Anti-human PD-L2 antibody

Abstract

The present invention relates to anti-human PD-L2 antibodies or antigen-binding portions thereof, which specifically bind to human PD-L2, so as to block PD-L2 binding to PD-1, wherein preferably, the antibody or antigen-binding portion does not bind to mouse PD-L2 and human PD-L1 but binds to cynomolgus monkey PD-L2, preferably as determined by FACS analysis. The present invention also relates to nucleotide sequences encoding anti-human PD-L2 antibodies, vectors and cells containing the nucleotide sequences. The antibodies and / or compositions of the present invention are suitable for human therapy, such as cancer therapy, and / or for cell line-based bioassays for determining T cell signaling.

Description

[0001] The present invention relates to an anti-human PD-L2 antibody or an antigen-binding portion thereof, which specifically binds to human PD-L2, so as to block PD-L2 binding to PD-1, wherein preferably, the antibody or antigen-binding portion does not bind to mouse PD-L2 and human PD-L1 but binds to cynomolgus monkey PD-L2, preferably determined by FACS analysis. The present invention also relates to nucleotide sequences encoding anti-human PD-L2 antibodies, vectors and cells containing the nucleotide sequences. The antibodies and / or compositions of the present invention are suitable for human therapy, such as cancer therapy, and / or for cell line-based bioassays for determining T cell signaling. Background Art

[0002] The development of inhibitors of immune checkpoint pathways has been the subject of intensive research and drug development efforts for cancer treatment. Programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2 represent one class of inhibitory pathways. Binding of PD-1 to either of its ligands results in the delivery of inhibitory stimuli to T cells. Immunotherapies targeting the PD-1 axis have been developed and include monoclonal antibodies directed against the PD-1 receptor (OPDIVO (nivolumab), Bristol-Myers Squibb, Princeton, NJ, and KEYTRUDA (pembrolizumab), Merck and Co., Inc. Kenilworth, NJ)) and antibodies that bind to the PD-L1 ligand (MPDL3280A; TECENTR1Q (atezolizumab), Genentech, San Francisco, CA, MEDI4736; IMFINZI (durvalumab), AstraZeneca, London, UK, and BAVENCIO (avelumab), Pfizer, New York / Merck, Darmstadt, Germany). York, NY / Merck, Darmstadt, Germany). Antitumor effects have been demonstrated in several cancer types using both approaches (Bräheimer et al., NEJM 2012, 366:2455-65; Garon et al., NEJM 2015, 372:2018-28; Hamid et al., NEJM 2013, 369:134-44; Robert et al., Lancet 2014, 384:1109-17; Robert et al., NEJM 2015, 372:2521-32; Robert et al., NEJM 2015, 3 72:320-30; Topalian et al., NEJM 2012, 366:2443-54; Topalian et al., J Clin Oncol 2014, 32:1020-30; Volkow et al., NEJM 2013, 369:122-33).

[0003] Since PD-L1 is found to be upregulated in many human cancers, targeting the PD-1 / PD-L1 interaction has attracted particular attention (Dong et al., Nature Medicine 2002, 8 8:793-800). Similar to PD-L1, PD-L2 binding to PD-1 inhibits T cell proliferation, cytokine production, and T cell lysis (Latschmann et al., Nature Immunology 2001, 2:261-8; Roediger et al., European Journal of Immunology 2003, 33:3117-26). However, PD-L1 and PD-L2 show significant differences in protein sequence, tissue distribution, expression pattern, receptor-ligand binding specificity and affinity, and biological regulation. Although both genes encoding human PD-L1 and PD-L2 are located in the same region on chromosome 9p24.1 (Lachman et al., Nature Immunology 2001, 2:261-8), human PD-L1 and PD-L2 share only 38% amino acid identity (Lin et al., Proc. Natl. Acad. Sci. USA 2008, 105(8):3011-3016; Laza-Morna et al., Proc. Natl. Acad. Sci. USA 2008, 105(30):10483-10488). Such sequence differences explain a unique binding mode to PD-1, characterized by a nearly 3- to 6-fold higher affinity for PD-L2 compared to PD-L1 (Yonak et al., Biochim. Biophys. Res. Commun. 2003, 307(3):672-7. Cheng et al., J. Biol. Chem. 288:11771-11785, Li et al., J. Biol. Chem. 2017, 292(16):6799-6809). It has been shown that anti-PD-L1 antibodies that block the interaction of PD-1 with PD-L1 do not interfere with the interaction of PD-1 with PD-L2 (Inman et al., Clinical Cancer Research 2017, 23(8):1886-1890, Mesquita and Planchard, Future Oncology 2017, fon-2017-0373, Gil-Bazo, Lung Cancer Translational Research 2017, 6(Suppl 1):S35-S38.), indicating a differential molecular mechanism of structural orientation of the interaction with PD-1. This pattern is also reflected by the unique specificity of other receptors such as CD80, a second receptor for PD-L1 that does not bind to PD-L2 (Bout et al., Immunity 2007, 27(1):111-122). On the other hand, it was shown that PD-L2, but not PD-L1, interacts with the resense targeting molecule b (RGMb), a bone morphogenetic protein (BMP) co-receptor of the resense targeting molecule family (Xiao et al., J. Exp. Med. 2014, 211(5):943-59).Similar to PD-1, PD-L1 binding to CD80 inhibits T cell proliferation and cytokine release, while PD-L2 binding to RGMb was previously reported to potentially play an immunostimulatory role in mice (Zio et al., J. Exp. Med. 2001, 193(7):839-46, Liu et al., J. Exp. Med. 2003, 197(12):1721-30, Shen et al., J. Exp. Med. 2003, 198(1):31-8.). However, these studies were performed using mouse cell lines or mouse tissues, and similar effects were not confirmed in humans in multiple independent studies using human cell lines or tissues (Sanders et al., Eur. J. Immunol. 2005, 35(12):3561-9, Fisterhammer et al., Eur. J. Immunol. 2006, 36(5):1104-13, Zhang et al., Proc. Natl. Acad. Sci. USA 2006, 103(31):11695-700, Ni et al., Cell. Mol. Immunol. 2017, cmi. 2017.17). It is possible that mouse PD-L2 is functionally different from human PD-L2 in a context-dependent manner. Unlike PD-L1, which exhibits a universal and constitutive expression pattern on antigen presenting cells (APCs), T cells, and a variety of non-hematopoietic cell types, PD-L2 expression has been identified as being more restricted to lower baseline levels of antigen presenting cells under physiological conditions during development, although it has been shown that expression can be induced by various microenvironmental stimuli in other immune and non-immune cells (Laciman et al., 2001, supra, Lester Hughes et al., Cell Mol Immunol 2011, 49: 1-3; Lester Hughes et al., J Clin Invest 2011, 121: 3100-8; Messara et al., Cell Mol Immunol 2011, 48: 2214-9). Biologically and pathologically, PD-L1 and PD-L2 are associated with unique regulatory signaling pathways. In addition to both being stimulated by IFN-γ (Garcia-Diaz, et al., Cell Rep. 2017, 19(6): 1189-1201), PD-L1 has been shown to favor stimulation of Th1 cells and promote M1 macrophage stimulation (such as LPS), while PD-L2 is stimulated by Th2 and tends to be associated with M2 macrophage activation (Locke and Allison, Proc. Natl. Acad. Sci. USA 2003, 100(9): 5336-41). These biological differences between PD-L1 and PD-L2 reduced attention to the important role of PD-L2 in cancer immunology until the first patent for a mouse anti-human PD-L2 antibody that could be used for diagnostics was recently published (WO2017053250 A1).Combined studies using such optimized antibodies have shown that PD-L2 is significantly overexpressed in many types of cancer (Delke et al., Cancer Immunol Res 2015, 3(10): 1123-1129, Sridharan et al., Cancer Immunol Res 2016, 4(8): 679-87, Yeli et al., Clinical Cancer Res 2017, 23(12): 3158-3167), which is able to predict response to PD-1 therapy and correlate with patient survival (Yang et al., Leukemia 2014, 28(6): 1280-8). In summary, the two ligands may have unique functions within the PD-1 axis, with PD-L1 mediating a broader anti-inflammatory effect and PD-L2 playing a role in T cell priming (Xie et al., Current Opinion in Oncology 2015, 27: 384-91). Importantly, PD-L2 expression was demonstrated in several human tumors in some samples where PD-L1 expression was absent (Herbst et al., 2014, supra, Taube et al., Clin Cancer Res 2014, 20:5064-74; Schindler et al., J Clin Oncol 2016, 34 Suppl 15, 11506.; Liu et al., J Exp Med 2003, 197(12):1721-30; Radhakrishnan et al., Cancer Res 2004, 64(14):4965-72).

[0004] In the case of resistance to commercial targeted small molecules such as BRAF or MEK inhibitors (trametinib, vemurafenib, dabrafenib), PD-L2 surface expression on tumor cells and immune cells has been shown to be upregulated in the tumor microenvironment. Together with the oncogenic role of PD-L2 in promoting tumor cell intrinsic resistance to BRAFi and / or MEKi (Song et al., Cancer Discov. 2017, 7(11): 1248-1265.), this suggests that PD-L2 has an important role in mediating the desired resistance to BRAFi and / or MEKi. In addition, current retrospective analysis of cancer patient tissues has demonstrated patients with higher PD-L2 expression and lower PD-L1 expression (Ye Li et al., Clinical Cancer Research 2017, 23(12): 3158-3167), which indicates that there may be cancers and patient subpopulations that will benefit from anti-PD-L2 therapy.

[0005] Provide an antibody that binds to human PD-L2 for use in immunohistochemical detection of human PD-L2 expression in a tissue sample suitable for diagnosing cancer (WO 2017 / 053250 A1). In addition, US 2015 / 0197571 A1 discloses antibodies that bind to both PD-L1 and PD-L2.

[0006] However, there are no known therapeutic antibodies that bind to PD-L2. As optimal therapies targeting PD-L2 have not yet been discovered, there is a large unmet medical need.

[0007] The above technical problem is solved by the embodiments as defined in the claims. Summary of the invention

[0008] The present invention relates to an anti-human PD-L2 antibody or an antigen-binding portion thereof, which specifically binds to human PD-L2 so as to block PD-L2 from binding to PD-1. Preferably, the antibody or antigen-binding portion thereof of the present invention does not bind to mouse PD-L2 and human PD-L1 but binds to cynomolgus monkey PD-L2.

[0009] That is, the present invention provides for the first time an antibody that can block PD-L2 binding to PD-1 by targeting PD-L2, which has not been suggested or considered feasible so far. The anti-PD-L2 antibody according to the present invention exhibits better blocking activity and stronger immune cell activation measured by IL-2 ELISA when compared to the commercial mouse monoclonal MIH18, and exhibits similar or better activity when compared to the commercial anti-PD-1 antibody nivolumab. Surprisingly, as demonstrated in the accompanying examples, the use of anti-PD-L2 antibodies to inhibit the PD-1 / PD-L2 interaction on the ligand side can exhibit a stronger effect than inhibiting the interaction on the receptor side.

[0010] In one embodiment, the present invention relates to an antibody, or an antigen binding portion thereof, that specifically binds to human PD-L2 with an EC50 between about 0.05 nM and about 2 nM, preferably determined by FACS analysis, particularly under the conditions as specified in the accompanying Examples. In a preferred embodiment of the invention, the antibody, or an antigen binding portion thereof, of the invention specifically binds to PD-L2 with an EC50 between about 0.05 nM and about 1.6 nM, preferably 1.5 nM, preferably determined by FACS analysis, particularly under the conditions as specified in the accompanying Examples. Thus, it is preferred within the present invention that the antibody or antigen binding portion thereof specifically binds to human PD-L2 with an EC50 of about 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 nM, preferably with an EC50 of about 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5 or 1.6 nM. Thus, in one embodiment, an antibody or antigen binding portion thereof is provided that binds to human PD-L2 with an EC50 of at least 2 nM, preferably at least 1.5 nM. Methods for determining EC50 values ​​are well known to those skilled in the art.A preferred method within the present invention is FACS analysis, especially when performed under the conditions as specified in the accompanying examples.

[0011] As demonstrated in the accompanying Examples, the binding of the antibodies of the invention is thus much stronger than that of the control mouse monoclonal antibody MIH18, which binds to human PD-L2 with an EC50 of 3 nM under the same conditions.

[0012] It is preferred within the present invention that the antibody or antigen binding portion thereof specifically binds to human PD-L2 with an EC50 of about 0.05, 0.075, 0.1, 0.2, 0.3, 0.4 or 0.45 nm. Thus, in one embodiment, an antibody or antigen binding portion thereof is provided that binds to human PD-L2 with an EC50 of at least 0.45 nM. Surprisingly, the EC50 of the antibody or antigen binding portion thereof of the present invention is lower than the EC50 of the reference antibody as disclosed in WO 2010 / 036959, in particular antibody 24F.10C12.

[0013] The antibodies or antigen-binding fragments thereof of the present invention bind to human PD-L2 with a higher affinity than the reference antibodies MIH18 and / or 24F.10C12, either or in addition. The skilled person is aware of different strategies for determining the binding affinity of an antibody to an antigen. For example, binding affinity is usually measured by determining the EC50 of an antibody bound to an antigen. The binding EC50 depends largely on the antigen concentration of the sample. In addition, a slight deviation in binding EC50 was detected between chimeric antibodies and fully human antibodies. For this reason, it is only possible to compare antibodies tested under the same conditions. Preferably, the antibodies or antigen-binding portions thereof of the present invention have a higher binding affinity or a lower EC50 than the prior art antibodies MIH18 and 24F.10C12 when measured under the same experimental conditions.

[0014] As shown in the accompanying Examples, antibodies 2C4E4, 10D1-G1, 19C3-B310A9-D2, 19B3-B3, 12A1-D4, 10D1-G1 N31Q.N92Q.LC, 10A9-D2.N31Q.LC, 19B3-B3.M23K.M63L.HC and 2-19H2 have higher binding affinity to human PD-L2 than the two reference antibodies MIH18 and 24F.10C12 when tested under the same conditions.

[0015] In one embodiment of the present invention, an antibody or antigen binding portion thereof is provided that has a higher binding affinity or a lower EC50 than the prior art antibodies MIH18 and 24F.10C12 when measured under the same experimental conditions.

[0016] In certain embodiments, the antibodies or antigen-binding portions thereof of the invention are antibodies or antigen-binding portions thereof that block the binding of PD-L2 to PD-1 with an IC50 between about 0.01 and about 1 nM, preferably determined by flow cytometry depending on the antigen concentration, in particular under conditions as specified in the accompanying examples. Thus, it is preferred within the present invention that the antibodies or antigen-binding portions thereof block the binding of PD-L2 to PD-1 with an IC50 of about 0.01, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1 nM, preferably with an IC50 of about 0.01, 0.2, 0.3, 0.4, 0.5, 0.6 or 0.7 nM. Thus, in one embodiment, an antibody or antigen-binding portion thereof is provided that blocks the binding of PD-L2 to PD-1 with an IC50 of at least 1 nM, preferably at least 0.7 nM. Methods for determining IC50 values ​​are well known to those skilled in the art. A preferred method within the present invention is a flow cytometry-based analysis that depends on antigen concentration, especially when performed under the conditions as specified in the accompanying examples.

[0017] In a preferred embodiment of the present invention, an antibody or antigen-binding portion thereof is provided, which, if provided with a higher antigen concentration (expressed as 1.5×10 5 If the antigen concentration is 100 pM, then the antibody or antigen-binding portion thereof is provided, which binds to human PD-L2 with an EC50 of at least 0.45 nM.

[0018] The antibodies or antigen-binding fragments thereof of the present invention additionally or alternatively block PD-L2 binding to PD-1 more effectively than the reference antibodies MIH18 and 24F.10C12. The blocking efficiency can be measured by determining the IC50 value of the antibody blocking PD-L2 binding to PD-1. The blocking IC50 depends largely on the antigen concentration of the sample, as well as on other experimental details. In addition, a slight deviation in the blocking IC50 was detected between the chimeric antibody and the fully human antibody. Therefore, in a preferred embodiment, the antibody or antigen-binding portion thereof of the present invention is more effective in blocking PD-L2 binding to PD-1 or with a lower IC50 than the prior art antibodies MIH18 and 24F.10C12 when measured under the same experimental conditions.

[0019] As shown in the accompanying examples, antibodies 10D1-G1, 11C11-H5, 19C3-B310A9-D2, 19B3-B3 and 12A1-D4 blocked PD-L2 binding to PD-1 more effectively than prior art antibodies MIH18 and 24F.10C12 at higher and lower antigen concentrations. In addition, antibodies 1A1-C2, 2C4-E4 and 8B5-B1 blocked PD-L2 binding to PD-1 more effectively than prior art antibodies MIH18 and 24F.10C12 at higher and lower antigen concentrations. As demonstrated in the accompanying examples, the antibodies or antigen-binding portions thereof of the present invention may have the unexpected advantage of being able to activate TCR-mediated IL-2 expression.

[0020] Therefore, in various embodiments, the antibodies of the present invention or their antigen-binding portions thereof preferably activate TCR-mediated IL-2 expression with an EC50 between about 0.2 nM and about 1.5 nM, preferably as determined by ELISA analysis. Therefore, in a preferred embodiment of the present invention, the antibodies of the present invention or their antigen-binding portions thereof activate TCR-mediated IL-2 expression with an EC50 of about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4 or 1.5 nM. In one embodiment, an antibody or its antigen-binding portion thereof is provided, which activates TCR-mediated IL-2 expression with an EC50 of at least 1.5 nM. Methods for determining the activation of TCR-mediated IL-2 expression are well known to those skilled in the art. The antibodies of the present invention or their antigen-binding portions thereof have the unexpected advantage of inducing higher IL-2 levels when TCR-mediated IL-2 expression compared to the reference antibodies MIH18 and 24F.10C12. Top IL-2 levels depend on many factors, such as cell type, incubation time and antibody type. For this reason, it is only possible to compare antibodies tested under the same conditions. Figure 5 Figures 13A and 17 show that all antibodies of the invention induce higher IL-2 levels when contacted with T cells expressing human PD-L2 and PD-1 than prior art antibodies MIH18 and 24F.10C12. In one embodiment, the antibody of the invention is a chimeric antibody, a humanized antibody or a fully human antibody.

[0021] In a preferred embodiment, the antibody or antigen-binding portion thereof of the invention comprises at least one, two, three, four, five or preferably six CDR sequences contained in the heavy chain variable region and / or the light chain variable region, wherein the heavy chain variable region and / or the light chain variable region are defined in any one of the following clauses a) to q), respectively.

[0022] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0023] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0024] c) a heavy chain variable region having the sequence of SEQ ID NO:34 and a light chain variable region having the sequence of SEQ ID NO:42;

[0025] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0026] e) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0027] f) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0028] g) a heavy chain variable region having the sequence of SEQ ID NO: 112 and a light chain variable region having the sequence of SEQ ID NO: 120;

[0029] h) a heavy chain variable region having the sequence of SEQ ID NO: 128 and a light chain variable region having the sequence of SEQ ID NO: 132;

[0030] i) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0031] j) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0032] k) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0033] l) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:212;

[0034] m) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0035] n) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0036] o) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0037] p) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 226; or

[0038] q) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 230.

[0039] Alternatively, the antibody or antigen-binding portion thereof of the invention comprises six CDR sequences contained in said heavy chain variable region and light chain variable region, said heavy chain variable region and light chain variable region being as defined in any one of the following clauses a) to q), respectively, wherein at most 1, 2, or 3 amino acid residues in said CDR sequences are substituted:

[0040] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0041] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0042] c) a heavy chain variable region having the sequence of SEQ ID NO:34 and a light chain variable region having the sequence of SEQ ID NO:42;

[0043] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0044] e) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0045] f) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0046] g) a heavy chain variable region having the sequence of SEQ ID NO: 112 and a light chain variable region having the sequence of SEQ ID NO: 120;

[0047] h) a heavy chain variable region having the sequence of SEQ ID NO: 128 and a light chain variable region having the sequence of SEQ ID NO: 132;

[0048] i) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0049] j) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0050] k) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0051] l) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:212;

[0052] m) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0053] n) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160; or

[0054] o) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 26; or

[0055] p) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 226; or

[0056] q) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 230.

