Therapeutic antibodies

Abstract

The present invention relates to antibodies that modulate the OX40 signaling pathway for treating inflammatory diseases in companion animals, such as atopic dermatitis (AD) and / or eczema. Related methods and uses are also described.

Description

[Technical field]

[0001] Introduction The present invention relates to antibodies that modulate the OX40 signaling pathway for the treatment of inflammatory diseases in companion animals. [Background technology]

[0002] Atopic dermatitis (AD) and / or eczema, characterized by chronic, dry, itchy, red skin, is a significant problem in dogs, affecting 10-15% of pet dogs.

[0003] Cytopoint is an existing treatment for atopic dermatitis in dogs, with a minimum dose of 1 mg kg -1 , monthly injections are recommended. Cytopoint is an anti-IL31 Ab (described, for example, in WO2013 / 011407A1 and WO2019 / 177697) specifically intended to treat the itching (pruritus) associated with atopic dermatitis. However, at least one-third of canine AD patients do not respond adequately to Cytopoint, and in some cases, efficacy may decrease after the first injection (see, for example, "CVMP Evaluation Report of CYTOPOINT EMA / 118401 / 2017 (EMEA / V / C / 003939 / 0000)" and Cytopoint Roundtable, World Academy of Veterinary Dermatology, May 2017, https: / / wavd.org / wp-content / uploads / cytopoint-roundtable-2017-05.pdf). The most common side effect of Cytopoint (which may affect up to 1 in 1,000 animals) is an allergic reaction, including anaphylaxis, facial swelling, and hives. Dogs weighing less than 3 kg should not be given Cytopoint. (https: / / www.ema.europa.eu / en / documents / product-information / cytopoint-epar-product-information_en.pdf).

[0004] There is a need for improved treatments, as well as drugs that treat the underlying cause of the disease rather than the symptoms, particularly treatments that are safe, have a long duration of action, and are effective in covering a wider range of patients, especially non-responders.

[0005] Advantageously, targeting OX40 / OX40L upstream of the inflammatory cascade offers the possibility to modulate multiple cytokines simultaneously.

[0006] Canine OX40L is described in US 10,196, 435. The protein sequence of canine OX40 has not been reported in the scientific or patent literature to date.

[0007] A monoclonal antibody (7D6) that binds to feline CD134 (OX40) and its effect on feline immunodeficiency virus is described in Willett et al, Journal of Virology, 81(18), 2007, pages 9665-9679.

[0008] The use of OX40L or antibodies against OX40 in the treatment of immunomodulatory disorders such as atopic dermatitis in companion animals (eg, dogs) has not previously been demonstrated. Summary of the Invention

[0009] In a first aspect, the present invention relates to an antibody or a fragment thereof that specifically binds to companion animal OX40L or companion animal OX40, wherein the antibody is selected from one of the following antibodies: an antibody comprising: HC CDR1 comprising SEQ ID NO:575 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:576 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:577 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:578 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:579 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:580 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: HC CDR1 comprising SEQ ID NO:741 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:742 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:743 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:744 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:745 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:746 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO:275 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:276 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:277 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:278 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO:279 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:280 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: HC CDR1 comprising SEQ ID NO:395 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:396 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:397 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:398 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:399 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:400 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO: 15 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 16 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 17 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 18 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 19 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 20 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 45 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 46 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 47 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 48 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 49 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 50 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO:65 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:66 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:67 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:68 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO:69 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:70 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 115 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 116 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 117 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 118 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 119 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 120 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO: 155 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 156 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 157 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 158 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 159 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 160 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO:235 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:236 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:237 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:238 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR comprising SEQ ID NO:2392 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:240 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: HC CDR1 comprising SEQ ID NO:285 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:286 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:287 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:288 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:289 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:290 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: HC CDR1 comprising SEQ ID NO: 365 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO: 366 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO: 367 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO: 368 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO: 369 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO: 370 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:665 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:666 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:667 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:668 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:669 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:670 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO: 751 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 752 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 753 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 754 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 755 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 756 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR1 comprising SEQ ID NO:761 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:762 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:763 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:764 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:765 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:766 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0010] The companion animal may be a dog or a cat.

[0011] In one embodiment, the antibody or fragment binds to canine OX40L.

[0012] In one embodiment, the antibody or fragment comprises: a) reducing, inhibiting, or neutralizing OX40 activity or activation in a companion animal or in cells of a companion animal; b) altering the secretion of cytokines in a companion animal or in cells of a companion animal; and / or c) It is capable of reducing leukocyte proliferation in companion animals or in cells of companion animals.

[0013] In one embodiment, the antibody or fragment comprises: a) reducing, inhibiting, or neutralizing OX40 activity or activation in a companion animal or in cells of a companion animal; b) reducing the secretion of proinflammatory cytokines in companion animals or cells of companion animals; and / or c) reducing the secretion of inflammatory chemokines or chemokine receptors in companion animals or cells of companion animals; and / or d) increasing the secretion of inhibitory cytokine(s) in the companion animal or in cells of the companion animal; and / or e) increasing the secretion of inhibitory chemokine(s) or chemokine receptors in companion animals or cells of companion animals; and / or f) It can reduce white blood cell proliferation in companion animals.

[0014] Suitable assays to assess these properties are described herein, such as the mixed lymphocyte reaction (MLR) assay or the HEK-blue assay to measure inhibition of NFkB activity, such as those shown in the Examples, such as the PBMC activation assay. Other assays will be known to those skilled in the art and may also be used.

[0015] The cytokine or cytokine receptor may be selected from TNF alpha, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, RANTES, GM-CSF, TGF-beta, and interferon gamma.

[0016] In one embodiment, the antibody or fragment binds to canine OX40. The antibody or fragment can reduce, inhibit, or neutralize OX40 activity or activation in a companion animal or a cell of a companion animal.

[0017] In the above-mentioned embodiment and various aspects of the present invention related to an antibody that binds to OX40 or OX40L, the antibody or fragment is a full canine antibody, a chimeric antibody or a caninized antibody. The terms full canine and canine are used interchangeably herein. According to a preferred embodiment, the antibody is canine (i.e., full canine).

[0018] For example, the fragment is selected from F(ab')2, Fab, Fv, scFv, heavy chain, light chain, variable heavy (VH), variable light (VL) chain, CDR region, single VH or VL domains, maxibody, minibody, intrabody, diabody, triabody, tetrabody, and bis-scFv, as well as polypeptides containing at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide.

[0019] In one embodiment, the antibody or fragment is conjugated to another moiety. The antibody or fragment may comprise a therapeutic moiety, a half-life extending moiety or a label.

[0020] In another aspect, the invention relates to a binding molecule comprising an antibody or fragment as described above.

[0021] In another aspect, the invention relates to an antibody or fragment or a binding molecule as described above for use in the treatment of a disease.

[0022] In another aspect, the present invention relates to a pharmaceutical composition comprising the above-mentioned antibody or fragment thereof, or binding molecule.

[0023] In another aspect, the invention relates to a pharmaceutical antibody or fragment thereof, binding molecule as described above, for use in the treatment of an OX40 or OX40L mediated disease.

[0024] In another aspect, the invention relates to a method for treating or preventing an OX40 or OX40L mediated disease, comprising administering to a subject in need thereof an antibody or fragment, binding molecule or pharmaceutical composition as described above.

[0025] For example, the disease is selected from an inflammatory disease or an autoimmune disease.

[0026] The disease may be an inflammatory skin disease, including atopic dermatitis, allergic dermatitis, pruritus, psoriasis, scleroderma, or eczema; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); ischemia-reperfusion; adult respiratory distress syndrome; asthma; meningitis; encephalitis; uveitis; autoimmune diseases such as rheumatoid arthritis, Sjogren's syndrome, vasculitis; diseases involving leukocyte extravasation; central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome following sepsis or trauma, bacterial pneumonia, antigen-antibody complex-mediated diseases; pulmonary inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, and cystic fibrosis.

[0027] In one embodiment, the antibody or fragment, binding molecule, pharmaceutical composition is administered with one or more therapeutic agents.

[0028] For example, the one or more therapeutic agents can be rapamycin (sirolimus), tacrolimus, cyclosporine (e.g., Atopica®), corticosteroids (e.g., methylprednisolone), methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12 / IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VI_A4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide ... and / or cyclosporine (ALK) antibodies. The therapeutic agent is selected from the group consisting of cyclosporine, cyclosporine, cyclosporine, cyclosporine amides, anti-thymocyte globulin, anti-complement C5 antibodies, anti-a4b7 integrin antibodies, anti-IL6 antibodies, anti-IL6-R antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa (TNFα) / TNFa-Fc molecules, HDAC inhibitors, JAK inhibitors such as JAK-1 and JAK-3 inhibitors, anti-IL-31 antibodies, SYK inhibitors, anti-IL-4Ra antibodies, anti-IL-13 antibodies, anti-TSLP antibodies, PDE4 inhibitors, lokietomab (Cytopoint®), and oclacitinib (Apoquel®).

[0029] In another aspect, the invention relates to a method for reducing cytokine secretion comprising administering to a subject in need thereof an antibody or fragment, binding molecule or pharmaceutical composition as described above.

[0030] In another aspect, the invention relates to a multispecific binding agent comprising an antibody or fragment or binding molecule as described above.

[0031] In another aspect, the invention relates to a combination therapy comprising the above-mentioned antibody or fragment, binding molecule or pharmaceutical composition.

[0032] In another aspect, the present invention relates to an immunoconjugate comprising an antibody or fragment, or a binding molecule as described above.

[0033] In another aspect, the present invention relates to a kit comprising an antibody or fragment thereof, conjugate or pharmaceutical composition as described above.

[0034] In another aspect, the present invention relates to a vector comprising the above-described nucleic acid.

[0035] In another aspect, the invention relates to a host cell comprising a nucleic acid or a vector as described above, optionally selected from a mammalian, yeast, plant or bacterial cell.

[0036] In another aspect, the invention relates to a method for detecting OX40L or OX40 in a companion animal, comprising contacting a test sample with an antibody or fragment or binding molecule as described above.

[0037] In another aspect, the invention relates to trimeric soluble companion animal OX40L extracellular domain probes and their use in methods of screening for companion animal OX40L antibodies.

[0038] The invention is described in the following non-limiting figures and tables. [Brief description of the drawings]

[0039] [Figure 1]Canine OX40 and OX40L gene and protein structures. A. Predicted number and arrangement of exons within the canine genome. Exons are represented by boxes. Numbers above the line represent the predicted size of each exon in nucleotides. Numbers below the line represent the predicted size of introns in nucleotides, 5'UTR and 3'UTR (shaded boxes). Predicted gene structures were generated based on NCBI assembly ID: 317138 (CanFam3.1). Predicted transcript sizes and sequences were confirmed by RT-PCR using RNA extracted from activated PBMCs. B. Schematic representation of OX40 and OX40L proteins. [Diagram 2] Alignment of the long and short amino acid sequences of canine OX40 (SEQ ID NOs: 4 and 6). Based on protein sequence homology with OX40 from other species, exon 6 is predicted to contain a transmembrane domain. A schematic representation of these sequences is shown in FIG. 1B. [Diagram 3] Relative abundance of the two canine OX40 splice variants in PHA-activated canine PBMCs as determined by the number of E. Coli colonies transformed with total OX40 cDNA. The long and short splice variants were identified from individual colonies by diagnostic PCR. Measurements were performed on independent PBMC samples 1 and 4 days after activation. Insert: PCR discrimination of the short (S) and long (L) splice variants. +ve=positive control. 1 kb plus DNA ladder (NEB), with brighter bands at 0.5, 1.0, and 3.0 bp. [Figure 4]Serum antibody titers from immunized and non-immunized mice measured using flow cytometry. A. In non-immunized mice, there was no significant antibody binding to non-transfected cells (△) or cells stably expressing OX40L (○). B. Serum from immunized mice was collected 10 days after the first boost, resulting in a clear distinction between non-transfected / wild type cells (▽) and cells stably expressing OX40L (□). In this example, hydrodynamic tail vein injection of OX40L-expressing plasmid was used for the first immunization, and OX40L-expressing mouse embryonic fibroblasts were used for the subsequent boost. [Diagram 5] Schematic diagram of soluble proteins containing the canine OX40L extracellular domain (ECD) (SEQ ID NOs: 807-811). A. Monomeric canine OX40L probe containing monomeric human IgG1 (mvhfc), a 6x histidine (HIS) tag, and a tobacco etch virus (TEV) protease cleavage peptide. B. Trimeric canine OX40L probe containing chicken tenascin-C trimerization domain and either human IgG1 Fc or a HIS tag. The term trimer refers to the conformation of the OX40L extracellular domain. [Figure 6] Single-dose cell-based binding assay of canine OX40L antibodies. The histograms show the overlay intensity of signals obtained by flow cytometry of OX40L-expressing HEK293 cells or parental lines stained with candidate OX40L antibodies followed by fluorescently labeled secondary antibodies. All antibodies shown in the figure bind with higher affinity to OX40L-expressing HEK cells compared to the parental lines, except for those labeled as non-binders. Table 4 shows some average intensity data. [Figure 7] Functional assay to measure OX40-OX40L interaction. A. Representative curves showing the enzymatic activity of secreted alkaline phosphatase released 6, 24 and 48 hours after mixing HEK-Blue-OX40 with HEK-OX40L cells. All curves are baseline subtracted with the signal obtained in medium alone. [Figure 8]Single-dose cell-based blocking assay based on the HEK blue system to determine the blocking effect of candidate antibodies on the OX40-OX40L interaction. Data are normalized to the maximum signal (100%) defined by the response obtained in the absence of antibody and the minimum signal (0%) measured in the presence of HEK-blue-OX40 cells alone. [Figure 9] HPLC-SEC chromatograms of antibodies PMX050, 51, 53 and 63. Quantification of the percentage of monomer is shown in Table 9. [Figure 10] Biophysical stability measurements of candidate antibodies using Uncle (Unchained Labs) for antibodies PMX051 and 063. A. Data shows intensity and mass distribution (left and center graphs, respectively) used to calculate the initial diameter of the molecule, and B. SLS / DLS data used to calculate Tm1 and Tagg266. Data is shown in Table 9. [Figure 11] Quantification of the first melting temperature (Tm1) and aggregation temperature as measured by fluorescence at 266 nm and 473 nm for PMX051, PMX063 PMX097, PMX098 and PMX154 molecules after incubation at 37° C. for 28 days. The data show that the tendency of all five molecules to melt or aggregate is relatively stable when incubated at 37° C. for 28 days. Data was acquired using an UNCLE machine (UNChained Labs). [Figure 12] Quantification of the average molecular size of PMX051, PMX063 PMX097, PMX098 and PMX154 molecules after incubation at 37°C for 28 days. The data show different tendencies of the five molecules to aggregate over time at 37°C. PMX097 and PMX154 showed the best stability when incubated at 37°C for 28 days. Data was acquired using an UNCLE machine (UNChained Labs). [Figure 13]Pharmacokinetic profiles of PMX097 (triangles) and PMX154 (squares) in dog serum after intravenous injection of 3.0 mg antibody per kg body weight. Data were analyzed by fitting biphasic decay curves using Prism. Degradation phase: PMX097=8.5 days, PMX154=8.9 days. [Figure 14] Canine interferon gamma (IFN-Y) ELISpot performed on PBMCs isolated from dogs treated with the indicated doses of PMX097 or PMX154 prior to KLH immunization according to the protocol illustrated in Table 11. Data show the number of spots obtained after culturing PBMCs either without stimulation (A.) or in the presence of 50 μg / ml KLH (B.C.). Both PMX097 and PMX154 reduced T cell activation for up to 35 days after a single dose when administered at 0.5 mg / kg, and for up to 77 days after a single dose when administered at 3.0 mg / kg. [Figure 15] Anti-KLH IgM (A, B) and IgG (C, D) serum titers performed on sera from dogs treated with the indicated doses of PMX097 or PMX154 prior to KLH immunization according to the protocol illustrated in Table 11. Data show results obtained from sera isolated from dogs at different time points and detailed views at 21 and 98 days post-dosing. Both PMX097 and PMX154 reduced anti-KLH IgM and IgG serum titers at both 3.0 mg / kg and 0.5 mg / kg for up to 77 days after a single dose. [Figure 16]Hematoxylin and eosin (HE) staining on sections taken from skin biopsies collected from dogs treated with PMX097 or PMX154 2 days after intradermal KLH injection. Images show subcutaneous fat area. (A, B) Biopsies from vehicle control injected dogs collected at the KLH injection site (B) or non-injected skin area (A). (C, D) Biopsies collected at the KLH injection site from dogs treated with PMX154 at 3.0 mg / kg (C) or 0.5 mg / kg (D). (E, F) Biopsies collected at the KLH injection site from dogs treated with PMX097 at 3.0 mg / kg (E) or 0.5 mg / kg (F). Both PMX097 and PMX154 reduce the presence of immune infiltrates compared to vehicle control dogs. PMX154 almost completely eliminated the presence of immune infiltrates.

[0040] Table 1. Examples of amino acid residues and conservative amino acid substitutions. Table 2. Nucleic acid and amino acid sequences. Table 3. VH and VL gene usage Table 4. Some averages obtained from cell binding assays. Table 5. Normalized cell-based inhibition assay based on the HEK blue system demonstrates the percentage of OX40 signal inhibition of candidate antibodies. Data are normalized to the SEAP activity detected in samples with only HEK blue OX40 cells, and the minimum signal (0%) measured in samples with HEK blue OX40 and HEK OX40L cells, with maximum inhibition (100%) defined as the absence of anti-canine OX40L antibodies. Table 6: Inhibition of IFN-γ release by candidate OX40L antibodies from activated PBMCs in the presence of OX40L-expressing HEK cells. Anti-OX40L antibodies were tested in 10 independent experiments. The level of IFN-γ in control samples in each experiment is also shown. Activated PBMCs only = PBMCs activated in the presence of CD3-CD28 antibodies only and in the absence of anti-OX40L antibodies. Activated PBMCs + HEK WT = PBMCs activated in the presence of CD3-CD28 antibodies and WT HEK cells and in the absence of anti-OX40L antibodies. Activated PBMCs + HEK OX40L = PBMCs activated in the presence of CD3-CD28 antibodies and HEK cells expressing OX40L antibodies and in the absence of anti-OX40L antibodies. Table 7: Normalized IFN-γ levels in supernatants from PBMCs activated with CD3 and CD28 antibodies in the presence of OX40L expressing HEK cells and the indicated anti-OX40L antibodies. Data from Table 6 were normalized using GraphPad to set IFN-γ levels in wells with PBMCs activated in the presence of CD3-CD28 antibody alone and in the absence of anti-OX40L antibody as 0%, and IFN-γ levels in wells with PBMCs activated in the presence of CD3-CD28 and OX40L expressing HEK cells and in the absence of anti-OX40L antibody as 100%. Table 8: Functional affinity of anti-OX40L antibodies to trimeric canine OX40L as determined by surface plasmon resonance (SPR). Data was analyzed using Biacore Insight Evaluation Software. Curves were fitted using a bivalent analyte binding model. Table 9: Protein stability determination of OX40L antibody. Tm1 = melting (unfolding) temperature 1; 266 = onset aggregation temperature determined by static light scattering at 266 nm; initial diameter = average molecular diameter before temperature increase, % monomer (SEC) = % monomer determined by HLPLC-SEC. Table 10: Long-term stability of PMX097 and PMX154 when incubated at 4° C. for 4 months. Data shows melting temperature 1 (Tm1), aggregation temperature measured at 266 nm (Tagg266 nm), average molecular diameter (Z AVG diam), and polydispersity index (PDI). Table 11: Treatment regime for dogs in the single dose antigen recall dog study. Table 12: Histological findings in non-injected skin areas from dogs in a single-dose antigen recall study. Table 13: Histological findings in KLH-injected skin areas from dogs in a single-dose antigen recall study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] OX40 and its binding partner OX40L are part of the TNF superfamily, and OX40 signaling is a costimulatory pathway that promotes T cell activation. OX40 (receptor) is expressed on the surface of T cells, and OX40L is expressed both on the surface of T cells and on antigen-presenting cells such as B cells and macrophages. Neither OX40 nor OX40L is constitutively expressed, but is increased 24-72 hours after activation of the respective cells. OX40L binding to the OX40 receptor on T cells promotes T cell survival, proliferation and cytokine production. Thus, OX40 has an important role in establishing, maintaining and regulating immune responses.

[0042] In humans, both the density of OX40L and the number of OX40-positive cells are significantly greater in lesional dermis than in healthy-appearing dermis in atopic dermatitis, and blockade of OX40 / OX40L signaling regulates several proinflammatory responses. OX40L also controls the response of dendritic cells to thymic stromal lymphopoietin (TSLP), which leads to the production of IL-21 and CXCL13. Thus, the OX40 / OX40L axis offers the potential to regulate multiple proinflammatory responses, as its costimulatory signals lie upstream of several cellular processes that release proinflammatory cytokines.

[0043] OX40 signaling is associated with a variety of diseases, including autoimmune and inflammatory-related diseases, including allergies, asthma, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, experimental autoimmune encephalomyelitis (EAE), experimental leishmaniasis, collagen-induced arthritis, colitis (such as ulcerative colitis), contact hypersensitivity reactions, diabetes, Crohn's disease, and Grave's disease. Evidence in humans suggests that disruption of the OX40 / OX40L axis reduces the proliferative response of immune cells and the like, and can be used to prevent, treat, or ameliorate symptoms of many diseases, including atopic dermatitis, diabetes, and cancer. Antibodies against either OX40 or OX40L can be used to achieve this disruption.

[0044] However, the role of antibody therapy for OX40 / OX40L-mediated diseases in companion animals, such as atopic dermatitis, has not previously been investigated.

[0045] Thus, in a first aspect, the present invention relates to an antibody or a fragment thereof that specifically binds to companion animal OX40L or companion animal OX40.

