9(78)4). Figure 1 highlights the opposing roles of TNFRI and TNFR2 in inflammation. [4] TNFR2+ Tregs have been identified as a particularly potent subset ofTregs (Chen X, et al. Journal of immunology. 2008;180(10):6467-71). Membrane-bound TNFa can promote expansion and function of Tregs through TNFR2 and can prevent pathogenic conversion of Tregs under inflammatory conditions (Chen X, et al Journal of immunology. 2013;190(3):1076-84). Recent studies have further advanced the understanding of the molecular basis and signaling events underlying the Treg-stimulatory effect of TNFa- TNFR2 interaction, such as through the maintenance of Foxp3 expression by limiting DNA methylation at Foxp3 promoters (Tseng WY, et al. PNAS. 2019;116(43):21666-72) and inhibiting conversion of Tregs into T cells that produce proinflammatory cytokines such as IL-17 (Urbano PCM, et al. Frontiers in immunology. 2019;10(3047)). Thus, targeting TNFR2 provides an opportunity to positively impact Treg stability and function in addition to numbers.

[0007] [5] The role of TNFR2 in Tregs has been confirmed in various animal models of autoimmune and inflammatory diseases in which TNFR2 deficiency in Tregs led to increased inflammation or administration of TNFR2 agonists induced Treg expansion and / or protected mice (Siegmund D, and Wajant H. Nature reviews Rheumatology. 2023;19(9):576-91). Importantly, TNFR2 agonists have also been shown to be effective at expanding human Tregs and enhancing their suppressive activity (Okubo Y, et al. Scientific reports. 2013;3(3153)) . Based on these observations, there is a strong rationale for using TNFR2 agonists to expand Tregs in patients with autoimmune disease to help correct the defect in numbers, stability, and functionality to allow for more durable responses.

[0008] [6] TNFR2 also exists as a soluble form that is cleaved from the cell surface by TNFa-converting enzyme (TACE) (Moss ML, et al. Drug discovery today. 2001 ;6(8):417-26). A splice variant forTNFR2 has also been described and contributes to total serum soluble TNFR2 (sTNFR2) levels in RA patients (Lainez B, et al. International immunology. 2004; 16(1):169-77). Anti-TNFR2 antibodies have not previously been investigated for their ability to bind specifically to one or both of these truncated variants. In addition, the soluble (shed) form ofTNFR2 can act as a sink, reducing the effectiveness of antibodies that bind to TNFR2 in vivo.

[0009] [7] There remains the need in the art for new therapeutic antibodies that bind specifically to TNFR2 with a favourable functional profile.

[0010] SUMMARY OF THE INVENTION

[0011] [8] The present invention provides anti-TNFR2 antibodies and antigen-binding fragments thereof (also referred to herein simply as “anti-TNFR2 antibodies”). The antibodies presented herein have an advantageous functional profile. For example, the anti-TNFR2 antibodies preferentially bind membranebound TNFR2 over shed TNFR2. The TNFR2 antibodies are also agonistic. Furthermore, the anti-TNFR2 antibodies specifically bind at least two variants of TNFR2, known as the M196 and R196 variants of TNFR2. Still further, the anti-TNFR2 antibodies do not block (or do not substantially block) the binding of TNFa to TNFR2. Thus, the present invention provides TNFR2 antibodies with unique properties that render them advantageous overthe anti-TNFR2 antibodies of the prior art in several respects. [9] According to a first aspect of the invention, there is provided an anti-TNFR2 antibody or antigenbinding fragment thereof that specifically binds to TNFR2.

[0012]

[0010] In a second aspect ofthe invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a) a heavy chain variable region comprising: i. a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 54, 60, 66, 72, 78, 84, 222, 228, 234, 240, 246, 252, 372, 378,

[0013] 384, 390, 396, 402, 408, 414, 420, 426, 432, 438, 450, 456, 462, 468, 474 and 480; ii. a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, 61 , 67, 73, 79, 85, 223, 229, 235, 241 , 247, 253, 373, 379,

[0014] 385, 391 , 397, 403, 409, 415, 421 , 427, 433, 439, 451 , 457, 463, 469, 475 and 481 ; and

[0015] Hi. a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 56, 62, 68, 74, 80, 86, 224, 230, 236, 242, 248, 254, 374, 380, 386, 392, 398, 404, 410, 416, 422, 428, 434, 440, 452, 458, 464, 470, 476 and 482; and / or b) a light chain variable region comprising: i. a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: 57, 63, 69, 75, 81 , 87, 90 to 221 , 225, 231 , 237, 243, 249, 255, 258 to 371 , 375, 381 , 387, 393, 399, 405, 411 , 417, 423, 429, 435, 441 , 444 to 449, 453, 459, 465, 471 , 477, 483, 486 to 491 and 545 to 552; ii. a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: 58, 64, 70, 76, 82, 88, 226, 232, 238, 244, 250, 256, 376, 382, 388, 394, 400,

[0016] 406, 412, 418, 424, 430, 436, 442, 454, 460, 466, 472, 478 and 484; and

[0017] Hi. a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 59, 65, 71 , 77, 83, 89, 227, 233, 239, 245, 251 , 257, 377, 383, 389, 395, 401 ,

[0018] 407, 413, 419, 425, 431 , 437, 443, 455, 461 , 467, 473, 479 and 485.

[0019]

[0011] In a third aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a) a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 1 to 5, 565 and 567; and / or b) a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 6 to 53, 557 to 564, 566, 568 and 569.

[0020]

[0012] In a fourth aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a) a heavy chain variable region comprising or consisting of an amino acid sequence having at least

[0021] 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 565; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 566; b) a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 568; or c) a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 569.

[0022]

[0013] In a fifth aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a) a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 492 to 496; and / or b) a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 497 to 544.

[0023]

[0014] In a sixth aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof selected from the group consisting of JNJ-TR2-01 , JNJ-TR2-02, JNJ-TR2-03, JNJ-TR2- 04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2-08, JNJ-TR2-09, JNJ-TR2-10, JNJ-TR2-11 , JNJ- TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ-TR2-16, JNJ-TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2-20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2-23, JNJ-TR2-24, JNJ-TR2-25, JNJ-TR2-26, JNJ-TR2- 27, JNJ-TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ-TR2-31 , JNJ-TR2-32, JNJ-TR2-33, JNJ-TR2-34, JNJ- TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-TR2-38, JNJ-TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2-43, JNJ-TR2-44, JNJ-TR2-45, JNJ-TR2-46, JNJ-TR2-47 and JNJ-TR2-48. Variants of those antibodies are also provided, for example antigen-binding fragments thereof, and / or antibodies that incorporate one or more sequences derived from these antibodies (for example 6 CDRs, or the variable heavy and light regions).

[0024]

[0015] In a seventh aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody preferentially binds to membrane-bound TNFR2 compared to shed TNFR2.

[0025]

[0016] In an eighth aspect of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody preferentially binds to membrane-bound TNFR2 compared to mammalian cell-expressed soluble monomeric TNFR2.

[0026]

[0017] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof: a) is agonistic; b) specifically binds to both the M196 and R196 variants of human TNFR2; and / or c) does not block (or does not substantially block) the binding of TNFa to TNFR2. d) preferentially binds to membrane-bound TNFR2 compared to shed TNFR2

[0027]

[0018] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof: a) is agonistic; b) specifically binds to both the M196 and R196 variants of human TNFR2; c) does not block (or does not substantially block) the binding of TNFa to TNFR2; and / or specifically binds to the CRD1 and CRD2 domains of TNFR2 d) preferentially binds to membrane-bound TNFR2 compared to shed TNFR2

[0028]

[0019] In a further aspect of the invention, there is provided a polynucleotide sequence or pair of polynucleotide sequences encoding an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention.

[0029]

[0020] In a further aspect of the invention, there is provided a polynucleotide sequence encoding a heavy chain variable region, a light chain variable region, a heavy chain or a light chain of an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention.

[0030]

[0021] In a further aspect of the invention, there is provided an expression vector comprising a polynucleotide sequence or pair of polynucleotide sequences of the invention, or a pair of expression vectors collectively comprising a pair of polynucleotide sequences of the invention.

[0031]

[0022] In a further aspect of the invention, there is provided a host cell comprising a polynucleotide sequence or pair of polynucleotide sequences of the invention, or comprising an expression vector or pair of expression vectors of the invention.

[0032]

[0023] In a still further aspect of the invention, there is provided a method for producing an antibody or antigen-binding fragment thereof of the invention, comprising culturing a host cell of the invention in a cell culture medium. Antibodies or antigen-binding fragments thereof that are obtained or obtainable by such methods are also provided.

[0033]

[0024] In a still further aspect of the invention, there is provided a composition comprising an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention. In further embodiments, there is provided a pharmaceutical composition comprising an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention.

[0034]

[0025] In a further aspect of the invention there is provided a kit comprising an anti-TNFR2 antibody or antibody binding fragment, a composition, or a pharmaceutical composition of the invention.

[0035]

[0026] In another aspect of the invention, there is provided a method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-TNFR2 antibody or antibody binding fragment thereof, or a pharmaceutical composition, of the invention. There is also provided an anti-TNFR2 antibody or antibody binding fragment thereof, or a pharmaceutical composition, for use in medicine.

[0036]

[0027] The invention will now be described in more detail, including by reference to several figures and non-limiting Examples.

[0037] DESCRIPTION OF THE FIGURES

[0038]

[0028] Figure 1 : A figure demonstrating the opposing roles of TNFRI and TNFR2 in inflammation.

[0039]

[0029] Figure 2: This figure summarises the generation and selection of the anti-TNFR2 antibodies of the invention.

[0040]

[0030] Figure 3: B cell supernatant screening to identify TNFR2 agonists that selectively bind to both human TNFR2 M196 and R196 variants but not to human TNFR1 on cells. (A) 2D scatter plot to demonstrate binding of hits to TNFR2 M196 vs R196. (B) 2D scatter plot to demonstrate binding of hits to TNFR2 M196 vs TNFR2- / TNFR1+ PEER cell line. (C) 2D scatter plot to demonstrate binding of hits to TNFR2 M196 vs TNFR2 Jurkat parental line.

[0041]

[0031] Figure 4: Select TNFR2 mab agonists demonstrate specificity and equivalent affinity to human TNFR2 M196 and R196 variants; and demonstrate cyno cross-reactivity: Graphs show 2D plots of EC50 cell binding comparisons for each TNFR2 mab following a 1 hr, 37°C incubation in the presence of 10% fetal bovine serum. Demonstrated in legend are select TNFR2 agonists identified.

[0042]

[0032] Figure 5: Select TNFR2 mAb agonist specifically bind to human TNFR2 M196 or R196+ Jurkat lines under physiological conditions. Select TNFR2 mAbs were tested for positive cell binding in the presence of culture media containing 10% fetal bovine serum for 1 hr at 37°C. Graphs demonstrate full dose response curves of the fold increase of fluorescent signal (MFI of mAb I MFI of secondary reagent alone).

[0043]

[0033] Figure 6: Select TNFR2 mab agonists do not block biotinylated TNFa binding to cells. Select TNFR2 mAbs were pre-incubated with TNFR2+ cells at or near receptor saturating levels based on previously generated cell binding curves and prior to addition of biotinylated TNFa. Graphs demonstrate Median fluorescence intensity + / - SD of biotinylated TNFa with streptavidin-PE detection.

[0044]

[0034] Figure 7: Select non-TNFa blocking TNFR2 mAb agonists activate the NF-KB pathway. Graphs show fold signal of relative luminescent units over background signal ± SD from TNFR2+ Jurkat reporter lines (expressing M196 or R196 variants) treated with select TNFR2 mabs but not isotype control mAb. Bioactive TNFa was used here at 370 pg / ml as a positive control for the assay

[0045]

[0035] Figure 8: A. TNFR2 mAbs demonstrating differential ability to capture soluble recombinant or cell membrane shed humanTNFR2 from 5 day conditioned Jurkat supernatants harvested from indicated parental or TNFR2 engineered lines compared to MSD standard controls. Based on standard MSD kit conditions, the measured soluble or shed TNFR2 component from indicated Jurkat cells measures a range from 5 ng / ml (R196) to 15 ng / ml (M196). B. TNFR2 mAbs demonstrating differential ability to capture soluble or shed TNFR2 pooled normal human AB serum compared to MSD standard controls. Based on standard MSD kit conditions, the measured soluble or shed TNFR2 component from normal human AB serum measures approximately 7 ng / ml.

[0046]

[0036] Figure 9: 9A, 9B, 9C. TNFR2 mAbs demonstrating differential ability to capture soluble recombinant mammalian cell-produced monomeric TNFR2-His versus soluble recombinant mammalian cell-produced dimeric TNFR2-Fc-His compared to MSD standard controls. 9D. Table of EC50 binding in ng / ml or nM derived from from Figures 9B-C which show TNFR2 mAbs demonstrating differential ability to capture soluble monomeric TNFR2-His versus dimeric TNFR2-Fc-His compared to MSD standard controls.

[0047]

[0037] Figure 10: Cell binding curves demonstrating effect of pooled normal sera on binding of PE- labeled TNFR2 mAbs. Based on measurements as in Figure 8, the soluble or shed TNFR2 component of 50% normal human AB serum measures approximately 3.5 ng / ml.

[0048]

[0038] Figure 11 : TNFR2 agonist antibodies expand human Tregs in vitro. FACS-sorted primary human Tregs from peripheral blood mononuclear cells were cultured with anti-CD3 / CD28 and IL-2 plus TNFR2 agonist antibodies or isotype control for 14 days. Treg expansion was evaluated by counting and flow cytometry. Each antibody was tested in two or more donors.

[0049]

[0039] Figure 12: TNFR2 agonist antibodies expand human Tregs in vitro. FACS-sorted primary human Tregs from peripheral blood mononuclear cells were cultured with anti-CD3 / CD28 and IL-2 plus TNFR2 agonist antibodies or isotype control for 14 days. Treg phenotype i.e. CD39 was evaluated by counting and flow cytometry. Each antibody was tested in two or more donors.

[0050]

[0040] Figure 13: TNFR2 agonist mAbs enhance the ability of Tregs to suppress the proliferation of CD4+ Tconv cells across several donors and different Tconv / Treg ratios relative to isotype control-treated Tregs.

[0051]

[0041] Figure 14: This figure provides the sequences of exemplary antibodies of the invention. Specifically, the VH and VL sequences are provided, with the CDR positions according to the AbM definition indicated. In the event of a discrepancy between the sequences provided in the accompanying sequence listing, and the sequences provided in the figures, the sequences of the figures should prevail.

[0052]

[0042] Figure 15: This figure provides the results of the domain mapping by SPR of Example 11 .

[0053]

[0043] Figure 16: This figure provides the results of the kinetics of binding of soluble recombinant monomeric TNFR2-his or dimeric TNFR2-Fc-His antigens to captured TNFR2 mAbs of Example 11 . N.D. represents “non-determinable” kinetics of binding due to no or very low binding up to 30 nM of antigen.

[0054] DEFINITIONS

[0055]

[0044] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.

[0045] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0056]

[0046] Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0057]

[0047] As used herein, the term "about" means that the numerical value is approximate, and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by + / -10% and remain within the scope of the disclosed embodiments. Additionally, although a value may be preceded by the term ‘‘about’’ the exact value is also provided for herein, i.e. , without the term ‘‘about.’’

[0058]

[0048] As used herein, the terms "comprising" (and any form of comprising, such as "comprise", "comprises", and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain"), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any step or composition that uses the transitional phrase of "comprise" or "comprising" can also be said to describe the same with the transitional phases of "consisting of," "consists," ‘‘consisting essentially of,’’ or ‘‘consists essentially of.’’

[0059]

[0049] The term “specific binding’’ or “specifically binds’’ or “binds’’ as used herein refers to antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen orthe epitope within the antigen with a dissociation constant (KD) of 1x10'7M or less, or 1x1 O'8M or less, for example 1x1 O'9M or less, 1x1 O'10M or less, 1x1 O'11M or less, or 1x10'12M or less, typically with a KD that is at least ten fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The dissociation constant can be measured using standard procedures. Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). Antibodies of the present invention have cross-reactivity to human and cyno TNFR2. However, the antibodies do not bind murine TNFR2.

[0060]

[0050] The term “TNFR2’’ refers to tumor necrosis factor receptor 2, also known as tumor necrosis factor receptor superfamily member 1 B (TNFRSF1 B) and CD120b. TNFR2 comprises four cysteine rich domains (CRDs), which allow for binding of TNFa to TNFR2. When expressed at the surface of a cell, TNFR2 comprises an intracellular domain, a transmembrane domain, and an extracellular domain. Unlike TNFR1 , TNFR2 does not comprise a death domain in its intracellular domain. In humans, the TNFRFS1 B gene contains two coding sequence alleles (coding nucleotides 587 T / G in exon 6, (GenBank dbsnp Short genetic variations; rs1061622), encoding amino acid residues 196). Thus, TNFR2 is expressed as one of two variants, either the R196 variant (SEQ ID NO: 573), where there is an arginine at position 196, or the M196 variant (SEQ ID NO: 572), where there is a methionine at position 196. The M196 and R196 forms may differ in their ability to mediate TNF signalling and activate downstream pathways and pathologic processes (such as apoptosis), such that the R196 form may allow for less activation of NF-KB and recruitment of TRAF2, and greater induction of apoptosis after activation of the TNFRI pathway.

[0061]

[0051] The sequence of the human M196 variant of TNFR2 is provided in SEQ ID NO: 572. The sequence of the human M196 variant of TNFR2 is provided in SEQ ID NO: 573. The sequence of cynomolgus (cyno) TNFR2 is provided in SEQ ID NO: 574. The sequence of murine TNFR2 is provided in SEQ ID NO: 575. References to TNFR2 herein may refer to any of human, cyno or murine TNFR2. Generally, the anti-TNFR2 antibodies and antigen-binding fragments thereof specifically bind to human and cyno TNFR2, but they do not specifically bind to murine TNFR2. Cyno cross-reactivity may be advantageous since it allows for in vivo studies to take place in cynomolgus monkeys.

[0062]

[0052] The term “membrane-bound TNFR2” refers to TNFR2 that is expressed at the cell surface. The membrane-bound TNFR2 comprises an intracellular domain inside the cell, a transmembrane domain traversing the cell membrane, and an extracellular domain on the outside of the cell. When expressed on the surface of the cell, TNFR2 may form multimers or clusters comprising multiple copies of the TNFR2 protein, for example dimers. Such TNFR2 may be referred to herein as “multimeric membrane-bound TNFR2 ”.

[0063]

[0053] The term “shed TNFR2” refers to human or cyno TNFR2 that has been shed by a mammalian cell and is non-membrane-bound. Instead the protein is present in soluble form (not bound to a membrane). Such TNFR2 may occur in vivo for example as a result of shedding of the TNFR2 protein expressed by cells. Shed TNFR2 is comprised of the extracellular domain of TNFR2, and does not comprise the transmembrane region or the intracellular region of TNFR2. When shed, TNFR2 may be monomeric, dimeric, or trimeric.

[0064]

[0054] “Preferential’’ or “preferentially’’ in the context of the selectivity of the anti-TNFR2 antibodies or antigen-binding fragments thereof refers to the tendency (or preference) of the anti-TNFR2 antibodies or antigen-binding fragments to selectively bind one form of TNFR2 over another. For example, the anti- TNFR2 antibodies or antigen-binding fragments thereof of the invention selectively bind to membranebound TNFR2 compared to shed TNFR2. Hence, the anti-TNFR2 antibodies or antigen-binding fragments thereof of the invention are said to preferentially bind to membrane-bound TNFR2 compared to shed TNFR2. Preferential binding may refer to an affinity of one form of TNFR2 (for example membrane-bound TNFR2) of at least 10 times over another form of TNFR2. Accordingly in some embodiments, the anti- TNFR2 antibody or antigen-binding fragment thereof binds to membrane-bound TNFR2 with an affinity that is at least 10 times greater than the affinity with which the anti-TNFR2 antibody or antigen-binding fragment thereof binds to shed TNFR2. Soluble TNFR2 is also represented as recombinant soluble monomeric form derived from mammalian cells. Accordingly, in some embodiments, the anti-TNFR2 antibodies or antigenbinding fragments thereof of the invention preferentially bind to membrane-bound TNFR2 compared to soluble monomeric TNFR2. In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof does not specifically bind to physiological concentrations of shed TNFR2 of supernatants derived from human TNFR2 expressing Jurkat cell line cultures. In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof does not specifically bind to physiological concentrations of shed TNFR2 naturally present in 50% human serum pooled and derived and normal healthy AB serotype donors. In some embodiments, a physiological concentration of shed TNFR2 may be up to about 15 ng / ml (Sennikov et al. Cytokine. 2015; 73:288-294; DeBerge et al. J Leukoc Biol. 2015; 98(3):423-424). In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof does not specifically bind to shed TNFR2 when the shed TNFR2 is at a concentration of 15 ng / ml.

[0065]

[0055] The term “antibodies” as used herein is meant in a broad sense and includes immunoglobulin molecules including polyclonal antibodies, monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antibody fragments, bispecific or multispecific antibodies formed from at least two intact antibodies or antibody fragments, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity. Generally, the antibodies of the invention are dimeric human monoclonal antibodies.

[0066]

[0056] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes lgA1 , lgA2, lgG1 , lgG2, lgG3 and lgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (K) and lambda (A), based on the amino acid sequences of their constant domains. Generally, the antibodies of the invention are lgG1 antibodies. In other words, the antibodies of the invention generally comprise the heavy and light chain constant regions of human IgG 1 . As noted elsewhere, the antibodies may have a disabled Fc effector function, as achieved by modification or mutation of one or more residues in the constant regions. However, even when incorporating such modifications or mutations, the antibodies are still considered IgG 1 antibodies. In some embodiments, the antibodies comprise a heavy chain constant region comprising the sequence of SEQ ID NO: 570 and a light chain constant region comprising the sequence of SEQ ID NO: 571 .

[0067]

[0057] The terms “antibody fragment” or “antigen-binding fragment” are used interchangeable and referto a portion of an immunoglobulin molecule that retains one or more heavy chain and / orthe light chain antigen-binding site, such as heavy chain complementarity determining regions (HCDR) 1 , 2 and 3, light chain complementarity determining regions (LCDR) 1 , 2 and 3, a heavy chain variable region (VH), or a light chain variable region (VL). Antibody fragments include well known Fab, F(ab')2, Fd and Fv fragments as well as domain antibodies (dAb) consisting of one VH domain. VH and VL domains can be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen-binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Pat. Publ. No. WO1998 / 44001 , Int. Pat. Publ. No. WO1988 / 01649; Int. Pat. Publ. No. WO1994 / 13804; Int. Pat. Publ. No. WO1992 / 01047. An antigen-binding fragment is a fragment of an antibody that retains the ability of the antibody to specifically bind its antigen. An antigen-binding fragment therefore retains the antigen specificity and selectivity of the antibody. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab1, F(ab')2, Fv fragment, and scFv. The fragments themselves may be comprised in larger constructs.

[0058] The term “heavy chain variable region’’, “heavy chain variable sequence ”, “VH ”, “VH region’’ and “VH sequence’’ are used interchangeably herein and refer to the residues of an antibody or antigenbinding fragment that make up the heavy chain variable region of the antibodies, i.e. the sequence of the heavy chain that excludes the constant region sequences. Antibodies or antigen-binding fragments thereof described herein by reference to a VH sequence (or the like) may further comprise a corresponding constant region sequence.

[0068]

[0059] The term “light chain variable region”, “light chain variable sequence ”, “VL”, “VL region’’ and “VL sequence” are used interchangeably herein and refer to the residues of an antibody or antigen-binding fragment that make up the light chain variable region of the antibodies, i.e. the sequence of the light chain that excludes the constant region sequences. Antibodies or antigen-binding fragments thereof described herein by reference to a VL sequence (or the like) may further comprise a corresponding constant region sequence.