[0057] In one embodiment, the present invention relates to an antibody or antigen-binding portion thereof, comprising three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0058] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of SEQ ID NO:14, CDR-L3 of SEQ ID NO:16; or

[0059] b) CDR-H1 of SEQ ID NO:20, CDR-H2 of SEQ ID NO:22, CDR-H3 of SEQ ID NO:24, and CDR-L1 of SEQ ID NO:28, CDR-L2 of SEQ ID NO:30, CDR-L3 of SEQ ID NO:32; or

[0060] c) CDR-H1 of SEQ ID NO:36, CDR-H2 of SEQ ID NO:38, CDR-H3 of SEQ ID NO:40 and CDR-L1 of SEQ ID NO:44, CDR-L2 of SEQ ID NO:46, CDR-L3 of SEQ ID NO:48; or

[0061] d) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0062] e) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0063] f) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0064] g) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 116, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 122, CDR-L2 of SEQ ID NO: 124, CDR-L3 of SEQ ID NO: 126; or

[0065] h) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 130, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 134, CDR-L2 of SEQ ID NO: 136, CDR-L3 of SEQ ID NO: 138; or

[0066] i) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0067] j) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0068] k) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0069] 1) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:216; or

[0070] m) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0071] n) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0072] o) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 28, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0073] p) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 228; or

[0074] q) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0075] r) variants of said CDR-H1 and said CDR-H2 and said CDR-H3 and said CDR-L1 and said CDR-L2 and said CDR-L3 as shown in a) to q), wherein at most 1, 2, or 3 amino acid residues in said CDR sequences are substituted, specifically, in a conservative substitution pattern as defined herein.

[0076] In a preferred embodiment, the antibody or antigen-binding portion thereof of the invention comprises three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0077] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of SEQ ID NO:14, CDR-L3 of SEQ ID NO:16; or

[0078] b) CDR-H1 of SEQ ID NO:20, CDR-H2 of SEQ ID NO:22, CDR-H3 of SEQ ID NO:24, and CDR-L1 of SEQ ID NO:28, CDR-L2 of SEQ ID NO:30, CDR-L3 of SEQ ID NO:32; or

[0079] c) CDR-H1 of SEQ ID NO:36, CDR-H2 of SEQ ID NO:38, CDR-H3 of SEQ ID NO:40 and CDR-L1 of SEQ ID NO:44, CDR-L2 of SEQ ID NO:46, CDR-L3 of SEQ ID NO:48; or

[0080] d) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0081] e) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0082] f) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0083] g) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 116, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 122, CDR-L2 of SEQ ID NO: 124, CDR-L3 of SEQ ID NO: 126; or

[0084] h) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 130, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 134, CDR-L2 of SEQ ID NO: 136, CDR-L3 of SEQ ID NO: 138; or

[0085] i) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0086] j) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0087] k) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0088] 1) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:216; or

[0089] m) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0090] n) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0091] o) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 28, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0092] p) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 228; or

[0093] q) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32.

[0094] In one embodiment, an antibody or antigen-binding portion thereof of the invention comprises a heavy chain variable region and a light chain variable region, wherein

[0095] a) the heavy chain variable region has the sequence of SEQ ID NO: 2 and the light chain variable region has the sequence of SEQ ID NO: 10;

[0096] b) the heavy chain variable region has the sequence of SEQ ID NO: 18 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0097] c) the heavy chain variable region has the sequence of SEQ ID NO:34 and the light chain variable region has the sequence of SEQ ID NO:42;

[0098] d) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:58;

[0099] e) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:66;

[0100] f) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0101] g) the heavy chain variable region has the sequence of SEQ ID NO: 112 and the light chain variable region has the sequence of SEQ ID NO: 120;

[0102] h) the heavy chain variable region has the sequence of SEQ ID NO: 128 and the light chain variable region has the sequence of SEQ ID NO: 132;

[0103] i) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0104] j) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0105] k) the heavy chain variable region has the sequence of SEQ ID NO: 166 and the light chain variable region has the sequence of SEQ ID NO: 174;

[0106] 1) the heavy chain variable region has the sequence of SEQ ID NO: 96 and the light chain variable region has the sequence of SEQ ID NO: 212;

[0107] m) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 218;

[0108] n) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0109] o) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0110] p) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 226;

[0111] q) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 230; or

[0112] r) variants of the heavy chain variable region and / or the light chain variable region as shown in a) to q), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in the form of conservative substitutions defined herein.

[0113] In a preferred embodiment, the antibody or antigen-binding portion thereof of the present invention comprises a heavy chain variable region and a light chain variable region, wherein

[0114] a) the heavy chain variable region has the sequence of SEQ ID NO: 2 and the light chain variable region has the sequence of SEQ ID NO: 10;

[0115] b) the heavy chain variable region has the sequence of SEQ ID NO: 18 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0116] c) the heavy chain variable region has the sequence of SEQ ID NO:34 and the light chain variable region has the sequence of SEQ ID NO:42;

[0117] d) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:58;

[0118] e) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:66;

[0119] f) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0120] g) the heavy chain variable region has the sequence of SEQ ID NO: 112 and the light chain variable region has the sequence of SEQ ID NO: 120;

[0121] h) the heavy chain variable region has the sequence of SEQ ID NO: 128 and the light chain variable region has the sequence of SEQ ID NO: 132;

[0122] i) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0123] j) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0124] k) the heavy chain variable region has the sequence of SEQ ID NO: 166 and the light chain variable region has the sequence of SEQ ID NO: 174;

[0125] 1) the heavy chain variable region has the sequence of SEQ ID NO: 96 and the light chain variable region has the sequence of SEQ ID NO: 212;

[0126] m) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 218;

[0127] n) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0128] o) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0129] p) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 226; or

[0130] q) the heavy chain variable region has the sequence of SEQ ID NO:220 and the light chain variable region has the sequence of SEQ ID NO:230.

[0131] Within the present invention, at most 1, 2 or 3 amino acids in the CDR sequence may be substituted. Preferably, the amino acids in the CDR sequence are substituted by any amino acid in such a way that the substitution does not substantially reduce the ability of the antibody to bind to human PD-L2, so as to block the binding of PD-L2 to PD-1. More preferably, the amino acid substitutions made in the CDR sequence are conservative substitutions.

[0132] Alternatively, the amino acid located in light chain residues N31 and / or N92 and / or located in heavy chain residues M23 and / or M63 may be substituted. Preferably, the substitution comprises N31Q, N92Q and / or N92Y substitutions in the light chain and / or M23K and / or M63L substitutions in the heavy chain.

[0133] In a specific embodiment of the invention, the antibody or its antigen binding portion may be an antibody or its antigen binding portion of IgG1, IgG2, IgG3 or IgG4 isotype. As used herein, "isotype" refers to the antibody class (e.g., IgG1, IgG2, IgG3 or IgG4) encoded by the heavy chain constant region gene. The antibody may be a full-length antibody or may include only an antigen binding portion, such as an antibody variable domain of IgG1, IgG2, IgG3 or IgG4, or may consist of a Fab fragment, a F(ab')2 fragment or a Fv fragment.

[0134] In a specific embodiment, the antibody or antigen binding portion of the invention is an antibody or antigen binding portion of the IgG1 isotype.

[0135] In one embodiment, the antibody or antigen binding portion of the present invention is a monospecific, bispecific, trispecific or multispecific antigen binding molecule. In this regard, the antibody or antigen binding portion thereof may comprise a portion that binds to human PD-L2 as defined above, and a second and / or additional portion that also binds to human PD-L2 but a different epitope and / or a second and / or additional portion that binds to a different protein. The different proteins may be, for example, proteins that are functionally similar to PD-L2 or proteins involved in the same or similar signaling cascade. Exemplary proteins are PD-L1, PD-1, but in one embodiment, may be tumor cell-specific antigens, antigens specific for virally infected cells, or T cell co-inhibitors.

[0136] In another embodiment, the antibodies or antigen binding portions of the invention block PD-L2 binding to another receptor in addition to PD-1. In this regard, the antibodies or antigen binding portions may bind to PD-L2 in a manner that blocks PD-L2 binding to other receptors (compared to PD-1). Preferably, these receptors may be receptors located on the surface of immune cells.

[0137] In another embodiment, an antibody, or antigen binding portion thereof, is provided that binds to the same epitope and / or competes for the same epitope as any of the antibodies or antigen binding portions of the present invention.

[0138] The present invention relates to a nucleic acid molecule comprising a nucleotide sequence encoding the antibody of the present invention.

[0139] In one embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0140] a) CDR-H1 of SEQ ID NO:3, CDR-H2 of SEQ ID NO:5, CDR-H3 of SEQ ID NO:7, and CDR-L1 of SEQ ID NO:11, CDR-L2 of SEQ ID NO:13, CDR-L3 of SEQ ID NO:15; or

[0141] b) CDR-H1 of SEQ ID NO: 19, CDR-H2 of SEQ ID NO: 21, CDR-H3 of SEQ ID NO: 23, and CDR-L1 of SEQ ID NO: 27, CDR-L2 of SEQ ID NO: 29, CDR-L3 of SEQ ID NO: 31; or

[0142] c) CDR-H1 of SEQ ID NO:35, CDR-H2 of SEQ ID NO:37, CDR-H3 of SEQ ID NO:39, and CDR-L1 of SEQ ID NO:43, CDR-L2 of SEQ ID NO:45, CDR-L3 of SEQ ID NO:47; or

[0143] d) CDR-H1 of SEQ ID NO:51, CDR-H2 of SEQ ID NO:53, CDR-H3 of SEQ ID NO:55 and CDR-L1 of SEQ ID NO:59, CDR-L2 of SEQ ID NO:61, CDR-L3 of SEQ ID NO:63; or

[0144] e) CDR-H1 of SEQ ID NO:51, CDR-H2 of SEQ ID NO:53, CDR-H3 of SEQ ID NO:55, and CDR-L1 of SEQ ID NO:59, CDR-L2 of SEQ ID NO:61, CDR-L3 of SEQ ID NO:67; or

[0145] f) CDR-H1 of SEQ ID NO:97, CDR-H2 of SEQ ID NO:99, CDR-H3 of SEQ ID NO:101, and CDR-L1 of SEQ ID NO:105, CDR-L2 of SEQ ID NO:107, CDR-L3 of SEQ ID NO:109; or

[0146] g) CDR-H1 of SEQ ID NO: 113, CDR-H2 of SEQ ID NO: 115, CDR-H3 of SEQ ID NO: 117, and CDR-L1 of SEQ ID NO: 121, CDR-L2 of SEQ ID NO: 123, CDR-L3 of SEQ ID NO: 125; or

[0147] h) CDR-H1 of SEQ ID NO: 113, CDR-H2 of SEQ ID NO: 129, CDR-H3 of SEQ ID NO: 117, and CDR-L1 of SEQ ID NO: 133, CDR-L2 of SEQ ID NO: 135, CDR-L3 of SEQ ID NO: 137; or

[0148] i) CDR-H1 of SEQ ID NO:97, CDR-H2 of SEQ ID NO:141, CDR-H3 of SEQ ID NO:143 and CDR-L1 of SEQ ID NO:105, CDR-L2 of SEQ ID NO:147, CDR-L3 of SEQ ID NO:149; or

[0149] j) CDR-H1 of SEQ ID NO: 153, CDR-H2 of SEQ ID NO: 155, CDR-H3 of SEQ ID NO: 157, and CDR-L1 of SEQ ID NO: 161, CDR-L2 of SEQ ID NO: 29, CDR-L3 of SEQ ID NO: 163; or

[0150] k) CDR-H1 of SEQ ID NO: 167, CDR-H2 of SEQ ID NO: 169, CDR-H3 of SEQ ID NO: 171, and CDR-L1 of SEQ ID NO: 175, CDR-L2 of SEQ ID NO: 177, CDR-L3 of SEQ ID NO: 179; or

[0151] 1) CDR-H1 of SEQ ID NO:97, CDR-H2 of SEQ ID NO:99, CDR-H3 of SEQ ID NO:101, and CDR-L1 of SEQ ID NO:213, CDR-L2 of SEQ ID NO:107, CDR-L3 of SEQ ID NO:215; or

[0152] m) CDR-H1 of SEQ ID NO:97, CDR-H2 of SEQ ID NO:141, CDR-H3 of SEQ ID NO:143, and CDR-L1 of SEQ ID NO:213, CDR-L2 of SEQ ID NO:147, CDR-L3 of SEQ ID NO:149; or

[0153] n) CDR-H1 of SEQ ID NO: 153, CDR-H2 of SEQ ID NO: 221, CDR-H3 of SEQ ID NO: 157, and CDR-L1 of SEQ ID NO: 161, CDR-L2 of SEQ ID NO: 29, CDR-L3 of SEQ ID NO: 163; or

[0154] o) CDR-H1 of SEQ ID NO: 153, CDR-H2 of SEQ ID NO: 221, CDR-H3 of SEQ ID NO: 157, and CDR-L1 of SEQ ID NO: 27, CDR-L2 of SEQ ID NO: 29, CDR-L3 of SEQ ID NO: 31; or

[0155] p) CDR-H1 of SEQ ID NO: 153, CDR-H2 of SEQ ID NO: 221, CDR-H3 of SEQ ID NO: 157, and CDR-L1 of SEQ ID NO: 161, CDR-L2 of SEQ ID NO: 29, CDR-L3 of SEQ ID NO: 227; or

[0156] q) CDR-H1 of SEQ ID NO:153, CDR-H2 of SEQ ID NO:221, CDR-H3 of SEQ ID NO:157 and CDR-L1 of SEQ ID NO:161, CDR-L2 of SEQ ID NO:29, CDR-L3 of SEQ ID NO:31.

[0157] In another embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding a heavy chain variable region and a light chain variable region, wherein the

[0158] a) the heavy chain variable region has the sequence SEQ ID NO: 1 and the light chain variable region has the sequence SEQ ID NO: 9;

[0159] b) the heavy chain variable region has the sequence of SEQ ID NO: 17 and the light chain variable region has the sequence of SEQ ID NO: 25;

[0160] c) the heavy chain variable region has the sequence of SEQ ID NO:33 and the light chain variable region has the sequence of SEQ ID NO:41;

[0161] d) the heavy chain variable region has the sequence of SEQ ID NO:49 and the light chain variable region has the sequence of SEQ ID NO:57;

[0162] e) the heavy chain variable region has the sequence of SEQ ID NO:49 and the light chain variable region has the sequence of SEQ ID NO:65;

[0163] f) the heavy chain variable region has the sequence of SEQ ID NO:95 and the light chain variable region has the sequence of SEQ ID NO:103;

[0164] g) the heavy chain variable region has the sequence of SEQ ID NO: 111 and the light chain variable region has the sequence of SEQ ID NO: 119;

[0165] h) the heavy chain variable region has the sequence of SEQ ID NO: 127 and the light chain variable region has the sequence of SEQ ID NO: 131;

[0166] i) the heavy chain variable region has the sequence of SEQ ID NO: 139 and the light chain variable region has the sequence of SEQ ID NO: 145;

[0167] j) the heavy chain variable region has the sequence of SEQ ID NO: 151 and the light chain variable region has the sequence of SEQ ID NO: 159;

[0168] k) the heavy chain variable region has the sequence of SEQ ID NO: 165 and the light chain variable region has the sequence of SEQ ID NO: 173;

[0169] 1) the heavy chain variable region has the sequence of SEQ ID NO: 95 and the light chain variable region has the sequence of SEQ ID NO: 211;

[0170] m) the heavy chain variable region has the sequence of SEQ ID NO: 139 and the light chain variable region has the sequence of SEQ ID NO: 217;

[0171] n) the heavy chain variable region has the sequence of SEQ ID NO: 219 and the light chain variable region has the sequence of SEQ ID NO: 159;

[0172] o) the heavy chain variable region has the sequence of SEQ ID NO: 219 and the light chain variable region has the sequence of SEQ ID NO: 25;

[0173] p) the heavy chain variable region has the sequence of SEQ ID NO: 219 and the light chain variable region has the sequence of SEQ ID NO: 225; or

[0174] q) the heavy chain variable region has the sequence of SEQ ID NO:219 and the light chain variable region has the sequence of SEQ ID NO:229.

[0175] In addition, the present invention relates to an expression vector comprising the nucleic acid sequence of the present invention. The present invention further relates to a cell comprising the expression vector of the present invention. In addition, the present invention relates to a method for producing an antibody, the method comprising culturing the cell of the present invention, wherein the cell comprises the nucleotide sequence of the present invention. In a specific embodiment, the method for producing an antibody comprises culturing the cell of the present invention under conditions suitable for allowing effective production of the antibody of the present invention.

[0176] Furthermore, the present invention relates to a pharmaceutical composition comprising the antibody or antigen-binding portion thereof of the present invention.

[0177] Furthermore, the present invention relates to a pharmaceutical composition comprising the nucleic acid molecule or expression vector of the present invention.

[0178] In another embodiment, a pharmaceutical composition is provided, comprising the antibody or nucleic acid molecule of the present invention and a pharmaceutically acceptable carrier and / or excipient.

[0179] In addition, the antibody of the present invention, the nucleic acid molecule of the present invention, the expression vector of the present invention or the pharmaceutical composition of the present invention is provided for use in human therapy. In a specific embodiment, the antibody of the present invention, the nucleic acid molecule of the present invention, the expression vector of the present invention or the pharmaceutical composition of the present invention is provided for use in cancer therapy, especially for human cancer therapy.

[0180] In a certain embodiment, the antibody of the present invention, the nucleic acid molecule of the present invention, the expression vector of the present invention or the pharmaceutical composition of the present invention is provided for use in human therapy or cancer therapy, in particular for use in human cancer therapy, wherein the therapeutic effect is based on blocking the interaction between PD-1 and PD-L2.

[0181] In another embodiment, an antibody of the present invention, a nucleic acid molecule of the present invention, an expression vector or a pharmaceutical composition for use according to the present invention is provided, wherein the therapeutic effect further comprises antibody-dependent cellular cytotoxicity (ADCC).

[0182] In one embodiment, an antibody or antigen binding portion of the invention, a nucleic acid molecule of the invention, an expression vector of the invention or a pharmaceutical composition of the invention is provided for use in human therapy or cancer therapy, in particular for use in human cancer therapy, in combination with other therapies, preferably such as chemotherapy, antibody therapy and / or radiation therapy.

[0183] In another aspect, the invention relates to a cell line based bioassay using serial dilutions of the antibodies of the invention to determine T cell signaling in a system that mimics the interaction between APCs (antigen presenting cells) and T cells.

[0184] In another embodiment, a kit is provided, comprising the antibodies of the present invention for use in cell line-based biological assays. BRIEF DESCRIPTION OF THE DRAWINGS

[0185] Figure 1 Anti-PD-L2 antibody binds to CHO-K1 cells expressing human PD-L2

[0186] CHO-K1 cells expressing human PD-L2 were incubated with different concentrations of chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0187] Figure 2 . Anti-PD-L2 antibody binds to NCI-H226 lung cancer cells

[0188] NCI-H226 cells were incubated with chimeric anti-PD-L2 antibodies at different concentrations. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0189] Figure 3 Blocking hPD-1 binding to CHO-K1 / hPD-L2 cells

[0190] CHO-K1 hPD-L2 cells were incubated with chimeric anti-PD-L2 antibodies at different concentrations. Cells were washed and recombinant hPD-1-hFc-biotin (BPS Life Sciences) was added at a concentration of 0.5 μg / ml. Bound human PD-1 was detected using streptavidin-PE (Biolegend) after washing. Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0191] Figure 4 Blocking hPD-L2 binding to HEK293 cells expressing hPD-1

[0192] Recombinant hPD-L2-hFc-biotin at a concentration of 100 pM was incubated with chimeric anti-PD-L2 antibodies for 1 hour and then added to HEK293T-hPD-1 cells. After washing, bound hPD-L2 was detected with streptavidin-APC (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0193] Figure 5 TCR-mediated IL-2 upregulation upon inhibition of PD-1 / PD-L2 interaction

[0194] Jurkat T cells expressing hPD-1 and hPD-L2 were treated with anti-CD3 antibodies combined with chimeric anti-PD-L2 antibodies at different concentrations and cultured for 18 hours. Supernatants were collected and IL-2 levels were determined using an IL-2 specific ELISA kit (Biolegend).