[0046] Companion animals of the present invention are suitably selected from dogs, cats, horses, birds, rabbits, goats, reptiles, fish and amphibians. Dogs are the preferred companion animals of the present invention. Cats are the preferred companion animals of the present invention. Horses are the preferred companion animals of the present invention. For the avoidance of doubt, humans are not companion animals.

[0047] In one aspect, the companion animal is a dog.

[0048] In one embodiment, the companion animal is a cat.

[0049] In one aspect, the companion animal is a horse.

[0050] In one embodiment, the antibodies and fragments described herein specifically bind to wild-type canine OX40L. The amino acid sequence (SEQ ID NO: 1) and nucleotide sequence of wild-type canine OX40L are shown in Table 2 (SEQ ID NO: 2). The antibodies and fragments described herein specifically bind to SEQ ID NO: 1. In one embodiment, the antibodies and fragments described herein specifically bind to a variant of SEQ ID NO: 1.

[0051] In one embodiment, the antibodies and fragments described herein specifically bind to wild-type canine OX40. The amino acid sequence (SEQ ID NO: 4 and 6) and nucleotide sequence of wild-type canine OX40 are shown in Table 2 (SEQ ID NO: 3 and 5). As described in the Examples, two different splice variants have been identified. The antibodies and fragments described herein specifically bind to proteins classified by SEQ ID NO: 3 and / or 5. In one embodiment, the antibodies and fragments described herein specifically bind to proteins classified by variants of SEQ ID NO: 3 and / or 5 (SEQ ID NO: 4 and 6).

[0052] Variants of the above sequences may have at least 75%, 80%, 85%, 90% or 95% sequence identity to the sequences shown above.

[0053] As used herein, the term "homology" or "identity" generally refers to the percentage of amino acid residues in a sequence that are identical to the residues of a reference polypeptide being compared, after aligning the sequences and, in some embodiments, after introducing gaps, if necessary, to achieve the maximum percentage homology, in some embodiments without considering any conservative substitutions as part of the sequence identity. Thus, the percentage of homology between two amino acid sequences is equal to the percentage of identity between the two sequences. Neither N-terminal nor C-terminal extensions, tags, or insertions should be construed as reducing the identity or homology. Methods and computer programs for alignment are well known. The percentage of identity between two amino acid sequences can be determined using well-known mathematical algorithms. As used herein, the term "sequence similarity" generally refers to the percentage of amino acid residues in a sequence that are identical and / or contain conservative amino acid substitutions, where the substituted amino acids have similar physicochemical properties. For example, if a positively charged amino acid is replaced with a different positively charged amino acid, the percentage similarity can be calculated using tools such as "EMBOSS Needle" which implements the Needleman-Wunch algorithm for pairwise percent identity or similarity, and amino acids can be considered similar if they have a positive score in the BLOSUM62 matrix. In embodiments, the term "sequence identity" as used herein may be replaced with the term "sequence similarity."

[0054] Unless otherwise specified, the term OX40L as used herein refers to companion animal OX40L, e.g., canine or feline OX40L. OX40L is also known as "OX40 antigen ligand," "OX40 ligand," "CD252," "TNFSF4," and "CD134 ligand." In one embodiment, the antibody or fragment thereof binds to canine OX40L. In one embodiment, the antibody or fragment thereof binds to feline OX40L.

[0055] Unless otherwise specified, the term OX40 as used herein refers to companion animal OX40, e.g., canine or feline OX40. OX40 is also known as "TNFR superfamily member 4", "TNFRSF4", "OX40 antigen" and "CD134". In one embodiment, the antibody or fragment thereof binds to canine OX40L. In one embodiment, the antibody or fragment thereof does not bind to feline OX40L. In one embodiment, the antibody or fragment thereof is not 7D6 as disclosed in Willett et al.

[0056] The terms "OX40L binding molecule / protein / polypeptide / drug / moiety", "OX40L antigen binding molecule / protein / polypeptide / drug / moiety", "anti-OX40L antibody", "anti-OX40L antibody fragment" all refer to a molecule capable of specifically binding to companion animal OX40L, e.g., canine or feline OX40L antigen. Binding reactions can be demonstrated by standard methods, for example, with reference to negative control tests using antibodies of irrelevant specificity.

[0057] The terms "OX40 binding molecule / protein / polypeptide / drug / moiety", "OX40 antigen binding molecule / protein / polypeptide / drug / moiety", "anti-OX40 antibody", "anti-OX40 antibody fragment" all refer to a molecule capable of specifically binding to companion animal OX40, e.g., canine or feline OX40 antigen. Binding reactions can be demonstrated by standard methods, for example, by reference to negative control tests using antibodies of irrelevant specificity.

[0058] In some embodiments, the antibodies or fragments provided herein bind to an OX40L epitope that is a three-dimensional surface feature of an OX40L polypeptide. In some embodiments, the antibodies or fragments provided herein bind to an epitope, including a conformational epitope resulting from a polypeptide from a single subunit, or from a multimeric form (e.g., an epitope of a monomeric or trimeric form of an OX40L polypeptide). The region of an OX40L polypeptide that contributes to an epitope may be contiguous amino acids of the polypeptide, or the epitope may come together from two or more non-contiguous regions of the polypeptide. An OX40L epitope may be present in: (a) a trimeric form of OX40L (a "trimeric OX40L epitope"), (b) a monomeric form of OX40L (a "monomeric OX40L epitope"), (c) both trimeric and monomeric forms of OX40L, (d) a trimeric form but not a monomeric form of OX40L, or (e) a monomeric form but not a trimeric form of OX40L.

[0059] For example, in some embodiments, the epitope is present or available for binding only in a trimeric form, but not present or available for binding in a monomeric form by an anti-OX40L antibody. In other embodiments, the OX40L epitope is a linear feature of an OX40L polypeptide (e.g., a trimeric or monomeric form of an OX40L polypeptide). The antibodies provided herein may specifically bind to (a) an epitope of a monomeric form of OX40L, (b) an epitope of a trimeric form of OX40L, (c) an epitope of a monomeric but not trimeric form of OX40L, (d) an epitope of a trimeric but not monomeric form of OX40L, or (e) both the monomeric and trimeric forms of OX40L. In some embodiments, the antibodies provided herein specifically bind to an epitope of the trimeric form of OX40L, but do not specifically bind to an epitope of the monomeric form of OX40L. In some embodiments, the antibodies provided herein specifically bind to an epitope of the monomeric form of OX40L, and may or may not bind to the trimeric form.

[0060] An antibody or fragment thereof that "binds" or is "capable of binding" to an antigen of interest, e.g., companion animal OX40L or companion animal OX40, respectively, is an antibody or fragment thereof that binds to the antigen with sufficient affinity such that the antibody or fragment is useful as a therapeutic agent in targeting cells or tissues that express the antigen OX40 or OX40L, respectively, as described herein.

[0061] The antibodies and fragments thereof described herein specifically bind to the target companion animal OX40L or the target companion animal OX40, respectively. For example, in one embodiment, the antibodies and fragments thereof described herein specifically bind to canine OX40L. In another embodiment, the antibodies and fragments thereof described herein specifically bind to feline OX40L. For example, in one embodiment, the antibodies and fragments thereof described herein specifically bind to canine OX40. In another embodiment, the antibodies and fragments thereof described herein specifically bind to feline OX40. The term "specifically" in the context of antibody binding refers to high binding capacity and / or high affinity binding of an antibody to a particular antigen, i.e., polypeptide, or epitope. In many embodiments, the specific antigen is the antigen (or a fragment or subfraction of the antigen) used to immunize the animal host from which the antibody-producing cells were isolated.

[0062] In other words, binding to the OX40L or OX40 antigen is stronger than binding of the same antibody to other antigens, i.e., is measurably different from non-specific interactions. Thus, in one embodiment, the antibodies or fragments of the invention do not cross-react with mouse or human OX40L or OX40 antigens.

[0063] As used herein, the terms "specific binding" or "specifically binds" or "specific for" a particular polypeptide or epitope on a particular polypeptide target means, for example, at least about 10 -6 M, alternatively at least about 10 -7 M, alternatively at least about 10 -8 M, alternatively at least about 10-9 M, alternatively at least about 10 -10 M, alternatively at least about 10 -11 M, alternatively at least about 10 -12 M or less KD(K d In one embodiment, the KD (K d ) is 10 -9 In a preferred embodiment, KD(K d ) is 10 -9 M or less, e.g., 10 -10 In embodiments, the antibodies of the invention have a mAb of about 10 -6 M~10 -12 M, or about 10 -7 M~10 -12 M, or about 10 -8 M~10 -12 M, or about 10 -9 M~10 -12 M, or about 10 -10 M~10 -12 M, or about 10 -11 M~10 -12 KD(K d In one embodiment, the term "specific binding" refers to binding where a molecule binds to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0064] In one embodiment, the antibodies of the invention are antagonistic antibodies that specifically bind to companion animal OX40L, eg, canine OX40L.

[0065] As used herein, an "antagonist" or "inhibitor" of OX40L / OX40 refers to a ligand (e.g., an antibody or fragment) that can inhibit or otherwise reduce one or more of the biological activities of OX40L / OX40 in cells expressing OX40L / OX40 or in cells expressing an OX40L / OX40 ligand. For example, in certain embodiments, an antibody of the present invention is an antagonist antibody that inhibits or otherwise reduces secretion of cytokines from cells having cell surface expression OX40L / OX40 when the antibody contacts the cell. In some embodiments, an antagonist of OX40L (e.g., an antagonist antibody of the present invention) can act, for example, by inhibiting or otherwise reducing activation and / or cell signaling pathways of cells expressing OX40L / OX40, thereby inhibiting OX40L / OX40-mediated biological activity of a cell compared to OX40L / OX40-mediated biological activity in the absence of the antagonist. In certain embodiments, the antibodies provided herein are whole canine, antagonistic anti-OX40L / OX40 antibodies, preferably whole canine, monoclonal, antagonistic anti-OX40L / OX40 antibodies.

[0066] The term "antibody" as used herein refers broadly to any immunoglobulin (Ig) molecule composed of four polypeptide chains, two heavy (H) chains and two light (L) chains, or an antigen-binding portion thereof, or any functional fragment, mutant, variant, or derivative thereof that retains the essential epitope-binding characteristics of an Ig molecule.

[0067] In a full-length antibody, each heavy chain is composed of a heavy chain variable region or domain (abbreviated herein as HCVR) and a heavy chain constant region. H 1. C H 2 and C H Each light chain is composed of three domains: a light chain variable region or domain (abbreviated herein as LCVR) and a light chain constant region. The light chain constant region is composed of one domain, C L It is composed of:

[0068] Heavy and light chain variable regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each heavy and light chain variable region is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0069] Immunoglobulin molecules can be of any type, class or subclass (e.g., canine IgG, IgE, IgM, IgD, IgA and IgY, including canine IgG subtypes such as IgG-A, IgG-B, IgG-C, and IgG-D). In dogs, there are four IgG heavy chains, designated A, B, C, and D. These heavy chains represent four different subclasses of canine IgG, designated IgGA, IgGB, IgGC, and IgGD. The DNA and amino acid sequences of these four heavy chains were first identified by Tang et al. (Vet. Immunol. Immunopathol. 80:259-270 (2001)). Exemplary amino acid and DNA sequences for these heavy chains are also available from the GenBank database (IgGA: Accession No. AAL35301.1, IgGB: Accession No. AAL35302.1, IgGC: Accession No. AAL35303.1, IgGD: Accession No. AAL35304.1). Canine antibodies also contain two types of light chains, kappa and lambda (GenBank Accession No. kappa light chain amino acid sequence ABY57289.1, GenBank Accession No. ABY55569.1). The amino acid sequences of IgG-A, IgG-B, IgG-C and IgG-D used by the inventors and according to aspects and embodiments of the present invention are shown in Table 2.

[0070] The term "CDR" refers to the complementarity determining region in an antibody variable sequence. In each of the heavy and light chain variable regions, there are three CDRs, designated CDR1, CDR2, and CDR3 for each variable region. The term "CDR set" refers to a group of three CDRs occurring in a single variable region that can bind to an antigen. The exact boundaries of these CDRs can be defined differently according to different systems known in the art.

[0071] The Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., (1971) Ann. NY Acad. Sci. 190:382-391 and Kabat, et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242). Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The Kabat numbering system is commonly used to refer to residues within the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain). Another system is the ImMunoGeneTics (IMGT) numbering scheme. The IMGT numbering scheme is described in Lefranc et al., Dev. Comp. Immunol., 29, 185-203 (2005). These art-recognized terms refer to a numbering system for amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or antigen-binding portion.

[0072] Unless otherwise specified, the IMGT numbering scheme is used herein.

[0073] Antibodies against OX40L or OX40 according to the present invention may be canine, humanized, feline, chimeric, felineized or canine antibodies.

[0074] A "chimeric antibody" is a recombinant protein that contains the variable domains, including the complementarity determining regions (CDRs), of an antibody derived from one species, while the constant domains of the antibody molecule are derived from the constant domains of another species, e.g., a canine antibody. An exemplary chimeric antibody is a chimeric human-canine antibody.

[0075] A "humanized antibody" is a recombinant protein in which the CDRs from an antibody derived from one species, e.g., a rodent, canine, feline antibody, are transferred from the heavy and light variable chains of a rodent, canine, or feline antibody to human heavy and light variable domains (e.g., framework region sequences). The constant domains of the antibody molecule are derived from the constant domains of a human antibody. In certain embodiments, a limited number of framework region amino acid residues from the parent (rodent, canine, or feline) antibody may be substituted into the human antibody framework region sequences. In embodiments, the CDRs disclosed herein may be transferred from the heavy and light variable chains of an antibody disclosed herein to the heavy and light variable domains (e.g., framework region sequences) of a different species.

[0076] As used herein, the term "caninized antibody" refers to a form of recombinant antibody that contains sequences from both canine and non-canine (e.g., murine) antibodies. In general, a caninized antibody contains substantially all of at least one or more, typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-canine immunoglobulin, and all or substantially all of the framework (FR) regions (and typically all or substantially all of the remaining frame) being of a canine immunoglobulin sequence. A caninized antibody may contain both three heavy chain CDRs and three light chain CDRSs from a murine or human antibody, together with a canine frame or a modified canine frame. The modified canine frame contains one or more amino acid changes that may further optimize the effectiveness of the caninized antibody, for example, to increase binding to its target. For example, the non-canine sequence of the hypervariable loops may be further compared to the canine sequence, and as many residues as possible may be changed to resemble the authentic canine sequence.

[0077] A "speciesized" antibody (e.g., humanized, canine, chimeric, feline) is one that has been engineered to resemble the antibody of the target species. In one embodiment, a "speciesized" antibody is more than about 80%, 85% or 90% similar to the antibody of the target species.

[0078] In one embodiment, the antibody or antibody fragment is canine. Canine means fully canine. The terms fully canine and canine are used interchangeably herein.

[0079] In contrast to speciesized antibodies, the complete canine antibodies of the present invention have canine variable regions and do not contain complete or partial CDRs or FRs from another species. Advantageously, the complete canine antibodies described herein are obtained from transgenic mice containing canine immunoglobulin sequences. The antibodies produced in these immunized mice are developed through in vivo B cell signaling and development to allow natural affinity maturation, including in vivo V(D)J recombination, in vivo junctional diversification, in vivo pairing of heavy and light chains, and in vivo hypermutation. Complete canine antibodies produced in this manner generate antibodies with optimal properties for potential development, minimizing lengthy lead optimization prior to large-scale production. Advantageously, such complete canine antibodies present the lowest possible risk of immunogenicity when introduced into patient animals, which facilitates repeated dosing regimens. Adverse in vivo immunogenicity can be assessed, for example, by assays to identify the production of anti-drug antibodies (ADA) or loss of efficacy over time in vivo. Considering that ex vivo mAb engineering runs the risk of introducing developmental liabilities, immunogenicity, and reduced affinity (as outlined above), the whole canine antibodies of the present invention are therefore most likely to be an effective therapy in a clinical context.

[0080] As used herein, the term "felined antibody" refers to a form of recombinant antibody that contains sequences from both feline and non-feline (e.g., murine) antibodies. In general, felined antibodies contain substantially all of at least one or more, typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-felined immunoglobulin, and all or substantially all of the framework (FR) regions (and typically all or substantially all of the remaining frame) being of a felined immunoglobulin sequence. A felined antibody may contain both three heavy chain CDRs and three light chain CDRs from a mouse or human antibody, together with a felined frame or a modified felined frame. The modified feline frame contains one or more amino acid changes that may further optimize the effectiveness of the felined antibody, for example, to increase binding to its target. For example, the non-feline sequences of the hypervariable loops may be further compared to the feline sequences, and as many residues as possible may be changed to resemble the authentic feline sequences.

[0081] In one embodiment, the antibody or antibody fragment is feline. Feline means entirely feline. The terms entirely feline and feline are used interchangeably herein.

[0082] In contrast to speciesized antibodies, the full feline antibodies of the present invention have feline variable regions and do not contain complete or partial CDRs or FRs from another species. Full feline antibodies may be obtained from transgenic mice containing feline immunoglobulin sequences. Antibodies produced in these immunized mice are developed through in vivo B cell signaling and development to allow natural affinity maturation, including in vivo V(D)J recombination, in vivo junctional diversification, in vivo pairing of heavy and light chains, and in vivo hypermutation. Full feline antibodies produced in this way generate antibodies with optimal properties for potential development, minimizing lengthy lead optimization prior to large-scale production. Advantageously, such full feline antibodies present the lowest possible risk of immunogenicity when introduced into patient animals, which facilitates repeated dosing regimens. Adverse in vivo immunogenicity can be assessed, for example, by assays to identify the production of anti-drug antibodies (ADA) or loss of efficacy over time in vivo. Ex vivo mAb engineering runs the risk of introducing developmental liabilities, immunogenicity, and reduced affinity (as outlined above), therefore such whole feline antibodies are most likely to be effective therapies in a clinical context.

[0083] As used herein, the term "equinized antibody" refers to a form of recombinant antibody that contains sequences from both equine and non-equine (e.g., murine) antibodies. In general, equine antibodies contain substantially all of at least one or more, typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-equine immunoglobulin, and all or substantially all of the framework (FR) regions (and typically all or substantially all of the remaining frame) being of equine immunoglobulin sequences. An equine antibody may contain both three heavy chain CDRs and three light chain CDRSs from a mouse or human antibody, together with an equine frame or a modified feline frame. The modified equine frame contains one or more amino acid changes that may further optimize the effectiveness of the equine antibody, for example, to increase binding to its target. For example, the non-equine sequences of the hypervariable loops may be further compared to the equine sequences, and as many residues as possible may be changed to resemble the authentic equine sequences.

[0084] In one embodiment, the antibody or antibody fragment is of equine origin. By equine origin is meant entirely equine. The terms entirely equine and equine are used interchangeably herein.

[0085] The term "monoclonal antibody" as used herein refers to an antibody derived from a single B cell or plasma cell. All antibody molecules in a monoclonal antibody preparation are identical except for possible naturally occurring post-translational modifications (e.g., isomerization, amidation, carbohydrate addition), which may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0086] The term "epitope" or "antigenic determinant" refers to a site on the surface of an antigen to which an immunoglobulin, antibody or antibody fragment specifically binds. Generally, an antigen has several or many different epitopes and reacts with many different antibodies. The term specifically includes linear and conformational epitopes. Epitopes in protein antigens can be formed both from contiguous amino acids (usually linear epitopes) or non-contiguous amino acids juxtaposed by tertiary folding of the protein (usually conformational epitopes). Epitopes formed from contiguous amino acids are typically, but not always, retained upon exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in a unique spatial conformation. Methods for determining the epitope bound by a given antibody or antibody fragment (i.e., epitope mapping) are well known in the art and include, for example, immunoblot and immunoprecipitation assays, in which overlapping or adjacent peptides are tested for reactivity with a given antibody or antibody fragment.

[0087] An antibody binds to "essentially the same epitope" as a reference antibody when the two antibodies recognize the same or sterically overlapping epitopes. The most widely used and rapid method for determining whether two epitopes bind to the same or sterically overlapping epitopes is a competitive assay, which can be configured in different formats using either labeled antigen or labeled antibody. An epitope may or may not be a three-dimensional surface feature of an antigen. In certain embodiments, an OX40L epitope is a three-dimensional surface feature of an OX40L polypeptide (e.g., in the trimeric form of an OX40L polypeptide). In other embodiments, an OX40L epitope is a linear feature of an OX40L polypeptide (e.g., in the trimeric or monomeric form of an OX40L polypeptide). The antibodies provided herein may specifically bind to an epitope of a monomeric form of OX40L, an epitope of a trimeric form of OX40L, or both the monomeric and trimeric forms of OX40L. In certain embodiments, the antibody provided herein specifically binds to the epitope of the trimer form of OX40L, but does not specifically bind to the monomeric form of OX40L.In some embodiments, the antibody can, for example, bind to the monomer / single subunit and block the formation of the active trimer form.Preferably, the antibody binds to the extracellular domain of OX40L.

[0088] The term "antigen-binding site" refers to the portion of an antibody or antibody fragment that comprises the area that specifically binds to an antigen. An antigen-binding site may be provided by one or more antibody variable domains. An antigen-binding site is typically associated with the relevant V domains of an antibody or antibody fragment. H and V L Included within.

[0089] The term "antibody" as used herein also includes antibody fragments. Specifically, the present invention also extends to antibody fragments. Antibody fragments are fragments of antibodies, e.g., F(ab')2, Fab, Fv, scFv, heavy chain, light chain, variable heavy (V) chain, and the like. H ), Variable Light (V L ) strand, CDR region, single V H Or V LAntibody fragments include domains, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, and bis-scFvs, as well as portions of a polypeptide that contain at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide. Thus, an antibody fragment comprises an antigen-binding portion.