[0069]

[0060] As used herein, the term “isolated antibody” refers to an antibody which has been separated and / or recovered from a component of its manufacturing host cell environment. Contaminant components of its manufacturing host cell environment are materials which would interfere with research, diagnostic, or therapeutic uses of the antibody. The antibodies or antigen-binding fragments thereof provided herein may be isolated.

[0070]

[0061] An antibody variable region consists of a “framework” region interrupted by three “antigenbinding sites”. The antigen-binding sites are defined using various terms: (i) “Complementarity Determining Regions” (“CDRs”), three in the VH (HCDR1 , HCDR2, HCDR3), and three in the VL (LCDR1 , LCDR2, LCDR3), are based on sequence variability (e.g. Wu and Kabat, J Exp Med 132:211-50, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). (ii) “Hypervariable regions”, “HVR”, or “HV”, three in the VH (H1 , H2, H3) and three in the VL (L1 , L2, L3), refer to the regions of an antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk, Mol Biol 196:901-17, 1987). Otherterms include “IMGT-CDRs” (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and “Specificity Determining Residue Usage” (SDRU) (Almagro, Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT) database (http: / / www_imgt_org) provides a standardized numbering and definition of antigen-binding sites. The correspondence between CDRs, HVs and IMGT delineations is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003. Since different CDR definitions can be used, the sequences of the framework regions will depend on the CDR definitions being used.

[0071]

[0062] “Monoclonal antibody” as used herein refers to a homogenous antibody population with singular molecular composition. Monoclonal antibodies may be monospecific or multispecific.

[0072]

[0063] The terms “CDR”, “HCDR1 ”, “HCDR2”, “HCDR3”, “LCDR1 ”, “LCDR2” and “LCDR3” as used herein include CDRs defined by any of the methods described herein, Kabat, Chothia, IMGT, Contact or AbM, unless otherwise explicitly stated in the specification.

[0064] The “AbM numbering system” as used herein are the antibody VL and VH residues numbered according to Martin and Thornton J Bmol Biol 263: 800-15, 1996. The ‘‘AbM CDRs” refers to the CDRs as defined by the AbM numbering system.

[0073]

[0065] The “Kabat numbering system” as used herein are the antibody VL and VH residues numbered according to Wu et al. (1970) J Exp Med 132: 211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The ‘‘Kabat CDRs” refers to the CDRs as defined by the Kabat numbering system

[0074]

[0066] The “Chothia numbering system” as used herein are the antibody VL and VH residues numbered according to Al-Lazikani (Al-Lazikani et al., J Mol Biol 273:927-48, 1997). ‘‘Chothia CDRs” are the CDRs as determined by using the Chothia numbering system.

[0075]

[0067] The “IMGT numbering system” as used herein are the antibody VL and VH residues numbered according to Lefranc (Lefranc et al. (2003) Dev Comp Immunol 27: 55-77). The ‘‘IMGT CDRs” refers to the CDRs as defined by the IMGT numbering system.

[0076]

[0068] The ‘‘Contact numbering system” as used herein are the antibody VL and VH residues numbered according to MacCallum (MacCallum RM, Martin ACR & Thornton JM, J. Mol. Biol. 262(1996)732-745). ‘‘Contact CDRs” refers to the CDRs as defined by the Contact numbering system.

[0077]

[0069] The positions of the CDRs according to the different definitions may be defined as set out in Table 1 below. Please note the table below uses the Chothia residue numbering system:

[0078] Table 1: CDR definitions using different CDR definitions

[0079]

[0070] ‘‘Overlap CDRs” as used herein as a shorthand to referto the amino acid resides that are included within the definition of all of the AbM, Kabat, Chothia, IMGT and Contact CDR definitions when the AbM, Kabat, Chothia, IMGT and Contact CDRs are aligned. Although an ‘‘overlap CDR” may itself ‘‘consist of’ such residues, the CDRs of the antibodies may comprise (i.e. are not necessarily limited to) the residues of the overlap CDRs, and the CDRs may comprise additional residues at one or both ends of the overlap CDR. For example, an IMGT, Kabat, AbM, Chothia or Contact CDR may comprise residues in addition to those residues in the corresponding ‘‘overlap CDR”.

[0071] “Framework’’ or “framework sequences’’ are the remaining sequences of a variable region other than those defined to be antigen-binding site or CDR. Because the antigen-binding site can be defined by various terms as described above, the exact amino acid sequence of a framework depends on how the antigen-binding site was defined.

[0080]

[0072] “Humanized antibodies’’ refers to antibodies in which the antigen-binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include substitutions in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.

[0081]

[0073] “Human-adapted’’ antibodies or “human framework adapted (HFA)’’ antibodies refers to humanized antibodies adapted according to methods described in U.S. Pat. Publ. No. US2009 / 0118127. Human-adapted antibodies are humanized by selecting the acceptor human frameworks based on the maximum CDR and FR similarities, length compatibilities and sequence similarities of CDR1 and CDR2 loops and a portion of light chain CDR3 loops.

[0082]

[0074] “Human antibody’’ refers to an antibody having heavy and light chain variable regions in which both the framework and the antigen-binding site regions are derived from sequences of human origin. If the antibody contains a constant region, the constant region also is derived from sequences of human origin. The constant region of the antibody may be modified, for example to abolish binding to Fc gamma receptors, although such an antibody would still be considered a human antibody.

[0083]

[0075] Human antibody comprises heavy or light chain variable regions that are “derived from’’ sequences of human origin if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice carrying human immunoglobulin loci as described herein. “Human antibody’’ may contain amino acid differences when compared to the human germline or rearranged immunoglobulin sequences due to for example naturally occurring somatic mutations or intentional introduction of substitutions. Typically, “human antibody’’ is at least about 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical in amino acid sequence to an amino acid sequence encoded by a human germline or rearranged immunoglobulin gene. In some cases, “human antibody’’ may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al (2000) J. Mol. Biol. 296:57-86), or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al (2010) J. Mol. Biol. 397:385-96, 2010 and Int. Pat. Publ. No. W02009 / 085462.

[0084]

[0076] Isolated humanized antibodies are synthetic. Human antibodies, while derived from human immunoglobulin sequences, may be generated using systems such as phage display incorporating synthetic CDRs and / or synthetic frameworks, or can be subjected to in vitro mutagenesis to improve antibody properties, resulting in antibodies that do not naturally exist within the human antibody germline repertoire in vivo.

[0077] Human antibodies may include substitutions in the framework or in the antigen-binding site so that they may not be exact copies of expressed human immunoglobulin or germline gene sequences. However, antibodies in which antigen-binding sites are derived from a non-human species are not included in the definition of “human antibody’’.

[0085]

[0078] As used herein, the term “percent (%) identity’’ refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence, e.g., an anti-FcRn antibody of the disclosure, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, e.g., a wild-type anti-FcRn antibody, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment overthe full length of the sequences being compared. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (which can alternatively be phrased as a given candidate sequence that has or includes a certain percent amino acid (or nucleic acid) sequence identity to, with, or against a given reference sequence) is calculated as follows:

[0086] 100 x (fraction of A / B) where A is the number of amino acid (or nucleic acid) residues scored as identical in the alignment of the candidate sequence and the reference sequence, and where B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In some embodiments where the length of the candidate sequence does not equal to the length of the reference sequence, the percent amino acid (or nucleic acid) sequence identity of the candidate sequence to the reference sequence would not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence.

[0087]

[0079] In some embodiments, a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purpose is at least 30%, e.g., at least 40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100% of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid (or nucleic acid) residue as the corresponding position in the reference sequence, then the molecules are identical at that position. A position may be altered by a substitution, deletion, or insertion. A substitution, deletion, or insertion may comprise a certain number of amino acids, (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or more). When describing a substitution, deletion, or insertion of no more than n amino acids, this is meant that the substitution, deletion, or insertion comprises, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or n amino acids. The number or substitutions, deletions, or insertions can comprise a percent of the total sequence (e.g., 1%, 5%, 10%, 15%, 20%, or more) where the number of substitutions, deletions, or insertions alters 5%, 10%, 15%, 20% or more, of the amino acids in the total sequence.

[0080] The term “recombinant” as used herein, includes antibodies and other proteins, such as TNFR2, that are prepared, expressed, created or isolated by recombinant means.

[0088]

[0081] The term "epitope" as used herein means a portion of an antigen to which an antibody specifically binds. Epitopes usually consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and can have specific three- dimensional structural characteristics, as well as specific charge characteristics. An epitope can be composed of contiguous and / or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3-dimensional space through the folding of the protein molecule.

[0089]

[0082] “Monospecific” as used herein refers to an antibody that binds one distinct antigen or one distinct epitope within an antigen. A monospecific antibody may have cross-reactivity to homologous antigens from different species. For example, a monospecific antibody may bind human and cyno versions of an antigen, such as human and cyno TNFR2.

[0090]

[0083] “Bispecific” as used herein refers to an antibody that binds two distinct antigens or two distinct epitopes within an antigen. A bispecific antibody may have cross-reactivity to other related antigens or can bind an epitope that is shared between two or more distinct antigens.

[0091]

[0084] “Multispecific” as used herein refers to an antibody that binds two or more distinct antigens or two or more distinct epitopes within an antigen. The multispecific antibody may have cross-reactivity to other related antigens or can bind an epitope that is shared between two or more distinct antigens.

[0092]

[0085] In some embodiments, the antibodies or antigen-binding fragments thereof provided herein can be monospecific (e.g., monovalent or bivalent). An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide.

[0093]

[0086] “Fc disabled” refers to an antibody that comprises a non-functional Fc region (fragment crystallizable region), i.e. a Fc region that has been disabled by mutation or otherwise. Fc disabled antibodies demonstrate attenuated Fc function. The Fc disabled antibody may comprise human IGHC heavy chain sequence as listed by IMGT that had been modified or engineered or constructed to reduce binding to one or more Fc gamma receptors. For example, via IGHC hinge mutation or by construction of an antibody comprising heavy chain constant domains which are chimeric or hybrid for lgG1 / lgG2A or lgG1 / lgG4 IGHC sequences. Antibodies or antigen-binding fragments thereof that are said to not bind to Fc gamma receptors may be referred to as “Fc disabled”. The antibodies or antigen-binding fragments thereof provided herein may be Fc disabled, such that they do not bind to any Fc gamma receptors. Embodiments referring to antigen-binding fragments of antibodies that are “Fc disabled” generally refer to antigen-binding fragments that comprise a (disabled) Fc domain. Alternatively, the antibody or antigenbinding fragment thereof can be prevented from binding to Fc gamma receptors because of the absence of an Fc domain.

[0087] “Isotype control’’ refers to an antibody that is used as a negative control in assays that determine a functional property of a test antibody. An isotype antibody is of the same immunoglobulin class as the test antibody but lacks specificity to the antigen specifically bound by the test antibody. “Test antibody’’ refers to the antibody (or antigen-binding fragment thereof) whose functional property is being determined. For example, the test antibody may be an anti-TNFR2 antibody or antigen-binding fragment thereof whose functional property is being measured or determined.

[0094]

[0088] The term “in combination with’’ as used herein means that the drugs or therapeutics can be administered to an animal species such as human together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0095]

[0089] The term “vector’’ means a polynucleotide capable of being duplicated within a biological system or that can be moved between such systems. Vector polynucleotides typically contain elements, such as origins of replication, polyadenylation signal or selection markers, that function to facilitate the duplication or maintenance of these polynucleotides in a biological system. Examples of such biological systems may include a cell, virus, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector. The polynucleotide comprising a vector may be DNA or RNA molecules or a hybrid of these.

[0096]

[0090] The term “expression vector’’ means a vector that can be utilized in a biological system or in a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector. The vectors provided herein may be expression vectors.

[0097]

[0091] The term “polynucleotide’’ means a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. Double and single-stranded DNAs and RNAs are typical examples of polynucleotides.

[0098]

[0092] The term “polypeptide’’ or “protein’’ means a molecule that comprises at least two amino acid residues linked by a peptide bond to form a polypeptide. Small polypeptides of less than 50 amino acids may be referred to as “peptides’’.

[0099]

[0093] The term "T cells’’, also known as “T lymphocytes’’, refers to white blood cells involved in the adaptive immune response. Derived from hematopoietic stem cells in the bone marrow, T cells undergo maturation in the thymus, where they develop specificity for antigens through the expression of T-cell receptors (TCRs). These receptors enable T cells to recognize and bind to specific antigens presented by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). T cells may be identified by cell surface expression of CD3 and the TCR. There are different subsets of T cells, including helper T cells (“CD4+ T cells’’), cytotoxic T cells (“CD8+ T cells’’) and regulatory T cells (“Tregs”). Markers for Treg cells include CD4, CD25, FOXP3, CTLA-4, and GITR. Treg cells may be identified as being CD4 positive, CD25 positive (or high) and CD127 negative (or low), i.e. CD4+CD25+CD127-. Treg cells may be activated by incubating them with anti-CD3 antibody, an anti-CD28 antibody, and IL-2. “Conventional CD4+ T helper cells’’ as used herein refers to non-Treg T cells that are CD4+ positive.

[0094] Using the three letter and one letter codes the naturally occurring amino acids may be referred to as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Vai), leucine (L or Leu), isoleucine (I or lie), proline (P or Pro), phenylalanine (F or Phe), tyrosine (Y or Tyr), tryptophan (W or Trp), lysine (K or Lys), arginine (R or Arg), histidine (H or His), aspartic acid (D or Asp), glutamic acid (E or Glu), asparagine (N or Asn), glutamine (Q or Gin), cysteine (C or Cys), methionine (M or Met), serine (S or Ser) and threonine (T orThr). Where a residue may be aspartic acid or asparagine, the symbols Asx or B may be used. Where a residue may be any amino acid the symbol Xaa orX may be used. Where a residue may be glutamic acid or glutamine, the symbols Glx or Z may be used. References to aspartic acid include aspartate, and glutamic acid include glutamate, unless the context specifies otherwise.

[0100]

[0095] As used herein, the term “pharmaceutically acceptable carrier’’ refers to an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to the Fc construct. The nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used; for oral administration, a solid carrier is generally used.

[0101]

[0096] As used herein, the term “therapeutically effective amount’’ refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired biological effect in a subject or patient or in treating a patient having a condition or disorder described herein. It is also to be understood herein that a “therapeutically effective amount’’ may be interpreted as an amount giving a desired therapeutic effect, either taken in one dose or in any dosage or route, taken alone or in combination with other therapeutic agents.

[0102]

[0097] As used herein, the terms “treatment’’ or “treating’’ referto reducing, decreasing, decreasing the risk of, or decreasing the side effects of a particular disease or condition. Reducing, decreasing, decreasing the risk of, or decreasing the side effects of are relative to a subject who did not receive treatment, e.g., a control, a baseline, or a known control level or measurement.

[0103] DETAILED DESCRIPTION OF THE INVENTION

[0104] Antibodies defined by structure

[0105]

[0098] The present invention provides antibodies and antigen-binding fragments thereof that may be categorised into 4 families, referred to herein as the JNJ-TR2-01 , JNJ-TR2-24, JNJ-TR2-45 and JNJ-TR2- 47 families, each containing related antibodies and antigen-binding fragments thereof, as well as an additional antibody (and antigen-binding fragments thereof) referred to herein as JNJ-TR2-44. Within each of the JNJ-TR2-01 , JNJ-TR2-24, JNJ-TR2-45 and JNJ-TR2-47 families, the heavy and light chain variable regions of the family members are the same, with the exception of a DG motif that is modified to reduce possible isomerisation liabilities. Each of the antibodies disclosed herein may be defined by reference to, for example, the CDRs (any definition provided herein), the VH and / or VL sequences, or the full heavy and light chain sequences.

[0099] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising: a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 54, 60, 66, 72, 78, 84, 222, 228, 234, 240, 246, 252, 372, 378, 384, 390, 396, 402, 408, 414, 420, 426, 432, 438, 450, 456, 462, 468, 474 and 480; a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, 61 , 67, 73, 79, 85, 223, 229, 235, 241 , 247, 253, 373, 379, 385, 391 , 397, 403, 409, 415, 421 , 427, 433, 439, 451 , 457, 463, 469, 475 and 481 ; and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 56, 62, 68, 74, 80, 86, 224, 230, 236, 242, 248, 254, 374, 380, 386, 392, 398, 404, 410, 416, 422, 428, 434, 440, 452, 458, 464, 470, 476 and 482; and / or a light chain variable region comprising: a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: 57, 63, 69, 75,

[0106] 81 , 87, 90 to 221 , 225, 231 , 237, 243, 249, 255, 258 to 371 , 375, 381 , 387, 393, 399, 405, 411 , 417, 423, 429, 435, 441 , 444 to 449, 453, 459, 465, 471 , 477, 483, and 486 to 491 and 545 to 552; a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: 58, 64, 70, 76,

[0107] 82, 88, 226, 232, 238, 244, 250, 256, 376, 382, 388, 394, 400, 406, 412, 418, 424, 430, 436, 442, 454, 460, 466, 472, 478 and 484; and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 59, 65, 71 , 77, 83, 89, 227, 233, 239, 245, 251 , 257, 377, 383, 389, 395, 401 , 407, 413, 419, 425, 431 , 437, 443, 455, 461 , 467, 473, 479 and 485.

[0108]

[0100] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 1 to 5, 565 and 567; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 6 to 53, 557 to 564, 566, 568 and 569.

[0109]

[0101] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 565; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 566. In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 568. In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 569.

[0102] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 492 to 496; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 497 to 544.

[0110]

[0103] In some embodiments, there is provided any of the anti-TNFR2 antibodies referred to herein as JNJ-TR2-01 , JNJ-TR2-02, JNJ-TR2-03, JNJ-TR2-04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2- 08, JNJ-TR2-09, JNJ-TR2-10, JNJ-TR2-11 , JNJ-TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ- TR2-16, JNJ-TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2-20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2-23, JNJ-TR2-24, JNJ-TR2-25, JNJ-TR2-26, JNJ-TR2-27, JNJ-TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ-TR2- 31 , JNJ-TR2-32, JNJ-TR2-33, JNJ-TR2-34, JNJ-TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-TR2-38, JNJ- TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2-43, JNJ-TR2-44, JNJ-TR2-45, JNJ-TR2-46, JNJ-TR2-47 or JNJ-TR2-48, as well as antigen-binding fragments thereof.

[0111] JNJ-TR2-01 family antibodies

[0112]

[0104] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising: a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 54, 60, 66, 72, 78 and 84; a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, 61 , 67, 73, 79 and 85; and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 56, 62, 68, 74, 80, 86; and / or a light chain variable region comprising: a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: 57, 63, 69, 75, 81 , 87 and 90 to 221 ; a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: 58, 64, 70, 76, 82 and 88; and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 59, 65, 71 , 77, 83 and 89.

[0113]

[0105] Taking the AbM definition of the JNJ-TR2-01 CDRs as an example, in some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 545, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65. In some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 549, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65.

[0114]

[0106] In some embodiments, there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: 60, 61 , 62, 63, 64 and 65, respectively; 60, 61 , 62, 112, 64 and 65, respectively; 60, 61 , 62, 113, 64 and 65, respectively; 60, 61 , 62, 114, 64 and 65, respectively; 60, 61 , 62, 115, 64 and 65, respectively; 60, 61 , 62, 116, 64 and 65, respectively; 60, 61 , 62, 117, 64 and 65, respectively; 60, 61 , 62, 118, 64 and 65, respectively; 60, 61 , 62, 119, 64 and 65, respectively; 60, 61 , 62, 120, 64 and 65, respectively; 60, 61 , 62, 121 , 64 and 65, respectively; 60, 61 , 62, 122, 64 and 65, respectively; 60, 61 , 62, 123, 64 and 65, respectively;60, 61 , 62, 124, 64 and 65, respectively; 60, 61 , 62, 125, 64 and 65, respectively; 60, 61 , 62, 126, 64 and 65, respectively; 60, 61 , 62, 127, 64 and 65, respectively; 60, 61 , 62, 128, 64 and 65, respectively; 60, 61 , 62, 129, 64 and 65, respectively; 60, 61 , 62, 130, 64 and 65, respectively; 60, 61 , 62, 131 , 64 and 65, respectively; 60, 61 , 62, 132, 64 and 65, respectively; or 60, 61 , 62, 133, 64 and 65, respectively.

[0115]

[0107] The above SEQ ID NOs refer to the AbM definitions of the CDRs, although alternative CDR definitions known to the skilled person may be used, for example the Kabat, Chothia, IMGT or Contact CDR definitions, or the overlap CDRs as described herein.

[0116]

[0108] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs: 1 and 6; 1 and 7; 1 and 8; 1 and 9; 1 and 10; 1 and 11 ; 1 and 12; 1 and 13; 1 and 14; 1 and 15; 1 and 16; 1 and 17; 1 and 18; 1 and 19; 1 and 20; 1 and 21 ; 1 and 22; 1 and 23; 1 and 24; 1 and 25; 1 and 26; 1 and 27; 1 and 28, 1 and 557; or 1 and 561. The CDRs may be according to any suitable definition known to the skilled person, for example any of AbM, Kabat, Chothia, IMGT or Contact, or the overlap CDRs. AbM CDRs may be preferred.

[0117]

[0109] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 1 ; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 6 to 28.

[0118]

[0110] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 557. In some embodiments, there is provided an ant-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 561 .

[0119]

[0111] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and a light chain variable region comprise or consist of the amino acid sequences of SEQ ID NOs: 1 and 6; 1 and 7; 1 and 8; 1 and 9; 1 and 10; 1 and 11 ; 1 and 12; 1 and 13; 1 and 14; 1 and 15; 1 and 16; 1 and 17; 1 and 18; 1 and 19; 1 and 20; 1 and 21 ; 1 and 22; 1 and 23; 1 and 24; 1 and 25; 1 and 26; 1 and 27; 1 and 28; 1 and 557; or 1 and 561. In some embodiments, the heavy chain variable region and a light chain variable region may comprise a sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the specified SEQ ID NO.

[0120]

[0112] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a heavy chain comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 492; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 497 to 519.

[0121]

[0113] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain and light chain respectively comprise the amino acid sequences of SEQ ID NOs: 492 and 497; 492 and 498; 492 and 499; 492 and 500; 492 and 501 ; 492 and 502; 492 and 503; 492 and 504; 492 and 505; 492 and 506; 492 and 507; 492 and 508; 492 and 509; 492 and 510; 492 and 511 ; 492 and 512; 492 and 513; 492 and 514; 492 and 515; 492 and 516; 492 and 517; 492 and 518; or 492 and 519.

[0122]

[0114] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 497.

[0123]

[0115] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 498.

[0124]

[0116] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 499.

[0125]

[0117] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 500.

[0118] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 501 .

[0126]

[0119] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 502.

[0127]

[0120] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 503.

[0128]

[0121] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 504.

[0129]

[0122] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 505.

[0130]

[0123] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 506.

[0131]

[0124] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 507.

[0132]

[0125] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 508.

[0133]

[0126] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 509.

[0134]

[0127] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 510.

[0135]

[0128] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 511.

[0129] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises or consist of the amino acid sequence of SEQ ID NO: 492, and the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 512.

[0136]

[0130] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 513.

[0137]

[0131] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 514.

[0138]

[0132] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 515.

[0139]

[0133] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 516.

[0140]

[0134] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 517.

[0141]

[0135] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 518.

[0142]

[0136] In one embodiment there is provided an anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 519.

[0143] JNJ-TR2-24 family antibodies

[0144]

[0137] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 222, 228, 234, 240, 246 and 252, a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 223, 229, 235, 241 , 247 and 253 and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of 224, 230, 236, 242, 248 and 254; and / or a light chain variable region comprising a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: 225, 231 , 237, 243, 249, 255 and 258 to 371 , a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: 226, 232, 238, 244, 250 and 256 and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: 227, 233, 239, 245, 251 and 257.