[0195] Figure 6 Deletion and cross-reactivity of mouse PD-L2

[0196] HEK293T cells expressing mouse PD-L2 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with FITC-labeled anti-rat IgG Ab (Thermo Fisher Scientific). Flow cytometry analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). PE-labeled anti-mouse PD-L2 clone TY25 served as a positive control. All peaks except the positive control in Figure 6F overlap.

[0197] Figure 7. Deletion cross-reactivity with human PD-L1

[0198] HEK293T cells expressing human PD-L1 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with FITC-labeled anti-rat IgG Ab (Thermo Fisher Scientific). Flow cytometry analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). PE-labeled anti-human PD-L1 clone MIH1 served as a positive control. All peaks overlap except the positive control in Figure 7F.

[0199] Figure 8 Cross-reactivity with cynomolgus monkey PD-L2

[0200] HEK293T cells expressing cynomolgus monkey PD-L2 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). In Figure 8A, the signal of cynomolgus monkey No. 2 APC.002 overlaps with that of cynomolgus monkey negative 001.

[0201] Fig. 9 Anti-PD-L2 binds to CHO-K1 expressing human PD-L2 (FACS)

[0202] CHO-K1 cells expressing human PD-L2 were incubated with different concentrations of chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0203] Fig.10 Anti-PD-L2 binds to endogenous PD-L2 on NCI-H226 cells

[0204] NCI-H226 cells were incubated with chimeric anti-PD-L2 antibodies at different concentrations. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0205] Fig.11 Blocking the interaction between PD-L2 and PD-1: Higher antigen concentration

[0206] CHO-K1 hPD-L2 cells were incubated with chimeric anti-PD-L2 antibodies at different concentrations. Cells were washed and recombinant hPD-1-hFc-biotin (BPS Life Sciences) was added at a concentration of 0.5 μg / ml. Bound human PD-1 was detected using streptavidin-PE (Biolegend) after washing. Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0207] Fig.12 Blocking the interaction between PD-L2 and PD-1: Lower antigen concentration

[0208] Recombinant hPD-L2-hFc-biotin at a concentration of 100 pM was incubated with chimeric anti-PD-L2 antibodies for 1 hour and then added to HEK293T-hPD-1 cells. After washing, bound hPD-L2 was detected with streptavidin-APC (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0209] Figure 13 TCR-mediated IL-2 upregulation upon PD-L2 blockade

[0210] Jacquard T cells expressing hPD-1 and hPD-L2 were treated with anti-CD3 antibody combined with chimeric anti-PD-L2 antibody at different concentrations and cultured for 18 hours. Supernatants were collected and IL-2 levels were determined using an IL-2 specific ELISA kit (Biolegend).

[0211] FIG14 Chimeric anti-human PD-L2 antibodies do not cross-react with human PD-L1

[0212] HEK293T cells expressing human PD-L1 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with FITC-labeled anti-rat IgG Ab (Thermo Fisher Scientific). Flow cytometry analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). PE-labeled anti-human PD-L1 clone MIH1 served as a positive control. All peaks overlap except the positive control in Figure 7F.

[0213] FIG. 15 Chimeric anti-human PD-L2 antibodies do not cross-react with mouse PD-L2

[0214] HEK293T cells expressing mouse PD-L2 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with FITC-labeled anti-rat IgG Ab (Thermo Fisher Scientific). Flow cytometry analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). PE-labeled anti-mouse PD-L2 clone TY25 served as a positive control. All peaks overlap except the positive control in Figure 6F.

[0215] Figure 16 Chimeric anti-human PD-L2 antibody cross-reacts with cynomolgus monkey PD-L2

[0216] HEK293T cells expressing cynomolgus monkey PD-L2 were incubated with chimeric anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-rat IgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). In Figure 8A, the signal of cynomolgus monkey No. 2 APC.002 overlaps with that of cynomolgus monkey negative 001.

[0217] FIG. 17 Dose response curve of TCR-mediated IL-2 upregulation when PD-1 and PD-L2 interaction is inhibited by anti-PD-L2 antibodies and anti-PD-L2 analog antibodies

[0218] HPD-1 and hPD-L2 expressing Jacquart T cells were treated with anti-CD3 antibodies in combination with different concentrations of human anti-PD-L2 antibodies and analog anti-PD-L2 antibodies and cultured for 18 hours. Supernatants were collected and IL-2 levels were determined using an IL-2 specific ELISA kit (Biolegend). The curves for the human anti-PD-L2 antibodies of the present invention are depicted with solid circles, and reference analog antibody data points are represented with solid blocks (VK2 / VH2) and diamonds (VK4 / VH4).

[0219] Fig.18Maximal IL-2 levels upon inhibition of PD1–PD-L2 interaction in cell-based assays

[0220] Calculations were performed using Graphpad Prism software Fig. 9 The maximum value of the fitted curve depicted in .

[0221] Fig.19 Blocking hPD-L2 binding to HEK293 cells expressing hPD-1

[0222] Recombinant hPD-L2-hFc-biotin at a concentration of 100 pM was incubated with fully human anti-PD-L2 antibodies or analog reference antibodies for 1 hour and then added to HEK293T-hPD-1 cells. After washing, bound hPD-L2 was detected with streptavidin-APC (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson). IC50 values ​​are depicted as bar graphs and tables.

[0223] Fig. 20 Blocking hPD-1 binding to CHO-K1 / hPD-L2 cells

[0224] CHO-K1 hPD-L2 cells were incubated with various concentrations of fully human anti-PD-L2 antibodies and analog reference antibodies. Cells were washed and recombinant hPD-1-mouse Fc (BPS Life Sciences) was added at a concentration of 0.5 μg / ml. Bound human PD-1 was detected using anti-mouse IgG2a-APC (Biolegend) after washing. Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson). IC50 values ​​are depicted as bar graphs and tables.

[0225] Fig.21 Human anti-PD-L2 antibody binds to CHO-K1 cells expressing human PD-L2

[0226] CHO-K1 cells expressing human PD-L2 were incubated with various concentrations of fully human anti-PD-L2 antibody (hIgG1). Cells were washed and binding was detected with APC-labeled anti-human IgG Fc Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0227] Fig. 22 Optimized anti-PD-L2 antibody binds to CHO-K1 cells expressing human PD-L2

[0228] CHO-K1 cells expressing human PD-L2 were incubated with various concentrations of fully human anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-human Fc Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson).

[0229] Fig.23 Optimized human PD-L2 antibody exhibits similar activity to the parental clone tested by TCR-mediated IL-2 upregulation

[0230] Jacquard T cells expressing hPD-1 and hPD-L2 were treated with anti-CD3 antibody combined with various concentrations of fully human anti-PD-L2 antibody and cultured for 18 hours. Supernatants were collected and IL-2 levels were determined using an IL-2 specific ELISA kit (Biolegend).

[0231] FIG. 24 Optimized human PD-L2 antibody binds to cynomolgus monkey PD-L2 and does not bind to mouse PD-L2 or human PD-L1

[0232] HEK293T cells expressing cynomolgus monkey PD-L2 (A) or mouse PD-L2 (B) or human PD-L1 (C) were incubated with fully human anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-human FcIgG Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton-Dickinson). APC-labeled anti-human PD-L2 MIH18 (Biolegend), PE-labeled anti-mouse PD-L2 clone TY25, and APC-labeled anti-human PD-L1 (MIH1, Biolegend) served as positive controls.

[0233] Figure 25. Optimized anti-PD-L2 antibody binds to CHO-K1 cells expressing human PD-L2

[0234] CHO-K1 cells expressing human PD-L2 were incubated with various concentrations of fully human anti-PD-L2 antibodies. Cells were washed and binding was detected with APC-labeled anti-human Fc Ab (Biolegend). Flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson). DETAILED DESCRIPTION

[0235] As used herein, an "antibody" is any molecule that can specifically or selectively bind to a target protein. An antibody may include or be an antibody or a portion / fragment thereof, wherein the portion / fragment exhibits substantially the same binding activity as a full-length antibody. An anti-human PD-L2 antibody is an antibody that binds to a human PD-L2 polypeptide at a specific recognition site. Other anti-human PD-L2 antibodies may also include multivalent molecules, multispecific molecules (e.g., bifunctional antibodies), fusion molecules, aptamers, affibodies, or other naturally occurring or recombinantly produced molecules. Illustrative antibodies suitable for use in the present invention include antibody-like molecules. Antibody-like molecules are molecules that can exhibit functions by binding to target molecules (see, e.g., Current Opinion in Biotechnology 2006, 17: 653-658; Current Opinion in Biotechnology 2007, 18: 1-10; Current Opinion in Structural Biology 1997, 7: 463-469; Protein Science 2006, 15: 14-27) and include, for example, DARPin (WO 2002 / 020565), Affibody (WO 1995 / 001937), Avimer (WO 2004 / 044011; WO 2005 / 040229), Adnectin (WO 2002 / 032925) and fynomer (WO 2013 / 135588). In general, the term "antibody" herein is used in the broadest sense and covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), fully human antibodies, and antibody fragments, as long as the antibody fragment exhibits the desired antigen-binding activity. The antibody within the present invention can also be a chimeric antibody, a recombinant antibody, an antigen-binding fragment of a recombinant antibody, or a humanized antibody.

[0236] The term "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; bifunctional antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibodies.

[0237] As used in the context of the present invention, the term "binding to" defines the binding (interaction) of at least two "antigen interaction sites" with each other. According to the present invention, the term "antigen interaction site" defines a motif of a polypeptide, i.e. a part of an antibody or antigen-binding fragment of the present invention, which exhibits the ability to specifically interact with a specific antigen or a specific group of antigens of PD-L2. Said binding / interaction is also understood to define "specific recognition". The term "specifically recognizes" means that according to the present invention the antibody is able to specifically interact with and / or bind to at least two amino acids of PD-L2.

[0238] As used according to the present invention, the term "specifically binds" means that the antibody of the present invention or its antigen-binding portion does not cross-react with a (poly)peptide having a similar structure or does not substantially cross-react with the (poly)peptide. Therefore, the antibody or its antigen-binding fragment of the present invention specifically binds to / interacts with the structure of PD-L2.

[0239] As used herein, the term "cross-reaction" or "cross-reactivity" refers to the ability of two molecules or ligands to react with the same site on the same specific binding partner, usually with different affinities. The cross-reactivity of an antibody (or more precisely, a group of antibodies or antigen-binding portions thereof under study) can be tested, for example, by evaluating the binding of the group of antibodies or antigen-binding portions thereof to the (poly)peptide of interest and to a number of substantially (structurally and / or functionally) closely related (poly)peptides under conventional conditions (see, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1988) and Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1999)). Only those constructs (i.e., antibodies, antigen-binding portions thereof, etc.) that bind to human PD-L2 are considered to be specific for the (poly)peptide / protein of interest and are selected for further study according to the methods provided herein. These methods may include, in particular, binding studies, blocking and competition studies with molecules that are closely related in structure and / or function. These binding studies also include FACS analysis, surface plasmon resonance (SPR, e.g., using BIACORE), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy, or ligand binding analysis by radiolabeling.

[0240] Thus, specificity can be determined experimentally by methods known in the art and described herein. Such methods include, but are not limited to, Western blot, ELISA-, RIA-, ECL-, IRMA-tests, and peptide scanning.

[0241] As used herein, the term "PD-L2" (programmed death-ligand 2) refers to a specific PD-1 ligand. PD-L2 is a member of the B7 family expressed on various antigen presenting cells (APCs), including dendritic cells, macrophages, and bone marrow-derived mast cells (Zhong et al. (2007) European Journal of Immunology 37: 2405). The term also includes naturally occurring variants of PD-L2, such as splice variants or allelic variants. Alternative names or synonyms for PD-L2 include PDCD1L2, PDL2, B7-DC, Bide, and CD273. As used herein, "human PD-L2" includes PD-L2 from humans. The nucleic acid and amino acid sequences of representative human PD-L2 are well known in the art and can be disclosed to the public in the gene bank database as NM_025239.3 and NP_079515.2. As used herein, "mouse PD-L2" refers to PD-L2 from mice. The nucleic acid and amino acid sequences of representative mouse PD-L2 are well known in the art and can be disclosed to the public in the GenBank database at NM_021396.2 and NP_067371.1. As used herein, "cynomolgus monkey PD-L2" refers to PD-L2 from cynomolgus monkeys. The nucleic acid and amino acid sequences of representative cynomolgus monkey PD-L2 are well known in the art and can be disclosed to the public in the GenBank database at NM_001083599.2 and NP_001077068.1.

[0242] The term "PD-L1" (programmed death-ligand 1) refers to a specific PD-1 ligand. PD-L1 is a member of the B7 family expressed on a variety of immune and non-immune cells. The term also includes naturally occurring variants of PD-L1, such as splice variants or allelic variants. Alternative names or synonyms for PD-L1 include PDCD1L1, PDCD1LG1, PDL1, B7-H, B7-H1, and CD274. The nucleic acid and amino acid sequences of representative human PD-L1 can be obtained in the gene bank database as NM_014143.3 and NP_054862.1.

[0243] The term "PD-1" (programmed cell death protein 1) refers to a cell surface receptor belonging to the immunoglobulin superfamily and expressed on T cells and B cells. PD-1 binds two ligands, PD-L1 and PD-L2. The nucleic acid and amino acid sequences of representative human PD-1 can be obtained in the gene bank database as NM_005018.2 and NP_005009.2 (see also Ishida et al. (1992) 20EMBO.711:3887; Shinohara et al. (1994) Genomics 23:704; U.S. Pat. No. 5,698,520). PD-1 has an extracellular region containing an immunoglobulin superfamily domain, a transmembrane domain, and an intracellular region including an immunoreceptor tyrosine-based inhibitory motif (ITIM) (Ishida et al. (1992) EMBO J. 11: 3887; Shinohara et al. (1994) Genomics 23: 704; U.S. Pat. No. 5,698,520).

[0244] As used herein, the term "blocking PD-L2 binding to PD-1" or "blocking PD-1 from interacting with PD-L2" and equivalents will mean reducing the interaction, i.e., the binding between PD-L2 and PD-1. In the context of the present invention, the reduced interaction / binding between PD-L2 and PD-1 is caused by the antibodies of the present invention, or antigen-binding portions thereof, as further illustrated by the examples below. Without being bound by theory, the antibodies of the present invention, or antigen-binding portions thereof, bind to PD-L2 within the binding interface of PD-L2 and PD-1, and thereby block PD-1 from binding to PD-L2.

[0245] As used herein, the term "flow cytometer" refers to any device that illuminates particles suspended in a fluid medium with light at a first wavelength and is capable of detecting light at the same or different wavelength, wherein the detected light indicates the presence of a cell or an indicator thereon. The flow cytometer can be coupled to a cell sorter that is capable of separating particles or cells from other particles or cells that do not emit a second light. The indicator can be an antibody coupled to a fluorophore, such as, but not limited to, FITC, which provides fluorescent antibody cell sorting (FACS). In the context of the present invention, FACS analysis is used for binding studies, for example, to evaluate the binding of the antibodies of the present invention to human PD-L2 / PD-L1, mouse PD-L2, or any cynomolgus monkey PD-L2. Exemplary FACS cell sorters include the MoFlo sorter (DakoCytomation, Fort Collins, Colorado), the FACSAria TM 、FACSArray TM , FACSVantage TM , BD TM LSR II and FACSCaiibur TM(BD Biosciences, San Jose, Calif.) and other equivalent cell sorters produced by other suppliers such as Sony, Bio-Rad, and Beckman Coulter.

[0246] As used herein, the term "EC50" refers to the concentration of an antibody or its antibody portion that induces a half-response of the baseline to the maximum value in an assay. Thus, it represents the antibody concentration at which 50% of the maximum effect is observed. As used herein, the term "IC50" refers to the concentration of an inhibitor (e.g., an antibody or antibody portion) that inhibits the half-response of the maximum response to the baseline in an assay. It represents the antibody concentration that reduces a given response by 50%. Both EC50 and IC50 can be measured by ELISA or FACS analysis or any other method known in the art.

[0247] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies constituting the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific for a single antigenic site. The advantage of monoclonal antibodies is that they can be synthesized by hybridoma cultures that are substantially not contaminated by other immunoglobulins. The modified "monoclonal" indicates that the characteristics of the antibody belong to a substantially homogeneous antibody population, and should not be construed as requiring antibodies to be produced by any particular method. As mentioned above, the monoclonal antibodies used according to the present invention can be prepared by the hybridoma method described in Kohler, Nature 256 (1975), 495.

[0248] As used herein, "MIH18" refers to the MIH18 monoclonal antibody, mouse monoclonal IgG1κ (Yongnak-Piboonratankit P et al., 2004 Immunol Lett, 94 215-220), which reacts with human PD-L2 as a blocking antibody. MIH18 can be purchased from commercial sources, such as Thermo Fisher Scientific or BD Life Sciences.

[0249] As used herein, "24F.10C12" refers to an antibody comprising the variable light chain and the variable heavy chain of antibody 24F.10C12 disclosed in WO 2010 / 036959.

[0250] As used herein, the term "same conditions" shall mean that the binding and inhibition studies for the antibodies of the invention and other antibodies tested in the study (e.g., MIH18 and nivolumab) are performed under the same conditions. For example, the following same conditions are applied for the antibody concentrations used and the incubation times in the experiments: Binding to human PD-L2 ( Figure 1 , 2 , 9, 10, 21, 22 and 25), blocking the interaction between PD-L2 and PD-2 ( Figure 3 , 4 , 11, 12, 19 and 20) and TCR-mediated IL-2 upregulation ( Figure 5 , 13, 17 and 18).

[0251] As used herein, "TCR-mediated IL-2 expression" refers to the expression of interleukin-2 (IL-2) regulated by the T cell receptor (TCR). Regulation of gene expression of IL-2 can be located at multiple levels or by different means. One of the checkpoints is through TCR signaling.

[0252] As used herein, the term "enzyme-linked immunosorbent assay" (ELISA) refers to an antibody-based assay in which detection of an antigen of interest is achieved via an enzymatic reaction that produces a detectable signal. ELISAs can be run in a competitive or noncompetitive format. ELISAs also include 2-site or "sandwich" assays that use two antibodies to an antigen, one to capture the antigen and one labeled with an enzyme or other detectable label to detect the captured antibody-antigen complex.

[0253] As used herein, the term "full human antibody" refers to an antibody comprising only human immunoglobulin sequences. If a full human antibody is produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, then the full human antibody may contain a murine carbohydrate chain. Similarly, "mouse antibody" or "murine antibody" refers to an antibody comprising only a mouse / murine immunoglobulin sequence. Alternatively, if a "full human antibody" is produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell, then the full human antibody may contain a rat carbohydrate chain. Similarly, the term "rat antibody" refers to an antibody comprising only a rat immunoglobulin sequence. Full human antibodies can also be produced, for example, by phage display, which is a widely used screening technique capable of producing and screening full human antibodies. Phage antibodies can also be used in the context of the present invention. Phage display methods are described in, for example, US 5,403,484, US 5,969,108, and US 5,885,793. Another technology for realizing the research and development of full human antibodies relates to the modification of mouse hybridoma technology. Mice are transgenic to contain human immunoglobulin loci in exchange for their own mouse genes (see, e.g., US 5,877,397).

[0254] As used herein, "nivolumab" refers to a human IgG4 anti-PD-1 monoclonal antibody disclosed, for example, in US 8,008,449 and sold as Opdivo.

[0255] The term "chimeric antibody" refers to antibodies comprising variable regions of the invention fused or chimerized to antibody regions (eg, constant regions) from another human or non-human species (eg, mouse, horse, rabbit, dog, cow, chicken).

[0256] The term "antibody" also relates to recombinant human antibodies, heterologous antibodies and hybrid hybrid antibodies. The term "recombinant (human) antibody" includes all human sequence antibodies prepared, expressed, produced or separated by recombinant means, such as antibodies separated from transgenic animals (e.g., mice) of human immunoglobulin genes; antibodies expressed using recombinant expression vectors transfected into host cells, antibodies separated from recombinant combinatorial human antibody libraries, or antibodies prepared, expressed, produced or separated by any other means, which involves splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions and constant regions (if present) derived from human germline immunoglobulin sequences. However, such antibodies can be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when using transgenic animals of human Ig sequences), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that may not be naturally present in the human antibody germline antibody library in vivo, although derived from and related to human germline VH and VL sequences.