[0090] Antibody fragments are functional fragments of full-length antibodies, i.e., they retain the target specificity of the full-length antibody. Thus, recombinant functional antibody fragments, such as Fab (fragment, antibody), scFv (single-chain variable fragment), and single domain antibodies (dAb), have been used to develop therapeutics as alternatives to mAb-based therapeutics.

[0091] "Fv" is the minimum antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of one heavy chain variable region domain and one light chain variable region domain in tight non-covalent association. From the folding of these two domains arise six hypervariable loops (three loops each from the H and L chain) that contribute amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although with a lower affinity than the entire binding site. "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment containing VH and VL antibody domains connected to a single polypeptide chain.

[0092] The scFv fragment (approximately 25 kDa) contains two variable domains, V H and V L Naturally, V H and V L The domains tend to associate and dissociate non-covalently through hydrophobic interactions, however stable fragments can be engineered by linking the domains with hydrophilic flexible linkers to create single chain Fvs (scFvs).

[0093] The smallest antigen-binding fragment is a single variable fragment, i.e., the variable heavy chain (V H ) or variable light chain (V L ) domain. V H and V L Each domain is capable of binding to an antigen. Binding to the respective light / heavy chain partner, or indeed the presence of other parts of the complete antibody, is not necessary for target binding. One single domain (V H Or V L Antigen-binding entities of antibodies that have been reduced in size to a number of domains (corresponding to V domains) are commonly referred to as "single domain antibodies" or "immunoglobulin single variable domains". Thus, single domain antibodies (approximately 12-15 kDa) have V H Or V L domain.

[0094] Thus, in one embodiment, the fragment is a F(ab')2, Fab, Fv, scFv, heavy chain, light chain, variable heavy (V H ), Variable Light (V L ) strand, CDR region, single V H Or V L The polypeptide is selected from domains, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, and bis-scFvs, as well as polypeptides that contain at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide.

[0095] In one embodiment, the present invention does not relate to an immunoglobulin domain, such as an Fc domain, fused to a companion animal, such as a dog, an OX40L extracellular domain polypeptide fragment, or a biological equivalent thereof.

[0096] The antibodies and antibody fragments of the present invention are isolated. As used herein, the term "isolated" refers to a moiety that is isolated from its natural environment. For example, the term "isolated" refers to a single domain antibody that is substantially free of other single domain antibodies, antibodies or antibody fragments. Furthermore, an isolated single domain antibody may be substantially free of other cellular material and / or chemicals.

[0097] In one aspect, the present invention relates to an antibody or fragment thereof that specifically binds to companion animals, such as dogs, OX40L, where the antibody blocks the binding of OX40L to OX40 and / or inhibits one or more functions associated with the binding of OX40L to OX40. Suitably, the antibody reduces, inhibits or neutralizes OX40 activity in the companion animal. In one embodiment, the antibody or fragment thereof exhibits one or more of the following properties: a) capable of altering cytokine secretion in a cell or animal; and / or b) The ability to reduce white blood cell proliferation in companion animals such as dogs.

[0098] "Altering" refers to increasing or decreasing the amount of a compound in the presence of an antibody compared to a control. As used herein, "decreasing" or "reducing" refers to a reduction, which can be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0099] For example, the antibody or fragment may be a) reducing the secretion of pro-inflammatory cytokines in companion animals or cells of companion animals; and / or b) reducing the secretion of inflammatory chemokines or chemokine receptors in companion animals or cells of companion animals; and / or c) increasing the secretion of inhibitory cytokine(s) in the companion animal or in cells of the companion animal; and / or d) increasing the secretion of inhibitory chemokine(s) or chemokine receptors in companion animals or cells of companion animals; and / or e) It can reduce white blood cell proliferation in companion animals.

[0100] The cytokine may be selected from TNF alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, RANTES, GM-CSF, TGF-β, and interferon gamma (IFN-γ). In embodiments, the antibody acts to reduce secretion of a proinflammatory cytokine in the companion animal or cells of the companion animal compared to the absence of the antibody. In a preferred embodiment, the proinflammatory cytokine is IFN-γ.

[0101] The antibody may act to reduce secretion of inflammatory cytokines in the companion animal or cells of the companion animal by more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90% compared to the absence of the antibody. The antibody may act to reduce secretion of inflammatory cytokines in the companion animal or cells of the companion animal by 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80%-100%, 90%-100% compared to the absence of the antibody. Reduction in secretion of inflammatory cytokines may be determined using a cell signaling inhibition assay such as that described in Example 7 herein, i.e., an aPBMC activation assay.

[0102] "Proinflammatory" compounds are compounds involved in promoting inflammation, whereas "inhibitory" compounds are compounds involved in suppressing or regulating inflammation. Proinflammatory cytokines include interleukin-1 (IL-1), IL-12, and IL-18, TNF alpha, interferon gamma (IFNγ), and GM-CSF. Inhibitory or anti-inflammatory cytokines or receptors include IL-4, IL-10, IL-11, IL-13, and TGF-β. The cytokine may be a chemokine. In one embodiment, the chemokine may be selected from, for example, CXCL13, CXCR5. The antibody according to the invention may also modify the expression of a cytokine or chemokine receptor.

[0103] The assays may be performed in vitro (eg, using cells, cells or tissues) or in vivo.

[0104] In one embodiment, the binding of OX40L to OX40 in the presence of an antibody according to the invention may be determined, for example, by SPR (surface plasmon resonance) assay. Other methods for determining inhibition of OX40L / OX40 interaction are described, for example, in WO2016 / 139482 or WO2013 / 008171, including, for example, flow cytometric monitoring of antibody binding to recombinant OX40L-expressing cells.

[0105] In one embodiment, the ability of an antibody against OX40L to block the binding of OX40L to OX40 can be measured by measuring inhibition of NFkB activity. Suitable assays for measuring NFkB activity include the HEK-blue assay described herein. Thus, in one embodiment, an antibody or fragment thereof that specifically binds to a companion animal, such as a dog, OX40L reduces, inhibits or neutralizes OX40R-mediated NFkB activity in a cell-based assay.

[0106] In one embodiment, the assay is a heterologous assay in which companion animal (e.g., canine) OX40 is used in a cell line derived from a different species, e.g., a human cell line such as HEK, substantially as described in Example 7 herein.

[0107] In one embodiment, the ability of an antibody against OX40L to block OX40L binding to OX40 can be measured by measuring the reduction in intracellular cytokine secretion compared to that observed in the absence of the antibody. In one embodiment, the ability of an antibody against OX40L to block OX40L binding to OX40 can be measured by measuring the inhibition of IL-2 or INF-gamma secretion from PBMCs. Thus, in one embodiment, an antibody or fragment thereof that specifically binds to a companion animal, such as a dog, OX40L reduces, inhibits or neutralizes OX40R-mediated IL-2 or INF-gamma (INFγ) secretion from PBMCs. In another embodiment, the ability of an antibody against OX40L to block OX40L binding to OX40 can be measured by measuring the inhibition of IL-13 secretion from PBMCs. It will be appreciated that the ability of an antibody against OX40 to block OX40L binding to OX40 can be measured in a similar manner.

[0108] The antibody or fragment can cause a decrease in proliferation of white blood cells (eg, monocytes) in an in vitro assay, where the antibody or fragment antagonizes the OX40L / OX40L receptor interaction.

[0109] As is known in the art, the term "leukocyte" includes, for example, one or more of lymphocytes, polymorphonuclear leukocytes, and monocytes. As would be readily apparent to one of skill in the art, the term "monocyte" includes, for example, peripheral blood mononuclear cells (PBMCs) or monocyte-derived cells, such as dendritic cells (DCs).

[0110] White blood cell proliferation may be measured, for example, in a mixed lymphocyte reaction (MLR) as described herein. The ability of an antibody according to the invention to reduce proliferation may be measured by comparing with proliferation in the absence of the antibody.

[0111] The proliferation of white blood cells, for example, lamina propria lymphocytes (LPL), can be evaluated using tissue biopsy, staining, and histology, as will be apparent to those skilled in the art. Hematoxylin and eosin staining (H&E staining or HE staining), for example, is commonly used in histology to look for infiltrating lymphocytes in the entire range of human tissues, and is one of the major stains in histology. This is the most widely used stain in medical diagnosis, and is often the gold standard, and therefore can be used to evaluate the proliferation of white blood cells according to the present invention. For example, gastrointestinal tissue (e.g., intestinal tissue) from a companion animal suffering from or at risk of OX40L-mediated disease or condition can be obtained, stained, and evaluated for the degree of infiltration of LPL.

[0112] Such tissues from companion animals that have received the antibodies of the invention can be compared to the degree of infiltration in tissues obtained from the same animals before administration of the antibodies, or from another companion animal that has not been treated and is at risk for or suffering from a disease or condition. For example, the comparison can be between companion animal intestinal tissues taken from the same (or different) companion animals, e.g., suffering from IBD. Anti-OX40L antibodies bind to OX40L and modulate the expression of cytokines and cell receptors, resulting in cytokine levels characteristic of non-disease states. Anti-OX40 antibodies bind to OX40 and modulate the expression of cytokines and cell receptors, resulting in cytokine levels characteristic of non-disease states.

[0113] Cytokines are essential signals of the mucosa-associated immune system to maintain normal intestinal homeostasis. An imbalance in their profile in favor of inflammatory initiation can lead to disease states such as those observed in inflammatory bowel diseases (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC). The role of proinflammatory cytokines such as IL-la, IL-Ιβ, IL-2, -6, -8, -12, -17, -23, IFN-gamma, or TNF-alpha in IBD is associated with the initiation and progression of UC and CD. CD is often described as a prototype of a T helper (Th)1-mediated disease, since the primary inflammatory mediators are Thl cytokines such as interleukin (IL)-12, interferon (IFN)-y, and tumor necrosis factor (TNF)-α. The cytokine or cytokine receptor may be selected from TNF alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, RANTES, GM-CSF, TGF-beta, and interferon gamma.

[0114] Further information regarding suitable assays for assessing antibody properties is provided in the Examples.

[0115] The antibodies disclosed herein can be classified into different groups, or families, based on the pair of V genes used to generate the antibodies. Family 1 includes antibodies generated from the heavy chain V gene IGHV3-5 and the light chain V gene IGLV3-14. Examples of antibodies in Family 1 include antibodies designated PMX025, PMX026, PMX027, PMX089, PMX090, PMX091, PMX092, PMX093, whose sequences are shown in Table 2.

[0116] Family 2 includes antibodies generated from the heavy chain V gene IGHV3-5 and the light chain V gene IGLV3-21. Examples of antibodies in Family 2 include antibodies designated PMX028, PMX029, PMX032, PMX033, PMX034, PMX036, PMX038, PMX042, PMX045, PMX064, PMX082, PMX083, the sequences of which are shown in Table 2.

[0117] Family 3 includes antibodies generated from the heavy chain V gene IGHV3-5 and the light chain V gene IGLV3-24. Examples of antibodies in Family 3 include antibodies designated PMX030 and PMX031, the sequences of which are shown in Table 2.

[0118] Family 4 includes antibodies generated from the heavy chain V gene IGHV3-8 and the light chain V gene IGLV3-24. Examples of antibodies in Family 4 include those designated PMX035, PMX037, PMX040, PMX048, PMX049, PMX065, whose sequences are shown in Table 2.

[0119] Family 5 includes antibodies generated from the heavy chain V gene IGHV3-18 and the light chain V gene IGLV3-3. Examples of antibodies in Family 5 include antibodies designated PMX039, PMX041, PMX043, PMX044, PMX046, PMX050, PMX055, PMX056, PMX057, PMX058, PMX059, PMX062, PMX085, whose sequences are shown in Table 2.

[0120] Family 6 includes antibodies generated from the heavy chain V gene IGHV3-19 and the light chain V gene IGKV2-5. Examples of antibodies in Family 6 include the antibodies designated PMX047 and PMX053, the sequences of which are shown in Table 2.

[0121] Family 7 includes antibodies generated from the heavy chain V gene IGHV3-44 and the light chain V gene IGLV3-8. Examples of antibodies in Family 7 include antibodies designated PMX051, PMX088, the sequences of which are shown in Table 2.

[0122] Family 8 includes antibodies generated from the heavy chain V gene IGHV3-19 and the light chain V gene IGKV2-4. Examples of antibodies in Family 8 include an antibody designated PMX052, the sequences of which are shown in Table 2.

[0123] Family 9 includes antibodies generated from the heavy chain V gene IGHV3-5 and the light chain V gene IGLV3-3. Examples of antibodies in Family 9 include antibodies designated PMX060 and PMX061, the sequences of which are shown in Table 2.

[0124] Family 10 includes antibodies generated from the heavy chain V gene IGHV3-5 and the light chain V gene IGLV3-8. Examples of antibodies in Family 10 include antibodies designated PMX063, PMX086, PMX087, PMX094, PMX095, PMX096, PMX097, PMX098, PMX099, PMX100, PMX101, PMX102, PMX103, PMX104, PMX105, PMX107, PMX108, PMX109, PMX110, PMX111, whose sequences are shown in Table 2.

[0125] Family 11 includes antibodies generated from the heavy chain V genes IGHV3-5 and the light chain V genes IGKV2-4. Examples of antibodies in Family 11 include an antibody designated PMX106, the sequences of which are shown in Table 2.

[0126] Family 12 includes antibodies generated from the heavy chain V gene IGHV3-18 and the light chain V gene IGLV3-24. Examples of antibodies in Family 12 include antibodies designated PMX054, PMX084, PMX154, PMX293, PMX294, the sequences of which are shown in Table 2.

[0127] Family 13 includes antibodies generated from the heavy chain V gene IGHV3-19 and the light chain V gene IGLV3-21. Examples of antibodies in Family 13 include antibodies designated PMX155 and PMX156, the sequences of which are shown in Table 2.

[0128] Family 14 includes antibodies generated from the heavy chain V gene IGHV3-41 and the light chain V gene IGLV3-24. Examples of antibodies in Family 14 include antibodies designated PMX291, PMX292, the sequences of which are shown in Table 2.

[0129] In one embodiment, the antibody or fragment may be selected from an antibody set forth in any of Families 1-14, or an antibody having at least 80% sequence identity thereto.

[0130] In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 1 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 2 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 3 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 4 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 5 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 6 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 7 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 8 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 9 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 10 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 11 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 12 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 13 sequence or a variant thereof. In one embodiment, the antibody or fragment thereof comprises an antibody comprising a Family 14 sequence or a variant thereof.

[0131] In one embodiment, the antibody that binds to canine OX40L may be selected from one of the following antibodies: an antibody comprising a Family 1 sequence or a variant thereof, for example an antibody comprising an HC CDR1 comprising SEQ ID NO: 15 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 16 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 17 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 18 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 19 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 20 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto;

[0132] an antibody comprising a Family 2 sequence or a variant thereof, such as an antibody comprising an HC CDR1 comprising SEQ ID NO: 45 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 46 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 47 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 48 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 49 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 50 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto;

[0133] an antibody comprising a Family 3 sequence or a variant thereof, such as an antibody comprising an HC CDR1 comprising SEQ ID NO:65 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:66 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:67 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:68 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:69 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:70 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto;

[0134] Antibodies comprising Family 4 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO: 115 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO: 116 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO: 117 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO: 118 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO: 119 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO: 120 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0135] Antibodies comprising Family 5 sequences or variants thereof, such as an HC CDR1 comprising SEQ ID NO: 155 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 156 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 157 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 158 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 159 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 160 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0136] Antibodies comprising Family 6 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO:235 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:236 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:237 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:238 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:239 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:240 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0137] Antibodies comprising Family 7 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO:275 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:276 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:277 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:278 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:279 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:280 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0138] Antibodies comprising Family 8 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO:285 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:286 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:287 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:288 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:289 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:290 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0139] Antibodies comprising Family 9 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO:365 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:366 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:367 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:368 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:369 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:370 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0140] Antibodies comprising a Family 10 sequence or a variant thereof, such as an HC CDR1 comprising SEQ ID NO:575 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:576 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:577 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:578 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO:579 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:580 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0141] Antibodies comprising a Family 10 sequence or a variant thereof, such as an HC CDR1 comprising SEQ ID NO:395 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:396 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:397 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:398 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO:399 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:400 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising:

[0142] Antibodies comprising Family 11 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO:665 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:666 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:667 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:668 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:669 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:670 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. An antibody comprising CDR3.

[0143] Antibodies comprising a Family 12 sequence or a variant thereof, such as an HC CDR1 comprising SEQ ID NO: 741 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 742 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 743 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 744 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 745 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 746 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. An antibody comprising CDR3.

[0144] Antibodies comprising Family 13 sequences or variants thereof, such as HC CDR1 comprising SEQ ID NO: 751 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO: 752 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO: 753 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO: 754 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO: 755 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO: 756 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. An antibody comprising CDR3.

[0145] Antibodies comprising a Family 14 sequence or a variant thereof, such as an HC CDR1 comprising SEQ ID NO: 771 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 772 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 773 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 774 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 775 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC CDR2 comprising SEQ ID NO: 776 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. An antibody comprising CDR3.

[0146] In one embodiment, the antibody that binds to canine OX40L may be selected from one of the following antibodies: an antibody comprising an HC CDR1 comprising SEQ ID NO: 15 or a sequence having at least 80% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 16 or a sequence having at least 80% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 17 or a sequence having at least 80% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 18 or a sequence having at least 80% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 19 or a sequence having at least 80% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 20 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:25 or a sequence having at least 80% sequence identity thereto, an HC CDR2 comprising SEQ ID NO:26 or a sequence having at least 80% sequence identity thereto, an HC CDR3 comprising SEQ ID NO:27 or a sequence having at least 80% sequence identity thereto, an LC CDR1 comprising SEQ ID NO:28 or a sequence having at least 80% sequence identity thereto, an LC CDR2 comprising SEQ ID NO:29 or a sequence having at least 80% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO:30 or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC CDR1 comprising SEQ ID NO: 35 or a sequence having at least 80% sequence identity thereto, an HC CDR2 comprising SEQ ID NO: 36 or a sequence having at least 80% sequence identity thereto, an HC CDR3 comprising SEQ ID NO: 37 or a sequence having at least 80% sequence identity thereto, an LC CDR1 comprising SEQ ID NO: 38 or a sequence having at least 80% sequence identity thereto, an LC CDR2 comprising SEQ ID NO: 39 or a sequence having at least 80% sequence identity thereto, and an LC CDR3 comprising SEQ ID NO: 40 or a sequence having at least 80% sequence identity thereto;

[0147] an antibody comprising: an HC CDR1 comprising SEQ ID NO: 45 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 46 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 47 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 48 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 49 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 50 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:55 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:56 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:57 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:58 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:59 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:60 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:65 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:66 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:67 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:68 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:69 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:70 or a sequence having at least 80% sequence identity thereto;

[0148] an antibody comprising: an HC CDR1 comprising SEQ ID NO: 75 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 76 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 77 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 78 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 79 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 80 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:85 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:86 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:87 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:88 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:89 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:90 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:95 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:96 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:97 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:98 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:99 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:100 or a sequence having at least 80% sequence identity thereto;

[0149] an antibody comprising: an HC CDR1 comprising SEQ ID NO: 105 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 106 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 107 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 108 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 109 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 110 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 115, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 116, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 117, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 118, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 119, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 120, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 125 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 126 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 127 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 128 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 129 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 130 or a sequence having at least 80% sequence identity thereto; An antibody comprising: an HC CDR1 comprising SEQ ID NO: 135 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 136 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 137 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 138 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 139 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 140 or a sequence having at least 80% sequence identity thereto.