[0145]

[0138] Taking the AbM definition of the JNJ-TR2-24 CDRs as an example, in some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 546, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233. In some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 550, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233.

[0146]

[0139] In some embodiments, there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: 228, 229, 230, 231 , 232 and 233, respectively; 228, 229, 230, 277, 232 and 233, respectively; 228, 229, 230, 278, 232 and 233, respectively; 228, 229, 230, 279, 232 and 233, respectively; 228, 229, 230, 280, 232 and 233, respectively; 228, 229, 230, 281 , 232 and 233, respectively; 228, 229, 230, 282, 232 and 233, respectively; 228, 229, 230, 283, 232 and 233, respectively; 228, 229, 230, 284, 232 and 233, respectively; 228, 229, 230, 285, 232 and 233, respectively; 228, 229, 230, 286, 232 and 233, respectively; 228, 229, 230, 287, 232 and 233, respectively; 228, 229, 230, 288, 232 and 233, respectively; 228, 229, 230, 289, 232 and 233, respectively; 228, 229, 230, 290, 232 and 233, respectively; 228, 229, 230, 291 , 232 and 233, respectively; 228, 229, 230, 292, 232 and 233, respectively; 228, 229, 230, 293, 232 and 233, respectively; 228, 229, 230, 294, 232 and 233, respectively; or 228, 229, 230, 295, 232 and 233, respectively.

[0147]

[0140] The above SEQ ID NOs refer to the AbM definitions of the CDRs, although alternative CDR definitions known to the skilled person may be used, for example the Kabat, Chothia, IMGT or Contact CDR definitions, or the overlap CDRs as described herein.

[0148]

[0141] In some embodiments, there is provided an ant-TNFR2 antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs: 2 and 29; 2 and 30; 2 and 31 ; 2 and 32; 2 and 33; 2 and 34; 2 and 35; 2 and 36; 2 and 37; 2 and 38; 2 and 39; 2 and 40; 2 and 41 ; 2 and 42; 2 and 43; 2 and 44; 2 and 45; 2 and 46; 2 and 47; 2 and 48; 2 and 558; 2 and 562. The CDRs may be according to any suitable definition known to the skilled person, for example any of AbM, Kabat, Chothia, IMGT or Contact, or the overlap CDRs. AbM CDRs may be preferred.

[0142] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 2; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 29 to 48.

[0149]

[0143] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 2; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NOs: 558. In some embodiments, there is provided an ant-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 2; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NOs: 562.

[0150]

[0144] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and a light chain variable region comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 29; 2 and 30; 2 and 31 ; 2 and 32; 2 and 33; 2 and 34; 2 and 35; 2 and 36; 2 and 37; 2 and 38; 2 and 39; 2 and 40; 2 and 41 ; 2 and 42; 2 and 43; 2 and 44; 2 and 45; 2 and 46; 2 and 47; 2 and 48; 2 and 558; 2 and 562. In some embodiments, the heavy chain variable region and a light chain variable region may comprise a sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the specified SEQ ID NO.

[0151]

[0145] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a heavy chain comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 493; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 520 to 539.

[0152]

[0146] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain and light chain comprise or consist of the amino acid sequences of SEQ ID NOs: 493 and 520; 493 and 521 ; 493 and 522; 493 and 523; 493 and 524; 493 and 525; 493 and 526; 493 and 527; 493 and 528; 493 and 529; 493 and 530; 493 and 531 ; 493 and 532; 493 and 533; 493 and 534; 493 and 535; 493 and 536; 493 and 537; 493 and 538; or 493 and 539.

[0153] JNJ-TR2-45 family antibodies

[0147] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising: a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 408, 414, 420, 426, 432 and 438, a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 409, 415, 421 , 427, 433 and 439 and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 410, 416, 422, 428, 434 and 440; and / or a light chain variable region comprising, a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 411 , 417, 423, 429, 435, 441 , and 444 to 449, a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 412, 418, 424, 430, 436 and 442; and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 413, 419, 425, 431 , 437 and 443.

[0154]

[0148] Taking the AbM definition of the JNJ-TR2-45 CDRs as an example, in some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 414, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 415 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 416; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of 547, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 418, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 419. In some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 414, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 415 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 416; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 551 , a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 418, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 419.

[0155]

[0149] In some embodiments, there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: 414, 415, 416, 417, 418 and 419, respectively; or 414, 415, 416, 445, 418 and 419, respectively.

[0156]

[0150] The above SEQ ID NOs refer to the AbM definitions of the CDRs, although alternative CDR definitions known to the skilled person may be used, for example the Kabat, Chothia, IMGT or Contact CDR definitions, or the overlap CDRs as described herein.

[0157]

[0151] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs: 4 and 50; 4 and 51 ; 4 and 559; or 4 and 563. The CDRs may be according to any suitable definition known to the skilled person, for example any of AbM, Kabat, Chothia, IMGT or Contact, or the overlap CDRs. AbM CDRs may be preferred.

[0152] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 4; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 50 to 51 .

[0158]

[0153] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 4; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NOs: 559. In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 4; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 563.

[0159]

[0154] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and a light chain variable region comprise or consist of the amino acid sequences of SEQ ID NOs: 4 and 50; 4 and 51 ; 4 and 559; or 4 and 563. In some embodiments, the heavy chain variable region and a light chain variable region may comprise a sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the specified SEQ ID NO.

[0160]

[0155] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a heavy chain comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 495; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 541 to 542.

[0161]

[0156] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain and light chain comprise or consist of the amino acid sequences of SEQ ID NOs: 495 and 541 ; or 495 and 542.

[0162] JNJ-TR2-47 family antibodies

[0163]

[0157] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising: a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 450, 456, 462, 468, 474 and 480; a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 451 , 457, 463, 469, 475 and 481 ; and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 452, 458, 464, 470, 476 and 482; and / or a light chain variable region comprising: a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO:: 453, 459, 465, 471 , 477, 483 and 486 to 491 ; a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 454, 460, 466, 472, 478 and 484; and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 455, 461 , 467, 473, 479 and 485.

[0164]

[0158] Taking the AbM definition of the JNJ-TR2-47 CDRs as an example, in some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 456, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 457 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 458; and a light chain variable region comprising or consisting of a VLCDR1 comprising the amino acid sequence of 548, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 460, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 461. In some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 456, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 457 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 458; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 552, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 460, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 461.

[0165]

[0159] In some embodiments, there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: 456, 457, 458, 459, 460 and 461 , respectively; or 456, 457, 458, 487, 460 and 461 , respectively.

[0166]

[0160] The above SEQ ID NOs refer to the AbM definitions of the CDRs, although alternative CDR definitions known to the skilled person may be used, for example the Kabat, Chothia, IMGT or Contact CDR definitions, or the overlap CDRs as described herein.

[0167]

[0161] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs: 5 and 52; 5 and 53; 5 and 560; or 5 and 564. The CDRs may be according to any suitable definition known to the skilled person, for example any of AbM, Kabat, Chothia, IMGT or Contact, or the overlap CDRs. AbM CDRs may be preferred.

[0168]

[0162] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence SEQ ID NOs: 5; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 52 to 53.

[0169]

[0163] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 5; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 560. In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 5; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 564.

[0170]

[0164] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and a light chain variable region comprise or consist of the amino acid sequences of SEQ ID NOs: 5 and 52; 5 and 53; 5 and 560; or 5 and 564. In some embodiments, the heavy chain variable region and a light chain variable region may comprise a sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the specified SEQ ID NO.

[0171]

[0165] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a heavy chain comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 496; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 543 to 544.

[0172]

[0166] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain and light chain comprise or consist of the amino acid sequences of SEQ ID NOs: 496 and 543; or 496 and 544.

[0173] JNJ-TR2-44 antibody

[0174]

[0167] Also provided herein is the JNJ-TR2-44 antibody and antigen-binding fragments thereof.

[0175]

[0168] In some embodiments, there is provided an anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region comprising: a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 372, 378, 384, 390, 396 and 402, a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 373, 379, 385, 391 , 397 and 403; and a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 374, 380, 386, 392, 398 and 404; and / or a light chain variable region comprising a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO:: 375, 381 , 387, 393, 399 and 405, a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 376, 382, 388, 394, 400 and 406 and a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NO: 377, 383, 389, 395, 401 and 407.

[0176]

[0169] Taking the AbM definition of the JNJ-TR2-44 CDRs as an example, in some embodiments there is provided an anti-TNFR2 antibody or an antigen-binding fragment thereof comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: 378, 379, 380, 381 , 382 and 383, respectively.

[0177]

[0170] The above SEQ ID NOs refer to the AbM definitions of the CDRs, although alternative CDR definitions known to the skilled person may be used, for example the Kabat, Chothia, IMGT or Contact CDR definitions, or the overlap CDRs as described herein.

[0178]

[0171] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs: 3 and 49. The CDRs may be according to any suitable definition known to the skilled person, for example any of AbM, Kabat, Chothia, IMGT or Contact, or the overlap CDRs. AbM CDRs may be preferred.

[0179]

[0172] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 3; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 49.

[0180]

[0173] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising: a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 494; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the sequence of SEQ ID NO: 540.

[0181]

[0174] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain and light chain comprise or consist of the amino acid sequences of SEQ ID NOs: 494 and 540.

[0182] Additional or alternative structural features

[0183]

[0175] The skilled person is aware that various amino acids have similar properties. One or more such amino acids of an antibody can often be substituted by one or more other such amino acids without eliminating a desired activity of that antibody. Thus, the amino acids glycine, alanine, valine, leucine and isoleucine can often be substituted for one another (amino acids having aliphatic side chains). Of these possible substitutions it may be preferred that glycine and alanine are used to substitute for one another (since they have relatively short side chains) and that valine, leucine and isoleucine are used to substitute for one another (since they have larger aliphatic side chains which are hydrophobic). Other amino acids which can often be substituted for one another include: phenylalanine, tyrosine, and tryptophan (amino acids having aromatic side chains); lysine, arginine, and histidine (amino acids having basic side chains); aspartate and glutamate (amino acids having acidic side chains); asparagine and glutamine (amino acids having amide side chains); and cysteine and methionine (amino acids having sulphur containing side chains).

[0184]

[0176] A “conservative amino acid substitution’’ is an amino acid substitution in which an amino acid residue is replaced with another amino acid residue of similar chemical structure, and which is expected to have little influence on the function, activity or other biological properties of the antibody. Such conservative substitutions suitably are substitutions in which one amino acid within the following groups of Table 2 is substituted by another amino acid residue from within the same group:

[0185] Table 2: Conservative amino acid substitutions

[0186]

[0177] Suitably, a hydrophobic amino acid residue is a non-polar amino acid. More suitably, a hydrophobic amino acid residue is selected from V, I, L, M, F, WorC. In some embodiments, a hydrophobic amino acid residue is selected from glycine, alanine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine, or tryptophan.

[0187]

[0178] Therefore, references to “conservative’’ amino acid substitutions refer to amino acid substitutions in which one or more of the amino acids in the sequence of the antibody (e.g. in the CDRs or in the VH or VL sequences) is substituted with another amino acid in the same class as indicated above. Conservative amino acid substitutions may be preferred in the CDR regions to minimise adverse effects on the function of the antibody. However, conservative amino acid substitutions may also occur in the framework regions. Therefore, in some embodiments, any substitutions in the CDRs may be conservative substitutions, whereas substitutions in the framework regions may by substitutions of naturally occurring amino acids with another other naturally occurring amino acids. In some embodiments, the amino acid substitutions are conservative substitutions, and the substations occur in one or more framework regions.

[0188]

[0179] Amino acid deletions or insertions can also be made relative to the amino acid sequences provided for the antibodies described herein. Thus, for example, amino acids which do not have a substantial effect on the activity of the polypeptide, or at least which do not eliminate such activity, can be deleted. Such deletions can be advantageous since the overall length and the molecular weight of a polypeptide can be reduced whilst still retaining activity. This can enable the amount of polypeptide required for a particular purpose to be reduced - for example, dosage levels can be reduced.

[0189]

[0180] Amino acid changes relative to the sequences provided herein can be made using any suitable technique e.g. by using site directed mutagenesis or solid-state synthesis.

[0190]

[0181] It should be appreciated that amino acid substitutions or insertions within the scope ofthe present invention can be made using naturally occurring or non-naturally occurring amino acids, although naturally occurring amino acids may be preferred. Whether or not natural or synthetic amino acids are used, it may be preferred that only L- amino acids are present.

[0191]

[0182] Various embodiments comprising optional amino acid substitutions the provided antibody sequences are provided herein. In addition, in one embodiment of the invention there is provided an antibody, or antigen-binding fragment thereof, of the invention comprising up to 10, suitably up to 5, or suitably up to 2 amino acid substitutions in the antibody binding domain or antigen-binding domains. For example, in one embodiment ofthe invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the 6 CDR regions of an antibody selected from the group consisting of JNJ-TR2-01 , JNJ-TR2-02, JNJ-TR2-03, JNJ-TR2-04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2-08, JNJ-TR2-09, JNJ-TR2-10, JNJ-TR2-11 , JNJ-TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ-TR2-16, JNJ-TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2- 20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2-23, JNJ-TR2-24, JNJ-TR2-25, JNJ-TR2-26, JNJ-TR2-27, JNJ- TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ-TR2-31 , JNJ-TR2-32, JNJ-TR2-33, JNJ-TR2-34, JNJ-TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-TR2-38, JNJ-TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2- 43, JNJ-TR2-44, JNJ-TR2-45, JNJ-TR2-46, JNJ-TR2-47 and JNJ-TR2-48 (according to any CDR definition herein, suitably the AbM definition), wherein the antibody or antigen-binding fragment thereof has up to 10 amino acid substitutions across all of its CDR regions, suitably up to 5 amino acid substitutions or up to 2 amino acid substitutions. In a further embodiment ofthe invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises the VH and VL regions of an antibody selected from the group consisting of JNJ-TR2-01 , JNJ-TR2-02, JNJ- TR2-03, JNJ-TR2-04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2-08, JNJ-TR2-09, JNJ-TR2-10, JNJ-TR2-11 , JNJ-TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ-TR2-16, JNJ-TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2-20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2-23, JNJ-TR2-24, JNJ-TR2-25, JNJ-TR2- 26, JNJ-TR2-27, JNJ-TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ-TR2-31 , JNJ-TR2-32, JNJ-TR2-33, JNJ- TR2-34, JNJ-TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-TR2-38, JNJ-TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2-43, JNJ-TR2-44, JNJ-TR2-45, JNJ-TR2-46, JNJ-TR2-47 and JNJ-TR2-48, wherein the antibody has up to 10 amino acid substitutions across its VH and VL sequences, suitably up to 5 amino acid substitutions or up to 2 amino acid substitutions. In a still further embodiment of the invention, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment thereof comprises the VH and VL regions of an antibody selected from the group consisting of JNJ-TR2-01 , JNJ-TR2-02, JNJ-TR2-03, JNJ-TR2-04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2-08, JNJ-TR2-09, JNJ-TR2-10, JNJ-TR2-11 , JNJ-TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ-TR2-16, JNJ-TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2-20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2- 23, JNJ-TR2-24, JNJ-TR2-25, JNJ-TR2-26, JNJ-TR2-27, JNJ-TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ- TR2-31 , JNJ-TR2-32, JNJ-TR2-33, JNJ-TR2-34, JNJ-TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-TR2-38, JNJ-TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2-43, JNJ-TR2-44, JNJ-TR2-45, JNJ-TR2- 46, JNJ-TR2-47 and JNJ-TR2-48, wherein the antibody has up to 10 amino acid substitutions, suitably up to 5 amino acid substitutions or up to 2 amino acid substitutions, wherein the substitutions are in the framework regions. Substitutions are of course substitutions with reference to the original CDR or variable chain sequences ofthe starting antibody.

[0192]

[0183] In some embodiments, the one or more amino acid substitutions are in the CDR region or regions. In other embodiments, the one or more amino acid substitutions are in the framework regions, i.e. in the variable heavy and light chains but not in the CDR region or regions. In other embodiments, the one or more amino acid substitutions may be at any position in the variable heavy and / or variable light regions. In some embodiments, the amino acid substitutions do not occur in a CDR sequence.

[0193]

[0184] In some embodiments, the amino acid substitutions do not adversely affect the binding specificity and / or affinity of the antibody. Accordingly, the variant antibody may have the same (or substantially the same) or a superior functional profile as the antibody from which is it derived.

[0194]

[0185] In some of the antibodies provided herein, there is a DG motif in the LCDR1 region. DG motifs are known potential isomerisation site. Therefore, in some embodiments, the DG motif in the LCDR1 region has been mutated to a replace one or both amino acids at this site with a different amino acid. Such mutations may remove or reduce the potential isomerisation risk, without substantially adversely affecting the functional properties of the antibody.

[0195]

[0186] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof comprise a heavy chain constant region and a light chain constant region. In some embodiments, the antibodies comprise a heavy chain constant region comprising or consisting of the sequence of SEQ ID NO: 570, and / or a light chain constant region comprising or consisting of the sequence of SEQ ID NO: 571 .

[0196]

[0187] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof is monospecific for TNFR2. In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof of is bivalent for TNFR2. In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof is bivalent and monospecific for TNFR2

[0197]

[0188] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof comprises an Fc domain. In some embodiments, the Fc domain is disabled. In some embodiments, the antibody or antigen-binding fragment thereof does not comprise an Fc domain. In some embodiments, the antibody or antigen-binding fragment thereof does not bind to one or more Fc gamma receptors. In some embodiments, the antibody or antigen-binding fragment thereof does not bind to one or more human Fc gamma receptors. In some embodiments, the antibody or antigen-binding fragment thereof does not bind to any Fc gamma receptors. In some embodiments, the antibody or antigen-binding fragment thereof does not bind to any human Fc gamma receptors.

[0198]

[0189] The anti-TNFR2 antibody or antigen-binding fragment thereof may be provided as an IgA, IgD, IgE, IgG or IgM antibody. In preferred embodiments, the antibody may be an IgG antibody, for example an IgG 1 antibody, specifically a human lgG1 antibody.

[0199]

[0190] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof is an lgG1 antibody having one or more substitutions or modifications in the constant region to reduce or preferably eliminate binding of the antibody to any human Fc gamma receptors. In some embodiments, the anti- TNFR2 antibody or antigen-binding fragment thereof is an lgG1 antibody having the substitutions L234A, L235Aand D265S (numbering according to the EU numbering scheme). Alternative substitutions to abolish the Fc effector function are known to the skilled person and could be employed instead.

[0200]

[0191] Generally, the anti-TNFR2 antibodies or antigen-binding fragments thereof of the invention are human.

[0201]

[0192] Any of the antibodies or antigen-binding fragments described herein by reference to one or more structural features, such as antibody sequences, may preferably exhibit one or more of the functional features of the antibodies or antigen-binding fragments described herein.

[0202] Antibodies defined by function

[0203]

[0193] As noted above, the anti-TNFR2 antibodies and antigen-binding fragments thereof of the invention provide antibodies having an advantageous functional profile. For example, the anti-TNFR2 antibodies preferentially bind membrane-bound TNFR2 over shed TNFR2. This is advantageous since it avoids or mitigates the issue of the antibodies binding to shed TNFR2 (i.e. TNFR2 that has been shed by cells) in vivo. Shed TNFR2 may act as a sink, binding to anti-TNFR2 antibodies and preventing them from exerting their biological effect on TNFR2 expressing cells. However, if the anti-TNFR2 antibodies preferentially bind membrane-bound TNFR2 over shed TNFR2 (or if they do not or specifically bind to physiological concentrations of shed TNFR2 at all), this problem can be mitigated or avoided altogether. When TNFR2 is in membrane-bound form, it may form multimers or clusters comprising multiple copies of the TNFR2 protein, for example dimers. The anti-TNFR2 antibodies and antigen-binding fragments thereof of the invention preferentially bind to membrane-bound TNFR2 over shed TNFR2, and anti-TNFR2 antibodies and antigen-binding fragments thereof that preferentially bind to membrane-bound TNFR2 can be made according to the protocol described in the Examples.

[0204]

[0194] In some embodiments, the TNFR2 antibodies are also agonistic. In addition, in some embodiments the anti-TNFR2 antibodies do not block (or do not substantially block) the binding of TNFa to TNFR2. Therefore, the antibodies can themselves act as an agonist of the TNFR2 receptor, whilst also allowing endogenous TNFa to bind to, and activate, TNFR2 on TNFR2 expressing cells.

[0195] The anti-TNFR2 antibodies specifically bind at least two variants of human TNFR2, known as the M196 and R196 variants of TNFR2. This may be advantageous as it means the antibodies are useful as therapeutic agents regardless ofthe variant expressed by a subject.

[0205]

[0196] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody preferentially binds to membrane-bound TNFR2 compared to shed TNFR2.

[0206]

[0197] In some embodiments, there is provided an anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody preferentially binds to membrane-bound TNFR2 compared to mammalian cell produced recombinant soluble monomeric TNFR2.

[0207]

[0198] In some embodiments, the antibodies are agonistic. Agonistic TNFR2 antibodies are able to effect NF-KB signalling, via activation of the TNFR2 receptors expressed by TNFR2 positive cells. Agonistic activity can be measured by measuring NF-KB activity in cells expressing TNFR2 receptors at their cell surface after contacting the cells with the antibodies or antigen-binding fragments thereof. Thus, in some embodiments, the antibodies effect NF-KB signalling in TNFR2+ cells. In some embodiments, agonistic activity is measured as luciferase activity from Jurkat NF-KB-responsive luciferase reporter cell line that have been engineered to express the R196 or M196 full length variants of human TNFR2.

[0208]

[0199] In some embodiments, agonistic activity may be measured according to the following method: a) providing a Jurkat NF-KB-responsive luciferase reporter cell line that has been engineered to express the R196 or M196 full length variant of human TNFR2; b) incubating the cell line with serial dilutions of an antibody or antigen-binding fragment thereof ofthe invention (for example from 0.01 to 10 nM), optionally incubating the cells in the presence of the antibody or antigen-binding fragment thereof for 6 hours in humidified incubators set to 5% CO2 and 37 °C; c) contacting the treated cells with luciferase substrate; and d) measuring the luminescence effected by the antibody or antigen-binding fragment thereof to determine agonism.

[0209]

[0200] In embodiments in which luciferase activity is measured to determine agonism of the antibodies, the antibodies may be said to be agonistic when luciferase activity is increased by at least about 50%, for example compared to a control, e.g. an isotype control.

[0210]

[0201] In some embodiments, agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (b). In some embodiments, the luminescence measured in step (d) is compared to the luminescence in an equivalent method in which the cell line was not incubated with an antibody or antigen-binding fragment thereof of the invention, and agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof is higher (e.g. at least about 50% higher) than the luminescence measured in the absence of the antibody or antigen-binding fragment thereof. In some embodiments, the luminescence measured in step (d) is compared to the luminescence in an equivalent method in which the cell line was incubated with a control (without an antibody or antigen-binding fragment thereof of the invention), and agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof is higher (e.g. at least about 50% higher) than the luminescence measured in the presence of the control (e.g. an isotype control).

[0211]

[0202] In some embodiments, agonistic activity may be measured according to the following method: a) culturing a Jurkat NF-KB-responsive luciferase reporter cell line that have been engineered to express the R196 or M196 full length variants of human TNFR2; b) harvesting the cells; c) optionally washing the cells; d) plating the cells at 200,000 cells per well in flat-bottom white-walled 96-well tissue culture plates e) treating the cells with serial dilutions of the antibody or antigen-binding fragment thereof (for example from 0.01 to 10 nM) at final 100 pl volume for 6 hr in humidified incubators set to 5% CO2 and 37 °C; f) after the incubation period, contacting the treated cells with an equal volume of 100 pl of luciferase substrate in each well; g) reading the plates for luminescence effected by the antibody or antigen-binding fragment thereof to determine agonism.