[0257] "Heterologous antibodies" are defined relative to the transgenic non-human organism or plant that produces such antibodies. This term refers to an antibody having an amino acid sequence or encoding nucleic acid sequence that corresponds to an antibody found in an organism that does not consist of the transgenic non-human animal, and generally an antibody from a species other than the transgenic non-human animal.

[0258] The term "antibody" also relates to humanized antibodies. The "humanized" form of non-human (e.g., murine or rabbit) antibodies is a chimeric immunoglobulin, immunoglobulin chain or fragment thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) containing the minimum sequence derived from non-human immunoglobulins. Generally, humanized antibodies are human immunoglobulins (acceptor antibodies) in which residues from the complementary determining regions (CDRs) of the acceptor are replaced by residues from non-human species (donor antibodies) with desired specificity, affinity and ability, such as mouse, rat, rabbit CDRs. In some cases, the Fv framework residues of human immunoglobulins are replaced by corresponding non-human residues. In addition, humanized antibodies may be included in the acceptor antibody or introduced into residues that are not present in the CDR or framework sequences. These modifications are carried out to further optimize antibody performance and to optimize it. In general, a humanized antibody will comprise substantially all of at least one and usually two variable domains, wherein all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin and all or substantially all of the FR regions are FR regions of a human immunoglobulin consensus sequence. A humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin. Methods for humanization of antibodies / antibody molecules are further described in Jones et al., Nature 321 (1986), 522-525; Reichman et al., Nature 332 (1988), 323-327 and Wehne et al., Science 239 (1988), 1534-1536. Specific examples of humanized antibodies (e.g., antibodies against EpCAM) are known in the art, see, e.g., (Robrio, American Society of Clinical Oncology Abstracts (1997), 1562 and Hall, American Society of Clinical Oncology Abstracts (1997), 847).

[0259] A popular method for humanization of antibodies involves CDR grafting, in which a functional antigen binding site from a non-human 'donor' antibody is grafted onto a human 'acceptor' antibody. CDR grafting methods are known in the art and are described, for example, in US 5,225,539, US 5,693,761, and US 6,407,213. Another related method is the production of humanized antibodies by transgenic animals that are genetically engineered to contain one or more humanized immunoglobulin loci capable of gene rearrangement and gene conversion (see, e.g., US 7,129,084).

[0260] Thus, in the context of the present invention, antibody molecules or antigen-binding fragments thereof are provided which are humanized and can be successfully used in pharmaceutical compositions.

[0261] In the context of the present invention, the term "antibody" refers to whole immunoglobulin molecules as well as parts of such immunoglobulin molecules (i.e., "antigen binding portions thereof"). In addition, as discussed above, the term refers to modified and / or altered antibody molecules. The term also refers to antibodies produced / synthesized recombinantly or synthetically. The term also refers to complete antibodies as well as antibody fragments thereof, such as individual light and heavy chains, Fab, Fv, Fab', Fab'-SH, F(ab')2. The term antibody also includes, but is not limited to, fully human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies, and antibody constructs, such as single-chain Fvs (scFv) or antibody fusion proteins.

[0262] In the context of the present invention, a "single-chain Fv" or "scFv" antibody fragment has a V H and V L domains, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide also comprises a V H and V L The polypeptide linker between the domains enables the scFv to form the desired structure for antigen binding. Techniques for producing single chain antibodies are described, for example, in Plukthun, The Pharmacology of Monoclonal Antibodies, Rosenberg and Moore, eds., Springer-Verlag, New York (1994), 269-315.

[0263] As used herein, a "Fab fragment" consists of a light chain and a C H 1 and the variable region of a heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0264] The "Fc" region contains two heavy chain fragments comprising the C H 2 and C H 3 domains. The two heavy chain fragments are connected by two or more disulfide bonds and by C H The 3 domains are held together by hydrophobic interactions.

[0265] The "Fab' fragment" contains a light chain and a V H Domain and C H 1 domain of a heavy chain, and C H 1 and C H The region between the two Fab' domains allows for the formation of an interchain disulfide bond between the two heavy chains of the two Fab' fragments to form the F(ab') 2 molecular.

[0266] “F(ab') 2 The "fragment" contains two light chains and two heavy chains, wherein the light chains and heavy chains contain H 1 and C HThe F(ab')2 fragment is composed of two Fab' fragments held together by the disulfide bonds between the two heavy chains.

[0267] The "Fv region" contains the variable regions from both the heavy and light chains, but lacks the constant regions.

[0268] The antibodies, antibody constructs, antibody fragments, antibody derivatives (all Ig-derived) or their corresponding immunoglobulin chains used according to the present invention can be further modified using conventional techniques known in the art, for example, by using amino acid deletions, insertions, substitutions, additions and / or recombination and / or any other modifications known in the art, alone or in combination. Methods for introducing such modifications in the DNA sequence underlying the amino acid sequence of the immunoglobulin chain are well known to those skilled in the art; see, for example, Sabrook (1989), loc. cit. The term "Ig-derived domain" specifically relates to a (poly)peptide construct comprising at least one CDR. The described fragments or derivatives of the Ig-derived domain define a (poly)peptide that is part of the above antibody molecule and / or modified by chemical / biochemical or molecular biological methods. Corresponding methods are known in the art and are described, inter alia, in laboratory manuals (see Sabrook et al., Molecular cloning: a laboratory manual; Cold Spring Harbor Laboratory Press, 2nd edition (1989) and 3rd edition (2001); Gerhardt et al., Methods in General and Molecular Bacteriology, ASM Press (1994); Lefkowitz, Manual of Immunomethods: A Comprehensive Manual of Techniques; Academic Press (1997); Golemis, Protein-Protein Interactions: A Manual of Molecular Cloning, Cold Spring Harbor Laboratory Press (2002)).

[0269] As used herein, the term "CDR" refers to a "complementarity determining region" as is well known in the art. CDR is the portion of an immunoglobulin that determines the specificity of the molecule and contacts a specific ligand. CDR is the most variable portion of the molecule and contributes to the diversity of these molecules. There are three CDR regions in each V domain, CDR1, CDR2, and CDR3. CDR-H depicts the CDR region of the variable heavy chain, and CDR-L relates to the CDR region of the variable light chain. VH means variable heavy chain, and VL means variable light chain. The CDR regions of the Ig-derived regions can be determined as described below: Kabat, "Sequences of Proteins of Interest in Immunology," 5th edition, NIH Publication No. 91-3242, U.S. Department of Health and Human Services (1991); Chothia, Journal of Molecular Biology, 196 (1987), 901-917 or Chothia, Nature, 342 (1989), 877-883.

[0270] Therefore, in the context of the present invention, the antibody molecules described herein above are selected from the group consisting of: whole antibodies (immunoglobulins, such as IgG1, IgG2, IgG3 or IgG4, F(ab)-, Fab'-SH-, Fv-, Fab'-, F(ab')2-fragments, chimeric antibodies, CDR-grafted antibodies, fully human antibodies, bivalent antibody-constructs, antibody-fusion proteins, synthetic antibodies, bivalent single-chain antibodies, trivalent single-chain antibodies and multivalent single-chain antibodies.

[0271] The present invention also relates to the production of specific antibodies against native polypeptides and recombinant polypeptides of PD-L2. This production is based on, for example, immunization of animals (such as mice). However, other animals for producing antibodies / antisera are also contemplated within the present invention. For example, monoclonal and polyclonal antibodies can be produced by rabbits, mice, goats, donkeys, etc. The polynucleotides corresponding to the selected polypeptides encoding PD-L2 can be subcloned into appropriate vectors, wherein the recombinant polypeptides will be expressed in organisms capable of expression, such as in bacteria. Therefore, the expressed recombinant protein can be injected intraperitoneally into mice, and the resulting specific antibodies can be obtained, for example, from mouse serum provided by intracardiac blood puncture. The present invention also contemplates the production of specific antibodies against native polypeptides and recombinant polypeptides by using a DNA vaccine strategy. The DNA vaccine strategy is well known in the art and covers lipid-mediated delivery, by gene gun or jet injection and intramuscular or intradermal injection. Therefore, the animal can be directly immunized by directly intramuscularly injecting a vector expressing the desired polypeptide or protein of PD-L2 to obtain antibodies against the polypeptide of PD-L2. The amount of the resulting specific antibodies can be quantified using ELISA. Other methods for generating antibodies are well known in the art, see, e.g., Harlow and Lane, "Antibodies: A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988.

[0272] Thus, under specified analytical conditions, the specified antibody and the corresponding polypeptide or protein of PD-L2 bind to each other and do not bind to other components present in the sample in large quantities. Specific binding to the target analyte under such conditions may require a binding moiety selected for its specificity for a specific target analyte. A variety of immunoassay formats can be used to select antibodies that are specifically reactive with a specific antigen. For example, solid phase ELISA immunoassays are routinely used to select monoclonal antibodies that specifically immunoreact with the analyte. See Sheppard and Dean (2000), Monoclonal Antibodies: A Practical Approach, Oxford University Press and / or Howard and Bethell (2000), Basic Methods for Antibody Production and Characterization, Crc.Pr. Company, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity. Typically, a specific or selective reaction will be at least twice the background signal-to-noise ratio and more typically more than 10 to 100 times the background signal-to-noise ratio. A person skilled in the art is able to provide and produce specific binding molecules for novel polypeptides. For specific binding assays, avoidance of undesired cross-reactivity can be readily employed, for example, polyclonal antibodies can be readily purified and selected by known methods (see Sheppard and Dean, loc. cit.).

[0273] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptide sequences when they are optimally aligned. When the positions in both of the two compared sequences are occupied by the same base or amino acid monomer subunit, for example, if the position of each of the two DNA molecules is occupied by adenine, the molecules are homologous at that position. The percentage of homology is the number of homologous positions shared by the two sequences divided by the total number of compared positions × 100. For example, if 8 of the 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, the two sequences are 80% homologous. In general, the two sequences are compared when they are aligned to produce the maximum homology percentage. For example, the comparison can be performed by the BLAST algorithm, wherein the parameters of the algorithm are selected to give the maximum match between the corresponding sequences over the entire length of the corresponding reference sequence.

[0274] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0275] The terms "cell," "cell line," and "cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Cells include "transformants" and "transformed cells," which include primary transformed cells and progeny derived therefrom, without regard to the number of passages. Progeny may not be completely identical to the parent cell in nucleic acid content, but may contain mutations. Mutant allogeneic progeny having the same function or biological activity as screened or selected for the original transformed cell are included herein.

[0276] The term "pharmaceutical composition" or "pharmaceutical formulation" refers to a preparation that is in such form as to render the biological activity of the active ingredient contained therein effective, and contains no additional components that would be unacceptably toxic to the subject to which the formulation would be administered.

[0277] "Pharmaceutically acceptable carrier" refers to ingredients in a pharmaceutical formulation other than the active ingredient that are non-toxic to an individual. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. As used herein, the term "excipient" includes any physiologically inert additive conventionally used in pharmaceutical dosage forms. Excipients are selected from the group comprising: diluents, binders, osmotic agents, acidifiers, surfactants, disintegrants, lubricants, and glidants.

[0278] As used herein, "human therapy" refers to clinical interventions that attempt to alter the natural course of a human individual under treatment, and can be performed before or during the clinical pathological process. The desired therapeutic effect includes, but is not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies of the present invention are used to delay the development of the disease or slow the progression of the disease. In some embodiments, human therapy is cancer therapy. The term "cancer" refers to or describes a physiological condition in mammals that is generally characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to, carcinomas, liver cancers, hepatocellular carcinomas, gastric cancers, lung cancers, esophageal cancers, breast cancers, prostate cancers, lymphomas (e.g., Hodgkin's and non-Hodgkin's lymphomas), blastomas, sarcomas, and leukemias.

[0279] As used herein, the term "antigen presenting cell" includes professional antigen presenting cells (e.g., B lymphocytes, monocytes, dendritic cells, Langerhans cells) as well as other antigen presenting cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes).

[0280] As used herein, "T cell signaling" refers to signaling directed by T cells. The T cell receptor (TCR) expressed on T cells allows T cells to recognize antigens presented on antigen presenting cells, which leads to a cascade of signaling events, ultimately producing T cell effector functions. The term "T cell" includes CD4+T cells and CD8+T cells. The term T cell also includes T helper type 1 T cells, T helper type 2 T cells, T helper type 17 T cells, and suppressor T cells.

[0281] As used herein, a "kit" is any manufacture (e.g., packaging or container) comprising at least one reagent (e.g., probe) for specifically detecting or regulating the expression of a marker of the invention. The kit can be promoted, distributed or sold as a unit for practicing the methods of the invention.

[0282] Furthermore, in the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "substantially", "about", "approximately" and the like in conjunction with an attribute or a value also specifically define the attribute or specifically define the value, respectively.

[0283] The scope of the present invention encompasses all pharmaceutically acceptable salt forms of the compounds disclosed herein, which can be formed, for example, by protonating an easily protonated atom (e.g., an amino group) carrying a lone pair of electrons with an inorganic or organic acid or in the form of a salt of an acid group (e.g., a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts or choline salts; arylalkylamine salts, such as N,N-dibenzylethylenediamine salts, benzathine salts, benzethamine salts; heterocyclic aromatic amine salts, such as pyridinium salts, picolinium salts, quinoline salts or isoquinoline salts; quaternary ammonium salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts, such as arginine salts, lysine salts or histidine salts. Exemplary acid addition salts include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates (e.g., sulfates or hydrogensulfates), nitrates, phosphates (e.g., phosphates, hydrogenphosphates or dihydrogenphosphates), carbonates, bicarbonates, perchlorates, borates or thiocyanates; organic acid salts such as acetates, propionates, butyrates, valerates, hexanoates, heptanoates, octanoates, cyclopentanepropionates, decanoates, undecanoates, oleates, stearates, lactates, maleates, oxalates, fumarates, tartrates, malates, citrates, succinates, adipates, Gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (enbolate), camphorate, gluconate or pivalate; sulfonate, such as methanesulfonate (mesylate), ethanesulfonate (ethanesulfonate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (benzenesulfonate / besylate), p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-phenylsulfonate or camphorsulfonate; glycerophosphate; and acidic amino acid salts, such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of the compounds disclosed herein include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. A particularly preferred pharmaceutically acceptable salt of the compounds disclosed herein is hydrochloride. Thus, it is preferred that the compounds disclosed herein are in the form of hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate or phosphate salts, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0284] In addition, the scope of the present invention covers compounds disclosed herein in any solvated form: including, for example, solvates with water, such as hydrates; or solvates with organic solvents such as methanol, ethanol or acetonitrile, i.e., methanolates, ethanolates or acetonitrile, respectively; or in any polymorphic form. It should be understood that such solvates of compounds disclosed herein also include solvates of pharmaceutically acceptable salts of compounds disclosed herein.

[0285] In one embodiment, the present invention provides an anti-human PD-L2 antibody or an antigen-binding portion thereof. In some embodiments, the anti-human PD-L2 antibody of the present invention has at least one or more of the following features (in any combination):

[0286] a) Specific binding to human PD-L2, thereby blocking PD-L2 from binding to PD-1

[0287] b) Does not bind to mouse PD-L2 and human PD-L1

[0288] c) Binds to cynomolgus monkey PD-L2

[0289] d) binds to human PD-L2 with an EC50 between about 0,05 nM and about 2 nM.

[0290] e) blocks PD-L2 binding to PD-1 with an IC50 between about 0.01 nM and about 1 nM.

[0291] f) activates TCR-mediated IL-2 expression with an EC50 between about 0.2 nM and about 1.5 nM.

[0292] In another embodiment, the invention relates to an antibody or antigen binding portion thereof according to the invention, which antibody or antigen binding portion satisfies at least one, preferably 2, 3 or 4 (in any combination) of the functional features listed in a) to d):

[0293] a) having a higher binding affinity to PD-L2 than the reference antibodies MIH18 and 24F.10C12;

[0294] b) more effectively blocking PD-L2 binding to PD-1 compared to the reference antibodies MIH18 and 24F.10C12;

[0295] c) more effectively activates TCR-mediated IL-2 expression compared to the reference antibodies MIH18 and 24F.10C12; and

[0296] d) Higher IL-2 levels when inducing TCR-mediated IL-2 expression compared to the reference antibodies MIH18 and 24F.10C12.

[0297] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a) and b).

[0298] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a) and c).

[0299] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a) and d).

[0300] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in b) and c).

[0301] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in b) and d).

[0302] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in c) and d).

[0303] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a), b) and c).

[0304] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a), b) and d).

[0305] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a), c) and d).

[0306] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in b), c) and d).

[0307] Alternatively, the invention relates to an antibody or antigen binding portion thereof according to the invention having the features recited in a), b), c) and d).

[0308] The examples show that all antibodies of the present invention are improved in at least one functional feature compared to the reference antibodies MIH18 and 24F.10C12. Therefore, in a preferred embodiment, the antibodies of the present invention or their antigen-binding portions comprise six CDR sequences contained in the heavy chain variable region and the light chain variable region, and the heavy chain variable region and the light chain variable region are defined as any one of the following clauses, respectively:

[0309] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0310] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0311] c) a heavy chain variable region having the sequence of SEQ ID NO:34 and a light chain variable region having the sequence of SEQ ID NO:42;

[0312] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0313] e) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0314] f) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0315] g) a heavy chain variable region having the sequence of SEQ ID NO: 112 and a light chain variable region having the sequence of SEQ ID NO: 120;

[0316] h) a heavy chain variable region having the sequence of SEQ ID NO: 128 and a light chain variable region having the sequence of SEQ ID NO: 132;

[0317] i) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0318] j) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0319] k) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0320] l) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:212;

[0321] m) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0322] n) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0323] o) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0324] p) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 226;

[0325] q) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 230; or

[0326] The antibodies or antigen-binding portions thereof of the present invention comprise three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0327] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of SEQ ID NO:14, CDR-L3 of SEQ ID NO:16; or

[0328] b) CDR-H1 of SEQ ID NO:20, CDR-H2 of SEQ ID NO:22, CDR-H3 of SEQ ID NO:24, and CDR-L1 of SEQ ID NO:28, CDR-L2 of SEQ ID NO:30, CDR-L3 of SEQ ID NO:32; or

[0329] c) CDR-H1 of SEQ ID NO:36, CDR-H2 of SEQ ID NO:38, CDR-H3 of SEQ ID NO:40 and CDR-L1 of SEQ ID NO:44, CDR-L2 of SEQ ID NO:46, CDR-L3 of SEQ ID NO:48; or

[0330] d) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0331] e) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0332] f) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0333] g) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 116, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 122, CDR-L2 of SEQ ID NO: 124, CDR-L3 of SEQ ID NO: 126; or

[0334] h) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 130, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 134, CDR-L2 of SEQ ID NO: 136, CDR-L3 of SEQ ID NO: 138; or

[0335] i) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0336] j) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0337] k) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0338] 1) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:216; or

[0339] m) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0340] n) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0341] o) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 28, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0342] p) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 228; or

[0343] q) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0344] The antibodies or antigen-binding portions thereof of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the

[0345] a) the heavy chain variable region has the sequence of SEQ ID NO: 2 and the light chain variable region has the sequence of SEQ ID NO: 10;

[0346] b) the heavy chain variable region has the sequence of SEQ ID NO: 18 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0347] c) the heavy chain variable region has the sequence of SEQ ID NO:34 and the light chain variable region has the sequence of SEQ ID NO:42;

[0348] d) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:58;

[0349] e) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:66;

[0350] f) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0351] g) the heavy chain variable region has the sequence of SEQ ID NO: 112 and the light chain variable region has the sequence of SEQ ID NO: 120;

[0352] h) the heavy chain variable region has the sequence of SEQ ID NO: 128 and the light chain variable region has the sequence of SEQ ID NO: 132;

[0353] i) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0354] j) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0355] k) the heavy chain variable region has the sequence of SEQ ID NO: 166 and the light chain variable region has the sequence of SEQ ID NO: 174;

[0356] 1) the heavy chain variable region has the sequence of SEQ ID NO: 96 and the light chain variable region has the sequence of SEQ ID NO: 212;

[0357] m) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 218;

[0358] n) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0359] o) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0360] p) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 226; or

[0361] q) the heavy chain variable region has the sequence of SEQ ID NO:220 and the light chain variable region has the sequence of SEQ ID NO:230.