[0150] an antibody comprising: an HC CDR1 comprising SEQ ID NO: 145, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 146, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 147, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 148, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 149, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 150, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 155, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 156, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 157, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 158, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 159, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 160, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 165, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 166, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 167, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 168, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 169, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 170, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 175, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 176, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 177, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 178, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 179, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 180, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 185, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 186, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 187, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 188, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 189, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 190, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO: 195, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO: 196, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO: 197, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO: 198, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO: 199, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO: 200, or a sequence having at least 80% sequence identity thereto;

[0151] an antibody comprising: an HC CDR1 comprising SEQ ID NO:205, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:206, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:207, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:208, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:209, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:210, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:215, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:216, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:217, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:218, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:219, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:220, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:225, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:226, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:227, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:228, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:229, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:230, or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:235, or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:236, or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:237, or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:238, or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:239, or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:240, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:245 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:246 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:247 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:248 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:249 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:250 or a sequence having at least 80% sequence identity thereto;

[0152] an antibody comprising: a HC CDR1 comprising SEQ ID NO:255, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:256, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:257, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:258, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:259, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:260, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:265 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:266 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:267 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:268 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:269 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:270 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:275 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:276 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:277 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:278 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:279 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:280 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:285 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:286 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:287 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:288 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:289 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:290 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:295 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:296 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:297 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:298 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:299 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:300 or a sequence having at least 80% sequence identity thereto;

[0153] an antibody comprising: an HC CDR1 comprising SEQ ID NO:305 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:306 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:307 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:308 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:309 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:310 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:315 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:316 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:317 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:318 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:319 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:320 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 325 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 326 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 327 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 328 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 329 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 330 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 335 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 336 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 337 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 338 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 339 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 340 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 345 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 346 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 347 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 348 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 349 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 350 or a sequence having at least 80% sequence identity thereto;

[0154] an antibody comprising: a HC CDR1 comprising SEQ ID NO: 355 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 356 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 357 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 358 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 359 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 360 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 365 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 366 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 367 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 368 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 369 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 370 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 375 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 376 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 377 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 378 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 379 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 380 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 385 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 386 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 387 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 388 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 389 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 390 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:395 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:396 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:397 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:398 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:399 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:400 or a sequence having at least 80% sequence identity thereto;

[0155] an antibody comprising: a HC CDR1 comprising SEQ ID NO: 405 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 406 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 407 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 408 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 409 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 410 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:415, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:416, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:417, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:418, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:419, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:420, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 425 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 426 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 427 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 428 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 429 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 430 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 435, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 436, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 437, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 438, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 439, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 440, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 445 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 446 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 447 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 448 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 449 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 450 or a sequence having at least 80% sequence identity thereto;

[0156] an antibody comprising: a HC CDR1 comprising SEQ ID NO: 455 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 456 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 457 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 458 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 459 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 460 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 465 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 466 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 467 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 468 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 469 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 470 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 475 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 476 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 477 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 478 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 479 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 480 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 485 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 486 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 487 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 488 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 489 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 490 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:495 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:496 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:497 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:498 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:499 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:500 or a sequence having at least 80% sequence identity thereto;

[0157] an antibody comprising: a HC CDR1 comprising SEQ ID NO:505 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:506 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:507 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:508 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:509 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:510 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:515 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:516 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:517 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:518 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:519 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:520 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:525 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:526 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:527 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:528 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:529 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:530 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:535 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:536 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:537 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:538 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:539 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:540 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:545 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:546 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:547 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:548 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:549 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:550 or a sequence having at least 80% sequence identity thereto;

[0158] an antibody comprising: a HC CDR1 comprising SEQ ID NO:555 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:556 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:557 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:558 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:559 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:560 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:565 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:566 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:567 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:568 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:569 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:570 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:575 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:576 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:577 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:578 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:579 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:580 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:585 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:586 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:587 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:588 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:589 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:590 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:595 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:596 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:597 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:598 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:599 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:600 or a sequence having at least 80% sequence identity thereto;

[0159] an antibody comprising: a HC CDR1 comprising SEQ ID NO:605 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:606 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:607 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:608 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:609 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:610 or a sequence having at least 80% sequence identity thereto; an antibody comprising: an HC CDR1 comprising SEQ ID NO:615 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:616 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:617 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:618 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:619 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:620 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:625 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:626 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:627 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:628 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:629 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:630 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:635 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:636 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:637 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:638 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:639 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:640 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:645 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:646 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:647 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:648 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:649 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:650 or a sequence having at least 80% sequence identity thereto;

[0160] an antibody comprising: a HC CDR1 comprising SEQ ID NO:655 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:656 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:657 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:658 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:659 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:660 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:665 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:666 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:667 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:668 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:669 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:670 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:675 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:676 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:677 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:678 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:679 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:680 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:685 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:686 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:687 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:688 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:689 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:690 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:695 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:696 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:697 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:698 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:699 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:700 or a sequence having at least 80% sequence identity thereto;

[0161] an antibody comprising: a HC CDR1 comprising SEQ ID NO: 705 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 706 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 707 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 708 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 709 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 710 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:715 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:716 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:717 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:718 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:719 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:720 or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO:741, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:742, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:743, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:744, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:745, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:746, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 751, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 752, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 753, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 754, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 755, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 756, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 761, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 762, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 763, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 764, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 765, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 766, or a sequence having at least 80% sequence identity thereto;

[0162] an antibody comprising: a HC CDR1 comprising SEQ ID NO: 771, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 772, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 773, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 774, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 775, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 776, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 781, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 782, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 783, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 784, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 785, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 786, or a sequence having at least 80% sequence identity thereto; an antibody comprising: a HC CDR1 comprising SEQ ID NO: 791, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 792, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 793, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 794, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 795, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 796, or a sequence having at least 80% sequence identity thereto; An antibody comprising: an HC CDR1 comprising SEQ ID NO:801 or a sequence having at least 80% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:802 or a sequence having at least 80% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:803 or a sequence having at least 80% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:804 or a sequence having at least 80% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:805 or a sequence having at least 80% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:806 or a sequence having at least 80% sequence identity thereto.

[0163] In embodiments, the antibody is selected from one of those listed above but comprises sequence identity of 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to the listed HC and / or LC CDR1, 2 and / or CDR3 sequences.

[0164] HC CDR1 comprising SEQ ID NO:741 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:742 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:743 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:744 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:745 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:746 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0165] HC CDR1 comprising SEQ ID NO:751 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:752 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:753 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:754 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:755 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:756 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0166] HC CDR1 comprising SEQ ID NO:761 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:762 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:763 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:764 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:765 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:766 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0167] HC CDR1 comprising SEQ ID NO:771 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:772 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:773 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:774 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:775 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:776 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0168] HC CDR1 comprising SEQ ID NO:781 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:782 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:783 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:84 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:785 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:786 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0169] HC CDR1 comprising SEQ ID NO:791 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:792 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:793 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:794 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:795 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:796 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0170] HC CDR1 comprising SEQ ID NO:801 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:802 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:803 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:804 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:805 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:806 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0171] In embodiments, the antibody is selected from one of those listed above but comprises sequence identity of 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to the listed HC and / or LC CDR1, 2 and / or CDR3 sequences.

[0172] In one embodiment, the antibody comprises one or more HC and / or LC CDR1, 2, and / or CDR3 sequences selected from one of those listed above, but having 1, 2, 3, 4, or 5 amino acid substitutions compared to the sequences defined in the above SEQ ID NOs.

[0173] In a preferred embodiment, the antibody comprises an HC CDR1 comprising SEQ ID NO:575 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR2 comprising SEQ ID NO:576 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an HC CDR3 comprising SEQ ID NO:577 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR1 comprising SEQ ID NO:578 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; an LC CDR2 comprising SEQ ID NO:579 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and an LC CDR3 comprising SEQ ID NO:580 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR1 comprising SEQ ID NO: 741 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO: 742 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO: 743 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO: 744 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO: 745 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO: 746 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, or

[0174] HC CDR1 comprising SEQ ID NO:275 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR2 comprising SEQ ID NO:276 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, HC CDR3 comprising SEQ ID NO:277 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR1 comprising SEQ ID NO:278 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, LC CDR2 comprising SEQ ID NO:279 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and LC CDR3 comprising SEQ ID NO:280 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, or HC CDR1 comprising SEQ ID NO:395 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:396 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:397 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:398 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:399 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR3 comprising SEQ ID NO:400 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0175] Fragments of the above listed antibodies are also provided and are within the scope of the present invention.

[0176] In one embodiment, the antibody may be selected from one of the following antibodies: an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 12, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 14, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:22, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:24, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 32, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 34, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 42, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 44, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:52, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:54, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:62, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:64, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 72, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 74, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 82, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 84, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 92, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 94, or a sequence having at least 80% sequence identity thereto;

[0177] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 102, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 104, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 112, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 114, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 122, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 124, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 132, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 134, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 142, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 144, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 152, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 154, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 162, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 164, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 172, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 174, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 182, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 184, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 192, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 194, or a sequence having at least 80% sequence identity thereto;

[0178] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 202, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 204, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 212, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 214, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 222, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 224, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 232, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 234, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 242, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 244, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 252, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 254, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 262, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 264, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 272, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 274, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 282, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 284, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 292, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 294, or a sequence having at least 80% sequence identity thereto;

[0179] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 302, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 304, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 312, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 314, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 322, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 324, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 332, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 334, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 342, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 344, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 352, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 354, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 362, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 364, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 372, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 374, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 382, ​​or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 384, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 392, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 394, or a sequence having at least 80% sequence identity thereto;

[0180] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 402, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 404, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:412, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:414, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 422, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 424, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 432, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 434, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 442, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 444, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 452, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 454, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 452, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 454, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 462, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 464, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 472, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 474, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 482, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 484, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:492, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:494, or a sequence having at least 80% sequence identity thereto;

[0181] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:502, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:504, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:512, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:514, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:522, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:524, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:532, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:534, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:542, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:544, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 552, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 554, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 562, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 564, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:572, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:574, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:582, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:584, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:592, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:594, or a sequence having at least 80% sequence identity thereto;

[0182] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:602, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:604, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:612, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:614, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:622, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:624, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:632, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:634, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:642, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:644, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 652, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 654, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 662, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 664, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 672, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 674, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:682, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:684, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:692, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:694, or a sequence having at least 80% sequence identity thereto;

[0183] an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 702, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 704, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:712, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:714, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 738, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 740, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 748, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 750, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 758, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 760, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 768, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 770, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 778, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 780, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 788, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 790, or a sequence having at least 80% sequence identity thereto; An antibody comprising an HC variable region comprising or consisting of SEQ ID NO:798, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:800, or a sequence having at least 80% sequence identity thereto.

[0184] In embodiments, the antibody is selected from one of those listed above, but comprises 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the listed HC and / or LC variable region sequences.

[0185] In one embodiment, the antibody comprises an HC variable region and / or an LC variable region selected from one of those listed above and which comprises 1 to 20, such as 1 to 10, such as 2, 3, 4 or 5 amino acid substitutions compared to the sequence defined by the SEQ ID NO: above.

[0186] In a preferred embodiment, the antibody comprises an HC variable region comprising or consisting of SEQ ID NO:572, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:574, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; or an HC variable region comprising or consisting of SEQ ID NO: 738, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 740, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; or an HC variable region comprising or consisting of SEQ ID NO: 272 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 274 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; or a HC variable region comprising or consisting of SEQ ID NO: 392, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto, and a LC variable region comprising or consisting of SEQ ID NO: 394, or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto.

[0187] Fragments of the above-listed antibodies are also provided.

[0188] The amino acid sequences of the VH and VL regions of the antibodies are shown in Table 2. Thus, the antibody or fragment may be selected from antibodies comprising or consisting of the sequences shown in Table 2. In one embodiment, the antibody is selected from the group consisting of PMX025, PMX026, PMX027, PMX028, PMX029, PMX030, PMX031, PMX032, PMX033, PMX034, PMX035, PMX036, PMX037, PMX038, PMX039, PMX040, PMX041, PMX042, PMX043, PMX044, PMX045, PMX046, PMX047, PMX048, PMX049, PMX050, PMX051, PMX052, PMX053, PMX054, PMX055, PMX056, PMX057, PMX058, PMX059, PMX060, PMX061, PMX062, PMX063, PMX064, PMX065, PMX082, PMX083, PMX084, PMX085, PMX086, PMX087, PMX088, PMX089, PMX090, PMX091, PMX092, PMX 093, PMX094, PMX095, PMX096, PMX097, PMX098, PMX099, PMX100, PMX101, PMX102, PMX103, PMX104, PMX105, PMX106, PMX107, PMX108, PMX109, PMX110, PMX111 The antibody is selected from PMX154, PMX155, PMX 156, PMX291, PMX292, PMX293, or PMX294. In one embodiment, the antibody is PMX051 or PMX063. The sequence is also shown in Table 2. In one embodiment, the antibody is selected from PMX051, PMX63, PMX97, or PMX154.

[0189] All sequences for antibodies and antibody fragments designated PMX shown in the figures and Table 2 herein are within the scope of the present invention.

[0190] The sequence identity described in the various embodiments above is at least 80%. In one embodiment, the sequence identity is at least 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In one embodiment, the sequence identity is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. The embodiments described herein also encompass sequences with at least 80% sequence similarity. In one embodiment, the sequence similarity is at least 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In one embodiment, the sequence similarity is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0191] As stated above, an antibody or fragment defined by reference to a sequence may contain one or more amino acid substitutions. In one embodiment, the modification is a conservative sequence modification. As used herein, the term "conservative sequence modification" is intended to refer to an amino acid modification that does not significantly affect or change the binding properties of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of the present invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues in one or more CDR regions and / or one or more framework regions of an antibody or fragment of the invention can be replaced with another amino acid residue from the same side chain family, and the altered antibodies can be tested for retained function (using functional assays described herein or known in the art).

[0192] Thus, these amino acid changes can typically be made without altering the biological activity, function, or other desired properties of the polypeptide, such as its affinity for an antigen or its specificity. In general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter the biological activity. Furthermore, substitutions of amino acids that are similar in structure or function are unlikely to destroy the biological activity of the polypeptide. Abbreviations for amino acid residues of the polypeptides and peptides described herein, as well as conservative substitutions for these amino acid residues, are shown in Table 1 below. [Table 1]

[0193] The antibodies described herein may comprise a suitable Fc region. In one embodiment, the antibody or antigen-binding portion thereof comprises an Fc region, e.g., a canine Fc region, e.g., a canine IgGB Fc region. In one embodiment, the Fc portion of the antibody may be modified. For example, modifications may be made to the Fc region to improve certain properties, e.g., to reduce complement and FcγR-mediated effector functions.

[0194] Exemplary modified Fc regions of the canine antibodies of the invention based on a canine IgG-B Fc region are provided in SEQ ID NOs: 722-730, which show IgG-B constant regions comprising the Fc region. These sequences include modifications compared to the wild-type Fc IgG-B region. The modified Fc region reduces or abolishes canine IgG-B effector function when compared to the same polypeptide comprising a wild-type IgG-B Fc domain. This is shown in the Examples. The amino acid substitutions are in the lower hinge, proline sandwich region and SHED region. Thus, the antibodies of the invention can include modified Fc regions having the modifications shown in SEQ ID NOs: 722-730. The modifications refer to the wt sequence shown in SEQ ID NO: 721.

[0195] Thus, with reference to the wild-type residues in the canine IgG-B constant region (SEQ ID NO: 721), the antibody may have the following amino acid substitutions at the following positions in the Fc domain: E119G; M120S or A; L121A; D153G; P154R; D156N; N211H; K212I; A213G; P215G, and / or P217S.

[0196] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 of SEQ ID NO: 721 to S, and b) comprising an amino acid substitution at position 211 of SEQ ID NO:721 with H, an amino acid substitution at position 212 of SEQ ID NO:721 with I, and an amino acid substitution at position 213 of SEQ ID NO:721 with G.

[0197] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 of SEQ ID NO: 721 to S; b) an amino acid substitution at position 153 of SEQ ID NO: 721 to G and an amino acid substitution at position 154 of SEQ ID NO: 721 to R, and c) comprising an amino acid substitution at position 211 of SEQ ID NO:721 with H, an amino acid substitution at position 212 of SEQ ID NO:721 with I, and an amino acid substitution at position 213 of SEQ ID NO:721 with G.

[0198] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 of SEQ ID NO: 721 to S; b) an amino acid substitution at position 153 of SEQ ID NO: 721 to G and an amino acid substitution at position 154 of SEQ ID NO: 721 to R, and c) comprising an amino acid substitution at position 211 of SEQ ID NO:721 to H, an amino acid substitution at position 212 of SEQ ID NO:721 to I, and an amino acid substitution at position 213 of SEQ ID NO:721 to G, and an amino acid substitution at position 217 of SEQ ID NO:721 to S.

[0199] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 of SEQ ID NO: 721 to S; b) an amino acid substitution at position 153 of SEQ ID NO: 721 to G and an amino acid substitution at position 154 of SEQ ID NO: 721 to R, and c) comprising an amino acid substitution at position 211 of SEQ ID NO: 721 with H, an amino acid substitution at position 212 of SEQ ID NO: 721 with I, and an amino acid substitution at position 213 of SEQ ID NO: 141 with G, and an amino acid substitution at position 215 of SEQ ID NO: 721 with G.

[0200] In one embodiment, the Fc region comprises amino acid substitutions at position 120 to A and at position 121 to A of SEQ ID NO:721.

[0201] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 to A and at position 121 to A of SEQ ID NO: 721, and b) Contains an amino acid substitution at position 217 of SEQ ID NO: 721.

[0202] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 to A and at position 121 to A of SEQ ID NO: 721, and b) comprising an amino acid substitution at position 215 of SEQ ID NO: 721 to G.

[0203] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 119 of SEQ ID NO: 721 to G, and b) Contains an amino acid substitution at position 156 of SEQ ID NO: 721 to N.

[0204] In one embodiment, the Fc region comprises: a) an amino acid substitution at position 120 to A and at position 121 to A of SEQ ID NO: 721; b) an amino acid substitution at position 156 of SEQ ID NO: 721 to N, and c) comprising an amino acid substitution at position 217 of SEQ ID NO: 721.

[0205] In another aspect, binding molecules, e.g., antibodies, antibody fragments, or antibody mimetics, are provided that bind at or near the same or overlapping epitopes on companion animal OX40L or OX40 (e.g., canine OX40 or OX40L), respectively, as any of the OX40L / OX40 antibodies of the invention (i.e., antibodies that have the ability to cross-compete with the antibodies of the invention for binding to OX40L / OX40). Thus, the antibodies of the invention can be used as reference antibodies.

[0206] Such cross-competing antibodies can be identified based on their ability to cross-compete with the antibodies described herein in standard OX40L / OX40 binding assays. For example, SPR analysis such as BIAcore® analysis, BLI analysis such as FortBio Octet®, ELISA assays, or flow cytometry can be used to demonstrate cross-competition with antibodies.

[0207] In one embodiment, a binding agent capable of binding to companion animal OX40L or OX40 (eg, canine OX40 or OX40L), respectively, is provided and an antibody of the invention displaces the binding agent in a competitive assay.

[0208] Included within the scope of the present invention are antibody derivatives. An antibody "derivative" contains additional chemical moieties that are not normally part of the protein. Covalent modifications of proteins are included within the scope of the present invention. Such modifications can be introduced into the molecule by reacting targeted amino acid residues of the antibody with organic derivatizing agents that can react with selected side chains or terminal residues. For example, derivatization with bifunctional agents well known in the art is useful for crosslinking antibodies or fragments to water-insoluble support matrices or other macromolecular carriers.

[0209] The antibodies or fragments thereof described herein may be used as building blocks in multispecific, e.g., bispecific or trispecific, binding agents that provide dual targeting of companion animal OX40L or OX40 (e.g., canine OX40 or OX40L) expressing cells, respectively. Thus, the antibodies or fragments thereof described herein are linked to another therapeutic entity that targets a different antigen. The other therapeutic entity is selected, for example, from an antibody or antibody fragment (e.g., Fab, F(ab')2, Fv, single chain Fv fragment (scFv), or single domain antibody, e.g., VH or VHH domain), CDR region, or antibody mimetic protein. Suitable non-immunogenic linker peptides are known in the art, e.g., linkers containing G and / or S residues, (G4S)n, (SG4)n, or G4(SG4)n peptide linkers, where "n" is generally a number between 1 and 10.

[0210] In another embodiment, the antibody or fragment thereof according to the invention is linked to a further moiety that may serve to extend the half-life of the molecule. The further moiety may comprise a protein, such as an antibody, or a portion thereof, that binds to serum albumin, such as dog or feline serum albumin. Other modifications that extend half-life are also known, including, for example, modification by PEG or by incorporation into liposomes.

[0211] In one embodiment, the antibody or fragment thereof according to the present invention is labeled with a detectable or functional label. The label can be any molecule that produces a signal or can be induced to produce a signal, including, but not limited to, a fluorophore, a fluorescent substance, a radioactive label, an enzyme, a chemiluminescent substance, a nuclear magnetic resonance active label, or a photosensitizer. Thus, binding can be detected and / or measured by detecting fluorescence or luminescence, radioactivity, enzyme activity, or light absorbance.

[0212] In yet another embodiment, the antibody or fragment thereof according to the invention is coupled to a toxin. In one embodiment, the therapeutic moiety is a toxin, for example a cytotoxic radionuclide, a chemical toxin, or a protein toxin.

[0213] The term "half-life" as used herein refers to the time required for the serum concentration of an amino acid sequence, compound or polypeptide to decrease by 50% in vivo, for example due to degradation of the sequence or compound and / or clearance or sequestration of the sequence or compound by natural mechanisms. The half-life may be extended by at least 1.5 times, preferably at least 2 times, such as at least 5 times, for example at least 10 times, or more than 20 times, than the half-life of the corresponding antibody of the invention. For example, the extended half-life may be more than 1 hour, preferably more than 2 hours, more preferably more than 6 hours, for example more than 12 hours, or even more than 24 hours, 48 ​​hours or 72 hours, compared to the corresponding antibody of the invention. The in vivo half-life of the amino acid sequence, compound or polypeptide of the invention can be determined in any manner known per se, such as by pharmacokinetic analysis. Suitable techniques will be clear to the skilled person. The half-life can be expressed, for example, using parameters such as t1 / 2-alpha t1 / 2-beta and area under the curve (AUC).

[0214] The antibodies and fragments of the invention may also be used in cell therapy, for example chimeric antigen receptor T cell (CAR-T) therapy.

[0215] nucleic acid In another aspect, the invention relates to nucleic acid sequences encoding the amino acid sequences of the antibodies or antibody fragments described herein.

[0216] In one embodiment, the nucleic acid is SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:151, SEQ ID NO:161, SEQ ID NO:171, SEQ ID NO:181, SEQ ID NO:191, SEQ ID NO:201, SEQ ID NO:211, SEQ ID NO:221, SEQ ID NO:231, SEQ ID NO:241, SEQ ID NO:251, SEQ ID NO:261, SEQ ID NO:271, SEQ ID NO:281, SEQ ID NO:291, SEQ ID NO:301, SEQ ID NO:311, SEQ ID NO:321, SEQ ID NO:331, SEQ ID NO:341, SEQ ID NO:351, SEQ ID NO:361, SEQ ID NO:371, SEQ ID NO:381, SEQ ID NO:391, SEQ ID NO:401, SEQ ID NO:411 , SEQ ID NO:421, SEQ ID NO:431, SEQ ID NO:441, SEQ ID NO:451, SEQ ID NO:461, SEQ ID NO:471, SEQ ID NO:481, SEQ ID NO:491, SEQ ID NO:501, SEQ ID NO:511, SEQ ID NO:521, SEQ ID NO:531, SEQ ID NO:541, SEQ ID NO:551, SEQ ID NO:561, SEQ ID NO:571, SEQ ID NO:581, SEQ ID NO:591, SEQ ID NO:601, SEQ ID NO:611, SEQ ID NO:621, SEQ ID NO:631, SEQ ID NO:641, SEQ ID NO:651, SEQ ID NO:661, SEQ ID NO:671, SEQ ID NO:681, SEQ ID NO:691, SEQ ID NO:701, SEQ ID NO:711, SEQ ID NO:737, SEQ ID NO:747, SEQ ID NO:757, SEQ ID NO:767, SEQ ID NO:777, SEQ ID NO:787, SEQ ID NO:797.