[0212]

[0203] In embodiments in which luciferase activity is measured to determine agonism of the antibodies, the antibodies may be said to be agonistic when luciferase activity is increased by at least about 50%, for example compared to a control, e.g. an isotype control.

[0213]

[0204] In some embodiments, agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (e). In some embodiments, the luminescence measured in step (g) is compared to the luminescence in an equivalent method in which the cell line was not incubated with an antibody or antigen-binding fragment thereof of the invention, and agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof is higher (e.g. at least about 50% higher) than the luminescence measured in the absence of the antibody or antigen-binding fragment thereof. In some embodiments, the luminescence measured in step (g) is compared to the luminescence in an equivalent method in which the cell line incubated with a control (in the absence of an antibody or antigen-binding fragment thereof of the invention), and agonism is determined when the luminescence effected by the antibody or antigen-binding fragment thereof is higher (e.g. at least about 50% higher) than the luminescence measured in the absence of the control (e.g. an isotype control).

[0214]

[0205] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof specifically bind to both M196 and R196 variants of TNFR2.

[0215]

[0206] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragment thereof do not compete with TNFa for binding to TNFR2, in particular membrane-bound TNFR2.

[0216]

[0207] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not compete with TNFa for binding to TNFR2 as measured by assessing biotinylated TNFa binding to TNFR2+ cells in the presence of the anti-TNFR2 antibody or antigen-binding fragment thereof (for example at a saturating concentration of the anti-TNFR2 antibody or antigen-binding fragment thereof), or by assessing the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to TNFR2+ cells (for example at a saturating concentration of the anti-TNFR2 antibody or antigen-binding fragment thereof) in the presence of TNFa.

[0217]

[0208] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragment thereof inhibit less than about 30% of the binding of TNFa to TNFR2, in particular membrane-bound, TNFR2, in the presence of the anti-TNFR2 antibodies or antigen-binding fragment thereof. In some embodiments, the anti-TNFR2 antibodies orantigen-binding fragment thereof inhibit less than about 30% of the binding ofTNFato TNFR2, in particular membrane-bound, TNFR2, in the presence of a saturating concentration of the anti-TNFR2 antibodies or antigen-binding fragment thereof.

[0218]

[0209] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not compete with TNFa for binding to TNFR2 as measured by assessing biotinylated TNFa binding to TNFR2+ cells in the presence of the anti-TNFR2 antibody or antigen-binding fragment thereof, or by assessing the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to TNFR2+ cells in the presence of TNFa.

[0219]

[0210] A saturating, or close to saturating, concentration of the anti-TNFR2 antibody or antigen-binding fragment thereof may be, for example, 60 nM.

[0220]

[0211] In some embodiments, the method comprises: a) providing a culture of TNFR2 positive cells; b) incubating the cells with unlabelled anti-TNFR2 antibodies or antigen-binding fragments thereof, for example at a saturating concentration; subsequently incubating the cells with serial dilutions of labelled TNFa (for example from 0.01 to 100 ng / nl); c) detecting cell-bound biotinylated TNFa; d) determining if the anti-TNFR2 antibody or antigen-binding fragment thereof does not compete with TNFa for binding to the TNFR2 positive cells, or that it reduces the binding of TNFa to TNFR2 by less than about 30%.

[0221]

[0212] In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as not competing with TNFa for the binding to the TNFR2 positive cells, or is identified as inhibiting less than about 30% of the binding ofTNFato TNFR2, if in step (d) it is determined that more that 70% maximum binding of TNFa to the TNFR2 positive cells in the presence of a control (for example an isotype control) is retained in the presence of the anti-TNFR2 antibody or antigen-binding fragment thereof. In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as not competing with TNFa for the binding to the TNFR2 positive cells, or is identified as inhibiting less than about 30% of the binding of TNFa to TNFR2, if in step (d) it is determined the EC50 of the binding of the TNFa to the TNFR2 positive cells is at least 70% of the EC50 of the binding of the TNFa to the TNFR2 positive cells in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof or in the presence of a control (for example an isotype control). Incubation of the cells with the serial dilutions of biotinylated TNFa may occur for 1 hour, 4°C.

[0222]

[0213] In some embodiments, the method comprises: a) providing a culture of TNFR2 positive cells; b) incubating the cells with unlabelled anti-TNFR2 antibodies or antigen-binding fragments thereof, for example at a saturating concentration; subsequently incubating the cells with serial dilutions of biotinylated TNFa (for example from 0.01 to 100 ng / nl); c) optionally washing the cells; d) detecting cell-bound biotinylated TNFa by incubating the cells with streptavidin-phycoerythrin; e) optionally washing the cells; f) fixing the cells, for example with a paraformaldehyde reagent; g) measuring the fluorescence intensity of phycoerythrin using flow cytometric analysis; h) determining if the anti-TNFR2 antibody or antigen-binding fragment thereof does not compete with TNFa for binding to the TNFR2 positive cells, or that it reduces the binding of TNFa to TNFR2 by less than about 30%.

[0223]

[0214] In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as not competing with TNFa for the binding to the TNFR2 positive cells, or is identified as inhibiting less than about 30% of the binding of TNFa to TNFR2, if in step (i) it is determined that more than 70% maximum binding of TNFa to the TNFR2 positive cells in the presence of a control (for example an isotype control) is retained in the presence of the anti-TNFR2 antibody or antigen-binding fragment thereof. In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as not competing with TNFa for the binding to the TNFR2 positive cells, or is identified as inhibiting less than about 30% of the binding of TNFa to TNFR2, if in step (i) it is determined the EC50 of the binding of the TNFa to the TNFR2 positive cells is at least 70% of the EC50 of the binding of the TNFa to the TNFR2 positive cells in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof or in the presence of a control (for example an isotype control). Incubation of the cells with the serial dilutions of biotinylated TNFa may occur for 1 hour 4 °C.

[0224]

[0215] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof stimulate proliferation of regulatory T cells that express TNFR2 at the cell surface upon binding of the antibody to the regulatory T cells.

[0225]

[0216] In some embodiments, the method of determining stimulation of proliferation of Treg cells comprises: a) providing a known quantity of Treg cells; b) incubating the cells with serial dilutions of an anti-TNFR2 antibody or antigen-binding fragment thereof for at least 7 days (for example for 14 days); c) determining the quantity of Treg cells after incubation with the serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof; d) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being capable of stimulating the proliferation of Treg cells if the number of Treg cells has increased.

[0226]

[0217] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to stimulate the proliferation of Treg cells is determined when the number of Treg cells has increased by at least 50% relative to a control, for example isotype control treated Tregs.

[0227]

[0218] In another embodiment, the method of determining stimulation of proliferation of Treg cells comprises: a) providing a known quantity of Treg cells; b) incubating the cells with serial dilutions of an anti-TNFR2 antibody or antigen-binding fragment thereof for at least 7 days (for example for 14 days); c) determining the quantity of Treg cells after incubation with the serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof; d) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being capable of stimulating the proliferation of Treg cells if the number of Treg cells has increased, wherein;

[0228]

[0219] The ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to stimulate the proliferation of Treg cells is determined when the stimulation of proliferation effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (b). In some embodiments, the quantity of Treg cells determined in step (c) is compared to the quantity of Treg cells in an equivalent method in which the population of cells was not incubated with an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention, and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the proliferation of Treg cells when the proliferation of Treg cells stimulated by the anti-TNFR2 antibody or antigen-binding fragment thereof is at least 50% higher than the proliferation of Treg cells stimulated in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof. In some embodiments, the quantity of Treg cells determined in step (c) is compared to the quantity of Treg cells in an equivalent method in which the population of cells was incubated in the presence of a control (without the anti-TNFR2 antibody or antigen-binding fragment thereof), and the anti- TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the proliferation of Treg cells when the proliferation of Treg cells stimulated by the anti-TNFR2 antibody or antigen-binding fragment thereof is at least 50% higherthan the proliferation of Treg cells stimulated in the presence of the control (e.g. an isotype control).

[0229]

[0220] In some embodiments, the method comprises: a) providing a population of CD4+ CD25+ CD127- Treg cells; b) activating the population of Treg cells, optionally by incubating the population of Treg cells with an anti-CD3 antibody, an anti-CD28 antibody, and IL-2 for at least 7 days (for example for 14 days); c) incubating the cells with serial dilutions of an anti-TNFR2 antibody or antigen-binding fragment thereof for at least 7 days (for example for 14 days); d) determining the quantity of Treg cells after incubation with the serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof; e) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being capable of stimulating the proliferation of Treg cells if the number of Treg cells has increased.

[0230]

[0221] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to stimulate the proliferation of Treg cells is determined when the number of Treg cells has increased by at least 50% relative to a control, for example isotype control treated Tregs.

[0231]

[0222] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to stimulate the proliferation of Treg cells is determined when the stimulation of proliferation effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (c). In some embodiments, the quantity of Treg cells determined in step (d) is compared to the quantity of Treg cells in an equivalent method in which the population of cells was not incubated with an anti-TNFR2 antibody or antigen-binding fragment thereof of the invention (or is incubated in the presence of a control), and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the proliferation of Treg cells when the proliferation of Treg cells stimulated by the anti-TNFR2 antibody or antigen-binding fragment thereof is at least 50% higher than the proliferation of Treg cells stimulated in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof. In some embodiments, the quantity of Treg cells determined in step (d) is compared to the quantity of Treg cells in an equivalent method in which the population of cells was in the presence of a control (without the anti- TNFR2 antibody or antigen-binding fragment thereof), and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the proliferation of Treg cells when the proliferation of Treg cells stimulated by the anti-TNFR2 antibody or antigen-binding fragment thereof is at least 50% higherthan the proliferation ofTreg cells stimulated in the presence of the control (e.g. an isotype control).

[0232]

[0223] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof stimulate the suppressive function of regulatory T cells that express TNFR2 at the cell surface upon binding of the antibody to the regulatory T cells.

[0233]

[0224] In some embodiments, the method of determining the ability of the antibodies to stimulate the suppressive function of Treg cells comprises: a) providing a population of Treg cells; b) incubating and activating the population ofTreg cells in the presence of an anti-TNFR2 antibody or antigen-binding fragment thereof for 5 days, optionally wherein activation of the Tregs is achieved by incubating the population of Treg cells with an anti-CD3 antibody, an anti-CD28 antibody, and IL-2; c) harvesting the Treg cells; d) co-culturing a known quantity of the harvested Treg cells with known quantities of conventional CD4+ T helper cells and immature monocyte-derived dendritic cells (moDCs) in the presence of anti-CD3 antibody, wherein the cells are co-cultured for 4 days; and e) determining the percentage of conventional CD4+ T helper cells that proliferated by flow cytometry.

[0234]

[0225] In some embodiments, the method of determining the ability of the antibodies to stimulate the suppressive function of Treg cells comprises: a) providing a population of Treg cells; b) incubating the population of Treg cells in the presence anti-CD3 antibody, an anti-CD28 antibody, and IL-2, and in the presence of an anti-TNFR2 antibody or antigen-binding fragment thereof Treg cells for 5 days; c) harvesting the Treg cells; d) co-culturing a known quantity of the harvested Treg cells with known quantities of conventional CD4+ T helper cells and immature monocyte-derived dendritic cells (moDCs) in the presence of anti-CD3 antibody, wherein the cells are co-cultured for 4 days; and e) determining the percentage of conventional CD4+ T helper cells that proliferated by flow cytometry.

[0235]

[0226] In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the suppressive function of regulatory T cells when the percentage of conventional CD4+ T helper cells that proliferated is lower compared to an isotype control.

[0236]

[0227] In some embodiments, the concentration of IL-2 used may be 30 lU / mL. The concentration of the anti-CD3 antibody used may be 0.01 pg / mL. The concentration of anti-CD28 antibody used may be 0.02 pg / mL. In some embodiments, the co-culture of step (d) uses a ratio of conventional CD4+ T helper cells to activated Treg cells ranging from 1 :1 to 128:1.

[0237]

[0228] In some embodiments, an anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of stimulating the suppressive function of regulatory T cells when the proliferation of the conventional CD4+ T helper cells is reduced compared to an equivalent method which is identical or substantially identical except in step (b) the anti-TNFR2 antibody or antigen-binding fragment thereof is absent, or wherein the anti-TNFR2 antibody or antigen-binding fragment thereof is replaced by an isotype control.

[0238]

[0229] Generally, methods that measure a functional feature of an antibody or antigen-binding fragment thereof may be compared to equivalent methods in the absence of the antibody or antigen-binding fragment thereof to determine the effect of the presence of the antibody or antigen-binding fragment thereof. In some embodiments, the effect of the tested antibody or antigen-binding fragment thereof may be compared to a reference value. In some embodiments, the effect of the tested antibody or antigen-binding fragment thereof may be compared to a control, for example an isotype control. Of course, when performing an assay in the presence of a control, the test substance (i.e. the antibody or antigen-binding fragment thereof) is not present.

[0230] The TNFR2 used in any of the assays to determine a functional property of the antibody may suitably be human TNFR2, for example the M196 or R196 variant of human TNFR2.

[0239]

[0231] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not bind to Fc gamma receptors. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not bind to human Fc gamma receptors.

[0240]

[0232] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof binds to FcRn.

[0241]

[0233] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to a TNFR2 multimer. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to clusters of two or more TNFR2 receptors.

[0242]

[0234] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to mammalian cell expressed, His-tagged, soluble monomeric TNFR2 with an affinity of more than about 1x10'6M, optionally as measured by surface plasmon resonance (SPR).

[0243]

[0235] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not specifically bind to physiological concentrations of shed TNFR2. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not specifically bind to shed when the shed is present at a concentration of 15 ng / ml. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not specifically bind to soluble monomeric TNFR2 when soluble monomeric TNFR2 is present at a concentration of 100 ng / ml.

[0244]

[0236] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof does not specifically bind to shed TNFR2 when the shed TNFR2 is present at a concentration of 15 ng / ml, as measured by incubating an immobilised anti-TNFR2 antibody or antigen-binding fragment thereof in the presence of 15 ng / ml shed TNFR2 and determining the presence or absence of binding between the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof and the shed TNFR2. In some embodiments, the presence or absence of binding between the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof and the shed TNFR2 may be done using a secondary antibody that specifically binds to shed TNFR2. In some embodiments, the shed (TNFR2 may be labelled, and the secondary antibody specifically binds to the label. In some embodiments, the incubation may be for 1 hour at room temperature (e.g. 25 °C).

[0245]

[0237] In some embodiments, the anti-TNFR2 antibody or antigen-binding fragment thereof does not preferentially bind to soluble monomeric TNFR2 when the soluble monomeric TNFR2 is present at a concentration of 100 ng / ml, as measured by incubating an immobilised anti-TNFR2 antibody or antigenbinding fragment thereof in the presence of 100 ng / ml soluble monomeric TNFR2 and determining the presence or absence of binding between the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof and soluble monomeric TNFR2. In some embodiments, the presence or absence of binding between the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof and soluble monomeric TNFR2 may be done using a secondary antibody that specifically binds to soluble monomeric TNFR2. In some embodiments, the soluble monomeric TNFR2 may be labelled and the secondary antibody specifically binds to the label. In some embodiments, the incubation may be for 1 hour at room temperature (e.g. 25 °C).

[0246]

[0238] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to specifically bind to soluble monomeric TNFR2) may be determined according to the following protocol: a) providing a immobilised anti-TNFR2 antibody or antigen-binding fragment thereof; b) incubating the immobilised anti-TNFR2 antibody orantigen-binding fragment thereof with 100 ng / ml soluble monomeric TNFR2; c) optionally washing the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof; d) detecting bound soluble monomeric TNFR2 with a labelled secondary antibody, wherein the labelled secondary antibody specifically binds to the soluble monomeric TNFR2; e) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being unable to specifically bind to the soluble monomeric TNFR2, if no bound soluble monomeric TNFR2 is detected in step (d).

[0247]

[0239] In some embodiments, the soluble monomeric TNFR2 may be labelled and the secondary antibody specifically binds to the label. The step of incubation may be at room temperature (e.g. 25°C) for 1 hour.

[0248]

[0240] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to specifically bind to shed (e.g. soluble monomeric TNFR2) may be determined according to the following protocol: a) providing a immobilised anti-TNFR2 antibody or antigen-binding fragment thereof; incubating the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof with serial dilutions of soluble monomeric TNFR2 (for example from 10 to 105pg / mL TNFR2); b) optionally washing the immobilised anti-TNFR2 antibody or antigen-binding fragment thereof; c) detecting bound soluble monomeric TNFR2 with a labelled secondary antibody, wherein the labelled secondary antibody specifically binds to the soluble monomeric TNFR2; d) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being unable to specifically bind to the soluble monomeric TNFR2, if no soluble monomeric TNFR2 is detected via the labelled secondary antibody in step (d) at a concentration of soluble monomeric TNFR2 of up to at least 100 ng / ml.

[0249]

[0241] In some embodiments, the soluble monomeric TNFR2 maybe labelled and the secondary antibody specifically binds to the label. The step of incubation may be at room temperature (e.g. 25°C) for 1 hour.

[0250]

[0242] The above assays may alternatively be done using physiologically shed TNFR2 (for example shed TNFR2 obtained from the supernatant of a cell culture, wherein the cells have been engineered to express TNFR2 at their cell surface).

[0243] The above assays may alternatively be done using physiologically shed TNFR2 from serum derived from normal human AB serotyped donors.

[0251]

[0244] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to the extracellular domain of TNFR2.

[0252]

[0245] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to cysteine-rich domains (CRD) 1 and / or 2 of TNFR2.

[0253]

[0246] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to the CRD1 and CRD2 domains of TNFR2. The sequence of the CRD1 and CRD2 domains of TNFR2 are provided as SEQ ID NO: 576. Accordingly, in some embodiments, the anti-TNFR2 antibodies or antigenbinding fragments thereof bind to an epitope comprised in SEQ ID NO: 576.

[0254]

[0247] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the R196 full length variant of human TNFR2 with an EC50 of from about 0.1 nM to about 1000 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the R196 full length variants of human TNFR2 with an EC50 of from about 0.1 nM to about 500 nM. In some embodiments, the anti-TNFR2 antibodies orantigen- binding fragments thereof bind to Jurkat cells engineered to express the R196 or M196 full length variants of human TNFR2 with an EC50 of from about 0.1 nM to about 250 nM. In some embodiments, the anti- TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the R196 or M196 full length variants of human TNFR2 with an EC50 of from about 1 nM to about 250 nM.

[0255]

[0248] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the M196 full length variant of human TNFR2 with an EC50 of from about 0.1 nM to about 1000 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the M196 full length variants of human TNFR2 with an EC50 of from about 0.1 nM to about 500 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the R196 or M196 full length variants of human TNFR2 with an EC50 of from about 0.1 nM to about 250 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to Jurkat cells engineered to express the R196 or M196 full length variants of human TNFR2 with an EC50 of from about 1 nM to about 250 nM.

[0256]

[0249] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to both Jurkat cells engineered to express the R196 full length variant of human TNFR2 and to Jurkat cells engineered to express the M196 full length variant of human TNFR2 with an EC50 of from about 0.1 nM to about 1000 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to both Jurkat cells engineered to express the R196 full length variant of human TNFR2 and to Jurkat cells engineered to express the M196 full length variant of human TNFR2 with an EC50 of from about 0.1 nM to about 500 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to both Jurkat cells engineered to express the R196 full length variant of human TNFR2 and to Jurkat cells engineered to express the M196 full length variant of human TNFR2 with an EC50 of from about 0.1 nM to about 250 nM. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to both Jurkat cells engineered to express the R196 full length variant of human TNFR2 and to Jurkat cells engineered to express the M196 full length variant of human TNFR2 with an EC50 of from about 1 nM to about 250 nM.

[0257]

[0250] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to TNFR2 R196 with the same or substantially the same affinity as TNFR2 M196. In some embodiments, “substantially the same’’ means having an EC50 for R196 that is within 10 fold of the EC50 for M196. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof have an EC50 of binding to TNFR2 R196 that is within 5 fold of the EC50 of binding to M196. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof has an EC50 of binding to TNFR2 R196 that is within 3 fold of the EC50 of binding to M196.

[0258]

[0251] In some embodiments, the EC50 of binding to the R196 and M196 variants of TNFR2 is determined using Jurkat cells engineered to express the R196 or M196 full length variants of human TNFR2.

[0259]

[0252] The EC50 values may the be EC50 values determined when incubating the engineered Jurkat cells with the anti-TNFR2 antibody or antigen-binding fragment thereof for 1 hour at 37°C,

[0260]

[0253] In some embodiments, the assay for determining the EC50 comprises: a) providing Jurkat cells engineered to express the R196 or M196 full length variant of human TNFR2; b) incubating the cells with serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof (for example at concentrations from about 0.01 nM to 1000 nM); c) determining a dose response curve for the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells; d) determining the EC50 of the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells.

[0261]

[0254] In some embodiments, the assay for determining the EC50 comprises: a) providing Jurkat cells engineered to express the R196 or M196 full length variant of human TNFR2; b) incubating the cells with serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof (for example at concentrations from about 0.01 nM to 1000 nM) at 37°C with 5% CO2 for 1 hour; c) incubating the cells with a labelled secondary antibody that specifically binds to the anti-TNFR2 antibody or antigen-binding fragment thereof; d) determining a dose response curve for the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells by flow cytometry; e) determining the EC50 of the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells.

[0262]

[0255] In some embodiments, the assay for determining the EC50 comprises: a) providing Jurkat cells engineered to express the R196 or M196 full length variant of human TNFR2; b) incubating the cells with serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof (for example at concentrations from about 0.01 nM to 1000 nM) at 37°C with 5% CO2 for 1 hour; c) washing the cells, for example with ice cold flow staining buffer; d) incubating the cells on ice for 30 minutes with a labelled secondary antibody that specifically binds to the anti-TNFR2 antibody or antigen-binding fragment thereof; e) washing the cells, for example with ice cold flow staining buffer, followed by resuspension in a final 1 :1 ratio (vol / vol) flow staining buffer; f) determining a dose response curve for the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells by flow cytometry; g) determining the EC50 of the binding of the anti-TNFR2 antibody or antigen-binding fragment thereof to the engineered Jurkat cells.

[0263]

[0256] In assays that use flow staining buffer, the flow staining buffer may be BSA buffer with 0.9% sodium azide.

[0264]

[0257] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to human TNFR2. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to cynomolgus (cyno) TNFR2. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not bind to murine TNFR2. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to human and cyno TNFR2. In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof bind to human and cyno TNFR2, but not to murine TNFR2.

[0265]

[0258] In some embodiments, the anti-TNFR2 antibodies or antigen-binding fragments thereof do not bind to physiological concentrations of shed TNFR2.

[0266]

[0259] In some embodiments, binding ofthe anti-TNFR2 antibodies or antigen-binding fragments thereof to TNFR2 on a Treg cell induces upregulation of expression of CD39 on the Treg cell.

[0267]

[0260] In some embodiments, the method comprises: a) providing a known quantity of Treg cells; b) incubating the cells with serial dilutions of an anti-TNFR2 antibody or antigen-binding fragment thereof for 7-14 days (for example for 14 days); determining the proportion of the population of Treg cells that are CD39 positive after incubation with the serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof; c) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being capable of inducing the upregulation of expression of CD39 on the Treg cells if the number of CD39 positive Treg cells has increased, for example compared to a control.

[0268]

[0261] In some embodiments, the ability ofthe anti-TNFR2 antibody or antigen-binding fragment thereof to upregulate the expression of CD39 on the Treg cells is determined when the number of Treg cells that are CD39 positive has increased by at least 50% relative to a control, for example isotype control treated Tregs.