[0362] More preferably, the antibody or antigen-binding portion thereof of the present invention comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, wherein the heavy chain variable region and the light chain variable region are defined as any one of the following clauses, respectively:

[0363] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0364] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0365] c) a heavy chain variable region having the sequence of SEQ ID NO:34 and a light chain variable region having the sequence of SEQ ID NO:42;

[0366] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0367] e) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0368] f) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0369] g) a heavy chain variable region having the sequence of SEQ ID NO: 112 and a light chain variable region having the sequence of SEQ ID NO: 120;

[0370] h) a heavy chain variable region having the sequence of SEQ ID NO: 128 and a light chain variable region having the sequence of SEQ ID NO: 132;

[0371] i) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0372] j) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0373] k) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0374] l) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:212;

[0375] m) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0376] n) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0377] o) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 26; or

[0378] The antibodies or antigen-binding portions thereof of the present invention comprise three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0379] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of SEQ ID NO:14, CDR-L3 of SEQ ID NO:16; or

[0380] b) CDR-H1 of SEQ ID NO:20, CDR-H2 of SEQ ID NO:22, CDR-H3 of SEQ ID NO:24, and CDR-L1 of SEQ ID NO:28, CDR-L2 of SEQ ID NO:30, CDR-L3 of SEQ ID NO:32; or

[0381] c) CDR-H1 of SEQ ID NO:36, CDR-H2 of SEQ ID NO:38, CDR-H3 of SEQ ID NO:40 and CDR-L1 of SEQ ID NO:44, CDR-L2 of SEQ ID NO:46, CDR-L3 of SEQ ID NO:48; or

[0382] d) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0383] e) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0384] f) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0385] g) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 116, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 122, CDR-L2 of SEQ ID NO: 124, CDR-L3 of SEQ ID NO: 126; or

[0386] h) CDR-H1 of SEQ ID NO: 114, CDR-H2 of SEQ ID NO: 130, CDR-H3 of SEQ ID NO: 118, and CDR-L1 of SEQ ID NO: 134, CDR-L2 of SEQ ID NO: 136, CDR-L3 of SEQ ID NO: 138; or

[0387] i) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0388] j) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0389] k) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0390] 1) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:216; or

[0391] m) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0392] n) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0393] o) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 28, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 32; or

[0394] The antibodies or antigen-binding portions thereof of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the

[0395] a) the heavy chain variable region has the sequence of SEQ ID NO: 2 and the light chain variable region has the sequence of SEQ ID NO: 10;

[0396] b) the heavy chain variable region has the sequence of SEQ ID NO: 18 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0397] c) the heavy chain variable region has the sequence of SEQ ID NO:34 and the light chain variable region has the sequence of SEQ ID NO:42;

[0398] d) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:58;

[0399] e) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:66;

[0400] f) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0401] g) the heavy chain variable region has the sequence of SEQ ID NO: 112 and the light chain variable region has the sequence of SEQ ID NO: 120;

[0402] h) the heavy chain variable region has the sequence of SEQ ID NO: 128 and the light chain variable region has the sequence of SEQ ID NO: 132;

[0403] i) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0404] j) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0405] k) the heavy chain variable region has the sequence of SEQ ID NO: 166 and the light chain variable region has the sequence of SEQ ID NO: 174;

[0406] 1) the heavy chain variable region has the sequence of SEQ ID NO: 96 and the light chain variable region has the sequence of SEQ ID NO: 212;

[0407] m) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 218;

[0408] n) the heavy chain variable region has the sequence of SEQ ID NO: 220 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0409] o) the heavy chain variable region has the sequence of SEQ ID NO:220 and the light chain variable region has the sequence of SEQ ID NO:26.

[0410] Antibodies 1A1-C2, 2C4-E4, 10D1-G1, 11C11-H5, 19C3-B3, 10A9-D2, 19B3-B3, 12A1-D4, 10D1-G1 N31Q.N92Q.LC, 10A9-D2.N31Q.LC and 19B3-B3.M23K.M63L.HC are improved over MIH18 and 24F.10C12 in at least two functional features. Therefore, in an even more preferred embodiment, the antibody or antigen-binding portion thereof of the present invention comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, and the heavy chain variable region and the light chain variable region are defined as any one of the following items, respectively.

[0411] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0412] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0413] c) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0414] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0415] e) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0416] f) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0417] g) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0418] h) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0419] i) a heavy chain variable region having the sequence of SEQ ID NO: 96 and a light chain variable region having the sequence of SEQ ID NO: 212;

[0420] j) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0421] k) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160; or

[0422] The antibodies or antigen-binding portions thereof of the present invention comprise three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0423] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of SEQ ID NO:14, CDR-L3 of SEQ ID NO:16; or

[0424] b) CDR-H1 of SEQ ID NO:20, CDR-H2 of SEQ ID NO:22, CDR-H3 of SEQ ID NO:24, and CDR-L1 of SEQ ID NO:28, CDR-L2 of SEQ ID NO:30, CDR-L3 of SEQ ID NO:32; or

[0425] c) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0426] d) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0427] e) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0428] f) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0429] g) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0430] h) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0431] i) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:216; or

[0432] j) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:214, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0433] k) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0434] The antibodies or antigen-binding portions thereof of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the

[0435] a) the heavy chain variable region has the sequence of SEQ ID NO: 2 and the light chain variable region has the sequence of SEQ ID NO: 10;

[0436] b) the heavy chain variable region has the sequence of SEQ ID NO: 18 and the light chain variable region has the sequence of SEQ ID NO: 26;

[0437] c) the heavy chain variable region has the sequence of SEQ ID NO:50 and the light chain variable region has the sequence of SEQ ID NO:58;

[0438] d) the heavy chain variable region has the sequence of SEQ ID NO: 50 and the light chain variable region has the sequence of SEQ ID NO: 66;

[0439] e) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0440] f) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0441] g) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160;

[0442] h) the heavy chain variable region has the sequence of SEQ ID NO: 166 and the light chain variable region has the sequence of SEQ ID NO: 174;

[0443] i) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:212;

[0444] j) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 218; or

[0445] k) the heavy chain variable region has the sequence SEQ ID NO: 220 and the light chain variable region has the sequence SEQ ID NO: 160.

[0446] Antibodies 10D1-G1, 11C11-H5, 19C3-B3, 10A9-D2, 19B3-B3 and 12A1-D4 are improved in at least three functional features compared to MIH18 and 24F.10C12. Therefore, in an even more preferred embodiment, the antibody or antigen-binding portion thereof of the present invention comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, and the heavy chain variable region and the light chain variable region are defined as any one of the following clauses, respectively

[0447] a) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0448] b) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0449] c) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0450] d) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0451] e) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0452] f) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174; or

[0453] The antibodies or antigen-binding portions thereof of the present invention comprise three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0454] a) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56, and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:64; or

[0455] b) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0456] c) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0457] d) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0458] e) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158, and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0459] f) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0460] The antibodies or antigen-binding portions thereof of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the

[0461] a) the heavy chain variable region has the sequence of SEQ ID NO: 50 and the light chain variable region has the sequence of SEQ ID NO: 58;

[0462] b) the heavy chain variable region has the sequence of SEQ ID NO: 50 and the light chain variable region has the sequence of SEQ ID NO: 66;

[0463] c) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0464] d) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0465] e) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160; or

[0466] f) the heavy chain variable region has the sequence of SEQ ID NO:166 and the light chain variable region has the sequence of SEQ ID NO:174.

[0467] Antibodies 10D1-G1, 19C3-B3, 10A9-D2, 19B3-B3 and 12A1-D4 are improved in four functional features compared to MIH18 and 24F.10C12. Therefore, in the most preferred embodiment, the antibody or antigen-binding portion thereof of the present invention comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, and the heavy chain variable region and the light chain variable region are defined as any one of the following items, respectively.

[0468] a) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0469] b) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0470] c) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0471] d) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0472] e) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174; or

[0473] The antibodies or antigen-binding portions thereof of the present invention comprise three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0474] a) CDR-H1 of SEQ ID NO:52, CDR-H2 of SEQ ID NO:54, CDR-H3 of SEQ ID NO:56 and CDR-L1 of SEQ ID NO:60, CDR-L2 of SEQ ID NO:62, CDR-L3 of SEQ ID NO:68; or

[0475] b) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:100, CDR-H3 of SEQ ID NO:102, and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:108, CDR-L3 of SEQ ID NO:110; or

[0476] c) CDR-H1 of SEQ ID NO:98, CDR-H2 of SEQ ID NO:142, CDR-H3 of SEQ ID NO:144 and CDR-L1 of SEQ ID NO:106, CDR-L2 of SEQ ID NO:148, CDR-L3 of SEQ ID NO:150; or

[0477] d) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO: 164; or

[0478] e) CDR-H1 of SEQ ID NO: 168, CDR-H2 of SEQ ID NO: 170, CDR-H3 of SEQ ID NO: 172, and CDR-L1 of SEQ ID NO: 176, CDR-L2 of SEQ ID NO: 178, CDR-L3 of SEQ ID NO: 180; or

[0479] The antibodies or antigen-binding portions thereof of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the

[0480] a) the heavy chain variable region has the sequence of SEQ ID NO: 50 and the light chain variable region has the sequence of SEQ ID NO: 66;

[0481] b) the heavy chain variable region has the sequence of SEQ ID NO:96 and the light chain variable region has the sequence of SEQ ID NO:104;

[0482] c) the heavy chain variable region has the sequence of SEQ ID NO: 140 and the light chain variable region has the sequence of SEQ ID NO: 146;

[0483] d) the heavy chain variable region has the sequence of SEQ ID NO: 152 and the light chain variable region has the sequence of SEQ ID NO: 160; or

[0484] e) the heavy chain variable region has the sequence of SEQ ID NO:166 and the light chain variable region has the sequence of SEQ ID NO:174.

[0485] If a first antibody has a stronger tendency to bind to PD-L2, then the antibody is said to have "higher binding affinity to PD-L2" than another antibody. The skilled person is aware of various methods and measures to determine and express binding affinity. Within the present invention, binding affinity is preferably expressed as a binding EC50, which is the antibody concentration in a sample at which 50% of the antigen (in the case of PD-L2) is bound by the antibody. If a first antibody has a lower binding EC50 than a second antibody, then the first antibody is said to have a higher binding affinity than the second antibody.

[0486] If a lower concentration of the first antibody is sufficient to inhibit PD-L2 binding to PD-1, then the antibody is considered to "block PD-L2 binding to PD-1 more effectively" than the other antibody. The skilled artisan is aware of various methods and measures to determine and express blocking efficiency. Within the present invention, blocking efficiency is preferably expressed as a blocking IC50, which is the antibody concentration that inhibits PD-L2 binding to PD-1 by 50%. If the first antibody has a lower blocking IC50 than the second antibody, then the first antibody is considered to have a higher blocking efficiency than the second antibody.

[0487] If a first antibody has a higher potential to induce TCR-mediated IL-2 expression by T cells, then the antibody is considered to cause "more effective activation of TCR-mediated IL-2 expression" compared to another antibody. The skilled person is aware of various methods and measures to determine and express activation efficiency. Within the present invention, the activation efficiency is preferably expressed as an activation EC50, which is the antibody concentration at which 50% of the maximum IL-2 expression by T cells is observed. If a first antibody has a lower activation EC50 than a second antibody, then the first antibody is considered to have a higher activation efficiency than the second antibody.

[0488] If contacting a first antibody with T cells produces a higher total IL-2 or top IL-2 level, then the antibody is considered to "induce higher IL-2 levels when TCR-mediated IL-2 expression" than the other antibody. As used herein, "top IL-2 levels" refers to the highest IL-2 concentration measured in a sample that typically contains antibodies and T cells. The skilled artisan is aware of various methods for determining top IL-2 levels. Within the present invention, top IL-2 levels are preferably expressed in pg / mL. If a first antibody has a higher IL-2 level than a second antibody, then the first antibody is considered to induce higher IL-2 levels when TCR-mediated IL-2 expression than the second antibody.

[0489] In certain embodiments, a characteristic or functional characteristic of an antibody is determined as described herein (eg, in the Examples below).

[0490] In some embodiments, the anti-human PD-L2 antibodies provided herein are chimeric antibodies. In certain embodiments, the anti-human PD-L2 antibodies provided herein are humanized antibodies or fully human antibodies.

[0491] Certain embodiments provided herein are based, in part, on the development of antibody 1A1-C2, which specifically binds to human PD-L2.

[0492] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 2 and the light chain variable region (VL) of SEQ ID NO: 10. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 4; (b) CDR-H2 of SEQ ID NO: 6; (c) CDR-H3 of SEQ ID NO: 8 and (d) CDR-L1 of SEQ ID NO: 12; (e) CDR-L2 of SEQ ID NO: 14; (f) CDR-L3 of SEQ ID NO: 16. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0493] In another aspect, an anti-human PD-L2 antibody is provided, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region and the light chain variable region comprise (a) VH of SEQ ID NO: 2 and (b) VL of SEQ ID NO: 10. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 2, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 2 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 2 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 2, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:4, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:6 and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:8. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO:10, the VL sequence containing substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO:10 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO:10 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 10, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:12, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:14 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:16.

[0494] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 2 and SEQ ID NO: 10, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 2 and SEQ ID NO: 10, respectively.

[0495] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 2C4-E4.

[0496] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 18 and the light chain variable region (VL) of SEQ ID NO: 26. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 20; (b) CDR-H2 of SEQ ID NO: 22; (c) CDR-H3 of SEQ ID NO: 24 and (d) CDR-L1 of SEQ ID NO: 28; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 32. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0497] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 18 and (b) the VL of SEQ ID NO: 26. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 18, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 18 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 18 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 18, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 20, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 22, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 24. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 26, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 26 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 26 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 26, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:28, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:32.

[0498] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 18 and SEQ ID NO: 26, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 18 and SEQ ID NO: 26, respectively.

[0499] Other examples provided herein are based, in part, on the development of antibody 8B5-B1, which specifically binds to human PD-L2.

[0500] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 34 and the light chain variable region (VL) of SEQ ID NO: 42. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 36; (b) CDR-H2 of SEQ ID NO: 38; (c) CDR-H3 of SEQ ID NO: 40 and (d) CDR-L1 of SEQ ID NO: 44; (e) CDR-L2 of SEQ ID NO: 46; (f) CDR-L3 of SEQ ID NO: 48. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0501] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 34 and (b) the VL of SEQ ID NO: 42. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 34, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 34 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 34 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 34, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 36, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 38, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 40. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 42, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 42 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 42 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 42, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:44, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:46 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:48.

[0502] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 34 and SEQ ID NO: 42, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 34 and SEQ ID NO: 42, respectively.

[0503] Certain embodiments provided herein are based, in part, on the development of antibody 11C11-H5, which specifically binds to human PD-L2.

[0504] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 50 and the light chain variable region (VL) of SEQ ID NO: 58. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 52; (b) CDR-H2 of SEQ ID NO: 54; (c) CDR-H3 of SEQ ID NO: 56 and (d) CDR-L1 of SEQ ID NO: 60; (e) CDR-L2 of SEQ ID NO: 62; (f) CDR-L3 of SEQ ID NO: 64. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0505] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 50 and (b) the VL of SEQ ID NO: 58. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 50, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 50 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 50 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 50, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 52, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 54 and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 58, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 58 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 58 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 58, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:60, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:62 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:64.

[0506] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 50 and SEQ ID NO: 58, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 50 and SEQ ID NO: 58, respectively.

[0507] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 19C3-B3.

[0508] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 50 and the light chain variable region (VL) of SEQ ID NO: 66. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 52; (b) CDR-H2 of SEQ ID NO: 54; (c) CDR-H3 of SEQ ID NO: 56 and (d) CDR-L1 of SEQ ID NO: 60; (e) CDR-L2 of SEQ ID NO: 62; (f) CDR-L3 of SEQ ID NO: 68. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0509] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 50 and (b) the VL of SEQ ID NO: 66. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 50, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 50 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 50 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 50, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 52, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 54 and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 66, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 66 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 66 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 66, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:60, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:62 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:68.

[0510] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 50 and SEQ ID NO: 66, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 50 and SEQ ID NO: 66, respectively.

[0511] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 10D1-G1.

[0512] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 96 and the light chain variable region (VL) of SEQ ID NO: 104. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 98; (b) CDR-H2 of SEQ ID NO: 100; (c) CDR-H3 of SEQ ID NO: 102 and (d) CDR-L1 of SEQ ID NO: 106; (e) CDR-L2 of SEQ ID NO: 108; (f) CDR-L3 of SEQ ID NO: 110. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0513] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 96 and (b) the VL of SEQ ID NO: 104. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 96, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 96 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 96 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 96, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 98, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 100, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 102. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 104, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 104 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 104 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 104, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:106, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:108 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:110.

[0514] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 96 and SEQ ID NO: 104, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 96 and SEQ ID NO: 104, respectively.

[0515] Other examples provided herein are based, in part, on the development of the antibody 7H5-C5, which specifically binds to human PD-L2.

[0516] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 112 and the light chain variable region (VL) of SEQ ID NO: 120. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 114; (b) CDR-H2 of SEQ ID NO: 116; (c) CDR-H3 of SEQ ID NO: 118 and (d) CDR-L1 of SEQ ID NO: 122; (e) CDR-L2 of SEQ ID NO: 124; (f) CDR-L3 of SEQ ID NO: 126. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0517] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 112 and (b) the VL of SEQ ID NO: 120. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 112, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 112 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 112 are substituted, inserted and / or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the CDR (i.e., in the FR). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 112, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 114, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 116, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 118. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 120, the VL sequence containing substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 120 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 120 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 120, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:122, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:124 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:126.

[0518] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 112 and SEQ ID NO: 120, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 112 and SEQ ID NO: 120, respectively.

[0519] Certain embodiments provided herein are based, in part, on the development of antibody 9A3-C7, which specifically binds to human PD-L2.

[0520] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 128 and the light chain variable region (VL) of SEQ ID NO: 132. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 114; (b) CDR-H2 of SEQ ID NO: 130; (c) CDR-H3 of SEQ ID NO: 118 and (d) CDR-L1 of SEQ ID NO: 134; (e) CDR-L2 of SEQ ID NO: 136; (f) CDR-L3 of SEQ ID NO: 138. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0521] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 128 and (b) the VL of SEQ ID NO: 132. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 128, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 128 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 128 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 128, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 114, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 130, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 118. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 132, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 132 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 132 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 132, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO:134, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO:136 and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO:138.

[0522] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 128 and SEQ ID NO: 132, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 128 and SEQ ID NO: 132, respectively.

[0523] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 10A9-D2.

[0524] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 140 and the light chain variable region (VL) of SEQ ID NO: 146. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 98; (b) CDR-H2 of SEQ ID NO: 142; (c) CDR-H3 of SEQ ID NO: 144 and (d) CDR-L1 of SEQ ID NO: 106; (e) CDR-L2 of SEQ ID NO: 148; (f) CDR-L3 of SEQ ID NO: 150. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0525] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 140 and (b) the VL of SEQ ID NO: 146. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 140, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 140 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 140 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 140, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 98, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 142, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 144. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 146, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 146 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 146 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 146, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:106, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:148 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:150.

[0526] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 140 and SEQ ID NO: 146, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 140 and SEQ ID NO: 146, respectively.

[0527] Certain embodiments provided herein are based, in part, on the development of antibody 19B3-B3, which specifically binds to human PD-L2.

[0528] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 152 and the light chain variable region (VL) of SEQ ID NO: 160. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 154; (b) CDR-H2 of SEQ ID NO: 156; (c) CDR-H3 of SEQ ID NO: 158 and (d) CDR-L1 of SEQ ID NO: 162; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 164. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0529] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 152 and (b) the VL of SEQ ID NO: 160. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 152, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 152 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 152 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 152, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 154, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 156, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 158. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 160, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 160 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 160 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 160, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:162, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:164.

[0530] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 152 and SEQ ID NO: 160, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 152 and SEQ ID NO: 160, respectively.

[0531] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 12A1-D4.