[0217] In one embodiment, the nucleic acid is SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, SEQ ID NO:133, SEQ ID NO:143, SEQ ID NO:153, SEQ ID NO:163, SEQ ID NO:173, SEQ ID NO:183, SEQ ID NO:193, SEQ ID NO:203, SEQ ID NO:213, SEQ ID NO:223, SEQ ID NO:233, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:263, SEQ ID NO:273, SEQ ID NO:283, SEQ ID NO:293, SEQ ID NO:303, SEQ ID NO:313, SEQ ID NO:323, SEQ ID NO:343, SEQ ID NO:353, SEQ ID NO:363, SEQ ID NO:373, SEQ ID NO:383, SEQ ID NO:393, SEQ ID NO:403, SEQ ID NO:413, SEQ ID NO:423, SEQ ID NO:433, SEQ ID NO:443, SEQ ID NO:453, SEQ ID NO:463, SEQ ID NO:473, SEQ ID NO:483, SEQ ID NO:493, SEQ ID NO:503, SEQ ID NO:513, SEQ ID NO:523, SEQ ID NO:533, SEQ ID NO:543, SEQ ID NO:553, SEQ ID NO:563, SEQ ID NO:573, SEQ ID NO:583, SEQ ID NO:593, SEQ ID NO:603, SEQ ID NO:613, SEQ ID NO:623, SEQ ID NO:633, SEQ ID NO:643, SEQ ID NO:653, SEQ ID NO:663, SEQ ID NO:673, SEQ ID NO:683, SEQ ID NO:693, SEQ ID NO:703, SEQ ID NO:713, SEQ ID NO:739, SEQ ID NO:749, SEQ ID NO:759, SEQ ID NO:769, SEQ ID NO:779, SEQ ID NO:789 or SEQ ID NO:799.

[0218] Exemplary Methods for Producing Antibodies The antibodies or fragments described herein can be obtained from a mammal, e.g., a rodent, e.g., a transgenic animal, that expresses the antibody when stimulated with a target companion animal OX40L or OX40 antigen, e.g., canine or feline OX40L or OX40. A companion animal antibody gene is preferably introduced so that a companion animal antibody is produced. The transgenic rodent, e.g., a mouse, preferably has a reduced ability to express endogenous antibody genes. Thus, in one embodiment, the rodent has a reduced ability to express endogenous light and / or heavy chain antibody genes. Thus, the rodent, e.g., a mouse, may include modifications to disrupt the expression of endogenous kappa and lambda light and / or heavy chain antibody genes, e.g., as further described below, so that functional mouse light and / or heavy chains are not produced. Such transgenic rodents have been described in the art, which are further described in the examples below.

[0219] Other methods may typically include immunizing mice with the OX40L or OX40 antigen of the target companion animal, isolating B cells, fusing them to a fusion partner cell line, and isolating mouse monoclonal antibodies by selection, followed by murine monoclonal speciesization. Speciation is then performed by chimerization and / or further information-guided speciesization. Strategies for speciesization, such as strategies for caninization or felinization, are described, for example, in WO2013 / 011407, see Example 5.

[0220] In other methods, the set, collection, or library of amino acid sequences can be displayed, for example, on a phage, phagemid, ribosome, or suitable microorganism (such as yeast) to facilitate screening. Suitable methods, techniques, and host organisms for displaying and screening (sets, collections, or libraries) of amino acid sequences will be apparent to those skilled in the art (see, for example, Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press; 1st edition (October 28, 1996) Brian K. Kay, Jill Winter, John McCafferty).

[0221] Cells or tissues expressing antigen-specific heavy chain-only antibodies are isolated, and mRNA derived from the isolated cells or tissues is used to generate V H Libraries, such as phage libraries, can also be generated by cloning sequences encoding the domain(s) and using the library to display the encoded proteins. Antibodies or fragments can be expressed in bacterial, yeast, or other expression systems.

[0222] Exemplary Therapeutic Applications In one aspect, there is provided an antibody or fragment as described herein for use in the treatment of a disease.

[0223] In another aspect, a pharmaceutical composition is provided comprising an antibody or fragment described herein and, optionally, a pharma- ceutically acceptable carrier. As used herein, the term "pharmaceutical composition" refers to a composition that is for veterinary use, that is used to treat companion animals, i.e., a veterinary composition. In a preferred embodiment, the animal to be treated is a dog or a cat.

[0224] The antibodies or fragments thereof described herein, or pharmaceutical compositions of the invention may be administered by any convenient route, including, but not limited to, orally, topically, parenterally, sublingually, rectally, vaginally, ocular, intranasal, pulmonary, intradermal, intravitreal, intramuscular, intraperitoneally, intravenously, subcutaneously, intracerebral, transdermal, transmucosal, by inhalation, or topically, particularly to the ear, nose, eye, or skin, or by inhalation.

[0225] In one embodiment, the administration is subcutaneous. The concentration of the antibody or antibody fragment may be 10-50 mg / ml, for example, 10, 20, 30, 40 or 50 mg / ml. In one embodiment, the concentration is 25-35 mg / ml, for example, about 30 mg / ml. In one embodiment, the antibody is provided as a dose in 1 ml of solution.

[0226] Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, rectal, intravesical, intradermal, topical, or subcutaneous administration. Preferably, the compositions are administered parenterally.

[0227] The pharma- ceutically acceptable carrier or vehicle may be particulate, such that the composition is, for example, in tablet or powder form. The term "carrier" refers to a diluent, adjuvant, or excipient with which the drug-antibody conjugate of the present invention is administered. Such pharmaceutical carriers may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used. In one embodiment, the antibody or fragment thereof or composition of the present invention and the pharma- ceutically acceptable carrier are sterile when administered to animals. Water is a preferred carrier when the drug-antibody conjugate of the present invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0228] The pharmaceutical compositions of the invention may be in the form of a liquid, such as a solution, emulsion, or suspension, which may be useful for delivery by injection, infusion (e.g., IV infusion), or subcutaneously.

[0229] When intended for oral administration, the compositions are preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included within the forms considered herein as either solid or liquid.

[0230] As a solid composition for oral administration, the composition can be formulated in the form of powder, granule, compressed tablet, pill, capsule, chewing gum, wafer, etc. Such solid composition typically contains one or more inert diluents. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose, or dextrin, disintegrating agents such as alginic acid, sodium alginate, corn starch, etc.; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavors such as peppermint, methyl salicylate, or orange flavor; and colorants. When the composition is in the form of a capsule (e.g., a gelatin capsule), it can contain liquid carriers such as polyethylene glycol, cyclodextrin, or fatty oils in addition to the above-mentioned types of materials.

[0231] The composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. This liquid may be useful for oral administration or delivery by injection. When intended for oral administration, the composition may contain one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer. The composition for administration by injection may also contain one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0232] The composition may be in the form of one or more dosage units.

[0233] In certain embodiments, it may be desirable to administer the compositions locally to the area in need of treatment or by injection, intravenous injection or infusion.

[0234] The amount of therapeutic agent that is effective / active in treating a particular disorder or condition depends on the nature of the disorder or condition and the animal to be treated, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can be optionally used to help identify optimal dosage ranges. The exact dose to be used in the composition also depends on the route of administration and the severity of the disorder or disease, and should be determined according to the physician's judgment and each subject's circumstances. Factors such as age, body weight, sex, diet, administration time, excretion rate, host condition, drug combination, reaction sensitivity, and disease severity should be taken into account.

[0235] Typically, this amount is at least about 0.01% of the antibody of the present invention by weight of the composition. When intended for oral administration, this amount can vary from about 0.1% to about 80% by weight of the composition. A preferred oral composition may contain about 4% to about 50% of the antibody of the present invention by weight of the composition.

[0236] Preferred compositions of the invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of an antibody of the invention.

[0237] For administration by injection, the composition may typically comprise about 0.1 mg / kg to about 250 mg / kg of the subject's body weight, preferably 0.1 mg / kg to about 20 mg / kg of the animal's body weight, and more preferably about 1 mg / kg to about 10 mg / kg of the animal's body weight. In one embodiment, the composition is administered at a dose of about 1 to 30 mg / kg, e.g., about 5 to 25 mg / kg, about 10 to 20 mg / kg, about 1 to 5 mg / kg, or about 3 mg / kg. Dosing schedules may vary, for example, from once weekly to once every 2, 3, 4, 5, 6, 7, 8 or more weeks.

[0238] In one embodiment, following treatment, the subject has no disease progression for at least 7 days, or at least 14 days, or at least 21 days, or at least 28 days, or at least 40 days, or at least 50 days, or at least 60 days.

[0239] In one embodiment, the number of days alive, disease free or disease progression free is at least 2 months, or at least 3 months, or at least 4 months, such as at least 5 months, for example at least 6 months.

[0240] In one embodiment, the number of days alive, disease free, or disease progression free is at least 9 months, or at least 1 year.The present invention provides a method of treating or preventing an OX40L / OX40 mediated disease or disorder in a companion animal, e.g., a dog, cat or horse, comprising administering to the animal in need thereof an effective amount of an antibody or fragment of the invention.

[0241] As used herein, "treat", "treating" or "treatment" means to inhibit or alleviate a disease or disorder. For example, treatment can include postponing the onset of symptoms associated with a disease or disorder and / or reducing the severity of such symptoms that would or are expected to occur with the disease. These terms include amelioration of existing symptoms, prevention of additional symptoms, and amelioration or prevention of the underlying causes of such symptoms. Thus, these terms indicate that a beneficial result is imparted to at least some of the mammalian, e.g., companion animal, patients being treated. Many medical treatments are effective in some, but not all, patients who receive the treatment.

[0242] Preferably, a reduction in the pruritus score is observed following treatment for a condition such as atopic dermatitis. Suitable methods for measuring the pruritus score will be known to those skilled in the art.

[0243] In one embodiment, the antagonistic antibody or fragment thereof according to the invention suppresses the GVHD response in xenografts as described in WO2013 / 0008171. In an embodiment, the antibody or fragment thereof according to the invention shows activity in an antigen recall test similar to that described in Saghari M.et al,Clin Pharmacol Ther.2022 Jan 29.doi:10.1002 / cpt.2539 or a house dust mites canine model as set out in Marsella R.et al,Vet.Dermatol 2006 Feb;17(1):24-35.doi:10.1111 / j.1365-3164.2005.00496.x.

[0244] The term "subject" or "patient" refers to a companion animal that is the object of treatment, observation, or experiment. By way of example only, subjects include, but are not limited to, dogs, cats, or horses. For the avoidance of doubt, the treatment of humans is excluded.

[0245] In one embodiment, the "patient" is a patient who is non-responsive to Cytopoint or Apoquel.

[0246] As used herein, the term "effective amount" means an amount of an anti-OX40L / OX40 antibody that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to achieve the desired therapeutic or prophylactic effect under the conditions of administration.

[0247] In another aspect, the present invention relates to the use of an antibody or fragment as described herein, or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment or prevention of a disease as defined herein.

[0248] As mentioned above, the antibodies or fragments according to the invention are useful for the treatment or prevention of OX40L / OX40 mediated diseases.

[0249] The term OX40L / OX40-mediated disease refers to any disease or disorder that is mediated by the OX40L / OX40 signaling pathway and can be treated / alleviated by targeting the OX40L / OX40 antigen. OX40L-mediated disease and OX40-mediated disease refer to any disease or condition that is caused completely or partially by or is the result of OX40L or OX40, respectively. In certain embodiments, OX40L or OX40 is abnormally (e.g., highly) expressed on the surface of a cell. In some embodiments, OX40L or OX40 can be abnormally upregulated in certain cell types. In other embodiments, normal, abnormal, or excessive cell signaling is caused by the binding of OX40 to OX40L.

[0250] Evidence in humans suggests that disruption of the OX40 / OX40L axis reduces T cell activation, proliferation and establishment of memory T cells, and therefore anti-OX40L / OX40 antibodies can be used to prevent, treat, or ameliorate symptoms of a number of diseases, including atopic dermatitis, type 1 diabetes, Crohn's disease, ulcerative colitis, and other autoimmune diseases.

[0251] In one embodiment, anti-OX40L / OX40 antibodies are used to treat or ameliorate the symptoms of a disease. In one embodiment, such diseases are selected from autoimmune and inflammation-related diseases, including allergies, asthma, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, experimental autoimmune encephalomyelitis (EAE), experimental leishmaniasis, collagen-induced arthritis, colitis (such as ulcerative colitis), contact hypersensitivity reactions, type 1 diabetes, Crohn's disease, and Grave's disease. In one embodiment, the disease is an inflammatory condition, which refers to a pathological condition that results in inflammation or an autoimmune disease. In particular, the disease is selected from the following non-limiting list: inflammatory skin diseases including atopic dermatitis (atopy), allergic dermatitis, pruritus, psoriasis, scleroderma, or eczema; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); type 1 diabetes, ischemia-reperfusion; adult respiratory distress syndrome; asthma; meningitis; encephalitis; uveitis; autoimmune diseases such as rheumatoid arthritis, Sjogren's syndrome, vasculitis; diseases involving extravasation of leukocytes; central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome following sepsis or trauma, bacterial pneumonia, antigen-antibody complex-mediated diseases; lung inflammation including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, and cystic fibrosis. Other diseases include equine indications such as sweet itch, summer recurrent dermatitis, or equine insect bite hypersensitivity.

[0252] Exemplary Combinations with Other Agents The antibody, antibody fragment or pharmaceutical composition of the invention may be administered as the sole active ingredient or in combination with one or more other therapeutic agents. A therapeutic agent is a compound or molecule that is useful in the treatment of a disease.

[0253] Examples of therapeutic agents include antibodies, antibody fragments, drugs, toxins, nucleases, hormones, anti-inflammatory agents, immunomodulatory agents, pro-apoptotic agents, anti-angiogenic agents, boron compounds, photoactive agents or dyes, and radioisotopes. Antibody molecules may be whole antibodies or fragments thereof (e.g., Fab, F(ab')2, Fv, single chain Fv fragments (scFv), or single domain antibodies, e.g., V H domain, or antibody mimetic protein).

[0254] In one embodiment, the antibodies or antibody fragments or pharmaceutical compositions described herein are used in combination with existing therapies or treatments. Thus, in another aspect, the invention also relates to combination therapies and other therapies that include administration of the antibodies or antibody fragments or pharmaceutical compositions described herein.

[0255] In one embodiment, the therapeutic agent is selected from the following non-limiting list: rapamycin (sirolimus), tacrolimus, cyclosporine, corticosteroids (e.g., methylprednisolone), methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12 / IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VI_A4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymic Cytoglobulin, anti-complement C5 antibodies, anti-a4b7 integrin antibodies, anti-IL6 antibodies, anti-IL6-R antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules, HDAC inhibitors, JAK inhibitors such as JAK-1 and JAK-3 inhibitors, anti-IL-31 antibodies, SYK inhibitors, anti-IL-4Ra antibodies, anti-IL-13 antibodies, anti-TSLP antibodies, and the PDE4 inhibitors lokietomab (Cytopoint®), cyclosporine (Atopica®), and oclacitinib (Apoquel®). In some embodiments, the antibody or antibody fragment or pharmaceutical composition described herein may be administered with two or more therapeutic agents.

[0256] The antibodies or antibody fragments or pharmaceutical compositions described herein can be administered at the same time as other therapies or therapeutic compounds or therapies, or at different times, e.g., simultaneously, separately or sequentially.

[0257] Exemplary Kits In another aspect, the present invention provides kits for treating or preventing diseases, such as those listed herein, and / or kits for detecting OX40L / OX40 for diagnosing, prognosing, or monitoring diseases, comprising the antibody or fragment of the present invention. Such kits may contain other components, packaging, instructions, or materials to aid in the detection of OX40L / OX40 protein. The kits may include a labeled antibody that binds to OX40L / OX40, or a binding molecule that includes an antibody that binds to OX40L / OX40 and one or more compounds for detecting the label.

[0258] In another aspect, the invention provides an antibody or fragment thereof that binds to OX40L / OX40 or a pharmaceutical composition as described herein packaged in lyophilized form or in an aqueous medium.

[0259] Exemplary Non-Therapeutic Applications In another aspect, the antibodies or fragments that bind OX40L / OX40 described herein are used for non-therapeutic purposes, such as diagnostic tests and assays. A method for detecting the presence of companion animal OX40L / OX40 in a test sample includes contacting the sample with an antibody or fragment thereof described herein and at least one detectable label, and detecting binding of the antibody to companion animal OX40L / OX40.

[0260] The modification of antibodies for diagnostic purposes is well known in the art.For example, antibodies can be modified with ligand groups such as biotin, or detectable marker groups such as fluorescent groups, radioisotopes, or enzymes.The compounds of the present invention can be used for diagnostic purposes, and can be labeled, for example, using conventional techniques.Suitable detectable labels include, but are not limited to, fluorophores, chromophores, radioactive atoms, electron-dense reagents, enzymes, and ligands with specific binding partners.

[0261] In some embodiments, the binding of the antigen to the antibody is detected without the use of a solid support, for example, the binding of the antigen to the antibody can be detected in liquid form.

[0262] In other embodiments, the antibody or fragment may be immobilized on, for example, nitrocellulose or another solid support capable of immobilizing cells, cell particles, or soluble proteins. The support may then be washed with a suitable buffer, followed by treatment with detectably labeled antibody. The solid support may then be washed twice with buffer to remove unbound peptides or antibodies. The amount of bound label on the solid support may then be detected by known method steps. "Solid support" or "carrier" refers to any support capable of binding peptides, antigens, or antibodies. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, polyvinylidene fluoride (PVDF), dextran, nylon, amylase, natural and modified cellulose, polyacrylamide, agarose, and magnetite. The nature of the carrier may be soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration, so long as the bound molecule is capable of binding to OX40L / OX40 or anti-OX40L / OX40 antibodies. Thus, the support configuration can be spherical, like a bead, or cylindrical, like the inner surface of a test tube, or the outer surface of a rod. Alternatively, the surface can be flat, such as a sheet, culture dish, test paper, etc. For example, the support can include polystyrene beads. Those skilled in the art will know, or can identify by routine experimentation, many other suitable carriers for binding antibodies, peptides, or antigens. Well-known method steps can determine the binding activity of a given lot of anti-OX40L / OX40 antibodies. Those skilled in the art can determine the operative and optimal assay conditions by routine experimentation.

[0263] For the purpose of the present invention, the OX40L / OX40 detected by the above assay can be present in a biological test sample.Any sample containing OX40L / OX40 can be used.For example, the sample is a biological fluid such as blood, serum, lymph, urine, feces, inflammatory exudate, cerebrospinal fluid, amniotic fluid, tissue extract or homogenate.

[0264] Nucleic Acid Constructs and Host Cells Furthermore, the present invention relates to a nucleic acid construct comprising at least one nucleic acid as defined herein, i.e. a nucleic acid molecule encoding an antibody of the invention or a nucleic acid molecule encoding an OX40 protein. The construct may be in the form of a plasmid, vector, transcription or expression cassette.

[0265] The expression vector can be, for example, a plasmid, such as pBR322, pUC, or ColE1, or an adenovirus vector, such as an adenovirus type 2 or type 5 vector. Vectors suitable for use in the present invention include, for example, bacterial vectors, mammalian vectors, viral vectors (such as retrovirus, adenovirus, adeno-associated virus, herpes virus, Simian Virus 40 (SV40), and bovine papilloma virus vectors), and baculovirus-derived vectors for use in insect cells. The polynucleotide in such a vector is preferably operably linked to a promoter selected, for example, based on the cell type in which expression is desired.

[0266] The expression vector can be transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. The invention includes host cells containing a polynucleotide encoding an antibody of the invention (e.g., a whole antibody, a heavy or light chain thereof, or a portion thereof, or a single chain antibody of the invention, or a fragment or variant thereof) operably linked to a heterologous promoter. For expression of the whole antibody molecule, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the whole immunoglobulin molecule. In one embodiment, the expression vector is one that allows for heterologous expression, e.g., expression in host organisms from different species.

[0267] The present invention also relates to isolated recombinant host cells comprising one or more of the nucleic acid constructs described herein, i.e., a nucleic acid molecule encoding an antibody of the invention, or a nucleic acid molecule encoding an OX40 protein. Host cells useful in the present invention may be prokaryotic, yeast, or higher eukaryotic cells, including, but not limited to, microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell lines infected with recombinant viral expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell lines infected with recombinant viral expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell lines (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., adenovirus late promoter; vaccinia virus 7.5K promoter).

[0268] Prokaryotes useful as host cells in the present invention include gram-negative or gram-positive organisms, such as E. coli, B. subtilis, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, Serratia, and Shigella, as well as Bacilli, Pseudomonas, and Streptomyces. One preferred E. coli cloning host is E. coli 294 (ATCC 31,446), although other strains such as E. coli B, E. coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are suitable. These examples are illustrative and not limiting. In one embodiment, a method of making an anti-OX40 antibody described herein is provided, the method comprising culturing a host cell under conditions suitable for expression of a polynucleotide encoding the antibody, and isolating the antibody.

[0269] In some embodiments, the nucleic acid may also include a leader sequence. Any suitable leader sequence may be used, including a native immunoglobulin germline leader sequence, or other sequences such as the Campath leader sequence (see US 8,362,208 B2), and may be selected to improve protein expression.

[0270] Assays and Expression Systems The present invention also relates to heterologous assays or expression systems comprising companion animal (eg, canine) OX40 and a cell line derived from a different species, for example a human cell line such as HEK.

[0271] The assay includes contacting companion animal (e.g., canine) OX40 with a cell line from a different species, e.g., a cell line from a different mammal, e.g., a rodent cell line or a human cell line such as HEK. For example, the cell line is transfected with companion animal (e.g., canine) OX40 to express companion animal (e.g., canine) OX40 in a stable or transient manner.