[0269]

[0262] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to upregulate the expression of CD39 on the Treg cells is determined when the upregulation of CD39 expression effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (b). In some embodiments, the proportion ofthe population of Treg cells that are CD39 positive determined in step (c) is compared to the proportion of the population of Treg cells that are CD39 positive in an equivalent method in which the population of cells was not incubated with an anti- TNFR2 antibody or antigen-binding fragment thereof of the invention, and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of upregulating the expression of CD39 on the Treg cells when there is a statistically significant increase in the proportion of Treg cells that are CD39 positive induced by the anti-TNFR2 antibody or antigen-binding fragment thereof compared to the proportion of Treg cells that are CD39 positive induced in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof. In some embodiments, the proportion ofthe population of Treg cells that are CD39 positive determined in step (c) is compared to the proportion of the population of Treg cells that are CD39 positive in an equivalent method in which the population of cells is incubated with a control (in the absence ofthe anti-TNFR2 antibody or antigen-binding fragment thereof), and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of upregulating the expression of CD39 on the Treg cells when there is a statistically significant increase in the proportion of Treg cells that are CD39 positive induced by the anti-TNFR2 antibody or antigen-binding fragment thereof compared to the proportion of Treg cells that are CD39 positive induced in the presence ofthe control (in the absence ofthe anti-TNFR2 antibody or antigen-binding fragment thereof). The control may suitably be an isotype control.

[0270]

[0263] In some embodiments, the method comprises: a) providing a population of CD4+ CD25+ CD127- Treg cells; b) activating the population of Treg cells, optionally by incubating the population of Treg cells with an anti-CD3 antibody, an anti-CD28 antibody, and IL-2 for 7-14 days (for example for 14 days); c) incubating the cells with serial dilutions of an anti-TNFR2 antibody or antigen-binding fragment thereof for 7-14 days (for example for 14 days); d) determining the proportion of the population of Treg cells that are CD39 positive after incubation with the serial dilutions of the anti-TNFR2 antibody or antigen-binding fragment thereof e) identifying the anti-TNFR2 antibody or antigen-binding fragment thereof as being capable of inducing the upregulation of expression of CD39 on the Treg cells if the number of CD39 positive Treg cells has increased by at least 50% relative to a control, for example isotype control.

[0271]

[0264] In some embodiments, the ability ofthe anti-TNFR2 antibody or antigen-binding fragment thereof to upregulate the expression of CD39 on the Treg cells is determined when the number of Treg cells that are CD39 positive has increased by at least 50% relative to a control, for example isotype control treated Tregs.

[0265] In some embodiments, the ability of the anti-TNFR2 antibody or antigen-binding fragment thereof to upregulate the expression of CD39 on the Treg cells is determined when the upregulation of CD39 expression effected by the antibody or antigen-binding fragment thereof increases with increasing concentration used in step (c). In some embodiments, the proportion of the population of Treg cells that are CD39 positive determined in step (d) is compared to the proportion of the population of Treg cells that are CD39 positive in an equivalent method in which the population of cells was not incubated with an anti- TNFR2 antibody or antigen-binding fragment thereof of the invention, and the anti-TNFR2 antibody or antigen-binding fragment thereof is identified as being capable of upregulating the expression of CD39 on the Treg cells when there is a statistically significant increase in the proportion of Treg cells that are CD39 positive induced by the anti-TNFR2 antibody or antigen-binding the proportion of Treg cells compared to the proportion of Treg cells that are CD39 positive induced in the absence of the anti-TNFR2 antibody or antigen-binding fragment thereof, or in the presence of a control. The control may suitably be an isotype control.

[0272]

[0266] Any of the antibodies or antigen-binding fragments described herein by reference to one or more functional features, may comprise one or more of the structural features (e.g. sequences) of the antibodies or antigen-binding fragments described herein.

[0273]

[0267] In some embodiments, the antibody or antigen-binding fragment thereof may be a member of the JNJ-TR2-01 , JNJ-TR2-24, JNJ-TR2-45 or JNJ-TR2-47 families, or may be an antibody or antigen-binding fragment thereof derived from a member of any of those families (e.g. by the presence of one or more sequences derived therefrom), and may further exhibit one or more of the functional properties described above.

[0274] Nucleotides sequences and host cells

[0275]

[0268] The present invention also provides one or more polynucleotide sequences encoding one or more sequences of the antibodies disclosed herein. The present invention also provides vectors (i.e. expression vectors) comprising one or more of the polynucleotide sequences disclosed herein. The present invention also provides host cells comprising one or more of the vectors or expression vectors disclosed herein.

[0276]

[0269] In some embodiments, there is provided a polynucleotide sequence or pair of polynucleotide sequences encoding an anti-TNFR2 antibody or antigen-binding fragment thereof as disclosed herein.

[0277]

[0270] In some embodiments, there is provided a polynucleotide sequence encoding a heavy chain variable region, a light chain variable region, a heavy chain or a light chain of an anti-TNFR2 antibody or antigen-binding fragment thereof as disclosed herein.

[0278]

[0271] In some embodiments, there is provided a polynucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 569. In some embodiments, there is provided a polynucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 544

[0272] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain variable region of an anti-TNFR2 antibody selected from the group consisting of SEQ ID NOs: 1 to 5, and the second member of the pair encodes a light chain variable region of an anti-TNFR2 antibody selected from the group consisting of SEQ ID NOs: 6 to 53.

[0279]

[0273] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain sequence of an anti-TNFR2 antibody selected from the group consisting of SEQ ID NOs: 492 to 496, and the second member of the pair encodes a light chain sequence of an anti-TNFR2 antibody selected from the group consisting of SEQ ID NOs: 497 to 544.

[0280]

[0274] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain variable region of an anti-TNFR2 antibody and the second member of the pair encodes a light chain variable region of an anti-TNFR2 antibody, wherein the heavy chain variable region and the light chain variable region respectively comprise or consist of SEQ ID NOs: 1 and 6; 1 and 7; 1 and 8; 1 and 9; 1 and 10; 1 and 11 ; 1 and 12; 1 and 13; 1 and 14; 1 and 15; 1 and 16; 1 and 17; 1 and 18; 1 and 19; 1 and 20; 1 and 21 ; 1 and 22; 1 and 23; 1 and 24; 1 and 25; 1 and 26; 1 and 27; 1 and 28; 2 and 29; 2 and 30; 2 and 31 ; 2 and 32; 2 and 33; 2 and 34; 2 and 35; 2 and 36; 2 and 37; 2 and 38; 2 and 39; 2 and 40; 2 and 41 ; 2 and 42; 2 and 43; 2 and 44; 2 and 45; 2 and 46; 2 and 47; 2 and 48; 3 and 49; 4 and 50; 4 and 51 ; 5 and 52; or 5 and 53.

[0281]

[0275] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain sequence of an anti-TNFR2 antibody and the second member of the pair encodes a light chain sequence of an anti-TNFR2 antibody, wherein the heavy chain sequence and the light chain sequence respectively comprise SEQ ID NOs: 492 and 497; 492 and 498; 492 and 499;

[0282] 492 and 500; 492 and 501 ; 492 and 502; 492 and 503; 492 and 504; 492 and 505; 492 and 506; 492 and

[0283] 507; 492 and 508; 492 and 509; 492 and 510; 492 and 511 ; 492 and 512; 492 and 513; 492 and 514; 492 and 515; 492 and 516; 492 and 517; 492 and 518; 492 and 519; 492 and 497; 493 and 520; 493 and 521 ;

[0284] 493 and 522;493 and 523; 493 and 524; 493 and 525; 493 and 526; 493 and 527; 493 and 528; 493 and

[0285] 529; 493 and 530; 493 and 531 ; 493 and 532; 493 and 533; 493 and 534; 493 and 535; 493 and 536; 493 and 537; 493 and 538; 493 and 539; 494 and 540; 495 and 541 ; 495 and 542; 496 and 543; or 496 and 544.

[0286]

[0276] In some embodiments, there is vector, in particular an expression vector, comprising a polynucleotide sequence or pair of polynucleotide sequences as disclosed herein. In some embodiments, there is provided a pair of expression vectors collectively comprising a pair of polynucleotide sequences as disclosed herein.

[0287]

[0277] The invention also provides a host cell comprising a polynucleotide sequence or pair of polynucleotide sequences as disclosed herein, orcomprising a vector or expression vectororpair of vectors or expression vectors as disclosed herein, optionally wherein the host cell is a recombinant host cell. In some embodiments, the host cell is a host cell selected from the group consisting of a Chinese hamster ovary (CHO) cell, a HEK293 cell, and a 293T cell. Methods for making antibodies

[0288]

[0278] The present invention also provides methods for making the antibodies and antigen-binding fragments thereof disclosed herein.

[0289]

[0279] In one embodiment, a method for producing an antibody or antigen-binding fragment thereof of the disclosure is provided, comprising culturing a host cell of the disclosure in a cell culture medium. In some embodiments, the method comprises culturing the host cell under conditions to allow for the production of the antibody or antigen-fragment thereof encoded by a vector or expression vector (or pair thereof) present in the host cell. In some embodiments, the methods comprise a step of isolating the antibody or antigen-binding fragment thereof from the culture medium. The method may comprise the further step of formulating the isolated antibody or antigen-binding fragment thereof with one or more pharmaceutically acceptable carriers, for example to provide a pharmaceutical composition. The present invention extends to antibodies or antigen-binding fragments thereof, and pharmaceutical compositions, obtained or obtainable by the methods disclosed herein.

[0290] Compositions

[0291]

[0280] The present invention provides compositions comprising the antibodies or antigen-binding fragments thereof disclosed herein. The present invention also provides pharmaceutical compositions in particular, which further comprise one of more pharmaceutically acceptable diluents.

[0292]

[0281] In some embodiments, the compositions, such as pharmaceutical compositions, are liquid pharmaceutical compositions. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous administration.

[0293] Kits

[0294]

[0282] The present invention also provides kits.

[0295]

[0283] In some embodiments, there is provided a kit comprising an anti-TNFR2 antibody or antibody binding fragment disclosed herein. In some embodiments, there is provided a kit comprising a composition disclosed herein. In some embodiments, there is provided a kit comprising a pharmaceutical composition disclosed herein.

[0296]

[0284] In some embodiments, the kits comprise one or more additional therapeutically active agents. In some embodiments, the one or more additional therapeutically active agents is selected from the group consisting of an immunosuppressant, a corticosteroid and a DMARD.

[0297]

[0285] In some embodiments, the kits further comprise instructions for use. The instructions may be for one or more of the medical methods or uses disclosed herein.

[0298]

[0286] The components of the kit may be disposed separately in separate containers.

[0299] Methods of treatment and medical uses

[0287] The present invention provides various methods of treatment and medical uses that comprise the use of one or more of the anti-TNFR2 antibodies or antigen-binding fragments thereof disclosed herein. In some embodiments, the invention does not comprise the use of the JNJ-TR2-44 antibody or antigenbinding fragments derived therefrom.

[0300]

[0288] In some embodiments there is provided a method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-TNFR2 antibody or antibody binding fragment thereof, or a pharmaceutical composition, disclosed herein.

[0301]

[0289] In some embodiments, the disease or disorder is an inflammatory disease or an autoimmune disease.

[0302]

[0290] In some embodiments, the disease or disorder is selected from the group consisting of rheumatoid arthritis (RA), atopic dermatitis (AD), systemic lupus erythematosus (SLE), Sjogren’s Disease (SjD), ulcerative colitis (UC), and Crohn’s disease (CD). Several autoimmune diseases are characterized by an imbalance of Treg to T effector cell responses thus enhancing Tregs has broad utility across disease indications (Yuan et al. Trends Mol Med. 2022; 28(7):596-612).

[0303]

[0291] In some embodiments, the methods may further comprise administering simultaneously or sequentially in any order, a second agent to the subject. In some embodiments, the second agent is selected from the group consisting of immunosuppressants, corticosteroids and DMARDs.

[0304]

[0292] There is also provided a method of modulating an immune response in a subject, comprising administering to the subject an anti-TNFR2 antibody or antibody binding fragment, or a pharmaceutical composition, disclosed herein.

[0305]

[0293] In some embodiments, the subject has an inflammatory disease or an autoimmune disease. In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), atopic dermatitis (AD), systemic lupus erythematosus (SLE), Sjogren’s Disease (SjD), ulcerative colitis (UC), and Crohn’s disease (CD). In some embodiments, the anti-TNFR2 antibody or antibody binding fragment thereof is administered subcutaneously.

[0306]

[0294] In some methods of treatment disclosed herein, the subject expresses TNFR2 variant R196. In some methods of treatment disclosed herein, the subject expresses TNFR2 variant M196. In some embodiments, the subject expresses either TNFR2 variant R196 or TNFR2 variant M196. The antibodies and antigen-binding fragments thereof disclosed herein advantageously bind to both variants of TNFR2, meaning they are more therapeutically useful than TNFR2 antibodies that bind to only one of the TNFR2 variants, or bind to one of the TNFR2 variants with a substantially higher affinity that the other TNFR2 variant. The antibodies and antigen-binding fragments thereof disclosed herein also exhibit the advantageous functional profiles discussed herein, regardless of whether the subject expresses TNFR2 variant R196 or TNFR2 variant M196.

[0307]

[0295] In some embodiments, the subject is a human.

[0296] The present invention also provides the anti-TNFR2 antibodies or antigen-binding fragments thereof, orthe pharmaceutical compositions, orthe kits, disclosed herein for use in medicine.

[0308]

[0297] The present invention also provides the anti-TNFR2 antibodies or antigen-binding fragments thereof, or the pharmaceutical compositions, or the kits, disclosed herein for use in the treatment of an inflammatory disease or an autoimmune disease. In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), atopic dermatitis (AD), systemic lupus erythematosus (SLE), Sjogren’s Disease (SjD), ulcerative colitis (UC), and Crohn’s disease (CD). In some embodiments, the anti-TNFR2 antibody or antibody binding fragment thereof is for subcutaneous administration. In some embodiments, the subject expresses TNFR2 variant R196. In some embodiments, the subject expresses TNFR2 variant M196. In some embodiments, the subject expresses either TNFR2 variant R196 or TNFR2 variant M196.

[0309]

[0298] The present invention also provides the use of an anti-TNFR2 antibody or antigen-binding fragment thereof disclosed herein in the manufacture of a medicament. The present invention also provides the use of an anti-TNFR2 antibody or antigen-binding fragment thereof disclosed herein in the manufacture of a medicament for the treatment of an inflammatory disease or an autoimmune disease. In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), atopic dermatitis (AD), systemic lupus erythematosus (SLE), Sjogren’s Disease (SjD), ulcerative colitis (UC), and Crohn’s disease (CD).

[0310]

[0299] The invention will now be further described by way of reference to one or more non-limiting Examples. As the skilled person will appreciate, the invention is not to be construed as being limited to the Examples, which instead referto specific embodiments of the invention.

[0311] EXAMPLES

[0312] EXAMPLE 1 Overall TNFR2 Hit-finding strategy

[0313]

[0300] As described above, functional and specific anti-TNFR2 antibodies were generated by immunizing female AlivaMab mice with His-tagged TNFR2 complexed with Zinc chitosan particles. After weekly intraperitoneal (IP) injections and final boost, spleens and lymph nodes were harvested to generate single B cell cultures. Single B cell supernatants were screened for binding to Jurkat cells engineered to express either of the 2 variants of human TNFR2 (M196 and R196) or cyno TNFR2 and cross-screened against TNFR2-negative Jurkat cells as well as a TNFR1-positive / TNFR2-negative T lymphocyte cell line. AlivaMab mice are engineered to exhibit fully human V regions consisting of human kappa light chains; therefore, B cells with positive hit supernatants were subsequently harvested for sequencing, and the V regions were directly cloned into mammalian expression constructs.

[0314]

[0301] Following mammalian expression of monoclonal antibodies (mAbs), the specificity and half maximal effective concentration (EC50) cell binding dose response curves were assessed at physiologically relevant temperature (37°C) against cell lines engineered to express human TNFR2 M196, human TNFR2 R196, or cynomolgus monkey TNFR2. Molecules that exhibited 2-fold increase of binding over isotype control were further cross-screened against non-specific cell binding as well as to binding of TNFR1+ / TNFR2- cells. Only molecules that bound specifically to both variants of human TNFR2 and cyno TNFR2 expressing lines but not to TNFR2 negative and / or TNFR1+ cells were selected for sequence analysis and functional assessments.

[0315]

[0302] Following binding characterizations, molecules were selected to assess functional agonism of TNFR2 signaling pathway by use of Jurkat NF-kB luciferase reporter lines engineered to express the M196 variant, the R196 variant or cyno TNFR2. Molecules that demonstrated at least 50% increase of NF-kB activity over isotype control were further selected for functional characterization of natural Tregs. Lead molecules were selected based on ranking of overall increased functional activity of natural Tregs which included ability to enhance natural Treg proliferation, CD39 expression, and for ability to suppress conventional T cell proliferation at different Tconv:Treg ratios.

[0316]

[0303] Figure 2 provides a pictorial explanation of the lead selection process.

[0317] EXAMPLE 2 - Immunization and antibody generation

[0318]

[0304] The following Example describes the methodology used to generate the antibodies disclosed herein via an immunisation protocol.

[0319]

[0305] Reagents and methods: 2% Acetic Acid in dHsO. 245 ml of Ultrapure distilled water was transferred into a new flask. 5 ml of glacial Acetic Acid was added to yield a 2% Acetic Acid solution. 2% Chitosan in 2% Acetic Acid. 4g of Chitosan (SIGMA Life Science, C3646-500G, Chitosan from shrimp shells) was added to a flask. 200 ml of 2% Acetic Acid were added to the flask and mixed gently overnight. The 2% Chitosan Solution in 2% Acetic Acid (“2% Chitosan Solution”) was autoclaved. 0.2M Zinc Acetate. 21.95g of Zinc Acetate were added to a flask and dFhO was added in. The solution was mixed and filtered through 0.2 pm filter. The ratio for preparation was 4 ml of 2% Chitosan Solution, and 6 ml of 0.2 M Zinc Acetate. For 40 ml total preparation volume, 24 ml of 0.2 M Zinc Acetate was added to a 50 ml conical vial. 2% Chitosan Solution was diluted 1 :1 in dFhO. 16 ml of 1 % Chitosan Solution was added to the conical vial. The preparation was mixed for 3 hours. Two aliquots of 900 pl each of 10N NaOH were added to the preparation and the mixture was sonicated for one minute. The mixture was then sonicated 4 more times for 1 minute each. The tubes were centrifuged for 3 minutes at 1000 xg to collect the Zinc Chitosan nanoparticles trapped in solution. The liquid phase was poured off. 25-30 ml of pH 7.4 dPBS was added to each tube and vortexed well to wash the particles. The remaining portion of each vial was filled to the 50 ml line with pH dPBS and centrifuged again for 3 minutes at 1000xg. A second wash was performed, then the dPBS was poured off. Then pH 8.0 PBS was added to the halfway mark, vortexed and topped off to the 50 mL with pH 8.0 PBS. To determine the concentration of Zinc Chitosan nanoparticles, a Zinc Chitosan preparation tube was centrifuged for 5 minutes at 1000xg to pellet the particles and aid in pouring off the supernatant. The tube containing the pellet was weighed, and the weight of an empty tube was subtracted to determine the mass of Zinc Chitosan in the tube. The volume of pH 8.0 PBS to add back to the tube in order to achieve a determined concentration of Zinc Chitosan appropriate for downstream use was determined (i.e. 200-500 mg / ml). His-Tagged TNFR2 were loaded onto zinc chitosan by mixing TNFR2 to zinc chitosan in a 1 :1000 w / w. Zinc chitosan was measured according to the dose [1 Opg per mouse per injection for AlivaMab mice (Ablexis™)], spun in centrifuge at 3000 xg for 5 mins. PBS was removed and zinc chitosan pellet was left in the tube. A pre-calculated volume was added. 10pg per mouse per injection was used for AlivaMab mice of soluble protein and PBS which was rocked / mixed for 3 hours at room temperature. Mice were immunized on a weekly basis via intrapleural injection route. 10 pg of the TNFR2 / nanoparticles mix obtained as described, in a total volume of 100 pl of PBS were injected per mouse. Serum samples were collected for antibody titer evaluations. Immunization using TNFR2 loaded onto zinc chitosan nanoparticles may be used to obtain antibodies with a preference for membrane-bound TNFR2 over shed (or soluble monomeric) TNFR2.

[0320] EXAMPLE 3 - TNFR2 binding specificity, with cyno cross-reactivity, and non TNFR1 binding

[0321]

[0306] The following Example describes the discovery and identification of human and cyno TNFR2- specific antibodies.

[0322]

[0307] B cell supernatant screening: Single B cell supernatants were screened by cell MSD on Jurkat cells expressing human TNFR2 to detect secreted anti-TNFR2 antibodies and subsequently confirmed for binding by flow cytometric analysis. B cell lysates from these hits were sent for variable region cloning. The recovered variable regions were cloned into a mammalian expression vector containing a human immunoglobulin domain and recombinantly expressed. The human antibodies were tested for cell binding to Jurkat cells expressing either human TNFR2 M196 variant orTNFR2 R196 variant. Jurkat parental cells with no TNFR2 expression and PEER cells with TNFR1 expression were included as negative controls.

[0323]

[0308] Flow cytometric analysis: TNFR2 agonist mAbs were characterized for binding affinity and specificity against human TNFR2+ (M196 and / or R196) or cyno TNFR2+ Jurkat lines. All cell binding experiments were performed using flow cytometry and analyzed on an I ntellicyt iQue Screener Plus (VBR) or iQue3 (VBR) model flow cytometer. Dose response curve binding studies against human TNFR2+ target cell lines were conducted under physiological conditions for 1 hour. Briefly, cells were pelleted at 300 xg for 5 minutes, washed twice with assay binding buffer (RPMI buffer +2 mM Glutamax + 10% FBS) and resuspended at 100,000 cells per well in V-bottom polypropylene 96-well plates (Greiner, 650261). Indicated test molecules were added to the wells at 1 :3 serial dilution in duplicate ortriplicate and incubated in humidified incubator at 37°C with 5% CO2for 1 hour. Following, 96-well plates were washed 3 times with ice cold flow staining buffer (BSA buffer with 0.9% sodium azide; BD Pharmingen). Plates were then resuspended in flow staining buffer in the presence of PE-labeled donkey anti-human Fc (gamma-specific) secondary antibody (Jackson ImmunoResearch) and incubated on ice for 30 min. Following LIVE / DEAD™ Fixable Near-IR Dead Cell Stain (ThermoFisher) was added to a final concentration of 1 :10,000 and further incubated on ice for 15 min. Plates were then washed 3 times with ice cold flow staining buffer and resuspended in final 1 :1 (vol / vol) flow staining buffer: Cytofix buffer (BD Pharmingen). Plates were subsequently kept at 4 °C, wrapped in aluminum foil to protect from light until acquisition by flow cytometer.

[0324]

[0309] The results are shown in Figure 3.

[0325] EXAMPLE 4 - EC50 cell binding, TNFa ligand blocking, or human serum inhibition determination using flow cytometric methodology and analysis

[0310] The following Example describes the flow cytometric methodology used to generate EC50 cell binding curves under physiological conditions; methodology used in the discovery and identification of TNFa ligand blocking or non-blocking antibodies; and the methodology used to identify molecules that are not inhibited by human serum components

[0326]

[0311] TNFR2 agonist mAbs were characterized for binding affinity and specificity against human TNFR2+ (M196 and / or R196) or cyno TNFR2+ Jurkat lines. All cell binding experiments were performed using flow cytometry and analyzed on an Intellicyt iQue Screener Plus (VBR) or iQue3 (VBR) model flow cytometer. Dose response curve binding studies against human TNFR2+ target cell lines were conducted under physiological conditions for 1 hour. Briefly, cells were pelleted at 300 xg for 5 minutes, washed twice with assay binding buffer (RPMI buffer +2 mM Glutamax + 10% FBS) and resuspended at 100,000 cells per well in V-bottom polypropylene 96-well plates (Greiner, 650261). Indicated test molecules were added to the wells at 1 :3 serial dilution in duplicate or triplicate and incubated in a humidified incubator at 37°C with 5% CO2for 1 hour. In some experiments, ligand blockade will be assessed by pre-incubating TNFR2 mAb agonists with cells prior to addition of biotinylated TNFa, which is subsequently detected for binding by addition of streptavidin-PE (Figure 6). In some experiments (Figure 10) cells will be incubated in RPMI media with and without a final concentration of 50% human serum. Following this, 96-well plates were washed 3 times with ice cold flow staining buffer (BSA buffer with 0.9% sodium azide; BD Pharmingen). Plates were then resuspended in flow staining buffer in the presence of PE-labeled donkey anti-human Fc (gamma-specific) secondary antibody (Jackson ImmunoResearch) and incubated on ice for 30 min. Following LIVE / DEAD™ Fixable Near-IR Dead Cell Stain (ThermoFisher) was added to a final concentration of 1 :10,000 and further incubated on ice for 15 min. Plates were then washed 3 times with ice cold flow staining buffer and resuspended in final 1 :1 (vol / vol) flow staining buffer: Cytofix buffer (BD Pharmingen). Plates were subsequently kept at 4 °C, wrapped in aluminum foil to protect from light until acquisition by flow cytometer.