[0532] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 166 and the light chain variable region (VL) of SEQ ID NO: 174. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 168; (b) CDR-H2 of SEQ ID NO: 170; (c) CDR-H3 of SEQ ID NO: 172 and (d) CDR-L1 of SEQ ID NO: 176; (e) CDR-L2 of SEQ ID NO: 178; (f) CDR-L3 of SEQ ID NO: 180. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0533] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 166 and (b) the VL of SEQ ID NO: 174. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 166, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 166 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 166 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 166, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 168, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 170, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 172. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 174, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 174 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 174 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 174, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO:176, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO:178 and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO:180.

[0534] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 166 and SEQ ID NO: 174, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 166 and SEQ ID NO: 174, respectively.

[0535] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 10D1-G1 N31Q.N92Q.LC.

[0536] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 96 and the light chain variable region (VL) of SEQ ID NO: 212. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 98; (b) CDR-H2 of SEQ ID NO: 100; (c) CDR-H3 of SEQ ID NO: 102 and (d) CDR-L1 of SEQ ID NO: 214; (e) CDR-L2 of SEQ ID NO: 108; (f) CDR-L3 of SEQ ID NO: 216. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0537] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 96 and (b) the VL of SEQ ID NO: 212. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 96, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 96 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 96 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 96, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 98, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 100 and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 212, the VL sequence containing substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 212 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 212 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 212, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:214, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:108 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:216.

[0538] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 96 and SEQ ID NO: 212, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 96 and SEQ ID NO: 212, respectively.

[0539] Other examples provided herein are based, in part, on the development of the anti-human PD-L2 antibody 10A9-D2.N31Q.LC.

[0540] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 140 and the light chain variable region (VL) of SEQ ID NO: 218. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 98; (b) CDR-H2 of SEQ ID NO: 142; (c) CDR-H3 of SEQ ID NO: 144 and (d) CDR-L1 of SEQ ID NO: 214; (e) CDR-L2 of SEQ ID NO: 148; (f) CDR-L3 of SEQ ID NO: 150. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0541] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 140 and (b) the VL of SEQ ID NO: 218. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 140, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 140 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 140 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 140, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 98, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 142, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 144. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 218, the VL sequence containing substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 218 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 218 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 218, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:214, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:148 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:150.

[0542] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 140 and SEQ ID NO: 218, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 140 and SEQ ID NO: 218, respectively.

[0543] Certain embodiments provided herein are based, in part, on the development of the antibody 19B3-B3.M23K.M63L.HC, which specifically binds to human PD-L2.

[0544] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 220 and the light chain variable region (VL) of SEQ ID NO: 160. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 154; (b) CDR-H2 of SEQ ID NO: 222; (c) CDR-H3 of SEQ ID NO: 158 and (d) CDR-L1 of SEQ ID NO: 162; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 164. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0545] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 220 and (b) the VL of SEQ ID NO: 160. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 220, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 220, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 154, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 222, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 158. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 160, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 160 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 160 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 160, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:162, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:164.

[0546] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 160, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 160, respectively.

[0547] Other examples provided herein are based, in part, on the development of the antibody 2-19H2, which specifically binds to human PD-L2.

[0548] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 220 and the light chain variable region (VL) of SEQ ID NO: 26. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 154; (b) CDR-H2 of SEQ ID NO: 222; (c) CDR-H3 of SEQ ID NO: 158 and (d) CDR-L1 of SEQ ID NO: 28; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 32. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0549] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 220 and (b) the VL of SEQ ID NO: 26. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 220, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 220, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 154, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 222, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 158. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 26, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 26 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 26 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 26, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:28, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:32.

[0550] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 26, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 26, respectively.

[0551] Certain embodiments provided herein are based, in part, on the development of the antibody 19B3-B3.N92Q.LC.M23K.M63L.HC, which specifically binds to human PD-L2.

[0552] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 220 and the light chain variable region (VL) of SEQ ID NO: 226. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 154; (b) CDR-H2 of SEQ ID NO: 222; (c) CDR-H3 of SEQ ID NO: 158 and (d) CDR-L1 of SEQ ID NO: 162; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 228. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0553] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 220 and (b) the VL of SEQ ID NO: 226. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 220, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 220, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 154, (b) CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 222, and (c) CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 158. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 226, and the VL sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 226 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 226 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 226, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:162, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:228.

[0554] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 226, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 226, respectively.

[0555] Certain embodiments provided herein are based, in part, on the development of the antibody 19B3-B3.N92Y.LC.M23K.M63L.HC, which specifically binds to human PD-L2.

[0556] Thus, an anti-human PD-L2 antibody is provided, comprising six CDR sequences as contained in the heavy chain variable region (VH) of SEQ ID NO: 220 and the light chain variable region (VL) of SEQ ID NO: 230. In one embodiment, the present invention provides an antibody comprising three heavy chain CDRs and three light chain CDRs, the heavy chain and light chain CDRs comprising (a) CDR-H1 of SEQ ID NO: 154; (b) CDR-H2 of SEQ ID NO: 222; (c) CDR-H3 of SEQ ID NO: 158 and (d) CDR-L1 of SEQ ID NO: 162; (e) CDR-L2 of SEQ ID NO: 30; (f) CDR-L3 of SEQ ID NO: 32. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0557] In another aspect, an anti-human PD-L2 antibody is provided, comprising a VH and a VL, wherein the VH and the VL comprise (a) the VH of SEQ ID NO: 220 and (b) the VL of SEQ ID NO: 230. In certain embodiments, the present invention provides an antibody having a variant of the heavy chain variable region and / or the light chain variable region as shown in (a) and (b), wherein the overall homology of the variant sequence is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, provided that at most 1, 2, 3 amino acid residues in the CDR sequence are substituted, specifically, in a conservative substitution pattern as defined herein. In certain embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 220, and the VH sequence contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 220 are substituted, inserted and / or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VH sequence of SEQ ID NO: 220, including post-translational modifications to that sequence. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 154, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 222, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 158. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall homology to the amino acid sequence of SEQ ID NO: 230, the VL sequence containing substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-human PD-L2 antibody comprising that sequence retains the ability to bind to PD-L2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 230 are substituted, inserted and / or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 230 are substituted, inserted and / or deleted. In certain embodiments, substitutions, insertions or deletions occur in regions outside of the CDRs (ie, in the FRs). Optionally, the anti-human PD-L2 antibody comprises the VL sequence of SEQ ID NO: 230, including post-translational modifications to that sequence.In a specific embodiment, VL comprises one, two or three CDRs selected from the following: (a) CDR-L1, which comprises the amino acid sequence of SEQ ID NO:162, (b) CDR-L2, which comprises the amino acid sequence of SEQ ID NO:30 and (c) CDR-L3, which comprises the amino acid sequence of SEQ ID NO:32.

[0558] In another aspect, an anti-human PD-L2 antibody is provided, wherein the antibody comprises a VH as in any embodiment provided above and a VL as in any embodiment provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 230, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-human PD-L2 antibody comprises a humanized form of the antibody comprising the VH and VL sequences in SEQ ID NO: 220 and SEQ ID NO: 230, respectively.

[0559] There are currently two widely used systems for CDR assignment of sequence-delimited antibodies, Kabat and Cossia CDR definitions. Kabat CDR definitions (Kabat et al., "Sequences of 20 proteins with immunological significance" National Institutes of Health, Bethesda, Maryland (National Institutes of Health, Bethesda, Md.) (1991)) used in the embodiments described above are based on antibody sequence variability. Unless otherwise specified, the CDR of the antibody of the present invention is defined using the Kabat system. Cossia definitions (Cossia et al., "Typical structure of the hypervariable region of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987); Lazikani et al., "Standard conformation of the typical structure of immunoglobulins", Journal of Molecular Biology, 273 (4), 927-948 (1997)) are based on the three-dimensional structure of antibodies and the topology of the CDR loop. Cossia CDR definitions are the same as Kabat CDR definitions, except that CDR-H1 and CDR-H2. Cossia et al. found that certain subsections within Kabat's CDRs adopt nearly identical peptide backbone conformations despite having great diversity at the level of amino acid sequence. These subsections are designated L1, L2, and L3 or H1, H2, and H3, where "L" and "H" represent light and heavy chain regions, respectively. These regions may be referred to as Cossia CDRs, which have borders that overlap with Kabat's CDRs. Table 1 illustrates the overlap of Cossia and Kabat's CDRs according to Kabat's residue numbering system.

[0560] Table 1

[0561]

[0562] Thus, in the following alternative embodiments, the CDRs of the antibodies of the invention are Coscia-defined CDR loops.

[0563] In one embodiment, the present invention provides an anti-human antibody 1A1-C2, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 69; (b) CDR-H2 of SEQ ID NO: 70; (c) CDR-H3 of SEQ ID NO: 71 and (d) CDR-L1 of SEQ ID NO: 81; (e) CDR-L2 of SEQ ID NO: 82; (f) CDR-L3 of SEQ ID NO: 83. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0564] In another embodiment, the present invention provides an anti-human antibody 2C4-E4, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 72; (b) CDR-H2 of SEQ ID NO: 73; (c) CDR-H3 of SEQ ID NO: 74 and (d) CDR-L1 of SEQ ID NO: 84; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 86. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0565] In another embodiment, the present invention provides an anti-human antibody 8B5-B1, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, comprising: (a) CDR-H1 of SEQ ID NO: 75; (b) CDR-H2 of SEQ ID NO: 76; (c) CDR-H3 of SEQ ID NO: 77 and (d) CDR-L1 of SEQ ID NO: 87; (e) CDR-L2 of SEQ ID NO: 88; (f) CDR-L3 of SEQ ID NO: 89. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0566] In yet another embodiment, the present invention provides an anti-human antibody 11C11-H5, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 78; (b) CDR-H2 of SEQ ID NO: 79; (c) CDR-H3 of SEQ ID NO: 80 and (d) CDR-L1 of SEQ ID NO: 90; (e) CDR-L2 of SEQ ID NO: 91; (f) CDR-L3 of SEQ ID NO: 92. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0567] The present invention further provides an anti-human antibody 19C3-B3, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 78; (b) CDR-H2 of SEQ ID NO: 79; (c) CDR-H3 of SEQ ID NO: 80 and (d) CDR-L1 of SEQ ID NO: 90; (e) CDR-L2 of SEQ ID NO: 91; (f) CDR-L3 of SEQ ID NO: 93. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0568] In another embodiment, the present invention provides an anti-human antibody 10D1-G1, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 181; (b) CDR-H2 of SEQ ID NO: 182; (c) CDR-H3 of SEQ ID NO: 183 and (d) CDR-L1 of SEQ ID NO: 194; (e) CDR-L2 of SEQ ID NO: 195; (f) CDR-L3 of SEQ ID NO: 196. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0569] In another embodiment, the present invention provides an anti-human antibody 7H5-C5, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, comprising: (a) CDR-H1 of SEQ ID NO: 184; (b) CDR-H2 of SEQ ID NO: 185; (c) CDR-H3 of SEQ ID NO: 186 and (d) CDR-L1 of SEQ ID NO: 197; (e) CDR-L2 of SEQ ID NO: 198; (f) CDR-L3 of SEQ ID NO: 199. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0570] In yet another embodiment, the present invention provides an anti-human antibody 9A3-C7, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 184; (b) CDR-H2 of SEQ ID NO: 185; (c) CDR-H3 of SEQ ID NO: 186 and (d) CDR-L1 of SEQ ID NO: 200; (e) CDR-L2 of SEQ ID NO: 201; (f) CDR-L3 of SEQ ID NO: 202. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0571] The present invention further provides an anti-human antibody 10A9-D2, comprising three heavy chain CDRs and three light chain CDRs according to the Coscia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 181; (b) CDR-H2 of SEQ ID NO: 187; (c) CDR-H3 of SEQ ID NO: 188 and (d) CDR-L1 of SEQ ID NO: 194; (e) CDR-L2 of SEQ ID NO: 203; (f) CDR-L3 of SEQ ID NO: 204. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0572] In yet another embodiment, the present invention provides an anti-human antibody 19B3-B3, comprising three heavy chain CDRs and three light chain CDRs according to the Coscia CDR definition, comprising: (a) CDR-H1 of SEQ ID NO: 189; (b) CDR-H2 of SEQ ID NO: 190; (c) CDR-H3 of SEQ ID NO: 191 and (d) CDR-L1 of SEQ ID NO: 205; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 206. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0573] The present invention further provides an anti-human antibody 12A1-D4, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 181; (b) CDR-H2 of SEQ ID NO: 192; (c) CDR-H3 of SEQ ID NO: 193 and (d) CDR-L1 of SEQ ID NO: 207; (e) CDR-L2 of SEQ ID NO: 208; (f) CDR-L3 of SEQ ID NO: 209. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0574] In another embodiment, the present invention provides an anti-human antibody 10D1-G1 N31Q.N92Q.LC, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 181; (b) CDR-H2 of SEQ ID NO: 182; (c) CDR-H3 of SEQ ID NO: 183 and (d) CDR-L1 of SEQ ID NO: 223; (e) CDR-L2 of SEQ ID NO: 195; (f) CDR-L3 of SEQ ID NO: 224. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0575] The present invention further provides an anti-human antibody 10A9-D2 N31Q.LC, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 181; (b) CDR-H2 of SEQ ID NO: 187; (c) CDR-H3 of SEQ ID NO: 188 and (d) CDR-L1 of SEQ ID NO: 222; (e) CDR-L2 of SEQ ID NO: 203; (f) CDR-L3 of SEQ ID NO: 204. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0576] In yet another embodiment, the present invention provides an anti-human antibody 19B3-B3 M23K.M63L.HC, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 189; (b) CDR-H2 of SEQ ID NO: 190; (c) CDR-H3 of SEQ ID NO: 191 and (d) CDR-L1 of SEQ ID NO: 205; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 206. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0577] In another embodiment, the present invention provides an anti-human antibody 2-19H2, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, wherein the CDRs comprise: (a) CDR-H1 of SEQ ID NO: 189; (b) CDR-H2 of SEQ ID NO: 190; (c) CDR-H3 of SEQ ID NO: 191 and (d) CDR-L1 of SEQ ID NO: 84; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 86. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0578] In yet another embodiment, the present invention provides an anti-human antibody 19B3-B3 N92Q.LC.M23K.M63L.HC, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 189; (b) CDR-H2 of SEQ ID NO: 190; (c) CDR-H3 of SEQ ID NO: 191 and (d) CDR-L1 of SEQ ID NO: 205; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 231. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0579] In yet another embodiment, the present invention provides an anti-human antibody 19B3-B3 N92Y.LC.M23K.M63L.HC, comprising three heavy chain CDRs and three light chain CDRs according to the Cossia CDR definition, the CDRs comprising: (a) CDR-H1 of SEQ ID NO: 189; (b) CDR-H2 of SEQ ID NO: 190; (c) CDR-H3 of SEQ ID NO: 191 and (d) CDR-L1 of SEQ ID NO: 205; (e) CDR-L2 of SEQ ID NO: 85; (f) CDR-L3 of SEQ ID NO: 86. In certain embodiments, the present invention provides an antibody, wherein at most 1, 2, 3 amino acid residues in the CDR sequences selected from (a) to (f) are substituted, in particular, in a conservative substitution pattern as defined herein.

[0580] In another aspect of the invention, the anti-human PD-L2 antibody according to any one of the above embodiments is a monoclonal antibody, including a human antibody. In one embodiment, the anti-human PD-L2 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, a bifunctional antibody or a F(ab')2 fragment. In another embodiment, the antibody is a substantially full-length antibody, such as an IgG1 antibody, an IgG2 antibody, an IgG3 or an IgG4 isotype. In a certain embodiment, the antibody is an IgG1 antibody.

[0581] In another aspect, an anti-human PD-L2 antibody according to any of the above embodiments may incorporate any of the features, alone or in combination, as described below.

[0582] In certain embodiments, the amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibodies. The amino acid sequence variants of the antibodies can be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibodies or by peptide synthesis. Such modifications include, for example, the deletion and / or insertion and / or substitution of residues in the amino acid sequence of the antibodies. Any combination of deletion, insertion and substitution can be performed to obtain the final construct, with the limiting condition that the final construct has the desired characteristics, for example, antigen binding.

[0583] In certain embodiments, antibody variants with one or more amino acid substitutions are provided. Sites of interest for substitution mutation induction include CDR and FR. Conservative substitutions are shown under the title "preferred substitutions" in Table 2. More significant changes are provided under the title "exemplary substitutions" in Table 2, and are further described below about amino acid side chain species. Amino acid substitutions can be introduced into the antibody of interest and for desired active screening products, such as retained / improved antigen binding, reduced immunogenicity or improved ADCC or CDC.

[0584] Table 2

[0585]

[0586]

[0587] Amino acids can be grouped according to common side chain properties:

[0588] (1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile;

[0589] (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

[0590] (3) Acidic: Asp, Glu;

[0591] (4) Basic: His, Lys, Arg;

[0592] (5) Residues that affect chain orientation: Gly, Pro;

[0593] (6) Aromatic: Trp, Tyr, Phe.

[0594] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0595] One class of substitution variants involves replacing one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). In general, certain biological properties (e.g., increased affinity, reduced immunogenicity) of the resulting variants selected for further study will have modifications (improvements) relative to the parent antibody, and / or will have certain biological properties that are substantially retained by the parent antibody. Exemplary substitution variants are affinity-matured antibodies, which are conveniently produced, for example, using affinity maturation techniques based on phage display (such as those described herein). In simple terms, one or more CDR residues are mutated and the variant antibodies are displayed on phage and screened for specific biological activities (e.g., binding affinity).

[0596] Changes (e.g., substitutions) can be made within the CDR to, for example, improve antibody affinity. Such changes can be made in CDR "hotspots", residues encoded by codons that undergo high-frequency mutations during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)), and / or SDR (a-CDR), and the resulting variant VH or VL binding affinity is tested. Affinity maturation is described in, for example, Hoogenboom et al., Methods Mol. Biol. 178: 1-37 (O'Brien et al., Human Press, Totowa, NJ (2001)) by constructing a secondary library and reselecting therefrom. In some embodiments of affinity maturation, diversity is introduced into the variable gene selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves a CDR-guided approach, in which several CDR residues (e.g., 4 to 6 residues at a time) are randomly grouped. CDR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR H3 and CDR-L3 are particularly commonly targeted.

[0597] In certain embodiments, substitutions, insertions or deletions may be made within one or more CDRs, as long as such changes do not substantially reduce the ability of the antibody to bind to antigen. For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in the CDRs. Such changes may be outside of CDR "hot spots" or SDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR is unchanged or contains no more than one, two or three amino acid substitutions.

[0598] A method suitable for identifying residues or regions that can be targeted for mutagenesis of antibodies is called "alanine scanning mutagenesis", as described in Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, the residue or group (e.g., charged residues, such as Arg, Asp, His, Lys, and Glu) of the target residue is identified and replaced with neutral or negatively charged amino acids (e.g., propylamino or polypropylamino) to determine whether the interaction between the antibody and the antigen is affected. Other substitutions can be introduced at amino acid positions that indicate functional sensitivity to the initial substitution. Alternatively or in addition, the crystal structure of the antigen-antibody complex is used to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues can be targeted or removed as candidates for substitution. Variants can be screened to determine whether they contain the desired properties.

[0599] Amino acid sequence insertions include amino and / or carboxyl terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertion variants of antibody molecules include fusions of enzymes or polypeptides that extend the serum half-life of the antibody to the N-terminus or C-terminus of the antibody.

[0600] In certain embodiments, the antibodies provided herein are altered to increase or decrease the extent of antibody glycosylation.Adding or deleting glycosylation sites to an antibody can be conveniently achieved by altering the amino acid sequence so that one or more glycosylation sites are generated or removed.

[0601] In the case where the antibody comprises an Fc region, the carbohydrate connected thereto can be changed. The primary antibody produced by mammalian cells generally comprises branched biantennary oligosaccharides, which are generally connected by the N-bond of the Asn297 of the CH2 domain in the Fc region. See, for example, Wright et al., TIBTECH 15:26-32 (1997). Oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and the fucose of the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In certain embodiments, the oligosaccharides in the antibody of the present invention can be modified to produce antibody variants with some improved properties.

