ANTI-PD-L1 ANTIBODIES

Abstract

The present invention relates to an antibody or fragment thereof comprising: (i) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 87, 88, and 89 respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 90, 91, and 92 respectively, (ii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 105, 106, and 107 respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 108, 109, and 110 respectively; (iii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 117, 118, and 119, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 120, 121, and 122, respectively;(iv) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 129, 130, and 131, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 1132, 133, and 134, respectively; or (v) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 135, 136, and 137, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 138, 139, and 140, respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION PD-L1 / PD-L1 interactions inhibit T cell receptor signaling by uptake of SHP1 and SHP2 phosphatases, which interferes with TCR signaling (Chemnitz et al. (2004) Immunol. 17:945-954). PD-L1 can not only promote tumor progression by inhibiting PD-1-expressing immune effectors, but it also modulates cell-mediated immunity in some infectious diseases (Mueller et al. (2010) Clin. Invest. 120:2508-2515). Furthermore, allogeneic effector T cell responses are susceptible to PD-1 pathway modulation in graft rejection (Lee et al. (2003) Immunol. 171:6929-6935). Therefore, the interaction of PD-1 with PD-L1 exerts a vital and diverse range of immunoregulatory roles in T-cell activation, tolerance, and immune system-mediated tissue damage. However, the interaction can be reversed by blocking the local binding of PD-1 to PD-L1 (Iwai et al.).(2002) Proc. Nat'l. Acad Sci. EUA 99: 12293-7; Brown et al. (2003) 1 Immunol. 170:1257-66). PD-1 has been found to correlate with cancer growth and development due to its role in protecting tumor cells from efficient immune destruction. Its ligand, PD-L1, has been shown to have significant expression in a number of mouse and human tumors, which is thought to mediate immune evasion (Iwai, Y. et al., Proc. Nati. Acad. Sci. USA.99: 12293-12297 (2002); Strome SE et al., Cancer Res., 63:6501-6505 (2003); Dong et al. (2002) Nat. Med. 8:787-9). In humans, PD-1 expression (in tumor-infiltrating lymphocytes) and / or PD-L1 expression (in tumor cells) has been found in a number of primary tumor biopsies, as assessed by immunohistochemistry.Such tissues include cancers of the lung, liver, ovary, cervix, skin, colon, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell, urothelial cell, and pancreas, as well as head and neck tumors (Brown A. et al., J. Immunol. 170: 1257-1266 (2003); Dong H. et al., Nat. Med. 8: 793-800 (2002); Wintterle et al., Cancer Res. 63:7462-7467 (2003); Strome SE et al., Cancer Res., 63: 6501-6505 (2003); Thompson RH et al., Cancer Res. 66: 3381-5 (2006); Thompson et al., Clin. Cancer Res. 13: 1757-61(2007); Nomi T. et al., Clin. Cancer Res. 13: 2151-7. (2007)). More surprisingly, PD-1 ligand expression on tumor cells has been correlated with poor prognosis in cancer patients across multiple tumor types (summarized in OkaZaki and Honjo, Int. Immunol. 19: 813-824 (2007)). While the interaction between PD-1 and PD-L1 generates a decrease in tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune evasion of cancer cells (Dong et al. (2003) Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54: 3 07-3 14; Konishi et al. (2004) Clin. Cancer Res. fracznn / zznz / E / Yii (10:5094-100), blocking the PD-1 / PD-L1 interaction has been shown to improve tumor-specific T cell immunity and has proven useful in clearing tumor cells by the immune system. In a murine model of aggressive pancreatic cancer, for example, Nomi T., et al. (Clin. Cancer Res. 13: 2151-2157, 2007) demonstrated the therapeutic efficacy of PD-1 / PD-L1 blockade. Administration of the antibody targeting PD-1 or PD-L1 significantly inhibited tumor growth. Blockade with the antibody effectively promoted the infiltration of tumor-reactive CD8+ T cells into the tumor, resulting in the upregulation of antitumor effectors, including IFN-γ, granzyme B, and perforin. Additionally, the authors showed that PDL1 / PD-1 blockade can be effectively combined with chemotherapy to produce a synergistic effect.In another study, using a mouse squamous cell carcinoma model, antibody blockade of PD-1 or PD-L1 significantly inhibited tumor growth (Tsushima F. et al., Oral Oncol. 