[0327]

[0312] For gating analysis and curve fit, the geometric mean fluorescent intensity (geoMFI) was recorded from live cell events that were gated as singlets and compared to isotype control. The Iog10 of the molecule concentration was plotted against the geoMFI and best fit curves were evaluated using a 4PL algorithm (log(agonist) vs. response -- variable slope) in GraphPad Prism version 10. Effective concentrations (EC20, EC50, EC90) and Emax (maximal geoMFI signal) values were derived from the best-fit curves and used for quantitative comparisons where statistically appropriate. Values with non-converged or ambiguous effective concentration determinations were not used for quantitative characterization and therefore listed in corresponding tables as NF (no fit). The graphs were generated using GraphPad Prism version 10.

[0328] EXAMPLE 5 - Dose Response Curves and EC50 binding determination on TNFR2+ cells

[0329]

[0313] The dose response curves and EC50 binding determination on TNFR2+ cells are shown in Table 3 and Figure 5.

[0330] Table 3: Summary ofEC50 Values for anti-TNFR2 antibodies binding TNFR2-expressing Jurkat for 1 hr, at 37°C. “N / A” means the test was not done. Cell Binding EC50 (nM) Cell Binding EC50 (nM)

[0331] Molecule # M196 R196 Molecule # M196 R196

[0332] JNJ-TR2-01 2.09 0.75 JNJ-TR2-24 1.56 7.45

[0333] JNJ-TR2-05 73.26 92.30 JNJ-TR2-26 5.20 N / A

[0334] JNJ-TR2-06 19.05 29.22 JNJ-TR2-27 1.72 N / A

[0335] JNJ-TR2-07 38.33 51.14 JNJ-TR2-28 13.41 N / A

[0336] JNJ-TR2-09 14.22 20.32 JNJ-TR2-29 2.06 N / A

[0337] JNJ-TR2-10 103.50 228.30 JNJ-TR2-30 20.28 32.06

[0338] JNJ-TR2-12 g.95 13.94 JNJ-TR2-33 111.80 562.30

[0339] JNJ-TR2-13 3.66 7.71 JNJ-TR2-34 0.19 555.30

[0340] JNJ-TR2-14 0.79 3.51 JNJ-TR2-35 0.07 0.81

[0341] JNJ-TR2-15 0.50 1.14 JNJ-TR2-36 30.27 1368.00

[0342] JNJ-TR2-16 0.52 1.82 JNJ-TR2-37 2.64 7.88

[0343] JNJ-TR2-17 0.16 0.85 JNJ-TR2-38 1.92 7.13

[0344] JNJ-TR2-18 0.32 1.19 JNJ-TR2-39 2.05 13.63

[0345] JNJ-TR2-19 1.54 5.76 JNJ-TR2-41 8.82 24.73

[0346] JNJ-TR2-21 0.26 0.28 JNJ-TR2-42 1.36 12.58

[0347] JNJ-TR2-22 5.41 7.53 JNJ-TR2-43 8.27 N / A

[0348] JNJ-TR2-23 1 .63 3.86 JNJ-TR2-44 0.75 0.78

[0349] EXAMPLE 6 - Assessment of TNFa blockade from binding to TNFR2+ cells

[0350]

[0314] To determine whether select TNFR2 mAb agonists could block TNFa, TNFR2+ cells were preincubated with unlabeled TNFR2 mAb agonists or isotype control and subsequently stained with biotinylated TNFa, followed by Streptavidin-PE as secondary detection. As demonstrated in Figure 6, the TNFR2 mAb agonists tested here could not block nor compete with the binding of biotinylated TNFa. This suggests that these TNFR2 agonist mAbs should not disrupt the natural anti-inflammatory agonist activities of TNFa binding to TNFR2.

[0351] EXAMPLE 7 - Assessment of NF-KB activity as a measure of TNFR2 aqonism

[0352]

[0315] NF-kB reporter assay: To determine whether select TNFR2 mAbs demonstrated TNFR2 functionally relevant signaling, NF-kB reporter assays were developed as a biochemical assessment to identify TNFR2 agonists. TNFR2+ Jurkat NF-kB reporter lines, expressing M196 or R196 variants, were cultured at low passage number to maintain high viability, replenished with growth medium at least twice a week, and grown to sub-confluent cell numbers before harvesting for assay initiation. Upon harvest, cells were washed twice with assay media (RPMI + Glutamax + 1X P / S + 0.1 % HI FBS) and plated at 200,000 cells per well in flat-bottom white-walled 96-well tissue culture plates (Perkin Elmer). Cells were treated with indicated molecules at indicated concentrations at final 100 pl volume for 6 hr in humidified incubators set to 5% CO2 and 37 °C. Recombinant trimeric bioactive TNFa was utilized for assay acceptance criteria and positive control for NF-kB activity. After the incubation time, an equal volume of 100 pl of Bio-Gio luciferase substrate (Promega) was dispensed into each well and plates were read for luminescence by Envision (Perkin Elmer) which converts the signal into raw data as relative luminescence units (RLU). The graphs were generated using GraphPad Prism version 10.

[0316] Results. Figure 7 demonstrates that select non-TNFa blocking bivalent TNFR2 mAbs potently signal through the NF-kB pathway in cells that express either human TNFR2 M196 variant or human TNFR2 R196 variant. Collectively, the panel of select TNFR2 mAbs demonstrate NF-kB activity with an EC50 range of approximately 0.4 nM to 132 nM for human TNFR2 variant M196 and approximately 0.5 nM to 82 nM for human TNFR2 variant R196; overall, the data suggests that the select panel of non-TNFa blocking TNFR2 mAbs are agonists and demonstrate very similar potency across both human TNFR2 variants, which reduces the likelihood and need for patient stratification based on TNFR2 genotype.

[0353] Table 11: NF-KB EC50 values

[0354] EC50 of NF-KB luciferase activity (nM) EC50 of NF-KB luciferase activity (nM)

[0355] JNJ number M196 R196 JNJ number M196 R196

[0356] JNJ-TR2-01 4.09 3.57 JNJ-TR2-23 1.34 3.58

[0357] JNJ-TR2-02 11.49 4.06 JNJ-TR2-24 1.48 4.04

[0358] JNJ-TR2-03 131.50 66.12 JNJ-TR2-26 22.50 24.83

[0359] JNJ-TR2-04 31.54 50.03 JNJ-TR2-27 13.60 35.46

[0360] JNJ-TR2-05 120.10 82.33 JNJ-TR2-28 21.32 13.65

[0361] JNJ-TR2-06 6.42 16.32 JNJ-TR2-29 13.64 45.48

[0362] JNJ-TR2-07 73.57 47.65 JNJ-TR2-30 10.70 1.71

[0363] JNJ-TR2-09 12.87 26.26 JNJ-TR2-32 76.26 57.37

[0364] JNJ-TR2-10 4.20 16.21 JNJ-TR2-33 3.95 9.75

[0365] JNJ-TR2-12 1.95 7.44 JNJ-TR2-34 1.01 3.48

[0366] JNJ-TR2-13 0.97 4.56 JNJ-TR2-35 0.85 5.35

[0367] JNJ-TR2-14 0.65 2.21 JNJ-TR2-36 2.34 4.37

[0368] JNJ-TR2-15 1.95 4.49 JNJ-TR2-37 2.59 12.29

[0369] JNJ-TR2-16 0.72 2.51 JNJ-TR2-38 2.42 7.58

[0370] JNJ-TR2-17 0.47 2.95 JNJ-TR2-39 0.89 5.87

[0371] JNJ-TR2-18 0.47 3.30 JNJ-TR2-41 3.51 17.50

[0372] JNJ-TR2-19 0.86 3.59 JNJ-TR2-42 1.30 4.81

[0373] JNJ-TR2-21 1.15 3.93 JNJ-TR2-43 0.43 0.52

[0374] JNJ-TR2-22 3.76 6.62 JNJ-TR2-44 0.42 79.92

[0375] EXAMPLE 8 - Assessment of TNFR2 agonist antibody binding to soluble monomeric human TNFR2 and human serum components

[0376]

[0317] Previous studies have determined that soluble TNFR2 can be generated by ADAM17-mediated shedding (DeBerge MP, et al. Journal of leukocyte biology. 2015;98(3):423-34), however, it is unknown whether the physiological state of soluble TNFR2 in normal or autoimmune disease patients is monomeric or multimeric in nature. Previously it has been proposed that TNFR2 is expressed on the cell surface as monomers as well as pre-formed clusters via pre-ligand binding assembly domains (Prada JP, Wangorsch G, et al. Bioinformatics. 2021 ;37(5):669-76). To determine whether TNFR2 agonist mAbs are capable of pulling down soluble and / or shed TNFR2, TNFR2 agonist mAbs were labeled with biotin and subsequently used in MSD assay as a capture reagent

[0318] Soluble TNFR2 Quantification & Engagement Assays: To determine the concentration of soluble TNFR2 found within various matrices (ie. conditioned cell culture media and human serum) a TNFR2-specific single-plex U-plex MSD (Meso Scale Discovery) kit was employed according to the manufacturer’s instructions and protocol. The U-plex system was selected based on the versatility of the kit and ability to compare biotinylated capture reagents and sources of recombinant TNFR2. To determine whether select TNFR2 agonist mAbs could engage soluble TNFR2 from recombinant or physiological sources, indicated TNFR2 agonist mAbs were biotinylated and utilized as a capture reagent according to MSD U-plex plating protocol. (Figure 8, Figure 9, Figure 10) In these studies, the biotinylated MSD capture reagent included with kit was used as a positive control for the assessments; and the recombinant soluble TNFR2 standard from MSD was utilized for soluble TNFR2 quantification. The TNFR2 standard from MSD was also used as a positive control to compare detection of other monomeric and dimeric TNFR2 sources. The graphs were generated using GraphPad Prism version 10.

[0377]

[0319] Results: To determine if select TNFR2 agonists bind to shed TNFR2 from cells, pre-conditioned supernatants from day 5 old Jurkat cell lines that expressed TNFR2 were used to determine whether select TNFR2 agonists were capable of pulling down cell-derived soluble or shed TNFR2. First, the supernatants were assessed for overall detectable levels of soluble or shed TNFR2 using standard MSD kit conditions as described in methods. The standard MSD assay measured approximately 5 ng / ml (R196 expressing cells) or 15 ng / ml (M196 expressing cells) of soluble shed TNFR2. (Figure 8A). Although an identified TNFR2 agonist (biotinylated JNJ-TR2-44) demonstrated a similar ability to bind and detect cellular derived shed TNFR2, other biotinylated TNFR2 agonists (biotinylated JNJ-TR2-30 and biotinylated JNJ-TR2-01) did not. In addition, pooled human AB serum was assessed forthe presence of soluble orshed TNFR2 as measured with the same MSD kit conditions. As demonstrated in Figure 8B, human AB serum was determined to contain approximately 7 ng / ml soluble TNFR2. As seen with the Jurkat supernatants, biotinylated JNJ-TR2-44 was capable of pulling down this level of soluble or shed TNFR2, but JNJ-TR2-30 and JNJ-TR2-01 were not.

[0378]

[0320] To determine whether biotinylated mAbs preferentially bind and capture dimeric TNFR2 over soluble monomeric TNFR2, either dimeric TNFR2-His-Fc or monomeric TNFR2-His was added to MSD plates as an alternative to the provided recombinant MSD standard. As shown in Figure 9 below, the MSD capture reagent is capable of binding to and pulling down the recombinant TNFR2 standard provided with the kit, dimeric TNFR2-Fc that is both 6X His- and Fc-tagged, as well as monomeric 6X-His tagged TNFR2. However, as indicated, only the MSD capture reagent and biotinylated TNFR2 agonist JNJ-TR2-44 can associate with monomeric TNFR2-His but not TNFR2 agonist JNJ-TR2-01. In contrast, the MSD capture reagent, as well as both JNJ-TR2-44 and JNJ-TR2-01 are all capable of associating with and pulling down dimeric TNFR2-Fc-His. This finding supports the idea that select TNFR2 agonists may preferentially bind dimeric or clustered TNFR2 (as it may be when membrane-bound) over shed TNFR2 (as it may be when shed from cells) (Figure 9).

[0379]

[0321] To determine whether components of human serum negatively impact the binding ofTNFR2 mabs to cells, select TNFR2 agonists were labeled with PE and analyzed for binding to TNFR2+ Jurkat cells in the presence of pooled normal human AB sera (Figure 10). As determined in Figure 8B, the tested pooled human sera contained approximately 7 ng / ml soluble or shed TNFR2 and was tested for binding at 50% final serum concentration (or tested at final soluble TNFR2 concentration of approximately 3.5 ng / ml). As shown in Figure 10, the binding of select TNFR2 agonist mAbs were not reduced, but rather seemed improved with addition of serum at the higher concentrations. This may suggest either a stabilizing effect of human serum on either the presence of cell surface TNFR2 or on the binding ofTNFR2 mAbs themselves to cell surface TNFR2.

[0380] EXAMPLE 9 - Treq expansion assay

[0381]

[0322] This example describes the methodology and impact of TNFR2 agonist mAbs on Treg expansion and phenotype in vitro.

[0382] Test System

[0383]

[0323] The test system consists of in vitro cultured human Treg cells activated with anti-CD3 / anti-CD28 antibodies and IL-2 to drive increased expansion in terms of cell numbers and phenotypic changes (such as CD39) in response to different concentrations of anti-TNFR2 antibodies.

[0384] Experimental Design

[0385]

[0324] 14-day human Treg expansion assay. Frozen vials of FACS-sorted CD4+CD25+CD127-Treg cells from different human donors were purchased from an external vendor, Cell Carta, and banked in liquid nitrogen. On the day of experiment vials of frozen Treg cells were thawed and washed twice in complete X-VIVO15-10% HS containing media. After centrifugation, cells were counted after a 2-hour rest in complete X-VIVO15-10% HS media at 37°C. Treg cells were resuspended in complete assay media (X-VIVO15-2.5% HS media) and cultured in 96-well round bottom plates at a concentration of 2.5 x 104cells / well with anti- CD3 / anti-CD28 dynabeads (Thermo Fisher Scientific) at 2 bead to 1 cell ratio and IL-2 (final concentration in assay was 30 lU / ml). Each of these components (Tregs, anti-CD3 / anti-CD28 dynabeads, IL-2) was made up with complete media and added to the wells at 50 pL / well. The anti-TNFR2 and control antibodies were serially diluted in complete media at 4X final concentration and 50 pL of the antibody dilution was added to each well, while “no antibody’’ control wells received 50 pL media. The final volume in each well was brought up to 200 pL. The plates were incubated at 37°C / 5% CO2 for 4 days. At Day 4, 50 pL of complete media containing IL-2 at 30 lU / ml was added to each well and the plate was kept back at 37°C / 5% CO2 for an additional 3 days.

[0386]

[0325] On Day 7, plates were centrifuged for 5 mins at 500 x g at room temperature and cell culture supernatant carefully taken off. Cells were then resuspended in a total volume of 200 pL of fresh complete media containing IL-2 (final concentration in assay was 30 lU / ml) and either anti-TNFR2, control antibodies, IL-2 muteins or media alone per well. The plates were incubated at 37°C / 5% CO2 for 4 days. At Day 11 , 100 pL of cell culture media was carefully taken from the top of the wells and replaced with 150 pL of fresh complete media containing IL-2 at 30 lU / ml and the plate was incubated at 37°C / 5% CO2 for an additional 3 days.

[0326] On Day 14, plates were mixed well by pipetting and then 25-35 pL were taken from plate wells for live cell counts using the Cellaca MX cell counter. The rest of the plate was centrifuged and processed for flow cytometry cell staining for assessing the Treg phenotype.

[0387]

[0327] Cell Surface and Intranuclear Staining-. For flow cytometric cell staining, cells were washed once with PBS and the pelleted cells were resuspended in Live / Dead solution (eBioscience™ Fixable Viability Dye eFluor™ 780, ThermoFisher Scientific) for 20 mins on ice in the dark. After incubation, samples are washed twice with stain buffer (BD Pharmingen Stain Buffer). Resuspension of Treg samples were carried out with surface staining mAb cocktail for 20 mins on ice in the dark. The surface staining mAb cocktail was prepared in brilliant stain buffer (BD Biosciences) and contained mAbs as described in Table 4.

[0388] Table 4: Cell Surface Staining Flow Cytometry Panel for human Treg cells.

[0389]

[0328] After surface staining, samples were washed twice with stain buffer, then fixed with freshly prepared 1X Fixation / Permeabilization buffer (eBioscience Foxp3 / Transcription factor staining buffer set, ThermoFisher Scientific) for 30 mins on ice in the dark. Samples were then washed twice with 1X permeabilization buffer (eBioscience Foxp3 / Transcription factor staining buffer set, ThermoFisher Scientific) and then resuspended in transcription factor staining mAb cocktail for 45 mins on ice in the dark. The transcription factor staining mAb cocktail was prepared as illustrated in Table 5.

[0390] Table 5: Transcription Factor Staining Flow Cytometry Panel for human Treg cells

[0391]

[0329] After staining, cells were washed twice in 1X permeabilization buffer and resuspended in 200 pL of stain buffer and stored at 4°C until acquisition. Samples were either acquired on the FACS Symphony A3 or the Fortessa using FACSDiva v.9.3.1 or FACSDiva v.9.0 software (BD Biosciences), respectively and analyzed using FlowJo software (FlowJo, LLC). Data Analysis

[0392]

[0330] After acquisition using FACSDiva v.9.3.1 or v.9.0 software, flow cytometry data were analyzed using FlowJo software (FlowJo, LLC) and expression of CD39 as a frequency of positive cells on total live CD4+CD3+ Treg cells was visualized using contour plots. Total Treg cells were gated on forward / side scatter, followed by gating on single cells, then live cells, and then CD4+CD3+ cells (referred to as CD4+ Treg cells). Further gating on CD39 was carried out using FMO controls. Additionally, total CD4+ Treg cell counts was back calculated using frequencies obtained as described above and using live cell counts acquired through AOPI staining of cells run on the Cellaca MX cell counter. Data were plotted using GraphPad Prism 9.5.1 .

[0393]

[0331] Results-. The effects of TNFR2 agonist mAbs on human Treg expansion and phenotype were evaluated using sort-purified human Tregs (CD4+CD25+CD127-). Tregs were cultured for 14 days with anti-CD3 / anti-CD28 beads and low dose IL-2 in the presence or absence of TNFR2 agonist mAbs, isotype control, or IL-2 mutein. On Day 14, cells were counted and stained for phenotypic analyses by flow cytometry. As demonstrated in Figures 11 and 12, TNFR2 agonist mAbs dose-dependently increased Treg numbers (Figure 11) and frequencies of CD39 positive Treg cells (Figure 12). CD39 is a marker associated with Treg suppressive function.

[0394] EXAMPLE 10 - Treg suppression assay

[0395]

[0332] The following example describes the methodology used to evaluate the impact of TNFR2 agonist mAbs on Treg suppressive activity in vitro.

[0396] Test System

[0397]

[0333] A co-culture assay using pre-activated Treg cells with CD4+ Tconv cells and moDCs was developed to evaluate the direct agonistic potential of TNFR2 on Treg function. First, Treg cells were primed with soluble anti-CD3, anti-CD28 antibodies and IL-2 in the presence ofTNFR2 agonist antibodies orcontrol antibodies for 5 days. After which activated Treg cells were harvested and any pre-existing stimulus (anti- CD3, anti-CD28, IL-2, anti-TNFR2 or isotype control mAb) were removed. These Treg cells were then used in a 4-day co-culture assay including CTV-labelled CD4+ Tconv cells and moDCs, to assess their impact on the proliferation of CTV-labelled CD4+ Tconv cells.

[0398] Experimental Design

[0399]

[0334] Treg cell priming-. Frozen vials of FACS sorted CD4+ Treg cells from healthy donors were sourced through a vendor and kept in liquid nitrogen. On the day of experiment, Treg cells were thawed, washed, and then left to recover at 37°C with 5% CO2 for 2 hours. After incubation, Treg cells were counted and then resuspended in complete X-VIVO15-2.5% HS containing media. 0.25 x 106Treg cells was incubated in each well of a 48-well plate in 500 p.L of complete X-VIVO15-2.5% HS media containing 0.01 pg / mL soluble anti-CD3 mAb (Clone CLB-T3 / 4.E, 1XE, Cell Sciences), 0.02 pg / mL soluble anti-CD28 mAb (Clone CLB-CD28 / 1 , 15E8, Cell Sciences) and 30 lU / mL IL-2. TNFR2 agonist mAbs were tested at a single concentration (20 pg / ml) or in some cases titrated with 10-fold serial dilutions beginning at 20 pg / ml and going as low as 0.0002 pg / ml in complete media. Isotype control mAb was tested at a single concentration of 20 pg / ml in complete media. The plates were incubated at 37°C / 5% CO2 for 5 days.

[0400]

[0335] Treg suppression assay. This portion of the assay consists of co-culture of activated Tregs with CD4+ Tconv cells in the presence of immature moDCs. On Day 5 of Treg cell priming, vials of frozen naive CD4+ Tconv cells (matched from the same donor as Treg cells) as well as mis-matched immature moDCs were each thawed, washed and then left to recover at 37°C with 5% CO2 for 2 hours in complete X-VIVO15- 10% HS media. After recovery, CD4+ Tconv cells were fluorescently labelled with proliferation dye CellTrace Violet, washed, counted, and then resuspended at 1 x 106cells / ml in complete X-VIVO15-2.5% HS media. At around the same time, Day 5 activated Treg cells were harvested from the 48-well plate, pre-existing stimuli was washed off and cells were fluorescently labelled with proliferation dye eFluor 670. After labelling, Treg cells were washed again, counted, and then resuspended at 1 x 106cells / ml in complete media. Next, labelled Treg cells from the different treatment conditions were added to a 96-well round bottom plate. CD4+ Tconv cells were typically co-cultured with Treg cells starting from 1 :1 or 2:1 ratio (Tconv : Treg ratio) going down to as low as 128:1 ratio. To achieve this, 50 pl of complete media were first added to wells # 5-11 of the 96-well plate, followed by 100 pl of Treg cells to well # 12. Well # 12 was gently mixed and, 50 pl of Treg cells taken out (leaving 5 x 104Treg cells in 50 pls behind in well # 12) and transferred to well # 11. Well # 11 was mixed thoroughly to generate a two-fold dilution and then 50 pl of diluted Treg cells taken out and transferred to the adjoining well (well # 10). The process was repeated to generate two-fold serial dilutions of Treg cells till well # 5. After the addition of Treg cells was completed, 5 x 104labelled CD4+ Tconv cells in 50 pls of complete media was added to wells # 4-12. While addition of CD4+ Tconv cells to wells # 5-12 generated ratios starting from 1 :1 to 128:1 , the addition to well # 4 was used to determine maximum proliferation of CD4+ Tconv cells in the absence of Treg cells. In addition to this, it was important to have additional conditions tested such as a moDC / anti-CD3 / IL-2 stimulated Treg only controls as well as unstimulated Treg only and Tconv only controls.