[0602] In one embodiment, an antibody variant is provided, which has a carbohydrate structure lacking fucose connected (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody can be 1% to 80%, 1% to 65%, 5% to 65% or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain relative to the sum of all sugar structures (e.g., complex, hybrid and higher mannose structures) connected to Asn 297 as measured by MALDI-TOF mass spectrometry, for example, as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, due to minor sequence changes in antibodies, Asn297 can also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylated variants can have improved ADCC function. See, e.g., U.S. Patent Publication Nos. US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US ​​2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al., Journal of Molecular Biology 336:1239-1249 (2004); Yamane-Ohkuni et al., Biotechnology and Bioengineering (Biotechnol. Bioeng.) 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Biochemistry and Biophysics 249: 533-545 (1986); U.S. Patent Application No. US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams et al., especially in Example 11) and gene knockout cell lines, such as α-1,6-fucosidase gene, FUT8, gene knockout CHO cells (see, e.g., Yamane-Ohkuni et al., Biotechnology and Bioengineering 87: 614 (2004); Kangda et al., Biotechnology and Bioengineering, 94 (4): 680-688 (2006) and WO2003 / 085107).

[0603] The antibody variant further has a bisecting oligosaccharide, for example a biantennary oligosaccharide connected to the Fc region of the antibody by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Merret et al.); U.S. Pat. No. 6,602,684 (Umana et al.) and US 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide connected to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in: WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.) and WO 1999 / 22764 (Raju, S.).

[0604] In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of the antibodies provided herein, thereby generating Fc region variants. The Fc region variants can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0605] In certain embodiments, the invention encompasses antibody variants with some but not all effector functions, which make them desirable candidates for applications where the in vivo half-life of the antibody is important and certain effector functions (e.g., complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays may be performed to confirm reduction / depletion of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays may be performed to ensure that the antibody lacks FcyR binding (and therefore may lack ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express only Fc(RIII), whereas monocytes express Fc(RI, Fc(RII), and Fc(RIII. FcR expression on hematopoietic cells is summarized in Table 3, on page 464 below: in Ravitch and Kinnett, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating ADCC activity of a molecule of interest are described. Described in U.S. Pat. Nos. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Natl. Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Natl. Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Brueggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)).

[0606] Alternatively, non-radioactive analytical methods can be used (see, e.g., ACTI for flow cytometry). TM Nonradioactive cytotoxicity assay (Cell Technology, Mountain View, CA; and Cytotoxicity Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.

[0607] Alternatively or additionally, ADCC activity of a molecule of interest can be assessed in vivo, for example, in an animal model as disclosed in Kleins et al., Proc. Natl. Acad. Sci. USA, 95:652-656 (1998).

[0608] A C1q binding assay can also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996); Krag, MS et al., Blood 101: 1045-1052 (2003) and Krag, MS and MJ Glennie, Blood 103: 2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determination can also be performed using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18 (12): 1759-1769 (2006)).

[0609] Antibodies with reduced effector function include antibodies with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant with substitutions of residues 265 and 297 to alanine (U.S. Pat. No. 7,332,581).

[0610] Certain antibody variants with improved or diminished binding to FcRs have been described (see, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312 and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0611] In certain embodiments, the antibody variants comprise an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues).

[0612] In some embodiments, alterations are made in the Fc region that result in altered (ie, improved or reduced) CIq binding and / or complement dependent cytotoxicity (CDC), such as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0613] Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn) are responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Keene et al., J. Immunol. 24:249 (1994)), as described in US 2005 / 0014934 A1 (Hinton et al.). Those antibodies comprise an Fc region having one or more substitutions that improve binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826).

[0614] For other examples of Fc region variants, see also Duncan and Winter, Nature, 322:738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821 and WO 94 / 29351.

[0615] In certain embodiments, it may be desirable to produce cysteine ​​engineered antibodies, such as "thioMAbs," in which one or more residues of an antibody are replaced with cysteine ​​residues. In particular embodiments, the substituted residue is present at an accessible site of the antibody. In certain embodiments, any one or more of the following residues may be replaced with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain and S400 (EU numbering) of the heavy chain Fc region. Cysteine ​​engineered antibodies can be produced as described, for example, in U.S. Patent No. 7,521,541.

[0616] In certain embodiments, the antibodies provided herein can be further modified to contain other non-protein moieties known in the art and readily available. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethyl cellulose, polydextrose, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers) and polydextrose or poly(n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, whether the antibody derivative will be used for therapy under defined conditions, etc.

[0617] In another embodiment, a conjugate of an antibody and a non-protein moiety is provided that can be selectively heated by exposure to radiation. In one embodiment, the non-protein moiety is a carbon nanotube (Com et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, and includes, but is not limited to, a wavelength that does not harm normal cells but heats the non-protein moiety to a temperature that kills cells near the antibody-non-protein moiety.

[0618] In one embodiment, the antibodies or antigen-binding portions of the invention are monospecific, bispecific, trispecific or multispecific antigen-binding molecules.

[0619] Bispecific antibodies include, for example, multivalent single-chain antibodies, bifunctional antibodies and trifunctional antibodies, as well as antibodies having the constant domain structure of a full-length antibody with additional antigen binding sites (e.g., single-chain Fv, VH domain and / or VL domain, Fab or (Fab)) attached via one or more peptide linkers. 2) is connected to the full-length antibody. The antibody can be a full-length antibody from a single species, or a chimeric or humanized antibody. For antibodies with more than two antigen binding sites, when the protein has binding sites for two different antigens, some of the binding sites may be the same. That is, although the first binding site is specific for human PD-L2, the second binding site is specific for a different antigen. In a certain embodiment, the second binding site specifically binds to an antigen selected from the group consisting of a cell-specific antigen, an antigen specific for a virus-infected cell, and a T cell co-inhibitor. In a preferred embodiment, the second binding site specifically binds to human PD-L1.

[0620] In one embodiment, the antibody, or antigen binding portion thereof, binds to the same epitope and / or competes for the same epitope as any of the antibodies or antigen binding portions of the invention.

[0621] As used herein, the term "epitope" refers to a portion or region of an antigen molecule (e.g., a peptide) that is specifically bound by the antibody binding site of an antibody. An epitope typically includes at least 3, and more typically at least 5 or 8, 10 residues (e.g., amino acids or nucleotides). Typically, the length of an epitope is also less than 20 residues (e.g., amino acids or nucleotides), such as less than 15 residues or less than 12 residues. Among them, the term "epitope" encompasses both linear epitopes in which continuous amino acids are recognized by an antibody and conformational epitopes in which an antibody recognizes amino acids in an appropriate configuration or conformation. Therefore, in some epitopes, conformation (three-dimensional structure) is as important as amino acid sequence (primary structure).

[0622] Antibodies can be produced using recombinant methods and compositions, such as those described in U.S. Pat. No. 4,816,567. In one embodiment, a nucleic acid molecule is provided that comprises a nucleotide sequence encoding an anti-human PD-L2 antibody described herein.

[0623] Therefore, in one embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 1A1-C2, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 3; (b) CDR-H2 of SEQ ID NO: 5; (c) CDR-H3 of SEQ ID NO: 7 and (d) CDR-L1 of SEQ ID NO: 11; (e) CDR-L2 of SEQ ID NO: 13; (f) CDR-L3 of SEQ ID NO: 15. In another aspect, a nucleic acid molecule is provided, comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 1 and (b) VL of SEQ ID NO: 9. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 15.

[0624] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 2C4-E4, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 19; (b) CDR-H2 of SEQ ID NO: 21; (c) CDR-H3 of SEQ ID NO: 23 and (d) CDR-L1 of SEQ ID NO: 27; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 31. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 17 and (b) VL of SEQ ID NO: 25. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 23. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 27, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31.

[0625] In yet another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 8B5-B1, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 35; (b) CDR-H2 of SEQ ID NO: 37; (c) CDR-H3 of SEQ ID NO: 39 and (d) CDR-L1 of SEQ ID NO: 43; (e) CDR-L2 of SEQ ID NO: 45; (f) CDR-L3 of SEQ ID NO: 47. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 33 and (b) VL of SEQ ID NO: 41. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0626] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 11C11-H5, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 51; (b) CDR-H2 of SEQ ID NO: 53; (c) CDR-H3 of SEQ ID NO: 55 and (d) CDR-L1 of SEQ ID NO: 59; (e) CDR-L2 of SEQ ID NO: 61; (f) CDR-L3 of SEQ ID NO: 63. In another aspect, a nucleic acid molecule is provided, comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 49 and (b) VL of SEQ ID NO: 57. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 51, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 53, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0627] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 19C3-B3, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 51; (b) CDR-H2 of SEQ ID NO: 53; (c) CDR-H3 of SEQ ID NO: 55 and (d) CDR-L1 of SEQ ID NO: 59; (e) CDR-L2 of SEQ ID NO: 61; (f) CDR-L3 of SEQ ID NO: 67. In another aspect, a nucleic acid molecule is provided, comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 49 and (b) VL of SEQ ID NO: 65. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 51, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 53, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 67.

[0628] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 10D1-G1, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 97; (b) CDR-H2 of SEQ ID NO: 99; (c) CDR-H3 of SEQ ID NO: 101 and (d) CDR-L1 of SEQ ID NO: 105; (e) CDR-L2 of SEQ ID NO: 107; (f) CDR-L3 of SEQ ID NO: 109. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 95 and (b) VL of SEQ ID NO: 103. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 101. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 105, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 107, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 109.

[0629] In yet another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 7H5-C5, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 113; (b) CDR-H2 of SEQ ID NO: 115; (c) CDR-H3 of SEQ ID NO: 117 and (d) CDR-L1 of SEQ ID NO: 121; (e) CDR-L2 of SEQ ID NO: 123; (f) CDR-L3 of SEQ ID NO: 125. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 111 and (b) VL of SEQ ID NO: 119. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 113, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 115, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 117. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 121, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 123, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0630] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 9A3-C7, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 113; (b) CDR-H2 of SEQ ID NO: 129; (c) CDR-H3 of SEQ ID NO: 117 and (d) CDR-L1 of SEQ ID NO: 133; (e) CDR-L2 of SEQ ID NO: 135; (f) CDR-L3 of SEQ ID NO: 137. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 127 and (b) VL of SEQ ID NO: 131. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 113, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 117. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 133, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 135, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 137.

[0631] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 10A9-D2, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 97; (b) CDR-H2 of SEQ ID NO: 141; (c) CDR-H3 of SEQ ID NO: 143 and (d) CDR-L1 of SEQ ID NO: 105; (e) CDR-L2 of SEQ ID NO: 147; (f) CDR-L3 of SEQ ID NO: 149. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 139 and (b) VL of SEQ ID NO: 145. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 143. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 105, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 147, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 149.

[0632] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 19B3-B3, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 153; (b) CDR-H2 of SEQ ID NO: 155; (c) CDR-H3 of SEQ ID NO: 157 and (d) CDR-L1 of SEQ ID NO: 161; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 163. In another aspect, a nucleic acid molecule is provided, comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 151 and (b) VL of SEQ ID NO: 159. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 155, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 161, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 163.

[0633] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 12A1-D4, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 167; (b) CDR-H2 of SEQ ID NO: 169; (c) CDR-H3 of SEQ ID NO: 171 and (d) CDR-L1 of SEQ ID NO: 175; (e) CDR-L2 of SEQ ID NO: 177; (f) CDR-L3 of SEQ ID NO: 179. In another aspect, a nucleic acid molecule is provided comprising a VH and a VL, the VH and VL comprising (a) VH of SEQ ID NO: 165 and (b) VL of SEQ ID NO: 173. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 167, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 175, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 179.

[0634] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 10D1-G1 N31Q.N92Q.LC, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 97; (b) CDR-H2 of SEQ ID NO: 99; (c) CDR-H3 of SEQ ID NO: 101 and (d) CDR-L1 of SEQ ID NO: 213; (e) CDR-L2 of SEQ ID NO: 107; (f) CDR-L3 of SEQ ID NO: 215. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 95 and (b) VL of SEQ ID NO: 211. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 99, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 101. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 107, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 215.

[0635] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 10A9-D2 N31Q.LC, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 97; (b) CDR-H2 of SEQ ID NO: 141; (c) CDR-H3 of SEQ ID NO: 143 and (d) CDR-L1 of SEQ ID NO: 213; (e) CDR-L2 of SEQ ID NO: 147; (f) CDR-L3 of SEQ ID NO: 149. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 139 and (b) VL of SEQ ID NO: 217. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 143. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 147, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 149.

[0636] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 19B3-B3 M23K.M63L.HC, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 153; (b) CDR-H2 of SEQ ID NO: 221; (c) CDR-H3 of SEQ ID NO: 157 and (d) CDR-L1 of SEQ ID NO: 161; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 163. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 219 and (b) VL of SEQ ID NO: 159. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 221, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 161, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 163.

[0637] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 2-H192, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 153; (b) CDR-H2 of SEQ ID NO: 221; (c) CDR-H3 of SEQ ID NO: 157 and (d) CDR-L1 of SEQ ID NO: 27; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 31. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 219 and (b) VL of SEQ ID NO: 25. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 221, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 27, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31.

[0638] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 19B3-B3 N92Q.LC.M23K.M63L.HC, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 153; (b) CDR-H2 of SEQ ID NO: 221; (c) CDR-H3 of SEQ ID NO: 157 and (d) CDR-L1 of SEQ ID NO: 161; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 227. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 219 and (b) VL of SEQ ID NO: 225. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 221, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 161, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 227.

[0639] In another embodiment, the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding an anti-human PD-L2 antibody 19B3-B3 M23K.M63L.HC, wherein the nucleic acid molecule comprises three heavy chain CDRs and three light chain CDRs, the CDRs comprising (a) CDR-H1 of SEQ ID NO: 153; (b) CDR-H2 of SEQ ID NO: 221; (c) CDR-H3 of SEQ ID NO: 157 and (d) CDR-L1 of SEQ ID NO: 161; (e) CDR-L2 of SEQ ID NO: 29; (f) CDR-L3 of SEQ ID NO: 31. In another aspect, a nucleic acid molecule is provided comprising VH and VL, the VH and VL comprising (a) VH of SEQ ID NO: 219 and (b) VL of SEQ ID NO: 229. In a specific embodiment, VH comprises one, two or three CDRs selected from the group consisting of: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 221, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157. In a certain embodiment, VL comprises one, two or three CDRs selected from the group consisting of: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 161, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31.

[0640] In another embodiment, the present invention relates to one or more vectors (e.g., expression vectors) comprising such nucleic acid sequences as provided above. In another embodiment, a cell comprising such nucleic acid is provided. In one such embodiment, the cell comprises (e.g., has been transformed as follows): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector and a second vector, the first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and the second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, such as a Chinese Hamster Ovary (CHO) cell or a lymphocyte (e.g., YO, NSO, Sp20). In one embodiment, a method for preparing an anti-human PD-L2 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expressing the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0641] To recombinantly produce an anti-human PD-L2 antibody, nucleic acid encoding the antibody is isolated (e.g., as described above) and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody).

[0642] Suitable host cells for cloning or expressing vectors encoding antibodies include prokaryotes or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, specifically, when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing the expression of antibody fragments in Escherichia coli.) After expression, antibodies can be separated from bacterial cell slurry with soluble elution fractions and can be further purified.

[0643] In addition to prokaryotes, eukaryotic microorganisms (such as filamentous fungi or yeast) are suitable cloning or expression hosts for antibody-encoding vectors (including fungi and yeast strains whose glycosylation pathways have been "humanized") to produce antibodies with a partially or fully human glycosylation pattern. See Jean Gross, Nature Biotechnology 22: 1409-1414 (2004) and Lee et al., Nature Biotechnology 24: 210-215 (2006).

[0644] Suitable host cells for expressing glycosylated antibodies are derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified that can be used in conjunction with insect cells, specifically, for transfection of Spodoptera frugiperda cells.

[0645] Plant cell cultures can also be used as hosts. See, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES for producing antibodies in transgenic plants). TM technology).

[0646] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to growth in suspension can be useful. Other examples of useful mammalian host cell lines are the macaque kidney CV1 cell line transformed by SV40 (COS-7); human embryonic kidney cell line (293 or 293 cells, as described, e.g., by Graham et al., J. Gen Viral. 36:59 (1977)); baby hamster kidney cells (BHK); mouse supporting cells (TM4 cells, as described, e.g., by Mather, Biol. Reprod. 23:243-251 (1980)); macaque kidney cells (CV 1); African green monkey kidney cells (VER0-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; Buffalo rat liver liver cells (BRL 3A)); human lung cells (W138); human liver cells (HepG2); mouse mammary tumor (MMT060562); TRI cells, as described, e.g., by Mather et al., Annals NY Aead.Sei.383:44-68 (1982); MRC 5 cells and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFRCHO cells (Ullraub et al., Proc. Natl. Acad. cii. USA 77:4216 (1980)); and myeloma cell lines, such as YO, NSO and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Totohua Humana Press, NJ), pp. 255-268 (2003).

[0647] The anti-PD-L2 antibodies provided herein can be identified, screened or characterized for their physical / chemical properties and / or biological activities by various assays known in the art.

[0648] In one aspect, the antigen binding activity of the antibodies of the invention is tested, for example, by known methods such as ELISA, FACS, immunofluorescence, or immunohistochemistry.

[0649] On the other hand, competition analysis can be used to identify antibodies that compete with any of the antibodies described herein for binding to PD-L2. In certain embodiments, such competing antibodies bind to the same epitope (e.g., a linear or conformational epitope) that is bound by the antibodies described herein. Specific exemplary methods for locating epitopes to which antibodies bind are provided in Morris (1996) "Epitope Mapping Protocols" Methods in Molecular Biology, Vol. 66 (Totohua Humana, NJ).

[0650] In an exemplary competition assay, fixed PD-L2 is incubated in a solution comprising a first labeled antibody (e.g., any of the antibodies described herein) that binds to PD-L2 and a second unlabeled antibody that is tested for its ability to compete with the first antibody for binding to PD-L2. As a control, fixed PD-L2 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to PD-L2, excess unbound antibody is removed and the amount of label associated with fixed PD-L2 is measured. If the amount of label associated with fixed PD-L2 in the test sample is substantially reduced relative to the control sample, it indicates that the second antibody competes with the first antibody for binding to PD-L2. See Harlow and Lane (1988), Antibodies: A Laboratory Manual 14, Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY).

[0651] In certain embodiments, any of the anti-human PD-L2 antibodies provided herein is suitable for detecting the presence of PD-L2 in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. A "biological sample" includes, for example, cells or tissues (e.g., biopsy material, including cancerous or potentially cancerous lymphoid tissues, such as lymphocytes, lymphoblasts, monocytes, granulocytes, and mixtures thereof).

[0652] In one embodiment, an anti-human PD-L2 antibody for use in a diagnostic or detection method is provided. On the other hand, a method for detecting the presence of anti-human PD-L2 in a biological sample is provided. In certain embodiments, the method comprises contacting a biological sample with an anti-human PD-L2 antibody as described herein under conditions that allow the anti-human PD-L2 antibody to bind to human PD-L2, and detecting whether a complex is formed between the anti-human PD-L2 antibody and PD-L2 in the biological sample. Such methods may be in vitro or in vivo methods. In one embodiment, the anti-human PD-L2 antibody is used to select an individual who is eligible for therapy with an anti-human PD-L2 antibody, for example, where PD-L2 is a biomarker for selecting a patient. In another embodiment, the biological sample is a cell or tissue.

[0653] In another embodiment, the anti-human PD-L2 antibody is used to detect PD-L2-positive cancer in an individual in vivo (e.g., by in vivo imaging), for example, for the purpose of diagnosing, prognosing, or grading cancer, determining the appropriate course of treatment, or monitoring the response of cancer to treatment. One method known in the art for in vivo detection is immunopositron emission tomography (immunoPET), as described, for example, in Van Dongen et al., The Oncologist 12: 1379-1389 (2007) and Wieler et al., J. Nucl. Med. 44: 1271-1281 (2003). In such embodiments, a method of detecting PD-L2-positive cancer in an individual is provided, the method comprising administering a labeled anti-PD-L2 antibody to an individual having or suspected of having PD-L2-positive cancer, and detecting the labeled anti-PD-L2 antibody in the individual, wherein detection of the labeled anti-PD-L2 antibody indicates PD-L2-positive cancer in the individual. In certain of such embodiments, the labeled anti-PD-L2 antibody comprises an anti-PD-L2 antibody conjugated to a positron emitter, such as 68 Ga, 18 F. 64 Cu, 86 Y. 76 Br, 89 Zr and 124 I.