42:268-274 (2006)). Furthermore, transfection of a murine mast cell line with PD-L1 led to decreased lysis of tumor cells when co-cultured with a tumor-specific CTL clone. Lysis was restored upon addition of anti-PD-L1 mAb (Iwai Y. et al., Proc. Nati. Acad. Sci. USA. 99: 12293-12297 (2002)). In vivo, blocking the PD1 / PD-L1 interaction was shown to increase the efficacy of adoptive T-cell transfer therapy in a mouse tumor model (Strome SE et al., Cancer Res. 63:6501-6505 (2003)). Further evidence for the role of PD-1 in cancer treatment comes from experiments performed with PD-1 transgenic mice. PD-L1-expressing myeloma cells grew only in wild-type animals (resulting in tumor growth and associated animal death), but not in PD-1-deficient mice (Iwai Y., et al., Proc. Nati. Acad. Sci. USA. 99: 12293-12297 (2002)). In human studies, RMWong et al. (Int. Immunol. 19:1223-1234 (2007)) demonstrated that PD-1 blockade with a fully human anti-PD-1 antibody increased the absolute number of tumor-specific CD8+ T lymphocytes (CTLs) in ex vivo stimulation assays using vaccine antigens and cells from vaccinated individuals. In a similar study, PD-L1 antibody blockade resulted in enhanced cytolytic activity of tumor-associated antigen-specific cytotoxic T lymphocytes and increased cytokine production by tumor-specific TH lymphocytes (Blank C. et al., Int. Cancer 119: 317-327 (2006)). The same authors demonstrated that PD-L1 blockade enhances tumor-specific T lymphocyte responses in vitro when used in combination with anti-CTLA-4 blockade. In general, the PD-1 / PD-L1 pathway is a target for the development of antibody therapeutic products for cancer treatment.Anti-PD-L1 antibodies may also be useful in chronic viral infections. Memory CD8+ T lymphocytes generated after an acute viral infection are highly functional and constitute an important component of protective immunity. In contrast, chronic infections are often characterized by varying degrees of functional deficiencies (depletion) of virus-specific T lymphocyte responses, and this defect is the main reason for the host's inability to clear the persistent pathogen. While functional effector T lymphocytes are initially generated during the early stages of infection, they gradually lose function during the course of a chronic infection. Barber et al. (Barber et al., Nature 439: 682-687 (2006)) demonstrated that mice infected with a laboratory strain of LCMV developed chronic infection, resulting in high levels of the virus in the blood and other tissues.These mice initially developed a strong T-cell response, but eventually succumbed to the infection after T-cell depletion. The authors found that the decline in the number and function of effector T cells in chronically infected mice could be reversed by injecting an antibody that blocked the interaction between PD-1 and PD-L1. In one aspect, the present invention provides antibodies or antigen-binding fragments thereof that bind to programmed cell death ligand 1 (PD-L1). In one embodiment, the antibodies or fragments thereof bind to human PD-L1. In another embodiment, the antibodies or fragments thereof bind to human and crab-eating macaque PD-L1. In another embodiment, the antibodies or fragments thereof block the interaction of PD-L1 with its receptor PD-1 on T lymphocytes. In one aspect, the present invention provides methods for preparing and using anti-PD-L1 antibodies or fragments thereof, and compositions comprising anti-PD-L1 antibodies or fragments thereof, including pharmaceutical compositions. As used herein, the term "antibody" refers to a binding protein having at least one antigen-binding domain. The antibodies and antibody fragments of the present invention may be whole antibodies or any fragment thereof. Therefore, the antibodies and fragments of the invention include monoclonal antibodies or fragments thereof, antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and antibody fragments may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-1 antibodies and fragments thereof described herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype.The term "isotype" refers to the class of antibodies encoded by the genes with a heavy-chain constant region. In one embodiment, the anti-PD-L1 antibodies and fragments thereof described herein are of IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the present invention may be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human. The