[0272] The cell line may contain a reporter gene, and activation of OX40 by OX40L may be assessed using the reporter gene, for example, by quantification of reporter gene expression. Suitable reporter genes are known to those skilled in the art and may include fluorescent markers or alkaline phosphatase (SEAP).

[0273] It will be understood that the specific embodiments described herein are shown by way of example and not by way of limitation. The principal features of the present invention can be employed in various embodiments without departing from the scope of the present invention. Those skilled in the art will recognize, or be able to ascertain, using no more than routine investigation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims. All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are incorporated by reference herein to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The use of the words "a" or "an" in the claims and / or this specification in conjunction with the term "comprising" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more." Use of the term "or" in the claims is used to mean "and / or," unless expressly stated to refer to alternatives only or the alternatives are mutually exclusive, but the present disclosure supports a definition that refers to alternatives only and "and / or." Throughout this specification, the term "about" is used to indicate that a value includes the inherent variation of error for the device, method being employed to determine the value, or the variation that exists among study subjects.

[0274] As used in this specification and claims, the word "comprising" (and any form of comprising, such as "comprise" and "comprises"), the word "having" (and any form of having, such as "have" and "has"), the word "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 and open-ended and do not exclude additional, unrecited elements or method steps.

[0275] The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, if order is important in the particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations including one or more repeats of an item or term, such as BB, AAA, ABAB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Those skilled in the art will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0276] Unless otherwise clear from the context, any part of this disclosure may be read in combination with any other part of this disclosure.

[0277] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods and to the steps or sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

[0278] The invention is described in more detail in the following non-limiting examples. EXAMPLES

[0279] Example 1: Cloning of canine OX40L and OX40 OX40L sequence prediction The nucleotide sequence and gene structure of canine OX40L were predicted based on the alignment of the human OX40L nucleotide sequence to the canine CamFam3.1 genome assembly from the UCSC genome browser (University of Santa Cruz). This resulted in three predicted exons (Figure 1A). Unlike many transmembrane proteins that consist of an extracellular domain followed by a 5' end, the OX40L protein structure is reversed (see Figure 1B).

[0280] OX40 sequence prediction The nucleotide sequence of canine OX40 was predicted based on a nucleotide sequence homology alignment of human OX40 to the canine reference genome, which resulted in seven predicted exons with an extracellular domain at the N-terminus (Figure 1A).

[0281] OX40L and OX40 cloning The sequences of both OX40L and OX40 were confirmed by cloning from PBMCs isolated from beagle blood using standard protocols. Beagle whole blood was provided by Envigo RMS (Alconbury, Huntingdon, UK) and PBMCs were isolated using a Ficoll gradient. Briefly, 10 ml of whole blood was diluted with 25 ml of phosphate-buffered saline (PBS) and layered over 15 ml of Ficoll Paque Plus (Sigma Aldrich) before centrifugation at 800 rcf for 10 min at room temperature with slow acceleration and no brake. Interphase discs representing the PBMC fraction were collected in PBS. PBMCs were counted and purified at 1 μg ml -1 10 in RPMI medium (Sigma Aldrich) supplemented with canine IL-2 6 cells ml - Resuspended in 1.

[0282] To stimulate the expression of OX40 and OX40L, 5 mg ml -1 Phytohemagglutinin-L (PHA-L, Fisher Scientific) was added and PBMCs were harvested 1 and 4 days later. Total RNA was isolated from activated PBMCs using the Qiagen RNeasy Mini Kit (Qiagen, Hilden, DE), yielding 160 μg to 440 μg of RNA after on-column DNAse digestion. Specific cDNA amplification of OX40 and OX40L was performed using the SuperScript IV One-Step RT-PCR Kit (ThermoFisher, Massachusetts, US) with 3' and 5' terminal primers generated from the predicted OX40 and OX40L nucleotide sequences. Primer sequences are shown in Table 2. (SEQ ID NOs: 7 to 10).

[0283] Before being transferred into pcDNA3.1 for mammalian expression, OX40 and OX40L RT-PCR products were subcloned into pJET using the CloneJET PCR cloning kit (ThermoFisher).

[0284] The nucleotide and amino acid sequences of canine OX40L (sequences of cloned OX40L / full length membrane form for cellular expression) are shown in Table 2 (SEQ ID NOs: 1 and 2).

[0285] For OX40, the presence of potential splice variants was observed in the RT-PCR products. To isolate the individual splice variant transcripts, the RT-PCR products were subcloned and two distinct transcripts were identified with the sequences shown in Table 2 (nucleotide, amino acid translation), short and long variants (SEQ ID NOs: 3-6).

[0286] Figure 2 shows an alignment of these splice variants. The long splice variant of OX40 consists of exons arranged in the sequence 1-2-3-4-5-6-7. The short splice variant does not include exon 6 and has the arrangement 1-2-3-4-5-7.

[0287] Single-step PCR of pJET-OX40 colonies was used to assess the relative abundance of the OX40 splice variants. Briefly, single colonies were selected from LB amp plates into 10 μl of OneTaq Quick-Load PCR mix (NEB) and amplified with the following PCR cycles: 1 cycle at 94°C for 30 s, 30 cycles at 94°C for 30 s, 30 cycles at 61°C for 30 s, 30 cycles at 68°C for 2 min, and 1 cycle at 68°C for 5 min. The abundance of the two splice variants was determined by assessing the relative length of the resulting PCR products (Figure 3). The short splice variant encodes a truncated product. This product lacks the transmembrane region in its entirety, making it most likely that the resulting short variant is secreted.

[0288] Example 2: Generation of canine OX40 and OX40L stably expressing cells Human embryonic kidney (HEK) 293 cells were grown on 90 mm circular tissue culture plates as monolayers in DMEM / F12 (Life Technologies, California, US) supplemented with 10% fetal bovine serum (FBS, Sigma Aldrich) at 37°C in a humidified atmosphere containing 5% CO2. HEK293 cells were transfected with plasmids encoding either OX40 (SEQ ID NO: 5) or OX40L (SEQ ID NO: 2) using polyethylenimine (PEI MAX: 40 kDa, Polysciences Inc., Eppelheim, Germany). 30 μl of PEI MAX (1 mg ml -1 ), 5 μg of cDNA, and 1 ml of DMEM / F12 were incubated at room temperature for 10 min and added dropwise to a 90 mm plate of 70-80% confluent HEK293 cells and incubated for 2-3 days. Stably transfected cells were selected after 48 h using the appropriate antibiotic.

[0289] Mouse embryonic fibroblasts (MEFs) were grown as monolayers in DMEM high glucose (Life Technologies) supplemented with 10% FBS, 10% β-mercaptoethanol, and 10% non-essential amino acids on 90 mm circular tissue culture plates in a humidified atmosphere at 37° C. and 5% CO2. Cells were transfected with a plasmid encoding OX40L cDNA (SEQ ID NO:2) using Lipofectamine LTX (ThermoFisher Scientific, Waltham, MA, USA) according to the manufacturer's recommended instructions. Stably transfected cells were selected after 48 hours using the appropriate antibiotic.

[0290] Example 3: Canine OX40L immunization using the Ky9™ transgenic platform For example, Ky9™ mice were immunized with an OX40L-expressing DNA construct or MEFs stably expressing OX40L, substantially as described in WO2018 / 189520 and WO2020 / 074874. The transgenic mice are modified compared to wild-type mice by insertion of immunoglobulin heavy (IGH) and light chain (IGL) variable (V) region genes, IGH D region genes, and IGH and IGL J region genes from dogs into the mice, allowing the production of antibody heavy chains that, in combination with constant regions, contain variable antibody regions derived from the expression of dog DNA in the mouse. The constant regions can be rodent immunoglobulin (IG) constant regions, resulting in the production of chimeric heavy chains with dog variable regions and rodent constant regions. Information about the variable regions of such chimeric antibody chains, or nucleic acids containing the variable regions of such chimeric antibody chains, can be used to generate complete dog antibodies, for example, for therapeutic use in dogs. Rodents containing canine DNA can also serve as animal models for understanding disease and testing pharmaceuticals.

[0291] For DNA immunization, a prime and boost regime was performed using hydrodynamic tail vein injection (HTVI) and tissues were harvested.

[0292] For cell-based immunization, a prime and boost regime using MEF cells stably expressing OX40L was performed and tissues were harvested.

[0293] An additional immunization regime was performed using HTVI DNA immunization for the prime combined with an OX40L-expressing MEF cell boost.

[0294] Serum titer determination: Mice were bled before immunization and 10 days after each subsequent boost. Serum and red blood cells were separated using Microvette 200 Z gel tubes (Starstedt AG&Co.KG, Germany). Post-immunization serum was serially diluted in FACS buffer (PBS+3% FBS) and diluted 10 5 wild-type cells or 10 5Mouse antibodies were added to either 100% of the same cells stably expressing OX40L. BB700-conjugated 20% IgG1, IgG2a, or IgG2b (BD OptiBuild™, Becton Dickinson) o Monoclonal antibody 1 / 200 The stained cells were analyzed by flow cytometry using a BD Accuri C6 flow cytometer (Becton Dickinson, NJ, USA) or Beckman Coulter's CytoFLEX S. Pre-immunization serum was used as a control (Figure 4).

[0295] Example 4: Isolation of OX40-L-specific antibody-producing cells Tissue isolation: Spleens, lymph nodes, and bone marrow were harvested from mice immunized with canine OX40L as described above. Splenocytes were prepared by cutting spleens into pieces and passing these through a 45 μm cell strainer (Falcon), rinsing with RPMI-1640 (Lonza, Basel, CH) + 10% FBS on ice. A similar process was used for lymphocytes from lymph nodes. Bone marrow was harvested from femurs and tibias, and the bone marrow was flushed with RPMI-1640 using a 21-gauge needle through a 45 μm cell strainer pre-wetted with RPMI-1640. All cell types were pelleted at 300 g for 5 min and then either used directly for flow sorting or resuspended in FBS + 10% dimethyl sulfoxide (DMSO) and frozen at -150°C.

[0296] Cell sorting: Antigen-specific cells can be captured by fluorescently labeled VLPs or antigen protein probes. VLPs are generated from HEK cells, stably transfected with OX40L, and then transiently transfected with retroviral gag protein and fluorescently labeled MA (gag matrix fragment p15-GFP fusion protein), where gag expression allows VLP budding from the cells and MA labels the VLPs for fluorescent detection.

[0297] Antigen-specific B cells can also be captured by labeled antigen protein probes. Monomeric OX40L protein containing canine OX40L extracellular domain (ECD) or trimeric soluble canine OX40L extracellular domain probe (shown in the schematic diagram of FIG. 5, see Willett et al. Mol Immunol. 2009, 46(6); 1020-1030) was synthesized in an expression vector and expressed in CHO cells. Fc-tagged probes were purified from culture supernatants using Mab Select SuRe Protein A resin (Cytiva) or by AKTA using Mab Select SuRe column (Cytiva). HIS-tagged trimeric canine OX40L protein was purified using HIS-Pur Ni-NTA resin (ThermoFisher).

[0298] Conjugation of OX40L ECD TNCc HIS (MW=62.143 kDa, trimer, SEQ ID NO: 811) to Alexa Fluor 647 was performed using a microscale protein labeling kit (Molecular Probes-Invitrogen Cat. No. A30009) according to the manufacturer's protocol. The degree of labeling was determined using a NanoDrop spectrophotometer.

[0299] Similarly, conjugation of monomeric dOX40L-mvhfc (MW=40.435 kDa) (SEQ ID NO: 807) and canine OX40L ECD TNCc Fc (MW=280.980 kDa, hexamer, SEQ ID NO: 809) to Alexa Fluor647 was performed using the Alexa Fluor647 antibody labeling kit (Molecular Probes-Invitrogen Catalog No. A20186) according to the manufacturer's protocol for antibody labeling. The degree of labeling was determined using a NanoDrop spectrophotometer.

[0300] Probe specificity was determined on splenocytes from OX40L- or irrelevant antigen-immunized mice. Optimal probe concentrations were also determined based on maximal signal in the relevant immunization and minimal staining in the irrelevant immunization.

[0301] Sorted B cells were prepared using 10X Genomics Chromium Single Cell Immune Profiling System and V(D)J kit (10X Genomics) according to the manufacturer's instructions. The nucleotide sequences of expressed antibodies were determined by Illumina MiSeq sequencing at 600 cycles (2x300 cycles) or by Illumina iSeq, Miseq, MiniSeq, Nextseq, Hiseq4000 or Novaseq sequencing at 2x150 cycles. Sequences were analyzed using a custom tool based on pRESTO / Change-O (Yale University) / IgBlast (NCBI,USA) software to identify paired VH and VL sequences, and also construct clone lineage information based on the identity of heavy chain V, D, J and light chain V, J genes.

[0302] An example of the analysis of antibody sequences of sorted Ag-specific single B cells is shown in FIG. 5 of WO2015 / 040401, which shows antibody sequences aligned by using heavy chain V gene families and clustered to generate a displayed phylogenetic tree. Candidate clones are selected from such trees. The nucleic acid and amino acid sequences of the candidate clones VH and VL and their corresponding CDRs are shown in Sequence Table 2 below.

[0303] For example, the anti-canine OX40L mAbs PMX025-027 are all encoded by the same heavy chain V gene (cIGHV3-5) and light chain V gene (cIGLV3-14), and the anti-canine OX40L mAbs PMX039, 041, 043, 044, 046, and 050 are all encoded by the same heavy chain V gene (cIGHV3-18) and light chain V gene (cIGLV3-3) (Table 3).

[0304] PMX025-065, PMX082-111, PMX154-156 and PMX291-294 have the sequences shown in Table 2 below.

[0305] Example 5: Generation of monoclonal antibodies from single cells In some examples, the heavy and light chain V(D)J sequences of the selected candidate clones are synthesized and cloned into an expression vector containing an Fc region, such as human IgG4, canine IgGB, and human IgGK or canine IGK or IGL constant regions for the heavy chain. In some examples, the IgGB constant region contains a mutation that renders the constant region effector deficient. Suitable sequences for these mutated Fc regions are shown in the sequence listing below (SEQ ID NOs: 723-730).

[0306] The DNA encoding the canine heavy chain variable region selected as described above is cloned into an expression vector upstream constant region (CH1-hinge-CH2-CH3) of canine IgGB Def2 (SEQ ID NO: 723). The DNA encoding the canine light chain variable region is cloned into an expression vector upstream constant region of canine kappa or lambda light chain.

[0307] Expression vectors encoding the heavy and light chains are co-transfected into a suitable mammalian cell line, such as CHO cells, to obtain stable or transient expression.

[0308] For antibody production, 6 x 10 6 The selected stably transfected CHO cells are seeded in 3 ml of culture medium and incubated at 32° C., 5% CO2 with shaking at 200 rpm. 4% HyClone Cell Boost 7a supplement + 0.4% HyClone Cell Boost 7b supplement + 1% glucose is added to the medium on days 1, 4, 7, and 10. Culture supernatants are collected on day 12 and IgG concentrations are determined on a Protein A chip using surface plasmon resonance (Biacore 8K, Cytiva Life Sciences).

[0309] Example 6: Binding assays of OX40L candidate antibodies Binding assay: Binding of OX40L candidate antibodies to cell surface expressed canine OX40L protein. CHO supernatants diluted in FACS buffer (PBS containing 3% FBS) at 1, 5 or 10 μg / ml were used to screen their binding ability to canine OX40L using a cell-based assay. Briefly, HEK293 or MEF cells (or any other commonly used cell line) expressing canine OX40L on the cell surface are incubated with 100 μl of FACS buffer containing candidate antibodies for 30' on ice. The cells are washed with 150 μl of FACS buffer, followed by centrifugation at 300 g for 3 minutes. The cell pellet is resuspended in FACS buffer containing a 1:1000 dilution of a fluorescently labeled secondary antibody that recognizes the canine Fc region of the test antibody for 30 minutes in the dark, followed by washing with 150 μl of FACS buffer. Cells are resuspended in FACS buffer and flow cytometry is performed using either a Cytoflex (Beckton Dickinson) or Accuri (Beckman Coulter) cytometer, followed by data analysis using FlowJo (Figure 6 and Table 4).

[0310] Example 7: Functional assays of OX40 and OX40L activity of candidate antibodies HEK-Blue-NF K B. Functional Assay: HEK-Blue-NF K Cell-Based Signaling Inhibition Using the B Assay: To quantify the signaling activity of OX40 and OX40L, we developed a cell-based reporter assay. KSince OX40 signals through the B signaling pathway, canine OX40 (long form) (SEQ ID NO: 5 and 6) was stably transfected into HEK-Blue™ Null1-v cells (HEK blue OX40 cells). HEK-Blue™ Null1-v cells express a secreted embryonic alkaline phosphatase (SEAP) reporter gene under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. Thus, stimulation of canine OX40 expressing HEK-Blue™ Null1-v cells induces the production and secretion of SEAP, whose activity can be detected using QuantiBlue detection kit (Invivogen, San Diego, USA). To provide the signaling molecule for canine OX40, canine OX40L (SEQ ID NO: 1 and 2) was transfected into wild-type HEK cells (HEK OX40L cells). Co-culture of HEK OX40L cells and HEK blue OX40 cells at a 1:1 ratio resulted in NF K B signaling activation (Figure 7).

[0311] Prior to the assay, candidate antibodies were batch purified from CHO supernatants using Protein A resin (MabSelect SuRe LX, Cytiva). Briefly, MabSelect SuRe LX resin is washed with PBS and diluted to a 10% slurry. An appropriate volume of the 10% slurry is added to the supernatant and incubated at room temperature for 5–10' before loading onto a filtration column. After three washes with PBS, antibodies are eluted directly into neutralization buffer (10 mM TRIS pH 8.0) using IgG elution buffer (Pierce) at an IgG elution:neutralization buffer ratio of 8:1. Antibody concentrations are quantified by measuring absorbance at 280 nm using a Nanodrop One (Thermo Fisher).

[0312] To determine the inhibitory effect of candidate antibodies on OX40L-OX40 signaling, 5,000 HEK-blue-OX40 cells and 5,000 HEK-OX40L cells are seeded in a 96-well plate in the presence of a fixed concentration of 6.6 nM protein A purified anti-OX40L antibody. After 24 h of incubation at 37° C., 20 μl of supernatant is collected and 180 μl of QuantiBlue reagent is added, followed by an additional 4 h of incubation at 37° C., followed by evaluation of the presence of SEAP by measuring absorbance at 630 nm using a ClarioStar plate reader (BMG Labtech). Data are analyzed using proprietary MARS software version 3.40R2 (BMG Labtech) and GraphPad Prism version 9.1. Data are shown in FIG. 8 and Table 5.

[0313] Ex vivo PBMC activation assay. PBMCs are isolated from freshly drawn canine whole blood using Ficoll-Paque plus (Cytiva, GE17-1440-02) density gradient centrifugation with sodium heparin anticoagulant. Briefly, canine blood is diluted 1:1 with phosphate buffered saline (PBS), carefully layered on top of Ficoll-paque plus and centrifuged at 800rcf for 20' with slow acceleration and no brake at the end. The top layer and interphase disk are diluted with PBS and centrifuged at 1300rpm for 10' to collect PBMCs. Pelleted PBMCs are washed twice with PBS to remove any Ficoll residues. After the second centrifugation, PBMCs are resuspended in medium (PBMC medium = RPMI + 10% heat inactivated fetal bovine serum + 1% penicillin-streptomycin + 1% non-essential amino acids + 1% L-glutamine + 1% sodium pyruvate + 1% HEPES) before use or freezing.

[0314] Freshly isolated or thawed PBMCs are seeded in 96-well plates in 200 μl / well of PBMC medium supplemented with PHA (Sigma Aldrich) or ConA (ThermoFisher) and cultured with or without purified anti-OX40L antibodies at specific concentrations at 37 °C, 5% CO2. Supernatants are then collected on days 3-5 for cytokine quantification. IFN-γ is measured by ELISA (MABtech) according to the manufacturer's recommendations.

[0315] Alternatively, freshly isolated or thawed PBMCs are seeded into 96-well plates pre-coated with a combination of anti-canine CD3 (Biorad) and CD28 (eBioscience) antibodies and cultured with or without additional canine OX40L trimeric protein or HEK cells expressing canine OX40L, and / or purified anti-OX40L antibodies at different concentrations at 37 °C, 5% CO2. Supernatants are then collected on days 3-5 for cytokine quantification. IFN-γ is measured by ELISA (MABtech) according to the manufacturer's recommendations.

[0316] Tables 6 and 7 show the results of 96-well plates (1-2 x 10^ per well) precoated with a combination of anti-canine CD3 (Biorad) and CD28 (eBioscience) antibodies and incubated with 5000 HEK cells expressing canine OX40L (or 5000 wild-type HEK cells as a control) and the indicated anti-OX40L antibodies at 66, 6.6 or 0.66 nM. 5Table 6 shows the raw and normalized IFN-γ levels obtained from PBMCs cultured for 3 days in 100% OX40L (100% PBMCs). Table 6 shows the calculated IFN-γ levels in the supernatant. Because the levels of secreted IFN-γ varied widely between experiments due to the use of different PBMC donors, the levels of secreted IFN-γ in wells with PBMCs activated with CD3-CD28 in the presence of HEK cells expressing OX40L and anti-OX40L antibodies were normalized to the levels of secreted IFN-γ in wells with PBMCs activated with CD3-CD28 (0%) and in wells with PBMCs activated with CD3-CD28 in the presence of HEK cells expressing OX40L but without anti-OX40L antibodies (100%) in the same experiment (Table 7).

[0317] Example 8: Affinity determination of anti-OX40L antibody candidates Determining antibody affinity by surface plasmon resonance (SPR) Affinity of OX40L antibody (K d ) is measured by SPR using recombinant canine OX40L ECD-TNCc-HIS protein (SEQ ID NO: 811) as a capture agent (FIG. 5B).