[0654] In other embodiments, the method of diagnosis or detection comprises contacting a first anti-human PD-L2 antibody fixed to a substrate with a biological sample to test for the presence of PD-L2, exposing the substrate to a second anti-human PD-L2 antibody, and detecting whether the second anti-human PD-L2 binds to a complex between the first anti-PD-L2 antibody and PD-L2 in the biological sample. The substrate can be any supporting medium, such as glass, metal, ceramic, polymeric beads, slides, chips, and other substrates. In certain embodiments, the biological sample comprises cells or tissues. In certain embodiments, the first or second anti-human PD-L2 antibody is any of the antibodies described herein.

[0655] Exemplary diseases that can be diagnosed or detected according to any of the above embodiments include, but are not limited to, PD-L2 positive cancers, such as PD-L2 positive liver cancer, PD-L2 positive hepatocellular carcinoma, PD-L2 positive gastric cancer, PD-L2 positive esophageal cancer, PD-L2 positive pancreatic cancer, PD-L2 positive lung cancer, PD-L2 positive colon cancer, PD-L2 positive breast cancer, PD-L2 positive prostate cancer, PD-L2 positive leukemia and PD-L2 positive lymphoma. In some embodiments, PD-L2 positive cancer is liver cancer. In some embodiments, PD-L2 positive cancer is hepatocellular carcinoma. In some embodiments, PD-L2 positive cancer is a cancer that receives an anti-PD-L2 immunohistochemistry (IHC) or in situ hybridization (ISH) score greater than "0", which corresponds to extremely weak or no staining of >90% of tumor cells. In another embodiment, PD-L2 positive cancer expresses 1+, 2+ or 3+ levels of PD-L2. In some embodiments, a PD-L2 positive cancer is a cancer that expresses PD-L2 according to a reverse transcriptase PCR (RT-PCR) analysis that detects PD-L2 mRNA. In some embodiments, the RT-PCR is a quantitative RT-PCR.

[0656] In certain embodiments, a labeled anti-PD-L2 antibody is provided. Labels include, but are not limited to, directly detectable labels or moieties (such as fluorescent, chromogenic, electron-dense, chemiluminescent, and radioactive labels), and indirectly detectable moieties (e.g., via an enzymatic reaction or molecular interaction), such as enzymes or ligands.

[0657] Exemplary labels include, but are not limited to, radioisotopes 32 P. 14 C. 125 I. 3 H and 131 I, fluorophores (such as rare earth chelators or fluorescein) and their derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luciferases, such as firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalhydrazide, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, sugar oxidases, such as glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase, heterocyclic oxidases (such as urine urease and xanthine oxidase), coupled with enzymes using hydrogen peroxide to oxidize dye precursors (such as HRP, lactoperoxidase or microperoxidase, biotin / avidin, spin labels, phage labels, stable free radicals, etc.). In another embodiment, the label is a positron emitter. Positron emitters include but are not limited to 68 Ga, 18 F. 64 Cu, 86Y. 76 Br, 89 Zr and 124 1. In a particular embodiment, the positron emitter is 89 Zr.

[0658] In another embodiment, the present invention provides a pharmaceutical composition comprising an anti-human PD-L2 antibody or an antigen-binding portion thereof according to the present invention. In another embodiment, a pharmaceutical composition is provided comprising a nucleic acid molecule or an expression vector as described above.

[0659] Pharmaceutical compositions of anti-human PD-L2 antibodies as described herein are prepared by mixing such antibodies having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th Edition, Osol, A. Ed. (1980)), in the form of a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations used, and include, but are not limited to: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexahydroxyquaternium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 1 0 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersants such as soluble neutralized active hyaluronidase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 ( BART International Inc. Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, sHASEGP is combined with one or more additional glucosaminoglycanases (such as chondroitinase).

[0660] Exemplary lyophilized antibody formulations are described in U.S. Pat. No. 6,267,958. Aqueous antibody formulations include those described in U.S. Pat. No. 6,171,586 and WO2006 / 044908, the latter formulations including histidine acetate buffer.

[0661] The formulations herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably active compounds having complementary activities that do not adversely affect each other.

[0662] The active ingredient can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

[0663] Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, the matrix being a shaped article, such as a film or microcapsule form. The formulations used for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtering through a sterile filtration membrane.

[0664] Any of the anti-human PD-L2 antibodies provided herein can be used in human therapy, such as cancer therapy.

[0665] In another aspect, an anti-human PD-L2 antibody suitable for use as a medicament is provided. In other aspects, an anti-human PD-L2 antibody for human therapy is provided. In certain embodiments, an anti-human PD-L2 antibody for cancer therapy is provided. In certain embodiments, the present invention provides an anti-human PD-L2 antibody for use in cancer therapy for treating an individual with a PD-L2-positive cancer, the method comprising administering to the individual an effective amount of the anti-PD-L2 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as described below.

[0666] In another aspect, the present invention provides the use of an anti-PD-L2 antibody in the manufacture or preparation of a medicament. In one embodiment, the medicament is used for cancer therapy. In one embodiment, the medicament is used to treat PD-L2 positive cancer. In another embodiment, the medicament is used in a method of treating PD-L2 positive cancer, the method comprising administering an effective amount of the medicament to an individual suffering from PD-L2 positive cancer. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as described below.

[0667] In another aspect, the present invention provides a method of treating a PD-L2 positive cancer. In one embodiment, the method comprises administering an effective amount of an anti-PD-L2 antibody to an individual suffering from such a PD-L2 positive cancer. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below.

[0668] According to any of the above embodiments, the PD-L2 positive cancer can be, for example, PD-L2 positive liver cancer, PD-L2 positive hepatocellular carcinoma, PD-L2 positive pancreatic cancer, PD-L2 positive lung cancer, PD-L2 positive colon cancer, PD-L2 positive breast cancer, PD-L2 positive prostate cancer, PD-L2 positive leukemia or PD-L2 positive lymphoma. In some embodiments, PD-L2 positive cancer is a cancer that receives an anti-PD-L2 immunohistochemistry (IHC) or in situ hybridization (ISH) score greater than "O", which corresponds to very weak or no staining of >90% of tumor cells. In another embodiment, PD-L2 positive cancer expresses 1+, 2+ or 3+ levels of PD-L2.

[0669] An "individual" or "individual" according to any of the embodiments described herein may be a human.

[0670] In another aspect, the present invention provides a pharmaceutical formulation comprising any of the anti-human PD-L2 antibodies provided herein, for example, for use in any of the above therapies. In one embodiment, the pharmaceutical formulation comprises any of the anti-human PD-L2 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulation comprises any of the anti-human PD-L2 antibodies provided herein and at least one additional therapeutic agent, for example, as described below.

[0671] The antibodies of the invention can be used alone or in combination with other agents in therapy. For example, the antibodies of the invention can be co-administered with at least one additional therapeutic agent.

[0672] Such combination therapies mentioned above encompass combined administration (wherein two or more therapeutic agents are included in the same or different formulations) and separate administration, in which case administration of the antibodies of the present invention can be performed before, simultaneously and / or after administration of the additional therapeutic agent and / or adjuvant. The antibodies of the present invention can also be used in combination with radiation therapy.

[0673] In one embodiment, an antibody or antigen binding portion of the invention, a nucleic acid molecule of the invention, an expression vector of the invention, or a pharmaceutical composition of the invention is provided for use in human therapy or cancer therapy in combination with other therapies, preferably chemotherapy, antibody therapy, and / or radiation therapy. The combined treatment may occur simultaneously or separately.

[0674] "Chemotherapy" refers to the use of compounds or drugs to treat disease, such as to treat cancer. Cancer chemotherapeutic agents are also often referred to as anti-tumor agents.

[0675] As used herein, the term "radiation therapy" refers to any exposure to ionizing radiation, and may include, for example, external beam radiation therapy, photon radiation therapy, electron radiation therapy, proton radiation therapy, carbon ion radiation therapy, lithium ion radiation therapy, silicon ion radiation therapy, helium ion radiation therapy, other forms of hadron therapy or other particle therapy, brachytherapy, radioisotope therapy, injectable isotopes, such as isotopes adhered to, within, or mixed with any type of matrix.

[0676] The antibodies of the present invention (and any additional therapeutic agents) can be administered by any suitable means, including parenteral, intrapulmonary and intranasal, and, if necessary, for local treatment, intralesional, intrauterine or intravesical administration. Parenteral infusions include intravenous, intraarterial, intraperitoneal or subcutaneous administration. Administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is transient or long-term. Various dosing regimens are contemplated herein, including but not limited to single or multiple administrations, bolus administrations and pulse infusions at various time points.

[0677] The antibodies of the present invention will be formulated, dosed and administered in a manner consistent with good medical practice. Factors considered in this context include the specific disorder treated, the specific mammal treated, the clinical condition of individual patients, the cause of the disorder, the delivery site of the medicament, the method of administration, the administration schedule and other factors known to medical practitioners. The antibody need not be but is optionally formulated with one or more medicaments currently used to prevent or treat the disorder in question. The effective amount of these other medicaments depends on the amount of the antibody present in the formulation, the type of disorder or treatment and other factors discussed above. These are generally in the same dosage and route of administration as described herein, or about 1 to 99% of the dosage described herein, or in any dosage determined to be appropriate empirically / clinically and used by any route.

[0678] For the treatment of diseases, the appropriate dosage of the antibodies of the present invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous treatments, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is appropriately administered to the patient once or over a series of treatments. Depending on the type and severity of the disease, an antibody of about 1 mg / kg to 15 mg / kg (e.g., 0.1 mg / kg-10 mg / kg) can be an initial candidate dose for administration to the patient, whether, for example, by one or more separate administrations or by continuous infusion. Depending on the factors mentioned above, a typical daily dose can be in the range of about 1 mg / kg to 100 mg / kg or more. For repeated administration over several days or longer, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. An exemplary dosage of the antibody will be in the range of about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, such as weekly or every three weeks (e.g., such that the patient receives about two to about twenty, or, for example, about <6 doses of the antibody). An initial higher starting dose may be administered, followed by one or more lower <doses. However, other dosage regimens may be useful. The progress of this therapy may be easily monitored by conventional techniques and analysis.

[0679] In another aspect of the present invention, a product is provided, which contains materials suitable for treating, preventing and / or diagnosing the above-mentioned illness. The product comprises a container and a label or drug instruction sheet on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The container can be formed by a variety of materials such as glass or plastic. The container holds a composition, which itself or in combination with another composition that can be effectively used to treat, prevent and / or diagnose the illness, and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic injection needle). At least one active agent in the composition is an antibody of the present invention. The label or drug instruction sheet indicates that the composition is used to treat the selected condition.

[0680] In addition, the article of manufacture may comprise (a) a first container containing a composition, wherein the composition comprises an antibody of the invention; and (b) a second container containing a composition, wherein the composition comprises an additional cytotoxic or additional therapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a drug instruction sheet indicating that the composition can be used to treat a specific condition. Alternatively or in addition, the article of manufacture may also comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0681] In one embodiment, the antibody or antigen-binding portion, nucleic acid molecule, expression vector or pharmaceutical composition of the present invention used as described above exhibits a therapeutic effect based on blocking the interaction between PD-1 and PD-L2.

[0682] In another embodiment, an antibody of the invention, a nucleic acid molecule of the invention, an expression vector or a pharmaceutical composition for use according to the invention is provided, wherein the therapeutic effect further comprises antibody-dependent cellular cytotoxicity (ADCC). "Antibody-dependent cellular cytotoxicity" (ADCC) is also known as antibody-dependent cell-mediated cytotoxicity, which is a cell-mediated immune defense mechanism in which effector cells of the immune system actively lyse target cells whose membrane surface antigens have been bound to specific antibodies.

[0683] In another embodiment, a cell line-based bioassay is provided that uses serial dilutions of anti-human PD-L2 antibodies to determine T cell signaling in a system that mimics the interaction between APCs (antigen presenting cells) and T cells.

[0684] In yet another embodiment, a kit comprising an anti-human PD-L2 antibody is provided for use in the analysis as described above.

[0685] The kit can be a packaged combination of a predetermined amount of reagent and the instructions for carrying out the analysis. In the case of an antibody enzyme labeling, the kit will include substrates and cofactors required for the enzyme (e.g., substrate precursors that can detect chromophores or fluorophores). In addition, other additives such as stabilizers, buffers (e.g., block buffers or lysis buffers) etc. may be included. The relative amounts of various reagents can vary widely to provide a concentration in a solution of a reagent that substantially optimizes analytical sensitivity. Specifically, reagents can be provided in the form of dry powders (usually lyophilized), including excipients that will provide a reagent solution with an appropriate concentration when dissolved. The kit may also include additional reagents, such as blocking reagents, washing reagents, enzyme substrates etc. for reducing nonspecific binding.

[0686] The present invention relates to the following embodiments:

[0687] 1. An anti-human PD-L2 antibody or an antigen-binding portion thereof, which specifically binds to human PD-L2 so as to block the binding of PD-L2 to PD-1,

[0688] wherein the antibody or antigen-binding portion thereof comprises six CDR sequences contained in a heavy chain variable region and a light chain variable region, the heavy chain variable region and the light chain variable region are respectively defined in any one of clauses a) to q) below, or

[0689] wherein the antibody or antigen-binding portion thereof comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, respectively, as defined in any one of clauses a) to q) below, wherein at most 1, 2, 3 amino acid residues in the CDR sequences are substituted, specifically in a conservative substitution pattern as defined herein:

[0690] a) a heavy chain variable region having the sequence of SEQ ID NO: 2 and a light chain variable region having the sequence of SEQ ID NO: 10;

[0691] b) a heavy chain variable region having the sequence of SEQ ID NO: 18 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0692] c) a heavy chain variable region having the sequence of SEQ ID NO:34 and a light chain variable region having the sequence of SEQ ID NO:42;

[0693] d) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 58;

[0694] e) a heavy chain variable region having the sequence of SEQ ID NO: 50 and a light chain variable region having the sequence of SEQ ID NO: 66;

[0695] f) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:104;

[0696] g) a heavy chain variable region having the sequence of SEQ ID NO: 112 and a light chain variable region having the sequence of SEQ ID NO: 120;

[0697] h) a heavy chain variable region having the sequence of SEQ ID NO: 128 and a light chain variable region having the sequence of SEQ ID NO: 132;

[0698] i) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 146;

[0699] j) a heavy chain variable region having the sequence of SEQ ID NO: 152 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0700] k) a heavy chain variable region having the sequence of SEQ ID NO: 166 and a light chain variable region having the sequence of SEQ ID NO: 174;

[0701] l) a heavy chain variable region having the sequence of SEQ ID NO:96 and a light chain variable region having the sequence of SEQ ID NO:212;

[0702] m) a heavy chain variable region having the sequence of SEQ ID NO: 140 and a light chain variable region having the sequence of SEQ ID NO: 218;

[0703] n) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 160;

[0704] o) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 26;

[0705] p) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 226; or

[0706] q) a heavy chain variable region having the sequence of SEQ ID NO: 220 and a light chain variable region having the sequence of SEQ ID NO: 230.

[0707] 2. The antibody or antigen-binding portion of embodiment 1, comprising three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise

[0708] a) CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:6, CDR-H3 of SEQ ID NO:8 and CDR-L1 of SEQ ID NO:12, CDR-L2 of S...

Claims

1. An anti-human PD-L2 antibody or an antigen-binding portion thereof, which specifically binds to human PD-L2 so as to block the binding of PD-L2 to PD-1, wherein the antibody or antigen binding portion thereof comprises six CDR sequences contained in the heavy chain variable region and the light chain variable region, wherein the antibody or antigen binding portion thereof comprises three heavy chain CDRs and three light chain CDRs, and the heavy chain and light chain CDRs comprise: n) CDR-H1 of SEQ ID NO: 154, CDR-H2 of SEQ ID NO: 222, CDR-H3 of SEQ ID NO: 158 and CDR-L1 of SEQ ID NO: 162, CDR-L2 of SEQ ID NO: 30, CDR-L3 of SEQ ID NO:

164.

2. The antibody or antigen-binding portion thereof according to claim 1, comprising a heavy chain variable region and a light chain variable region, wherein the n) the heavy chain variable region has the sequence of SEQ ID NO:220 and the light chain variable region has the sequence of SEQ ID NO:

160.

3. The antibody or antigen-binding portion thereof according to claim 1, which satisfies at least one of the functional characteristics listed in a) to d), a) higher binding affinity to PD-L2 compared to reference antibodies MIH18 and 24F.10C12; b) more effectively blocked PD-L2 binding to PD-1 compared to reference antibodies MIH18 and 24F.10C12; c) more effectively activates TCR-mediated IL-2 expression compared to reference antibodies MIH18 and 24F.10C12; and d) Higher IL-2 levels when inducing TCR-mediated IL-2 expression compared to reference antibodies MIH18 and 24F.10C12.

4. The antibody or antigen-binding portion thereof according to claim 3, which satisfies at least two of the functional characteristics listed in a) to d).

5. The antibody or antigen-binding portion thereof according to claim 3, which satisfies at least three of the functional characteristics listed in a) to d).

6. The antibody or antigen-binding portion thereof according to claim 3, which satisfies at least four of the functional characteristics listed in a) to d).

7. The antibody or antigen-binding portion thereof of claim 1, which is a humanized or fully human antibody.

8. The antibody or antigen-binding portion thereof according to claim 1, which is of IgG1, IgG2, IgG3 or IgG4 isotype.

9. The antibody or antigen-binding portion thereof according to claim 1, which is of IgG1 isotype.

10. The antibody or antigen-binding portion thereof of claim 1, wherein the antibody or antigen-binding portion thereof is a monospecific, bispecific or trispecific antibody or antigen-binding portion thereof.

11. The antibody or antigen binding portion thereof of claim 1, wherein the antibody or antigen binding portion thereof blocks the binding of PD-L2 to another receptor other than PD-1.

12. A nucleic acid molecule comprising a nucleotide sequence encoding the antibody or antigen-binding portion thereof according to any one of claims 1 to 11.

13. The nucleic acid molecule of claim 12, comprising a nucleotide sequence encoding three heavy chain CDRs and three light chain CDRs, wherein the heavy chain and light chain CDRs comprise n) CDR-H1 of SEQ ID NO:153, CDR-H2 of SEQ ID NO:221, CDR-H3 of SEQ ID NO:157 and CDR-L1 of SEQ ID NO:161, CDR-L2 of SEQ ID NO:29, CDR-L3 of SEQ ID NO:

163.

14. The nucleic acid molecule according to claim 12, comprising a nucleotide sequence encoding a heavy chain variable region and a light chain variable region, wherein the n) the heavy chain variable region has the sequence of SEQ ID NO:219 and the light chain variable region has the sequence of SEQ ID NO:

159.

15. An expression vector comprising the nucleotide sequence according to any one of claims 12 to 14.

16. A cell comprising the expression vector according to claim 15.

17. A pharmaceutical composition comprising the antibody or antigen-binding portion thereof according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the nucleic acid molecule according to any one of claims 12 to 14 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the expression vector according to claim 15 and a pharmaceutically acceptable carrier.

20. Use of the antibody or antigen binding portion thereof according to any one of claims 1 to 11 in the preparation of a medicament for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

21. Use of a nucleic acid molecule according to any one of claims 12 to 14 in the preparation of a medicament for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

22. Use of the expression vector according to claim 15 in the preparation of a drug for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

23. Use of the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

24. Use of the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

25. Use of the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating cancer, wherein the cancer is PD-L2 positive lung cancer.

26. A cell line based bioassay method using serial dilutions of an anti-human PD-L2 antibody according to any one of claims 1 to 11 to determine T cell signaling in a system that mimics the interaction between APCs (antigen presenting cells) and T cells.

27. A kit comprising: (i) an anti-human PD-L2 antibody according to any one of claims 1 to 11; and (ii) instructions for performing a cell line-based bioassay for determining T cell signaling in a system that mimics the interaction between APCs (antigen presenting cells) and T cells using serial dilutions of the anti-human PD-L2 antibody according to any one of claims 1 to 11.

28. The antibody or antigen binding portion thereof of claim 1, wherein the antibody or antigen binding portion thereof is a multispecific antibody or antigen binding portion thereof.

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