[0401]

[0336] Then immature moDCs were taken, resuspended at 4 x 105cells / ml in complete media, and 4 pg / ml anti-CD3 monoclonal antibody (clone UCHT1) and IL-2 (80 lU / ml) added. This was mixed well and incubated at RT for 10 mins, following which 50 pl of the moDC / anti-CD3 / IL-2 mix was added per well of the 96-well plate (except for the unstimulated conditions). This gave a final concentration of 2 x 104moDCs / well, 1 pg / ml anti-CD3 and 20 lU / ml IL-2 when the total volume in each well of the 96-well plate was brought up to 200 pls. The 96-well plate was centrifuged carefully up to 100 x g (& then stopped) to get cells at the bottom and the plate was placed in the incubator at 37°C for 4 days. On Day 4 of Treg suppression assay, plates were taken out and then processed for flow cytometry staining to assess Tconv cell proliferation.

[0402]

[0337] Cell surface and intranuclear staining-. For flow cytometric cell staining, cells were washed once with PBS and then pelleted cells were resuspended in 100 pL of Live / Dead solution (eBioscienceTM Fixable Viability Dye eFluor 780) for 20 mins on ice in the dark. After two washes with stain buffer (BD Pharmingen Stain Buffer), samples were resuspended in 56 pL of surface staining mAb cocktail for20 mins on ice in the dark. The surface staining mAb cocktail was prepared in brilliant stain buffer (BD biosciences) and contained mAbs as described in Table 4. (see above)

[0338] After surface staining, samples were washed twice with stain buffer, then fixed with 100 pL of freshly prepared 1X Fixation / Permeabilization buffer (eBioscience Foxp3 / Transcription factor staining buffer set) for 30 mins on ice in the dark. Samples were then washed twice with 1X permeabilization buffer (eBioscience Foxp3 / Transcription factor staining buffer set) and resuspended in 100 pL of transcription factor staining mAb cocktail for 45 mins on ice in the dark. The transcription factor staining mAb cocktail was prepared in 1X permeabilization buffer and contained mAbs as described in Table 5. (see above)

[0403]

[0339] After staining, cells were washed twice in 1X permeabilization buffer and resuspended in 200 pL of stain buffer and stored at 4 until acquisition. Samples were acquired on the FACS Symphony A3 or the Fortessa using FACSDiva v.9.3.1 or FACSDiva v.9.0 software (BD Biosciences), respectively and analyzed using FlowJo software (FlowJo, LLC).

[0404] Data Analysis

[0405]

[0340] After acquisition using FACSDiva v.9.3.1 or v.9.0 software, flow cytometry data was analyzed using FlowJo software (FlowJo, LLC) and reduction or dilution of CTV staining intensity was visualized as histograms of mean fluorescence intensity on CD4+ Tconv cells. Total cells were gated on forward / side scatter, followed by gating on single cells, then live cells, then total CD4+ T cells. Further gating was carried out by creating a contour plot of proliferation dye eFluor670 labelled Treg cell vs proliferation dye CTV labelled Tconv cells, using the moDC / anti-CD3 / IL-2 mix stimulated Treg alone and Tconv cell alone conditions to set the “Treg” and “Tconv” gates. Additional CTV gating is done to determine the frequency of proliferating Tconv cells (CTVMedium / Low) by distinguishing it from unstimulated Tconv controls, which contains a single CTVhipeak.

[0406]

[0341] Results-. TNFR2 agonist mAbs were evaluated for their capacity to expand Tregs with enhanced suppressive capacity to inhibit conventional T cell (Tconv) proliferation. To assess this functional activity, an in vitro co-culture assay was developed using sort-purified Tregs with CD4+ Tconv cells isolated from healthy human donors. Tregs were activated first with soluble anti-CD3 / anti-CD28 antibodies and IL-2 in the presence or absence of TNFR2 agonist mAbs or isotype control at 20 pg / mL for 5 days. Tregs were then washed and co-cultured with CellTrace™ Violet (CTV)-labeled CD4+ Tconv cells for4 days at different Tconv:Treg ratios. Proliferation of CD4+ Tconv cells was then measured by flow cytometry. TNFR2 agonist mAbs enhanced the ability of Tregs to suppress the proliferation of CD4+ Tconv cells across several donors and different Tconv / Treg ratios relative to isotype control-treated Tregs (Figure 13).

[0407] EXAMPLE 11 - Kinetics of binding and domain mapping by method of surface plasmon resonance

[0408]

[0342] The kinetics of binding and mapping of select TNFR2 mAbs onto chimeric human / mouse TNFR2- Fc fusions was performed on a Biacore 8K+1 . Briefly, select TNFR2 mAbs were captured onto CM4 chips that were coated with goat anti-human Fab. Full human ECD of TNFR2 (CRD1-CRD4)-Fc fusion or human TNFR2-Fc fusion with indicated swapped mouse TNFR2 domains were diluted in 1XHBSP buffer and injected at indicated concentrations. Binding determinations were made for interactions with responses > 5 RU. The results are shown in Figure 15, and demonstrate that for most of the mAbs, the human CRD1 and CRD2 domains are both required for binding (with the exception of the JNJ-TR2-44 antibody, which is able to bind to TNFR2 when only the CRD2 domain is present). For Figure 16. The kinetics of binding was determined by injecting either monomeric his-tagged TNFR2 (ECD) or dimeric TNFR2-Fc fusion (as used in domain mapping for Figure 15).

[0409] EXAMPLE 12 - Antibody sequences and SEQ ID NOs

[0410]

[0343] Following the above described immunisation, lead identification and characterisation protocols, the following antibodies were identified and are disclosed herein. Table 6 below provides the SEQ ID NOs for the variable heavy region (“VH”), variable light region (“VL”), full heavy chain (“Heavy”), full light chain (“Light”) and the 6 CDRs (according to the AbM definition) for each of the disclosed antibodies.

[0411] Table 6: SEQ ID NOs of antibodies described herein (AbM CDRs).

[0412]

[0344] The antibodies of the “JNJ-TR2-01 family” are either the JNJ-TR2-01 antibody, or are variants of the JNJ-TR2-01 antibody, since the JNJ-TR2-01 antibody includes a DG motif in the LCDR1 region. The non-JNJ-TR2-01 members of the family are alternative versions of the JNJ-TR2-01 antibody in which this DG motif has been engineered out, either by substitution of the aspartic acid (D) or the glycine (G). The experimental data provided for the JNJ-TR2-01 antibody or any other member of this family is considered to apply, for the most part, to other members of this family.

[0413]

[0345] The antibodies of the “JNJ-TR2-24 family” are either the JNJ-TR2-24 antibody, or are variants of the JNJ-TR2-24 antibody, since the JNJ-TR2-24 antibody includes a DG motif in the LCDR1 region. The non-JNJ-TR2-24 members of the family are alternative versions of the JNJ-TR2-24 antibody in which this DG motif has been engineered out, either by substitution of the aspartic acid (D) or the glycine (G). The experimental data provided for the JNJ-TR2-24 antibody or any other member of this family is considered to apply, for the most part, to other members of this family.

[0414]

[0346] The antibodies of the “JNJ-TR2-45 family” are eitherthe JNJ-TR2-45 antibody, or a variant of the JNJ-TR2-45 antibody, since the JNJ-TR2-45 antibody includes a DG motif in the LCDR1 region. The non- JNJ-TR2-45 members of the family are alternative versions of the JNJ-TR2-45 antibody in which this DG motif has been engineered out, either by substitution of the aspartic acid (D) or the glycine (G). The experimental data provided for the JNJ-TR2-45 antibody is considered to apply, for the most part, to other members of this family.

[0415]

[0347] The antibodies of the “JNJ-TR2-47 family” are eitherthe JNJ-TR2-47 antibody, or a variant of the JNJ-TR2-47 antibody, since the JNJ-TR2-47 antibody includes a DG motif in the LCDR1 region. The non- JNJ-TR2-47 members of the family are alternative versions of the JNJ-TR2-47 antibody in which this DG motif has been engineered out, either by substitution of the aspartic acid (D) or the glycine (G). The experimental data provided for the JNJ-TR2-47 antibody is considered to apply, for the most part, to other members of this family.

[0416]

[0348] JNJ-TR2-44 is an alternative antibody ofthe invention, that may forsome purposes be considered a comparator antibody, since it binds to both membrane and shed TNFR2.

[0417]

[0349] The sequences of the above antibodies are provided in the appended sequence listing, and in Figure 14. Figure 14 shows the heavy and light chain variable region sequences for all the above antibodies. The positions of the CDRs according to the AbM definitions are provided. In the event of any discrepancy between the sequences provided in the sequence listing and the sequences provided in the Figures, the sequences in the Figures should prevail.

[0418]

[0350] Alternative CDR numbering systems may be used, for example the overlap, AbM or Kabat definitions, as set out in the following SEQ ID NOs shown in Table 7:

[0419] Table 7 SEQ ID NOs of different CDR numbering systems

[0420]

[0351]

[0421]

[0352] Or according to the Chothia, IMGT or Contact definitions, as set out in the following SEQ ID NOs shown in Table 8.

[0422] Table 8: SEQ ID NOs of different CDR numbering systems

[0423]

[0353] Additional sequences provided include the following in Table 9, which relate to each of the JNJ-

[0424] TR2-01 , 24, 45 and 47 families. Table 9: Additional SEQ ID NO descriptions JB JB

[0425]

[0354] Note: SEQ ID NOs: 553 to 556 are unassigned. In the sequence listing, “X” refers to any naturally occurring amino acid, unless specified otherwise.

[0426]

[0355] Note that some sequences are fewer than 4 amino acid resides in length and therefore do not appear in the accompanying sequence listing. The sequence of those SEQ ID NOs are as follows, as provided in Table 10:

[0427] Table 10: Sequences shorter than 4 amino acids in length

[0428] EMBODIMENTS

[0429]

[0356] The present invention provides at least the following numbered embodiments. All of the following numbered embodiments are embodiments of the invention that may be combined with any of the further or preferred features of the invention described above. Equally any of the features of the invention described above may be combined with one or more of the listed embodiments.

[0430] All antibodies

[0431] 1. An anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a. a heavy chain variable region comprising: i. a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 54, 60, 66, 72, 78, 84, 222, 228, 234, 240, 246,

[0432] 252, 372, 378, 384, 390, 396, 402, 408, 414, 420, 426, 432, 438, 450, 456, 462,

[0433] 468, 474 and 480; ii. a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 55, 61 , 67, 73, 79, 85, 223, 229, 235, 241 , 247,

[0434] 253, 373, 379, 385, 391 , 397, 403, 409, 415, 421 , 427, 433, 439, 451 , 457, 463,

[0435] 469, 475 and 481 ; and

[0436] Hi. a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 56, 62, 68, 74, 80, 86, 224, 230, 236, 242, 248,

[0437] 254, 374, 380, 386, 392, 398, 404, 410, 416, 422, 428, 434, 440, 452, 458, 464,

[0438] 470, 476 and 482; and / or b. a light chain variable region comprising: i. a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 57, 63, 69, 75, 81 , 87, 90 to 221 , 225, 231 , 237, 243, 249, 255, 258 to 371 , 375, 381 , 387, 393, 399, 405, 411 , 417, 423, 429, 435, 441 , 444 to 449, 453, 459, 465, 471 , 477, 483, 486 to 491 and 545 to 552; ii. a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 58, 64, 70, 76, 82, 88, 226, 232, 238, 244, 250,

[0439] 256, 376, 382, 388, 394, 400, 406, 412, 418, 424, 430, 436, 442, 454, 460, 466,

[0440] 472, 478 and 484; and

[0441] Hi. a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 59, 65, 71 , 77, 83, 89, 227, 233, 239, 245, 251 ,

[0442] 257, 377, 383, 389, 395, 401 , 407, 413, 419, 425, 431 , 437, 443, 455, 461 , 467,

[0443] 473, 479 and 485. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 1 to 5, 565 and 567; and / or b. a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 6 to 53, 557 to 564, 566, 568 and 569. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 565; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 566. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 568. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, comprising a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 567; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 569.

[0444] 6. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, comprising: a. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 492 to 496; and / or b. a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 497 to 544.

[0445] 7. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding embodiment, wherein the antibody is an antibody selected from the group consisting of JNJ-TR2-01 , JNJ-TR2- 02, JNJ-TR2-03, JNJ-TR2-04, JNJ-TR2-05, JNJ-TR2-06, JNJ-TR2-07, JNJ-TR2-08, JNJ-TR2-09,

[0446] JNJ-TR2-10, JNJ-TR2-11 , JNJ-TR2-12, JNJ-TR2-13, JNJ-TR2-14, JNJ-TR2-15, JNJ-TR2-16, JNJ-

[0447] TR2-17, JNJ-TR2-18, JNJ-TR2-19, JNJ-TR2-20, JNJ-TR2-21 , JNJ-TR2-22, JNJ-TR2-23, JNJ-

[0448] TR2-24, JNJ-TR2-25, JNJ-TR2-26, JNJ-TR2-27, JNJ-TR2-28, JNJ-TR2-29, JNJ-TR2-30, JNJ-

[0449] TR2-31 , JNJ-TR2-32, JNJ-TR2-33, JNJ-TR2-34, JNJ-TR2-35, JNJ-TR2-36, JNJ-TR2-37, JNJ-

[0450] TR2-38, JNJ-TR2-39, JNJ-TR2-40, JNJ-TR2-41 , JNJ-TR2-42, JNJ-TR2-43, JNJ-TR2-44, JNJ-

[0451] TR2-45, JNJ-TR2-46, JNJ-TR2-47 and JNJ-TR2-48.

[0452] JNJ-TR2-01 family antibodies

[0453] 8. An anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a. a heavy chain variable region comprising: i. a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 54, 60, 66, 72, 78 and 84; ii. a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 55, 61 , 67, 73, 79 and 85; and

[0454] Hi. a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 56, 62, 68, 74, 80, 86; and / or b. a light chain variable region comprising: i. a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 57, 63, 69, 75, 81 , 87, 90 to 221 , 545 and 549; ii. a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 58, 64, 70, 76, 82 and 88; and

[0455] Hi. a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 59, 65, 71 , 77, 83 and 89.

[0456] All CDRs grouped The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising: a. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 54, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 55 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 56; and a light chain variable region comprising or consisting of a VLCDR1 comprising or consisting of the amino acid sequence of 57 or 90 to 111 , a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 58, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 59; b. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 63 or 112 to 133, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; c. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 66, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 67 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 68; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 69 or 134 to 155, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 70, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 71 ; d. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 72, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 73 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 74; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 75 or 156 to 177, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 76, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 77; e. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 78, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 79 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 80; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 81 or 178 to 199, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 82, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 83; f. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 84, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 85 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 86; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 87 or 200 to 221 , a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 88, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 89; g. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 545, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; or h. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 549, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65.

[0457] Overlap CDRs

[0458] 10. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising VHCDR1 , VHCDR2, VHCDR3, VLCDR1 , VLCDR2 and VLCDR3 sequences comprising the sequences of SEQ ID NOs: a. 54, 55, 56; 57, 58, and 59, respectively; b. 54, 55, 56; 90, 58, and 59, respectively; c. 54, 55, 56; 91 , 58, and 59, respectively; d. 54, 55, 56; 92, 58, and 59, respectively; e. 54, 55, 56; 93, 58, and 59, respectively; f. 54, 55, 56; 94, 58, and 59, respectively; g. 54, 55, 56; 95, 58, and 59, respectively; h. 54, 55, 56; 96, 58, and 59, respectively; i. 54, 55, 56; 97, 58, and 59, respectively; j. 54, 55, 56; 98, 58, and 59, respectively; k. 54, 55, 56; 99, 58, and 59, respectively; l. 54, 55, 56; 100, 58, and 59, respectively; m. 54, 55, 56; 101 , 58, and 59, respectively; n. 54, 55, 56; 102, 58, and 59, respectively; o. 54, 55, 56; 103, 58, and 59, respectively; p. 54, 55, 56; 104, 58, and 59, respectively; q. 54, 55, 56; 105, 58, and 59, respectively; r. 54, 55, 56; 106, 58, and 59, respectively; s. 54, 55, 56; 107, 58, and 59, respectively; t. 54, 55, 56; 108, 58, and 59, respectively; u. 54, 55, 56; 109, 58, and 59, respectively; v. 54, 55, 56; 110, 58, and 59, respectively; or w. 54, 55, 56; 111 , 58, and 59, respectively;

[0459] AbM CDRs

[0460] 11 . The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 60, 61 , 62, 63, 64 and 65, respectively; b. 60, 61 , 62, 112, 64 and 65, respectively; c. 60, 61 , 62, 113, 64 and 65, respectively; d. 60, 61 , 62, 114, 64 and 65, respectively; e. 60, 61 , 62, 115, 64 and 65, respectively; f. 60, 61 , 62, 116, 64 and 65, respectively; g. 60, 61 , 62, 117, 64 and 65, respectively; h. 60, 61 , 62, 118, 64 and 65, respectively; i. 60, 61 , 62, 119, 64 and 65, respectively; j. 60, 61 , 62, 120, 64 and 65, respectively; k. 60, 61 , 62, 121 , 64 and 65, respectively; l. 60, 61 , 62, 122, 64 and 65, respectively; m. 60, 61 , 62, 123, 64 and 65, respectively; n. 60, 61 , 62, 124, 64 and 65, respectively; o. 60, 61 , 62, 125, 64 and 65, respectively; p. 60, 61 , 62, 126, 64 and 65, respectively; q. 60, 61 , 62, 127, 64 and 65, respectively; r. 60, 61 , 62, 128, 64 and 65, respectively; s. 60, 61 , 62, 129, 64 and 65, respectively; t. 60, 61 , 62, 130, 64 and 65, respectively; u. 60, 61 , 62, 131 , 64 and 65, respectively; v. 60, 61 , 62, 132, 64 and 65, respectively; w. 60, 61 , 62, 133, 64 and 65, respectively; x. 60, 61 , 62, 545, 64 and 65, respectively; or y. 60, 61 , 62, 549, 64 and 65, respectively.

[0461] Kabat CDRs

[0462] 12. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 66, 67, 68, 69, 70 and 71 , respectively; b. 66, 67, 68, 134, 70 and 71 , respectively; c. 66, 67, 68, 135, 70 and 71 , respectively; d. 66, 67, 68, 136, 70 and 71 , respectively; e. 66, 67, 68, 137, 70 and 71 , respectively; f. 66, 67, 68, 138, 70 and 71 , respectively; g. 66, 67, 68, 139, 70 and 71 , respectively; h. 66, 67, 68, 140, 70 and 71 , respectively; i. 66, 67, 68, 141 , 70 and 71 , respectively; j. 66, 67, 68, 142, 70 and 71 , respectively; k. 66, 67, 68, 143, 70 and 71 , respectively; l. 66, 67, 68, 144, 70 and 71 , respectively; m. 66, 67, 68, 145, 70 and 71 , respectively; n. 66, 67, 68, 146, 70 and 71 , respectively; o. 66, 67, 68, 147, 70 and 71 , respectively; p. 66, 67, 68, 148, 70 and 71 , respectively; q. 66, 67, 68, 149, 70 and 71 , respectively; r. 66, 67, 68, 150, 70 and 71 , respectively; s. 66, 67, 68, 151 , 70 and 71 , respectively; t. 66, 67, 68, 152, 70 and 71 , respectively; u. 66, 67, 68, 153, 70 and 71 , respectively; v. 66, 67, 68, 154, 70 and 71 , respectively; or w. 66, 67, 68, 155, 70 and 71 , respectively.

[0463] Chothia CDRs

[0464] 13. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 72, 73, 74, 75, 76 and 77, respectively; b. 72, 73, 74, 156, 76 and 77, respectively; c. 72, 73, 74, 157, 76 and 77, respectively; d. 72, 73, 74, 158, 76 and 77, respectively; e. 72, 73, 74, 159, 76 and 77, respectively; f. 72, 73, 74, 160, 76 and 77, respectively; g. 72, 73, 74, 161 , 76 and 77, respectively; h. 72, 73, 74, 162, 76 and 77, respectively; i. 72, 73, 74, 163, 76 and 77, respectively; j. 72, 73, 74, 164, 76 and 77, respectively; k. 72, 73, 74, 165, 76 and 77, respectively; l. 72, 73, 74, 166, 76 and 77, respectively; m. 72, 73, 74, 167, 76 and 77, respectively; n. 72, 73, 74, 168, 76 and 77, respectively; o. 72, 73, 74, 169, 76 and 77, respectively; p. 72, 73, 74, 170, 76 and 77, respectively; q. 72, 73, 74, 171 , 76 and 77, respectively; r. 72, 73, 74, 172, 76 and 77, respectively; s. 72, 73, 74, 173, 76 and 77, respectively; t. 72, 73, 74, 174, 76 and 77, respectively; u. 72, 73, 74, 175, 76 and 77, respectively; v. 72, 73, 74, 176, 76 and 77, respectively; or w. 72, 73, 74, 177, 76 and 77, respectively.

[0465] IMGT CDRs

[0466] 14. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 78, 79, 80, 81 , 82 and 83, respectively; b. 78, 79, 80, 178, 82 and 83, respectively; c. 78, 79, 80, 179, 82 and 83, respectively; d. 78, 79, 80, 180, 82 and 83, respectively; e. 78, 79, 80, 181 , 82 and 83, respectively; f. 78, 79, 80, 182, 82 and 83, respectively; g. 78, 79, 80, 183, 82 and 83, respectively; h. 78, 79, 80, 184, 82 and 83, respectively; i. 78, 79, 80, 185, 82 and 83, respectively; j. 78, 79, 80, 186, 82 and 83, respectively; k. 78, 79, 80, 187, 82 and 83, respectively; l. 78, 79, 80, 188, 82 and 83, respectively; m. 78, 79, 80, 189, 82 and 83, respectively; n. 78, 79, 80, 190, 82 and 83, respectively; o. 78, 79, 80, 191 , 82 and 83, respectively; p. 78, 79, 80, 192, 82 and 83, respectively; q. 78, 79, 80, 193, 82 and 83, respectively; r. 78, 79, 80, 194, 82 and 83, respectively; s. 78, 79, 80, 195, 82 and 83, respectively; t. 78, 79, 80, 196, 82 and 83, respectively; u. 78, 79, 80, 197, 82 and 83, respectively; v. 78, 79, 80, 198, 82 and 83, respectively; or w. 78, 79, 80, 199, 82 and 83, respectively.

[0467] Contact CDRs

[0468] 15. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 8, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 84, 85, 86, 87, 88 and 89, respectively; b. 84, 85, 86, 200, 88 and 89, respectively; c. 84, 85, 86, 201 , 88 and 89, respectively; d. 84, 85, 86, 202, 88 and 89, respectively; e. 84, 85, 86, 203, 88 and 89, respectively; f. 84, 85, 86, 204, 88 and 89, respectively; g. 84, 85, 86, 205, 88 and 89, respectively; h. 84, 85, 86, 206, 88 and 89, respectively; i. 84, 85, 86, 207, 88 and 89, respectively; j. 84, 85, 86, 208, 88 and 89, respectively; k. 84, 85, 86, 209, 88 and 89, respectively; l. 84, 85, 86, 210, 88 and 89, respectively; m. 84, 85, 86, 211 , 88 and 89, respectively; n. 84, 85, 86, 212, 88 and 89, respectively; o. 84, 85, 86, 213, 88 and 89, respectively; p. 84, 85, 86, 214, 88 and 89, respectively; q. 84, 85, 86, 215, 88 and 89, respectively; r. 84, 85, 86, 216, 88 and 89, respectively; s. 84, 85, 86, 217, 88 and 89, respectively; t. 84, 85, 86, 218, 88 and 89, respectively; u. 84, 85, 86, 219, 88 and 89, respectively; v. 84, 85, 86, 220, 88 and 89, respectively; or w. 84, 85, 86, 221 , 88 and 89, respectively.