[0318] OX40L ECD-TNCc-HIS protein is purified from CHO supernatant using HIS-Pur Ni NTA resin (ThermoFisher). Briefly, CHO supernatant is buffer exchanged into PBS (pH 8.0) containing 10 mM imidazole using PD10 desalting columns (Cytiva). The buffer exchanged supernatant is then incubated with HIS-Pur Ni NTA resin for 1 h at 4° C. with rotation. The resin is applied to a gravity filter column and washed three times with PBS (pH 8.0) containing 10 mM imidazole, then eluted with 2.5 ml of PBS (pH 8.0) containing 500 mM imidazole and buffer exchanged into PBS (pH 7.4) using PD10 desalting columns.

[0319] Functional affinity was determined using Biacore 8K (Cytiva), in brief, purified OX40L ECD-TNCc-HIS protein was covalently coupled at low density to the surface of a CM5 sensor chip (Cytiva) by amine coupling using the manufacturer's recommended protocol. Candidate antibodies were then passed over the chip surface at a range of concentrations and affinities determined using proprietary software (Biacore Insight Evaluation Software). Curves were fitted using a bivalent analyte binding model. The results are summarized in Table 8.

[0320] Example 9: Determination of the stability of candidate anti-OX40L antibodies After Protein A purification, anti-OX40L antibodies were eluted using IgG elution buffer (Pierce) and buffer acidity was neutralized using 1 M TRIS pH 8.0. Candidate stability was assessed in such buffers or after buffer exchange into sodium acetate buffer pH 5.5 (20 mM sodium acetate 100 mM NaCl pH 5.5).

[0321] The tendency of candidates to form aggregates or fragments was first evaluated by high performance liquid chromatography size exclusion chromatography (HPLC-SEC). Briefly, HPLC-SEC chromatography (column: BioResolve SEC mAb 200A, 2.5um column WATERS) was performed using an ACQUITY H-class Bio (WATERS) using PBS as the mobile phase with an isocratic flow rate of 0.575mL / min. 10uL of each sample was injected into the H-SEC using the protocol described above. The percentage of monomer species and area (indicative of antibody concentration) were determined for each molecule by manual integration on the chromatogram (Figure 9 and Table 9).

[0322] The stability, fragmentation and aggregation tendency of the candidates were further evaluated by assessing the melting temperature (Tm1), aggregation temperature (Tagg266) and initial diameter by static light scattering (SLS) and dynamic light scattering (DLS) using UNcle (Unchained lab). Briefly, 3 × 9 μL of each sample was loaded into a Uni. Data from individual experiments were analyzed, outliers were discarded and the remaining data were averaged. Thermal ramp stability measurements were performed over 25-95 °C with a ramp rate of 0.3 °C / min and an incubation period of 120 s, with 10 DLS measurements recorded per sample at the beginning and end. DLS measurements (size distribution and polydispersity) were calculated using the UNcle software (version 5.03) correlation function. For SLS, the intensity of scattered light was measured at 266 nm and the aggregation temperature (Tagg) was calculated using UNcle software (version 5.03). Intrinsic fluorescence emission was measured at 473 nm and the centroid mean (BCM) was used to calculate the melting temperature (Tm) using the same software. The data is summarized in Table 9 and example profiles showing PMX051 and PMX063 are shown in Figure 10.

[0323] Example 10: Sequence analysis and candidate clustering. To expand the existing identified candidates with the desired properties, we searched for paired B cell receptor sequences derived from canine OX40L immunization. Given the query CDR3H peptide, we searched for candidate sequences with the same length of CDR3H but allowing up to two amino acid mutations. Using PMX051 and PMX063 as lead sequences, we identify 26 novel antibodies (PMX086-PMX111) (Table 2).

[0324] The 78 anti-OX40L antibodies were then subgrouped into 14 family groups according to V gene pairs.

[0325] Example 11 Fc variants Fc variant construction For antibody production, DNA constructs were generated to encode chimeric antibodies comprising selected canine IgG constant regions fused to the variable regions of the anti-human CD20 antibodies, rituximab (see US 5,736,137) or ofatumumab (sequences available at Drugbank https: / / go.drugbank.com / drugs / DB06650).

[0326] Canine IgG-B mutant variants (Def1-9, SEQ ID NOs: 722-730) were generated by site-directed mutagenesis. Specifically, human ofatumumab or rituximab variable regions and canine IgG-B mutant variants are PCR amplified using Q5 high fidelity DNA polymerase and assembled into a mammalian expression vector upstream sequence encoding either canine IgGB WT or Def1-9 (SEQ ID NOs: 721-730) using NEBuilder HIFI DNA Assembly (New England Biolabs). The Ofa-VH-cIgGB WT ofatumumab sequence is shown in SEQ ID NO: 731. In the expression vector, the heavy chain and antibiotic resistance gene expression units are flanked by DNA transposon piggyBac terminal inverted repeats, which mediate stable integration into host cells in the presence of piggyBac transposase. The expression vectors encoding the heavy and light chains are co-transfected with piggyBac transposase into a suitable mammalian cell line, such as CHO cells, to obtain stable expression. For antibody production, 3 x 10 6 The selected CHO cells are seeded in 3 ml of culture medium and incubated at 32° C., 5% CO2 with shaking at 200 rpm. 4% HyClone Cell Boost 7a supplement + 0.4% HyClone Cell Boost 7b supplement + 1% glucose is added to the medium on days 1, 4, 7, and 10. Culture supernatants are collected on day 12 and IgG concentrations are determined using surface plasmon resonance (Biacore 8K, Cytiva Life Sciences) using a Protein A chip.

[0327] Complement-dependent cytotoxicity (CDC) activity Canine lymphocytic tumor cell lines such as CLBL1 (University of Veterinary Medicine Vienna) or CLC (Umeki S. et al J.Vet.Med.Sci.,75:467-474(2013) PubMed=23196801;DOI=10.1292 / jvms.12-0448) can be used as target cells. These cells are stably transfected or nucleofected with an expression construct encoding the human CD20 protein (SEQ ID NO:732) to generate hCD20 expressing cells. Expression constructs were generated using the same methods as described above for antibody expression.

[0328] Transfected cells were selected for puromycin resistance and expressed hCD20 高 (Top 5%) cells were FACS sorted by staining for hCD20 expression using anti-human CD20 antibody (clone: ​​2H7, BioLegend).

[0329] To assess CDC activity, non-transfected (wild type) target lymphocytes or equivalent hCD20 expressing cells were used in a cell killing assay, where 5000 target cells per well of a 96-well plate were incubated with the anti-human CD20 canine Fc chimeric antibody described above and canine complement-preserved serum (BioIVT) at a final dilution of 1:12 for 2 hours at 37° C. and 5% CO2. The assay was set up using CLBL-1 cell medium (RPMI+1% L-glutamine+20% fetal bovine serum) made with heat-inactivated serum, such that the canine complement-preserved serum was the only source of complement.

[0330] Viable cells were then quantified using the CellTitre-Glo® Luminescent Cell Viability Assay (Promega) according to the assay protocol. This assay uses the ATP content of viable cells as an indicator of cell viability. Luminescence was measured on a CLARIOstar (BMG Labtech). Data was analyzed using MARS software (BMG Labtech) and the number of remaining viable cells was used to calculate the percentage killing in the presence of antibody using Microsoft Excel. Background signal was obtained from a sample of cells treated with 1% triton (there were no viable cells) and subtracted from the signal obtained from each test sample. Maximum signal (0% killing) was obtained from a sample of cells treated identically but where the antibody was omitted. Graphs were plotted in Microsoft Excel or GraphPad Prism. An exemplary CDC assay was performed using hCD20 expressing CLBL1 cells and WT CLBL1 cells, and titrations of IgGB WT or Def mutant antibodies with the ofatumumab variable region. Antibodies were used in serial 1:3 dilutions ranging from 10 μg / ml to 0.01 10 μg / ml.

[0331] All Def mutants tested (Def1, 2, 3, 5, 6, 7, 8, 9) completely abolished the ability of canine IgGB WT to kill hCD20 CLBL1 cells by complement-dependent cytotoxicity (data not shown).

[0332] Antibody-dependent cellular cytotoxicity (ADCC) activity Canine cell lines such as MDCK II cells (ATCC) were stably transfected or nucleofected with constructs encoding human CD20 protein and constructs expressing fluorescent proteins (i.e., GFP) as described above. Wild-type MDCK II cells expressing GFP were used as a control. Canine peripheral blood mononuclear cells (PBMCs, Envigo) were used as a source of effector cells. PBMCs were isolated from freshly drawn whole blood using Ficoll-Paque plus (Cytiva, GE17-1440-02) density gradient centrifugation with sodium heparin anticoagulant. Briefly, 10 ml of blood was diluted 1:1 with phosphate buffered saline (PBS), carefully layered on top of 15 ml of Ficoll-paque plus, and centrifuged at 800 rcf for 20' with slow acceleration and no brake at the end. The top layer and interphase discs were diluted with PBS and centrifuged at 1300 rpm for 10' to collect the PBMCs in a pellet and washed twice with PBS to remove any residual Ficoll. After the second centrifugation, the PBMCs were resuspended in medium (PBMC medium = RPMI + 10% heat inactivated fetal bovine serum + 1% penicillin-streptomycin + 1% non-essential amino acids + 1% L-glutamine + 1% sodium pyruvate + 1% HEPES) supplemented with 50 ng / ml recombinant canine IL-2 (R&D systems) and incubated at 37°C, 5% CO2 for 24 hours before use in the ADCC assay.

[0333] To evaluate the ADCC activity of the Def mutant antibodies, wild-type or hCD20-expressing MDCK II cells (both expressing GFP) were co-cultured with PBMCs at an effector to target ratio of 50:1 or 100:1, and IgGB WT or Def mutant antibodies bearing the ofatumumab variable region were titrated in a 1:1 mixture of MDCK II medium (DMEM + 1% L-glutamine + 10% fetal bovine serum) and PBMC medium for 24 hours at 37°C, 5% CO2.

[0334] The GFP signal, which is proportional to the number of viable cells per well, was used as a measure of the number of viable cells remaining in the well at the end of the 24-hour incubation. The GFP signal was measured on a CLARIOstar (BMG Labtech). Data was analyzed using MARS (BMG Labtech) and the percentage of killing in the presence of antibody was calculated using Microsoft Excel. A background signal was obtained from a sample of cells treated with 1% triton (there were no viable cells) and subtracted from the signal obtained from each test sample. A maximum signal (0% killing) was obtained from a sample of cells treated identically but in which the antibody was omitted. Graphs were plotted in Microsoft Excel or GraphPad Prism.

[0335] Def mutants 2, 3, and 7 were the best at reducing canine IgGB ADCC activity, significantly reducing canine IgGB ADCC activity up to 10 μg / ml (data not shown).

[0336] Example 12 Long-term and thermal stability After Protein A purification, anti-OX40L antibodies were eluted using IgG elution buffer (Pierce) and buffer acidity was neutralized using 1M TRIS pH 8.0. Candidate stability was assessed in such buffers or after buffer exchange into sodium acetate or glycine buffers at pH 5.5. After buffer exchange, candidate antibodies were concentrated to 5mg / ml before proceeding with analysis or incubation at 4°C or 37°C.

[0337] For long-term stability, candidate antibodies were incubated at 4° C. for up to 4 months. For thermal stability assessment, candidate antibodies were incubated at 37° C. for up to 28 days.

[0338] The stability, denaturation and aggregation tendency of the candidates were further evaluated by assessing the melting temperature (Tm1), aggregation temperature (Tagg266 and Tagg473) and initial diameter by static light scattering (SLS) and dynamic light scattering (DLS) using UNcle (Unchained lab). Briefly, 3 × 9 μL of each sample was loaded into a Uni. Data from individual experiments were analyzed, outliers were discarded and the remaining data were averaged. Thermal ramp stability measurements were performed over 25-95 °C with a ramp rate of 0.3 °C / min and a 120 s incubation period, with 10 DLS measurements recorded per sample at the beginning and end. DLS measurements (size distribution and polydispersity) were calculated using the correlation function of UNcle software (version 5.03). For SLS, the intensity of scattered light was measured at 266 nm or 473 nm and used to calculate the aggregation temperature (Tagg266 and Tagg473, respectively) using UNcle software (version 5.03). Intrinsic fluorescence emission was measured at 473 nm and the centroid mean (BCM) was used to calculate the melting temperature (Tm) using the same software. Thermal stability data at 37°C for PMX051, PMX063, PMX097, PMX098 and PMX154 are shown in Figures 11 and 12. Long-term stability data at 4°C for PMX097 and PMX154 are summarized in Table 10.

[0339] Example 13 Pharmacokinetic Profile To determine the pharmacokinetic profile of anti-OX40L antibodies, laboratory beagle dogs were intravenously injected with either PMX097 or PMX154 at 3.0 mg / kg. Blood samples were collected the day before and 2, 6, 24, 48 hours, 4, 8, 15, 21, 29, and 35 days after injection. After clotting, the blood was centrifuged at 7000 g for 5 minutes to separate the serum, which was then stored at -80°C.

[0340] After collection of all time points, pharmacokinetic profiles were determined by enzyme-linked immunosorbent assay (ELISA). Briefly, ELISA plates were coated with HIS-tagged trimeric OX40L protein (0.2 μg / ml in PBS, SEQ ID NO: 811) overnight at 4°C. The following day, plates were blocked for 2 hours with blocking buffer (PBS containing 0.05% tween20 and 1% bovine serum albumin fraction V (BSA)) and then washed 5 times with PBS containing 0.05% tween20. Serum was diluted 1 in 2000 in blocking buffer before application. Serial dilutions (1 in 2 dilutions) of PMX097 or PMX154 were prepared from a highest concentration of 50 μg / ml in dog serum. Standard dilutions were also diluted 1 in 2000 in blocking buffer before application to the ELISA plate. After 2 hours of incubation of serum and standards, the plates were washed 5 times and incubated for 1 hour with secondary antibody anti-dog IgG conjugated with biotin (Merck) diluted 1:100.000 in blocking buffer. After 5 more washes, the plates were incubated with streptavidin-HRP (Biolegend) diluted 1:5000 in blocking buffer, then washed again before adding TMB substrate (Pierce) and stopping the reaction with 0.2N sulfuric acid just before data acquisition. Absorbance at 450 nm and 650 nm was quantified using a plate reader (CLARIOstar, BMB Labtech). Data was analyzed using MARS software (BMG Labtech). Concentrations of samples in serum are determined by the MARS software using standard curves generated from serial dilutions of PMX097 or PMX154 plotted as a 4-parameter logistic curve fitting algorithm. The data shown in FIG. 13 was plotted using Prism and the half-life was calculated by fitting the points with a biphasic decay curve fit.

[0341] Example 14 Pharmacodynamic Profile The ability of PMX097 and PMX157 to suppress T cell activation in vivo was evaluated in laboratory beagle dogs. To induce T cell activation, dogs were immunized with keyhole limpet hemocyanin (KLH). The procedure schedule is shown in Table 11. Briefly, 20 dogs were divided into 5 groups that received different treatment regimens (Table 11). A single dose of 3 mg / kg or 0.5 mg / kg PMX097 or PMX154, or vehicle control, was injected intravenously on day 0. The day after antibody injection, all dogs received the first KLH injection. A second, intradermal, KLH injection was performed 3 weeks later, and 2 days later, two full thickness skin biopsies (punch biopsies) were collected: one at the KLH injection site and one in a non-injected area as a control.

[0342] For serum preparation, blood samples were collected the day before and 2, 6, 24, 48, 4, 8, 15, 21, 29, and 35 days after injection. After clotting, blood was centrifuged at 7000g for 5 min, and then frozen serum was separated. For PBMC isolation, whole blood was collected in tubes containing sodium heparin the day before and 8, 15, 21, 29, and 35 days after antibody injection. PBMC were isolated from whole blood on the same day of collection using lymphocyte separation medium (Corning), immediately frozen, and stored long-term in liquid nitrogen. Briefly, dog blood was diluted 1:1 with phosphate buffered saline (PBS), carefully layered on top of lymphocyte separation medium, and centrifuged at 800rcf for 20' with slow acceleration and without final braking. The top layer and interphase discs were diluted with PBS and centrifuged at 400rcf for 10' to collect PBMCs. The pelleted PBMCs were washed twice with PBS to remove any residual lymphocyte separation medium. After the second centrifugation, the PBMCs were resuspended in medium (PBMC medium = RPMI + 10% heat inactivated fetal bovine serum + 1% penicillin-streptomycin + 1% non-essential amino acids + 1% L-glutamine + 1% sodium pyruvate + 1% HEPES) and diluted 1:1 with freezing medium (80% heat inactivated FBS, 20% DMSO) before being frozen or used.

[0343] Determination of T cell activation by interferon gamma ELISpot The number of T cells activated in response to KLH stimulation was determined by interferon gamma (IFNγ) enzyme-linked immunosorbent spot (ELISpot) using a canine IFNγ ELISpot flex ALP kit (Mabtech).

[0344] Frozen PBMCs were thawed and rested to remove stained cells by culturing them in PBMC medium in low-attachment polypropylene tubes for 18-48 hours in a humidified incubator at 37 °C with 5% CO2. The day before setting up the experiment, ELISpot plates (Millipore) were activated by adding 15 μl of 35% ethanol per well and immediately washed five times with sterile distilled water. After activation, the plates were coated by incubating overnight at 4 °C with anti-canine IFNγ antibody (MT13) diluted to 15 μg / ml in PBS. The next day, the plates were washed five times with PBS and blocked for at least 30 min with PBMC medium. 50 μl of PBMC medium was added to each well after blocking alone (for no stimulation control) or after containing KLH (MERK) at 100 μg / ml (twice). As a positive control, 50 μl of PBMC medium containing 20 μg / ml (in duplicate) of phytohemagglutinin-L (PHA) (sigma-Aldrich) was added to corresponding wells.

[0345] Prior to seeding into ELISpot plates, PBMCs were counted using an automated CellDrop (DeNovix) cell counter with primary AO / PI settings. Briefly, PBMCs were resuspended and 10 μl of PBMCs were mixed with 10 μl of acridine orange / propidium iodine (AO / PI) working solution to distinguish live from dead cells before loading into the CellDrop automated cell counter. After centrifugation to remove dead cells and debris, PBMCs were resuspended at 4.4×10^6 cells per ml of PBMC medium and 50 μl of cell suspension was added to the plate on top of the stimulator and incubated for 20 hours in a humidified incubator at 37°C with 5% CO2.

[0346] The next day, cells are discarded and plates are washed 5 times with PBS before being incubated for 1 hour with detection antibody (MT166-biotin) diluted to 0.5 μg / ml in PBS with 0.5% FBS. After another 5 washes with PBS, plates are then incubated for 1 hour with streptavidin-ALP diluted 1:1000 in PBS with 0.5% FBS, washed 5 more times with PBS, and then BCIP / NBT+substrate (Mabtech) is added until spots are evident. After stopping the reaction with water washes, plates are air-dried. Spots were quantified using an ELISpot counter (Immunospot). After quality control using the ELISpot counter integrated software, data were plotted using Prism. Data are presented in FIG. 14 and show a significant reduction in the number of KLH-responsive circulating T cells in dogs treated with PMX097 and PMX154 at all time points analyzed. These data demonstrate the ability of both PMX097 and PMX154 to suppress T cell activation in vivo for up to 35 days when administered at both 3.0 mg / ml and 0.5 mg / ml.

[0347] Determination of anti-KLH IgM and IgG serum titers B cell activation and antibody secretion are also dependent on T helper cell stimulation. Therefore, a reduction in T cell activation should translate into a reduction in humoral responses. To evaluate the ability of PMX097 and PMX154 to reduce T cell-dependent antibody responses (TCDAR) after KLH immunization (Kawai R., Aida T. et al, The Journal of Toxicological Sciences, Vol. 38, No. 4, 571-579, 2013; Saghari M, Gal P, et al, Clinical Pharmacology & Therapeutics, Vol 111, N 5, May 2022), anti-KLH IgM and IgG serum titers were quantified by ELISA.

[0348] ELISA plates were coated overnight at 4° C. with KLH protein diluted to 1 μg / ml in PBS. The following day, plates were blocked for 2 h with blocking buffer (PBS containing 0.05% tween 20 and 1% bovine serum albumin fraction V (BSA)) and then washed 5 times with PBS containing 0.05% tween 20. Serum before application was diluted 1:6000 or 1:15000 in blocking buffer for anti-KLH IgM or IgG detection, respectively. After 2 h incubation with serum and standards, plates were washed 5 times and incubated for 1 h with secondary antibodies: anti-dog IgG conjugated with biotin (Merck) or goat anti-dog IgM diluted 1:5000 or 1:500 in blocking buffer, respectively. After five further washes, the plates are incubated with either streptavidin-HRP (Biolegend) or anti-goat HRP conjugated antibody diluted 1 in 5000 or 1 in 10000, respectively, in blocking buffer, then TMB substrate (Pierce) is added and washed again before the reaction is stopped with 0.2 N sulfuric acid immediately prior to data acquisition. Absorbance at 450 nm and 650 nm was quantified using a plate reader (CLARIOstar, BMB Labtech). Data were analyzed using MARS software (BMG Labtech). As standards were not available, data are presented as blank-corrected absorbance difference (Abs) at 450 nm minus blank-corrected Abs at 650 nm (Figures 15A and C) and normalized to vehicle control treated samples (Figures 14B and D). The data shown in FIG. 15 was plotted using Prism and demonstrates the ability of both PMX097 and PMX154 to reduce both anti-KLH IgM and IgG serum titers for up to 98 days post-dosing.

[0349] Effect of PMX097 and PMX154 on local inflammation of the skin. To evaluate the ability of PMX097 and PMX154 to reduce local inflammation in the skin, a second KLH immunization was administered intradermally. This allowed for the collection of skin biopsies and histological analysis of the injection site. As a control, each dog also produced a skin biopsy from a non-injected site. The skin biopsies were fixed overnight in 10% normal buffered formalin and then transferred to 70% ethanol the following day. After complete dehydration by incubation in ethanol 95% and then ethanol absolute for 1 hour each, the biopsies were transferred to xylene and then embedded in paraffin before being cut into 5 μm thick sections. The skin sections were then stained with hematoxylin and eosin and imaged using a wide-field microscope (Nikon). Figure 16 shows representative images showing the severe reduction in immune infiltration in the subcutaneous fat near the KLH injection site in dogs treated with PMX097 and PMX154.

[0350] To obtain an objective assessment of the phenotype, the hematoxylin and eosin stained slides were then submitted for histopathological evaluation. Microscopic changes were graded for severity utilizing a standard grading system: 0 = no significant change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked. The International Harmonization of Nomenclature and Diagnostic (INHAND) Criteria criteria were used as the basis for the evaluation--https: / / www.toxpath.org / inhand.asp. All tissue sections contained parts of the epidermis and dermis, but deeper subcutaneous adipose tissue and muscle layers were variably present. When subcutaneous adipose tissue or muscle layers were not present in the tissue sections, findings related to those layers were excluded from the analysis and are represented by a "-" symbol in the tables. The use of a numerical grade allows for a mechanism to calculate a total score lesion score that can be used to assess the prevalence and severity of tissue changes within and between groups. The results of the histopathological analysis are summarized in Tables 12 and 13.

[0351] Treatment with PMX097 and PMX154 at both 3.0 mg / kg and 0.5 mg / kg reduced the severity of immune infiltration in the KLH-injected area.

[0352] Example 15. Safety profile of PMX097 and PMX154 in laboratory beagle dogs.

[0353] The safety profile of PMX097 and PMX154 was evaluated in laboratory beagle dogs after intravenous injection of the two compounds at either 3.0 mg / kg or 0.5 mg / kg (Table 11). The dogs were monitored periodically during and after antibody infusion. To determine the effects of PMX097 and PMX154 on the health of the animals, complete blood chemistry and blood cell counts were performed on each dog at three time points immediately before (pre-bleed), 24 hours and 15 days after antibody infusion.

[0354] Regular monitoring revealed no abnormalities. All animals in all groups tolerated the treatment well and showed no visible side effects throughout the study. Blood cell counts and biochemical parameters were mostly within range at all time points, and there were no signs of toxicity in all treatment groups. All sequences of antibodies and antibody fragments designated "PMX" in Table 2, followed by a number, shown below, are within the scope of the present invention. [Table 2] TIFF2025506488000004.tif235153 TIFF2025506488000005.tif242153 TIFF2025506488000006.tif210153 TIFF2025506488000007.tif236153 TIFF2025506488000008.tif227153 TIFF2025506488000009.tif236153 TIFF2025506488000010.tif205153 TIFF2025506488000011.tif236153 TIFF2025506488000012.tif233153 TIFF2025506488000013.tif236153 TIFF2025506488000014.tif210153 TIFF2025506488000015.tif231153 TIFF2025506488000016.tif227153 TIFF2025506488000017.tif236153 TIFF2025506488000018.tif205153 TIFF2025506488000019.tif231153 TIFF2025506488000020.tif227153 TIFF2025506488000021.tif242153 TIFF2025506488000022.tif194153 TIFF2025506488000023.tif247153 TIFF2025506488000024.tif217153 TIFF2025506488000025.tif231153 TIFF2025506488000026.tif210153 TIFF2025506488000027.tif231153 TIFF2025506488000028.tif227153 TIFF2025506488000029.tif231153 TIFF2025506488000030.tif199153 TIFF2025506488000031.tif226153 TIFF2025506488000032.tif227153 TIFF2025506488000033.tif188153 TIFF2025506488000034.tif188153 TIFF2025506488000035.tif178153 TIFF2025506488000036.tif236153 TIFF2025506488000037.tif210153 TIFF2025506488000038.tif231153 TIFF2025506488000039.tif233153 TIFF2025506488000040.tif231153 TIFF2025506488000041.tif199153 TIFF2025506488000042.tif226153 TIFF2025506488000043.tif227153 TIFF2025506488000044.tif231153 TIFF2025506488000045.tif252153 TIFF2025506488000046.tif227153 TIFF2025506488000047.tif231153 TIFF2025506488000048.tif252153 TIFF2025506488000049.tif227153 TIFF2025506488000050.tif231153 TIFF2025506488000051.tif205153 TIFF2025506488000052.tif231153 TIFF2025506488000053.tif227153 TIFF2025506488000054.tif231153 TIFF2025506488000055.tif205153 TIFF2025506488000056.tif231153 TIFF2025506488000057.tif227153 TIFF2025506488000058.tif231153 TIFF2025506488000059.tif205153 TIFF2025506488000060.tif231153 TIFF2025506488000061.tif227153 TIFF2025506488000062.tif197153 TIFF2025506488000063.tif197153 TIFF2025506488000064.tif171153 TIFF2025506488000065.tif208153 TIFF2025506488000066.tif213153 TIFF2025506488000067.tif231153 TIFF2025506488000068.tif205153 TIFF2025506488000069.tif231153 TIFF2025506488000070.tif227153 TIFF2025506488000071.tif178153 TIFF2025506488000072.tif178153

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

[0355] Sequences used in the experiment SEQ ID NO:807 Monomeric OX40L probe amino acid sequence NGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVNLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLNSTLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSHHHHHHENLYFQGQVPPQYPPIQSIRVQFTRCENEKGCIITSPSKDETMKVQDNSIIINCDGFYLISLKGYFSEELSLSLYYRKGRGPLFSLSKVTSVDSIGVAYLAFKDKVYFNVTTHSTSYKDIQVNGGELILIHQNPGGFCAY SEQ ID NO:808 Trimeric OX40L probe (hIgG1 Fc fusion) DNA sequence SEQ ID NO:809 Trimeric OX40L probe (hIgG1 Fc fusion) amino acid sequence DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGKRSPQPQPKPQPKPEPEGSLHACGCAAAPDIKDLLSRLEELEGLVSSLREQGTGGGSGGRGLQQVPPQYPPIQSIRVQFTRCENEKGCII TSPSKDETMKVQDNSIIINCDGFYLISLKGYFSEELSLSLYYRKGRGPLFSLSKVTSVDSIGVAYLAFKDKVYFNVTTHSTSYKDIQVNGGELILIHQNPGGFCAY SEQ ID NO:810 Trimeric OX40L probe (HIS tag) DNA sequence CACCATCACcatcaccatGGCCCCGGCCAGGTGCAGCTGCACGCCTGCGGCTGCGCCGCCGCCCCCGACATCAAGGACCTGCTGAGCAGGCTGGAGGAGCTGGAGGGCCTGGTGAGCAGCCTGAGGGAGCAGGGCACCGGCGGCGGCAGCGGCGGCAGGGGCCTGCAGCAGGTGCCGCCTCAGTATCCTCCAATTCAAAGTATCAGAGTACAATTTACCAGGTGTGAGAATGAGAAAGGTTGCATCATCACATCCCCAAGCAAGGATGAAACTATGAAGGTGCAAGACAACTCAATCATCATTAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGTTACTTCTCTGAGGAGCTCAGCCTCAGCCTTTATTACCGAAAGGGTCGGGGACCCCTCTTCTCTCTGAGCAAGGTCACATCTGTTGACTCCATTGGAGTGGCCTATCTGGCTTTCAAGGACAAAGTCTACTTTAATGTGACCACTCACAGTACCTCCTACAAAGACATCCAGGTGAATGGTGGGGAATTGATTCTCATTCATCAAAATCCTGGTGGCTTCTGTGCCTAC Accession No. 811 Trimeric OX40L Probe (HIS-tag) Amino Acid Sequence HHHHHHGPGQVQLHACGCAAAPDIKDLLSRLEELEGLVSSLREQGTGGGSGGRGLQQVPPQYPPIQSIRVQFTRCENEKGCIITSPSKDETMKVQDNSIIINCDGFYLISLKGYFSEELSLSLYYRKGRGPLFSLSKVTSVDSIGVAYLAFKDKVYFNVTTHSTSYKDIQVNGGELILIHQNPGGFCAY

Claims

1. An antibody or fragment thereof that specifically binds to companion animal OX40L, wherein the antibody is selected from one of the following antibodies: HC CDR1 comprising SEQ ID NO:575 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:576 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:577 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:578 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:579 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:580 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:741 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:742 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:743 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:744 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:745 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:746 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising HC CDR1 comprising SEQ ID NO:275 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:276 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:277 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:278 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:279 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:280 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:395 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:396 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:397 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:398 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:399 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:400 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: an antibody comprising: a HC CDR1 comprising SEQ ID NO: 15 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 16 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 17 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 18 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 19 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 20 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR1 comprising SEQ ID NO:45 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:46 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:47 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:48 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:49 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:50 or a sequence having at least 60%, 70%, 80%, 90%, or 95% sequence identity thereto. an antibody comprising: an antibody comprising: a HC CDR1 comprising SEQ ID NO:65 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:66 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:67 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:68 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:69 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:70 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR1 comprising SEQ ID NO: 115 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO: 116 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO: 117 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO: 118 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO: 119 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO: 120 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO: 155 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO: 156 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO: 157 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO: 158 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO: 159 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO: 160 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:235 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:236 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:237 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:238 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:239 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:240 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:285 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:286 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:287 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:288 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:289 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:290 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:365 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:366 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:367 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:368 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:369 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:370 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising: HC CDR1 comprising SEQ ID NO:665 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:666 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:667 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:668 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:669 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:670 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising a CDR3; or HC CDR1 comprising SEQ ID NO:751 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:752 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:753 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:754 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:755 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:756 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. an antibody comprising a CDR3; or HC CDR1 comprising SEQ ID NO:771 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR2 comprising SEQ ID NO:772 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; HC CDR3 comprising SEQ ID NO:773 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR1 comprising SEQ ID NO:774 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; LC CDR2 comprising SEQ ID NO:775 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto; and LC CDR2 comprising SEQ ID NO:776 or a sequence having at least 60%, 70%, 80%, 90% or 95% sequence identity thereto. CDR3.

2. An antibody or fragment thereof that specifically binds to companion animal OX40L, wherein the antibody is selected from one of the following antibodies: an antibody comprising a HC CDR1 comprising SEQ ID NO:575, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:576, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:577, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:578, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:579, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:580, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:741 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:742 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:743 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:744 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:745 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:746 or a sequence having at least 80% sequence identity thereto; or an antibody comprising a HC CDR1 comprising SEQ ID NO:275, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:276, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:277, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:278, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:279, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:280, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:395, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:396, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:397, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:398, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:399, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:400, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 15 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 16 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 17 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 18 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 19 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 20 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:25, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:26, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:27, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:28, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:29, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:30, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:35, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:36, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:37, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:38, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:39, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:40, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:45, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:46, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:47, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:48, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:49, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:50, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:55, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:56, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:57, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:58, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:59, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:60, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:65, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:66, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:67, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:68, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:69, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:70, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:75, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:76, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:77, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:78, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:79, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:80, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:85, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:86, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:87, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:88, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:89, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:90, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:95, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:96, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:97, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:98, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:99, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:100, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 105, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 106, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 107, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 108, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 109, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 110, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 115, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO: 116, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO: 117, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO: 118, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO: 119, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO: 120, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 125 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 126 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 127 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 128 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 129 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 130 or a sequence having at least 80% sequence identity thereto; or an antibody comprising a HC CDR1 comprising SEQ ID NO: 135, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 136, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 137, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 138, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 139, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 140, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 145, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 146, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 147, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 148, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 149, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 150, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 155, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 156, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 157, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 158, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 159, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 160, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 165, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 166, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 167, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 168, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 169, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 170, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 175, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 176, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 177, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 178, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 179, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 180, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 185, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 186, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 187, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 188, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 189, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 190, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 195, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 196, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 197, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 198, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 199, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 200, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:205, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:206, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:207, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:208, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:209, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:210, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:215 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:216 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:217 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:218 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:219 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:220 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:225, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:226, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:227, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:228, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:229, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:230, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:235, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:236, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:237, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:238, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:239, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:240, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:245 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:246 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:247 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:248 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:249 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:250 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:255 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:25 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:257 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:258 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:259 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:260 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:265, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:266, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:267, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:268, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:269, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:270, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:285, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:286, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:287, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:288, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:289, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:290, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:295, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:296, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:297, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:298, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:299, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:300, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO: 305 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO: 306 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO: 307 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO: 308 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO: 309 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO: 310 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:315, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:316, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:317, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:318, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:319, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:320, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:325, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:326, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:327, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:328, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:329, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:330, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:335, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:336, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:337, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:338, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:339, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:340, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:345, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:346, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:347, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:348, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:349, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:350, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:355, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:356, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:357, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:358, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:359, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:360, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:365, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:366, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:367, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:368, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:369, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:370, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:375, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:376, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:377, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:378, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:379, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:380, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:385 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:386 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:387 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:388 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:389 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:390 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:405, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:406, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:407, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:408, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:409, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:410, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:41 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:416 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:417 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:418 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:419 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:420 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:425, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:426, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:427, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:428, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:429, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:430, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:435, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:436, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:437, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:438, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:439, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:440, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:445, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:446, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:447, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:448, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:449, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:440, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:455, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:456, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:457, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:458, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:459, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:460, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:465, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:466, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:467, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:468, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:469, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:470, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:475, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:476, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:477, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:478, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:479, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:480, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:485, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:486, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:487, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:488, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:489, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:490, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:495, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:496, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:497, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:498, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:499, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:500, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:505, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:506, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:507, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:508, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:509, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:510, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:515, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:516, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:517, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:518, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:519, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:520, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:525 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:526 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:527 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:528 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:529 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:530 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:535, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:536, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:537, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:538, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:539, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:540, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:545, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:546, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:547, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:548, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:549, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:550, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:555 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:556 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:557 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:558 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:559 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:560 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:565, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:566, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:567, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:568, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:569, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:570, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:585, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:586, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:587, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:588, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:589, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:590, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:595, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:596, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:597, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:598, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:599, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:600, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:605, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:606, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:607, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:608, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:609, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:610, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:615, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:616, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:617, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:618, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:619, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:620, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:625, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:626, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:627, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:628, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:629, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:630, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:635, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:636, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:637, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:638, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:639, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:640, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:645, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:646, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:647, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:648, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:649, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:650, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:655 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:656 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:657 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:658 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:659 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:660 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR comprising SEQ ID NO:665, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:666, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:667, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:668, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:669, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:670, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:675, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:676, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:677, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:678, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:679, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:680, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:685 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:686 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:687 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:688 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:689 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:690 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:695, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:696, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:697, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:698, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:699, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:700, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:705, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:706, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:707, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:708, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:709, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:710, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:715, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:716, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:717, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:718, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:719, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:720, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:751, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:752, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:753, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:754, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:755, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:756, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:761 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:762 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:763 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:764 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:765 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:766 or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:771, or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:772, or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:773, or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:774, or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:775, or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:776, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:781, or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:782, or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:783, or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:784, or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:785, or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:786, or a sequence having at least 80% sequence identity thereto; an antibody comprising a HC CDR1 comprising SEQ ID NO:791 or a sequence having at least 80% sequence identity thereto, a HC CDR2 comprising SEQ ID NO:792 or a sequence having at least 80% sequence identity thereto, a HC CDR3 comprising SEQ ID NO:793 or a sequence having at least 80% sequence identity thereto, a LC CDR1 comprising SEQ ID NO:794 or a sequence having at least 80% sequence identity thereto, a LC CDR2 comprising SEQ ID NO:795 or a sequence having at least 80% sequence identity thereto, and a LC CDR3 comprising SEQ ID NO:796 or a sequence having at least 80% sequence identity thereto; 1. An antibody comprising: a HC CDR1 comprising SEQ ID NO:801 or a sequence having at least 80% sequence identity thereto; a HC CDR2 comprising SEQ ID NO:802 or a sequence having at least 80% sequence identity thereto; a HC CDR3 comprising SEQ ID NO:803 or a sequence having at least 80% sequence identity thereto; a LC CDR1 comprising SEQ ID NO:804 or a sequence having at least 80% sequence identity thereto; a LC CDR2 comprising SEQ ID NO:805 or a sequence having at least 80% sequence identity thereto; and a LC CDR3 comprising SEQ ID NO:806 or a sequence having at least 80% sequence identity thereto.

3. The antibody or fragment of claim 1 , wherein the companion animal is a dog or a cat.

4. The antibody or fragment of claim 1 , wherein the antibody or fragment binds to canine OX40L.

5. the antibody or fragment thereof a) reducing, inhibiting, or neutralizing OX40 activity or activation in said companion animal or in cells of said companion animal; b) altering cytokine secretion in said companion animal or in cells of said companion animal, and / or c) The antibody or fragment of claim 1, which is capable of reducing leukocyte proliferation in the companion animal.

6. The antibody or fragment of claim 1 , wherein the antibody is a canine or caninized antibody.

7. 2. The antibody or antibody fragment of claim 1, wherein the antibody is selected from one of the following antibodies: an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 12, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 14, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 22, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 24, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 32, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 34, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 42, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 44, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 52, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 54, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 62, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 64, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 72, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 74, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 82, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 84, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 92, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 94, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 102, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 104, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 112, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 114, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 122, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 124, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 132, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 134, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 142, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 144, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 152, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 154, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 162, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 164, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 172, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 174, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 182, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 184, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 192, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 194, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 202, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 204, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 212, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 214, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 222, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 224, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 232, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 234, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 242, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 244, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 252, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 254, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 262, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 264, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 272, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 274, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 282, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 284, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 292, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 294, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 302, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 304, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 312, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 314, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 322, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 324, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 332, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 334, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 342, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 344, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 352, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 354, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 362, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 364, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 372, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 374, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 382, ​​or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 384, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 392, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 394, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 402, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 404, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 412, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 414, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 422, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 424, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 432, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 434, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 442, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 444, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 452, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 454, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 462, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 464, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 472, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 474, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 482, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 484, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:492, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:494, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 502, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 504, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 512, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 514, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 522, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 524, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 532, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 534, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 542, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 544, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 552, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 554, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 562, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 564, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 572, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 574, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 582, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 584, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 592, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 594, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 602, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 604, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO:612, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO:614, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 622, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 624, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 632, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 634, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 642, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 644, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 652, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 654, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 662, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 664, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 672, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 674, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 682, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 684, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 692, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 694, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 702, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 704, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 712, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 714, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 738, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 740, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 748, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 750, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 758, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 760, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 768, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 770, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 778, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 780, or a sequence having at least 80% sequence identity thereto; an antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 788, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 790, or a sequence having at least 80% sequence identity thereto; An antibody comprising an HC variable region comprising or consisting of SEQ ID NO: 798, or a sequence having at least 80% sequence identity thereto, and an LC variable region comprising or consisting of SEQ ID NO: 800, or a sequence having at least 80% sequence identity thereto.

8. 2. The antibody or fragment of claim 1, wherein the fragment is selected from F(ab')2, Fab, Fv, scFv, heavy chain, light chain, variable heavy (VH) chain, variable light (VL) chain, CDR region, single VH or VL domain, maxibody, minibody, intrabody, diabody, triabody, tetrabody, and bis-scFv, and said polypeptide containing at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide.

9. the antibody or fragment thereof a) conjugated to another moiety, and / or b) comprises a therapeutic moiety, a half-life extending moiety, or a label; The antibody or fragment of claim 1.

10. A pharmaceutical composition comprising the antibody or fragment thereof according to any one of claims 1 to 9.

11. The pharmaceutical composition according to claim 10 for the treatment or prevention of an OX40 or OX40L-mediated disease.

12. The pharmaceutical composition of claim 11 , wherein the disease is selected from an inflammatory disease or an autoimmune disease.

13. 12. The pharmaceutical composition of claim 11, wherein the disease is selected from atopic dermatitis, allergic dermatitis, pruritus, psoriasis, scleroderma, or eczema; responses associated with inflammatory bowel disease; ischemia-reperfusion; adult respiratory distress syndrome; asthma; meningitis; encephalitis; uveitis; autoimmune diseases; diseases involving leukocyte extravasation; central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome following sepsis or trauma, bacterial pneumonia, antigen-antibody complex-mediated diseases; and pulmonary inflammation.

14. The pharmaceutical composition of claim 11 , wherein the antibody or fragment is administered in combination with one or more therapeutic agents.

15. The one or more therapeutic agents may be selected from the group consisting of rapamycin (sirolimus), tacrolimus, cyclosporine, corticosteroids, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12 / IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VI_A4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulin, 15. The pharmaceutical composition of claim 14, wherein the antibody is selected from an anti-complement C5 antibody, an anti-a4b7 integrin antibody, an anti-IL6 antibody, an anti-IL6-R antibody, an anti-IL2R antibody, an anti-CD25 antibody, an anti-TNFa / TNFa-Fc molecule, an HDAC inhibitor, a JAK inhibitor, an anti-IL-31 antibody, an SYK inhibitor, an anti-IL-4Ra antibody, an anti-IL-13 antibody, an anti-TSLP antibody, a PDE4 inhibitor, loquietomab (Cytopoint®), and oclacitinib (Apoquel®).

16. 12. The pharmaceutical composition of claim 11 for use in a method for reducing cytokine secretion, the method comprising administering the pharmaceutical composition to a subject in need thereof.

17. A multispecific binding agent comprising the antibody or fragment thereof according to any one of claims 1 to 9.

18. A combination therapy comprising the antibody or fragment thereof according to any one of claims 1 to 9.

19. An immune complex comprising the antibody or fragment thereof according to any one of claims 1 to 9.

20. A kit comprising the antibody or fragment thereof according to any one of claims 1 to 9.

21. A method for detecting OX40L or OX40 in a companion animal, comprising contacting a test sample with the antibody or fragment of any of claims 1-9.

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