[0469] VH and VL

[0470] 16. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of embodiments 8 to 15, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 1 ; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 6 to 28.

[0471] 17. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of embodiments 8 to 15, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 6; b. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 7; c. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 8; d. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 9; e. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 10; f. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 11 ; g. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 12; h. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 13; i. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 14; j. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 15; k. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 16; l. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 17; m. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 18; n. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 19; o. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 20; p. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 21 ; q. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 22; r. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 23; s. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 24; t. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 25; u. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 26; v. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 27 or w. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 28; x. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 557; or y. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 561. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of embodiments 8 to 15, comprising: a. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; b. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 7; c. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 8; d. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 9; e. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 10; f. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 11 ; g. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 12; h. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 13; i. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 14; j. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 15; k. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 16; l. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 17; m. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 18; n. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 19; o. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 20; p. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 21 ; q. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 22; r. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 23; s. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 24; t. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 25; u. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 26; v. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 27; w. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 28; x. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 557; or y . a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 1 ; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 561.

[0472] Heavy and Light

[0473] 19. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of embodiments 8 to 18, comprising: a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NOs: 492; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 497 to 519. The anti-TNFR2 antibody or antigen-binding fragment thereof any one of embodiments 8 to 18, comprising: a. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 497; b. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 498; c. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 499; d. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 500; e. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 501 ; f. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 502; g. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 503; h. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 504; i. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 505; j. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 506; k. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 507; l. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 508; m. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 509; n. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 510; o. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 511 ; p. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 512; q. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 513; r. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 514; s. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 515; t. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 516; u. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 517; v. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 518; or w. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 492; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 519. The anti-TNFR2 antibody or antigen-binding fragment thereof any one of embodiments 8 to 18, comprising: a. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 497; b. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 498; c. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 499; d. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 500; e. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 501 ; f. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 502; g. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 503; h. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 504; i. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 505; j. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 506; k. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 507; l. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 508; m. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 509; n. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 510; o. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 511 ; p. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 512; q. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 513; r. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 514; s. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 515; t. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 516; u. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 517; v. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 518; or w. a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 492; and a light chain comprising or consisting ofthe amino acid sequence of SEQ ID NO: 519.

[0474] Picture embodiments

[0475] 22. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 497.

[0476] 23. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 498.

[0477] 24. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 499.

[0478] 25. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 500.

[0479] 26. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 501 . An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 502. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 503. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 504. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 505. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 506. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 507. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 508. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 509. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 510. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 511. 37. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 512.

[0480] 38. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 513.

[0481] 39. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 514.

[0482] 40. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 515.

[0483] 41. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 516.

[0484] 42. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 517.

[0485] 43. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 518.

[0486] 44. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 519.

[0487] JNJ-TR2-24 family antibodies

[0488] 45. An anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a. a heavy chain variable region comprising: i. a VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 222, 228, 234, 240, 246 and 252; ii. a VHCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 223, 229, 235, 241 , 247 and 253; and iii. a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 224, 230, 236, 242, 248 and 254; and / or b. a light chain variable region comprising: i. a VLCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 225, 231 , 237, 243, 249, 255, 258 to 371 , 546 and 550; ii. a VLCDR2 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 226, 232, 238, 244, 250 and 256; and iii. a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of: SEQ ID NOs: 227, 233, 239, 245, 251 and 257.

[0489] All CDRs grouped

[0490] 46. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising: a. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 222, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 223 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 224; and a light chain variable region comprising or consisting of a VLCDR1 comprising or consisting of the amino acid sequence of SEQ ID NOs: 225 or 258 to 276, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 226, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 227; b. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230 and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 231 or 277 to 295, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233; c. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 234, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 235 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 236; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 237 or 296 to 314, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 238, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 239; d. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 240, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 241 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 242; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 243 or 315 333, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 244, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 245; e. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 246, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 247 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 248; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 249 or 334 to 352, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 250, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 251 ; f. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 252, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 253 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 254; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 255 or 353 to 371 , a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 256, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 257; g. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 546, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233; or h. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 550, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233.

[0491] Overlap CDRs

[0492] 47. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising VHCDR1 , VHCDR2, VHCDR3, VLCDR1 , VLCDR2 and VLCDR3 sequences comprising the sequences of SEQ ID NOs: a. 222, 223, 224, 225, 226, 227, respectively; b. 222, 223, 224, 258, 226, 227, respectively; c. 222, 223, 224, 259, 226, 227, respectively; d. 222, 223, 224, 260, 226, 227, respectively; e. 222, 223, 224, 261 , 226, 227, respectively; f. 222, 223, 224, 262, 226, 227, respectively; g. 222, 223, 224, 263, 226, 227, respectively; h. 222, 223, 224, 264, 226, 227, respectively; i. 222, 223, 224, 265, 226, 227, respectively; j. 222, 223, 224, 266, 226, 227, respectively; k. 222, 223, 224, 267, 226, 227, respectively; l. 222, 223, 224, 268, 226, 227, respectively; m. 222, 223, 224, 269, 226, 227, respectively; n. 222, 223, 224, 270, 226, 227, respectively; o. 222, 223, 224, 271 , 226, 227, respectively; p. 222, 223, 224, 272, 226, 227, respectively; q. 222, 223, 224, 273, 226, 227, respectively; r. 222, 223, 224, 274, 226, 227, respectively; s. 222, 223, 224, 275, 226, 227, respectively; or t. 222, 223, 224, 276, 226, 227, respectively.

[0493] AbM CDRs

[0494] 48. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 228, 229, 230, 231 , 232 and 233, respectively; b. 228, 229, 230, 277, 232 and 233, respectively; c. 228, 229, 230, 278, 232 and 233, respectively; d. 228, 229, 230, 279, 232 and 233, respectively; e. 228, 229, 230, 280, 232 and 233, respectively; f. 228, 229, 230, 281 , 232 and 233, respectively; g. 228, 229, 230, 282, 232 and 233, respectively; h. 228, 229, 230, 283, 232 and 233, respectively; i. 228, 229, 230, 284, 232 and 233, respectively; j. 228, 229, 230, 285, 232 and 233, respectively; k. 228, 229, 230, 286, 232 and 233, respectively; l. 228, 229, 230, 287, 232 and 233, respectively; m. 228, 229, 230, 288, 232 and 233, respectively; n. 228, 229, 230, 289, 232 and 233, respectively; o. 228, 229, 230, 290, 232 and 233, respectively; p. 228, 229, 230, 291 , 232 and 233, respectively; q. 228, 229, 230, 292, 232 and 233, respectively; r. 228, 229, 230, 293, 232 and 233, respectively; s. 228, 229, 230, 294, 232 and 233, respectively; t. 228, 229, 230, 295, 232 and 233, respectively; u. 228, 229, 230, 546, 232 and 233, respectively; or v. 228, 229, 230, 550, 232 and 233, respectively. Kabat CDRs

[0495] 49. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 234, 235, 236, 237, 238 and 239, respectively; b. 234, 235, 236, 296, 238 and 239, respectively; c. 234, 235, 236, 297, 238 and 239, respectively; d. 234, 235, 236, 298, 238 and 239, respectively; e. 234, 235, 236, 299, 238 and 239, respectively; f. 234, 235, 236, 300, 238 and 239, respectively; g. 234, 235, 236, 301 , 238 and 239, respectively; h. 234, 235, 236, 302, 238 and 239, respectively; i. 234, 235, 236, 303, 238 and 239, respectively; j. 234, 235, 236, 304, 238 and 239, respectively; k. 234, 235, 236, 305, 238 and 239, respectively; l. 234, 235, 236, 306, 238 and 239, respectively; m. 234, 235, 236, 307, 238 and 239, respectively; n. 234, 235, 236, 308, 238 and 239, respectively; o. 234, 235, 236, 309, 238 and 239, respectively; p. 234, 235, 236, 310, 238 and 239, respectively; q. 234, 235, 236, 311 , 238 and 239, respectively; r. 234, 235, 236, 312, 238 and 239, respectively; s. 234, 235, 236, 313, 238 and 239, respectively; or t. 234, 235, 236, 314, 238 and 239, respectively.

[0496] Chothia CDRs

[0497] 50. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 240, 241 , 242, 243, 244 and 245, respectively; b. 240, 241 , 242, 315, 244 and 245, respectively; c. 240, 241 , 242, 316, 244 and 245, respectively; d. 240, 241 , 242, 317, 244 and 245, respectively; e. 240, 241 , 242, 318, 244 and 245, respectively; f. 240, 241 , 242, 319, 244 and 245, respectively; g. 240, 241 , 242, 320, 244 and 245, respectively; h. 240, 241 , 242, 321 , 244 and 245, respectively; i. 240, 241 , 242, 322, 244 and 245, respectively; j. 240, 241 , 242, 323, 244 and 245, respectively; k. 240, 241 , 242, 324, 244 and 245, respectively; l. 240, 241 , 242, 325, 244 and 245, respectively; m. 240, 241 , 242, 326, 244 and 245, respectively; n. 240, 241 , 242, 327, 244 and 245, respectively; o. 240, 241 , 242, 328, 244 and 245, respectively; p. 240, 241 , 242, 329, 244 and 245, respectively; q. 240, 241 , 242, 330, 244 and 245, respectively; r. 240, 241 , 242, 331 , 244 and 245, respectively; s. 240, 241 , 242, 332, 244 and 245, respectively; or t. 240, 241 , 242, 333, 244 and 245, respectively.

[0498] IMGT CDRs

[0499] 51 . The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 246, 247, 248, 249, 250 and 251 , respectively; b. 246, 247, 248, 334, 250 and 251 , respectively; c. 246, 247, 248, 335, 250 and 251 , respectively; d. 246, 247, 248, 336, 250 and 251 , respectively; e. 246, 247, 248, 337, 250 and 251 , respectively; f. 246, 247, 248, 338, 250 and 251 , respectively; g. 246, 247, 248, 339, 250 and 251 , respectively; h. 246, 247, 248, 340, 250 and 251 , respectively; i. 246, 247, 248, 341 , 250 and 251 , respectively; j. 246, 247, 248, 342, 250 and 251 , respectively; k. 246, 247, 248, 343, 250 and 251 , respectively; l. 246, 247, 248, 344, 250 and 251 , respectively; m. 246, 247, 248, 345, 250 and 251 , respectively; n. 246, 247, 248, 346, 250 and 251 , respectively; o. 246, 247, 248, 347, 250 and 251 , respectively; p. 246, 247, 248, 348, 250 and 251 , respectively; q. 246, 247, 248, 349, 250 and 251 , respectively; r. 246, 247, 248, 350, 250 and 251 , respectively; s. 246, 247, 248, 351 , 250 and 251 , respectively; or t. 246, 247, 248, 352, 250 and 251 , respectively.

[0500] Contact CDRs

[0501] 52. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of embodiment 45, comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequence of SEQ ID NOs: a. 252, 253, 254, 255, 256 and 257, respectively; b. 252, 253, 254, 353, 256 and 257, respectively; c. 252, 253, 254, 354, 256 and 257, respectively; d. 252, 253, 254, 355, 256 and 257, respectively; e. 252, 253, 254, 356, 256 and 257, respectively; f. 252, 253, 254, 357, 256 and 257, respectively; g. 252, 253, 254, 358, 256 and 257, respectively; h. 252, 253, 254, 359, 256 and 257, respectively; i. 252, 253, 254, 360, 256 and 257, respectively; j. 252, 253, 254, 361 , 256 and 257, respectively; k. 252, 253, 254, 362, 256 and 257, respectively; l. 252, 253, 254, 363, 256 and 257, respectively; m. 252, 253, 254, 364, 256 and 257, respectively; n. 252, 253, 254, 365, 256 and 257, respectively; o. 252, 253, 254, 366, 256 and 257, respectively; p. 252, 253, 254, 367, 256 and 257, respectively; q. 252, 253, 254, 368, 256 and 257, respectively; r. 252, 253, 254, 369, 256 and 257, respectively; s. 252, 253, 254, 370, 256 and 257, respectively; or t. 252, 253, 254, 371 , 256 and 257, respectively.

[0502] VH and VL

[0503] 53. The anti-TNFR2 antibody orantigen-binding fragmentthereof of any one of embodiments 45 to 52, comprising: a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 2; and / or a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 29 to 48.

[0504] 54. The anti-TNFR2 antibody orantigen-binding fragmentthereof of any one of embodiments 45 to 52, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 29; b. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 30; c. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 31 ; d. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 32; e. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 33; f. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 34; g. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 35; h. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 36; i. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 37; j. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 38; k. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 39; l. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 40; m. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 41 ; n. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 42; o. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 43; p. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 44; q. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 45; r. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 46; s. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 47; or t. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 48; u. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 558; or v. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 562. The anti-TNFR2 antibody orantigen-binding fragmentthereof of any one of embodiments 45 to 52, comprising: a. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 29; b. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 30; c. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 31 ; d. a heavy chain variable region comprising or consisting ofthe amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 32; e. a heavy chain variable region comprising or consisting ofthe amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 33; f. a heavy chain variable region comprising or consisting ofthe amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 34; g. a heavy chain variable region comprising or consisting ofthe amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 35; h. a heavy chain variable region comprising or consisting ofthe amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 36; i. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 37; j. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 38; k. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 39; l. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 40; m. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 41 ; n. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 42; o. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 43; p. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 44; q. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 45; r. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 46; s. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 47; t. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 48; u. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 558; or v. a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 562. Heavy and Light

[0505] 56. The anti-TNFR2 antibody orantigen-binding fragmentthereof of any one of embodiments 45 to 55, comprising: a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 493; and / or a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to a sequence selected from the group consisting of: SEQ ID NOs: 520 to 539.

[0506] 57. The anti-TNFR2 antibody orantigen-binding fragmentthereof of any one of embodiments 45 to 55, comprising: a. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 520; b. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 521 ; c. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 522; d. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 523; e. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 524; f. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 525; g. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 526; h. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 527; i. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 528; j. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 529; k. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 530; l. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 531 ; m. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 532; n. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 533; o. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 534; p. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 535; q. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 536; r. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 537; s. a heavy chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 493; and a light chain comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 538; or t. a heavy chain comprising or consisting of an amino acid sequence...

Claims

CLAIMSWhat is claimed is:

1. An anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof, comprising: a. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NO: 545, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; b. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NO: 546, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233; c. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 414, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 415 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 416; and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 547, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 418, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 419; or d. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 456, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 457 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 458; and a light chain variable region comprising or consisting of a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 460, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 461 .

2. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of claim 1 , comprising: a. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 60, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 61 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NOs: 549, aVLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 64, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; b. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 228, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 229 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 230; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NO: 550, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 232, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 233; c. a heavy chain variable region comprising a VHCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 414, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 415 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 416; and a light chain variable region comprising a VLCDR1 comprising or consisting of the amino acid sequence of any of SEQ ID NO: 551 , a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 418, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 419; or d. a heavy chain variable region comprising a VHCDR1 comprising or consisting ofthe amino acid sequence of SEQ ID NO: 456, a VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 457 and a VHCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 458; and a light chain variable region comprising a VLCDR1 comprising or consisting ofthe amino acid sequence of any of SEQ ID NO: 552, a VLCDR2 comprising or consisting of the amino acid sequence of: SEQ ID NO: 460, and a VLCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 461.

3. The anti-tumor necrosis factor (TNF) receptor 2 (TNFR2) antibody or an antigen-binding fragment thereof of claim 1 or claim 2, respectively comprising the VHCDR1 , the VHCDR2, the VHCDR3, the VLCDR1 , the VLCDR2 and the VLCDR3 sequences of SEQ ID NOs: 60, 61 , 62, 63, 64 and 65; 60, 61 , 62, 112, 64 and 65; 60, 61 , 62, 113, 64 and 65; 60, 61 , 62, 114, 64 and 65; 60, 61 , 62, 115, 64 and 65; 60, 61 , 62, 116, 64 and 65; 60, 61 , 62, 117, 64 and 65; 60, 61 , 62, 118, 64 and 65; 60, 61 , 62, 119, 64 and 65; 60, 61 , 62, 120, 64 and 65; 60, 61 , 62, 121 , 64 and 65; 60, 61 , 62, 122, 64 and 65; 60, 61 , 62, 123, 64 and 65; 60, 61 , 62, 124, 64 and 65; 60, 61 , 62, 125, 64 and 65; 60, 61 , 62, 126, 64 and 65; 60, 61 , 62, 127, 64 and 65; 60, 61 , 62, 128, 64 and 65; 60, 61 , 62, 129, 64 and 65; 60, 61 , 62, 130, 64 and 65; 60, 61 , 62, 131 , 64 and 65; 60, 61 , 62, 132, 64 and 65; 60, 61 , 62, 133, 64 and 65; 228, 229, 230, 231 , 232 and 233; 228, 229, 230, 277, 232 and 233; 228, 229, 230, 278, 232 and 233; 228, 229, 230, 279, 232 and 233; 228, 229, 230, 280, 232 and 233; 228, 229, 230, 281 , 232 and 233; 228, 229, 230, 282, 232 and 233; 228, 229, 230, 283, 232 and 233; 228, 229, 230, 284, 232 and 233; 228, 229, 230, 285, 232 and 233; 228, 229, 230, 286, 232 and 233; 228, 229, 230, 287, 232 and 233; 228, 229, 230, 288, 232 and 233; 228, 229, 230, 289, 232 and 233; 228, 229, 230, 290, 232 and 233; 228, 229, 230, 291 , 232 and 233; 228, 229, 230, 292, 232 and 233; 228, 229, 230, 293, 232 and 233; 228, 229, 230, 294, 232 and 233; 228, 229, 230, 295, 232 and 233; 414, 415, 416, 417, 418 and 419; 414, 415, 416, 445, 418 and 419; 456, 457, 458, 459, 460 and 461 ;or 456, 457, 458, 487, 460 and 461 .

4. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 1 to 3, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 557; b. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 558; c. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 4; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 559; or d. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 5; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 560.

5. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 1 to 3, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 561 ; b. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 562; c. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 4; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 563; or d. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ IDNO: 5; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 564.

6. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding claim, comprising: a. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 6; b. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 7; c. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 8; d. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 9; e. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 10; f. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 11 ; g. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 12; h. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ IDNO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 13; i. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 14; j. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 15; k. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 16; l. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 17; m. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 18; n. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 19; o. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 20; p. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequencehaving at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 21 ; q. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 22; r. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 23; s. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 24; t. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 25; u. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 26; v. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 27 w. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 1 ; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 28; x. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 29;y. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 30; z. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 31 ; aa. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 32; bb. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 33; cc. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 34; dd. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 35; ee. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 36; ff. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 37; gg. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ IDNO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 38; hh. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 39; ii. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 40; jj. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 41 ; kk. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 42;II. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 43; mm. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 44; nn. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 45; oo. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequencehaving at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 46; pp. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 47; qq. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 48; rr. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 4; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 50; ss. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 4; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 51 ; tt. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 5; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 52; or uu. a heavy chain variable region comprising or consisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 5; and a light chain variable region comprising orconsisting of an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 53.

7. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding claim, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and a light chain variable region respectively comprise or consist of the amino acid sequences of SEQ ID NOs: 1 and 6; 1 and 7; 1 and 8; 1 and 9; 1 and 10; 1 and 11 ; 1 and 12; 1 and 13; 1 and 14; 1 and 15; 1 and 16; 1 and 17; 1 and 18; 1 and 19; 1 and 20; 1 and 21 ; 1 and 22; 1 and 23; 1 and 24; 1 and 25; 1 and 26; 1 and 27; 1 and 28; 2 and 29; 2 and 30; 2 and 31 ; 2 and 32; 2 and 33; 2 and 34; 2 and 35; 2 and 36; 2 and 37; 2 and 38; 2 and 39; 2 and 40; 2 and 41 ; 2 and 42; 2 and 43; 2 and 44; 2 and 45; 2 and 46; 2 and 47; 2 and 48; 4 and 50; 4 and 51 ; 5 and 52; or 5 and 53.

8. The anti-TNFR2 antibody or antigen-binding fragment thereof of any preceding claim, comprising a heavy chain and a light chain, wherein the heavy chain and light chain respectively comprise the amino acid sequence of SEQ ID NOs: 492 and 497; 492 and 498; 492 and 499; 492 and 500; 492 and 501 ; 492 and 502; 492 and 503; 492 and 504; 492 and 505; 492 and 506; 492 and 507; 492 and 508; 492 and 509; 492 and 510; 492 and 511 ; 492 and 512; 492 and 513; 492 and 514; 492 and 515; 492 and 516; 492 and 517; 492 and 518; or 492 and 519; 493 and 520; 493 and 521 ; 493 and 522; 493 and 523; 493 and 524; 493 and 525; 493 and 526; 493 and 527; 493 and 528; 493 and 529; 493 and 530; 493 and 531 ; 493 and 532; 493 and 533; 493 and 534; 493 and 535; 493 and 536; 493 and 537; 493 and 538; or 493 and 539; 495 and 541 ; or 495 and 542; 496 and 543; or 496 and 544.

9. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 497.

10. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 498.

11. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 499.

12. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 500.

13. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 501 .

14. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 502.

15. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 503.

16. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 504.

17. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 505.

18. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 506.

19. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 507.

20. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 508.

21. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of 509.

22. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 510.

23. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 511.

24. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 512.

25. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 513.

26. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 514.

27. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 515.

28. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 516.

29. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 517.

30. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 492, and the light chain comprises the amino acid sequence of SEQ ID NO: 518.

31. An anti-TNFR2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 492, and the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 519.

32. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 1 to 7, wherein the antibody comprises a heavy chain constant region comprising or consisting of the sequence of SEQ ID NO: 570, and / or a light chain constant region comprising or consisting of the sequence of SEQ ID NO: 571.

33. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 1 to 7, wherein the antibody is an lgG1 antibody having the substitutions L234A, L235A and D265S.

34. An anti-TNFR2 antibody or antigen-binding fragment thereof, wherein the antibody preferentially binds to membrane-bound TNFR2 compared to shed TNFR2.

35. The anti-TNFR2 antibody or antigen-binding fragment thereof of claim 34, wherein the antibody is an agonistic antibody.

36. The anti-TNFR2 antibody or antigen-binding fragment thereof of claim 34 or 35, wherein the antibody or antigen-binding fragment thereof is an agonistic antibody, as measured by NF-KB activity.

37. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 34 to 36, wherein the antibody specifically binds to both M196 and R196 variants of TNFR2.

38. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 34 to 37, wherein the antibody or antigen-binding fragment thereof inhibits less than about 30% of the binding ofTNFa to TNFR2 in the presence of the anti-TNFR2 antibody or antigen-binding fragment thereof.

39. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 34 to 38, wherein the antibody or antigen-binding fragment thereof does not bind to physiological concentrations of shed TNFR2.

40. The anti-TNFR2 antibody or antigen-binding fragment thereof of any one of claims 34 to 39, wherein the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof as defined in any one of claims 1 to 33.41 . A polynucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 569.

42. A pharmaceutical composition comprising the anti-TNFR2 antibody or antibody binding fragment thereof as defined in any one of claims 1 to 40 and one or more pharmaceutically acceptable carriers.

43. A kit comprising an anti-TNFR2 antibody or antibody binding fragment of any one of claims 1 to 40 or the pharmaceutical composition of claim 42.

44. A method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-TNFR2 antibody or antibody binding fragment thereof of any one of claims 1 to 40, or the pharmaceutical composition claim 42.

45. The method of claim 44, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis (RA), atopic dermatitis (AD), systemic lupus erythematosus (SLE), Sjogren’s Disease (SjD), ulcerative colitis (UC), and Crohn’s disease (CD).

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