PD-L1 antibodies and fragments thereof may be chimeric, humanized, or fully human antibodies. In one embodiment, the anti-PD-L1 antibodies are produced using a mouse-derived hybridoma cell line. Therefore, in one embodiment, the anti-PD-L1 antibodies are murine antibodies. In another embodiment, the anti-PD-L1 antibodies are chimeric antibodies. In a further embodiment, the chimeric antibodies are mouse-human chimeric antibodies.In another modality, the antibodies are humanized antibodies. In a further modality, the antibodies are derived from murine antibodies and are humanized. A "chimeric antibody" is an antibody that has at least a portion of the heavy-chain variable region and at least a portion of the light-chain variable region derived from one species, and at least a portion of a constant region derived from another species. For example, in one modality, a chimeric antibody may comprise murine variable regions and a human constant region. A "humanized antibody" is an antibody containing complementarity-determining regions (CDRs) derived from a non-human antibody, and framework regions as well as constant regions derived from a human antibody. For example, the anti-PD-L1 antibodies provided herein may comprise CDRs derived from one or more murine antibodies and human constant and framework regions. Thus, in one embodiment, the humanized antibody provided herein binds to the same epitope on PD-L1 as the murine antibody from which the antibody's CDRs are derived. Example humanized antibodies are provided herein. Additional anti-PD-L1 antibodies, comprising heavy-chain and light-chain CDRs, provided herein, or variants thereof, may be generated using any human framework sequence and are also included in the present invention.In one embodiment, suitable frame sequences for use in the present invention include those frame sequences that are structurally similar to the frame sequences provided herein. Additional modifications may be made to the frame regions to improve the properties of the antibodies provided herein. Such additional frame modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T-cell epitopes; or back mutations to the residue in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to the germline sequence.For example, in one embodiment, one or more amino acids in the human VH and / or VL framework regions of the humanized antibodies provided herein are backmutated to the corresponding amino acid in the original murine antibody. For instance, for the humanized 5G11 and 13C5 VH and VL, several amino acid framework sites of the aforementioned human template antibody are backmutated to the corresponding frQcznn / zznz / E / Yi amino acid sequences in the mouse 5G11 and 13C5 antibodies. In another embodiment, the amino acid at positions 53 and / or 60 and / or 67 of the light chain variable region is backmutated to the corresponding amino acid at that position in the mouse 5G11 or 13C5 light chain variable region.In another embodiment, the amino acid at positions 24 and / or 28 and / or 30 and / or 49 and / or 73 and / or 83 and / or 94 of the heavy chain variable region is backmutated to the corresponding amino acid at that position in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, the humanized 5G11 antibody comprises a light chain variable region where the amino acid at position 60 mutates from Ser (S) to Asp (D) and the amino acid at position 67 mutates from Ser (S) to Tyr (Y); and a variable heavy chain region where the amino acid at position 24 mutates from Phe (F) to Val (V), the amino acid at position 49 mutates from Ala (A) to Gly (G), the amino acid at position 73 mutates from Thr (T) to Asn (N) and the amino acid at position 83 mutates from Thr (T) to Asn (N).In one embodiment, the humanized antibody 13C5 comprises a light-chain variable region where the amino acid at position 53 mutates from Tyr (Y) to Lys (K); and a heavy-chain variable region where the amino acid at position 28 mutates from Thr (T) to He (I), the amino acid at position 30 mutates from Ser (S) to Arg (R), the amino acid at position 49 mutates from Ser (S) to Ala (A), and the amino acid at position 94 mutates from Tyr (Y) to Asp (D). Additional or alternative back-mutations may be performed in the framework regions of the humanized antibodies provided herein to enhance the properties of the antibodies. The present invention also encompasses humanized antibodies that bind to PD-L1 and comprise framework modifications corresponding to the example modifications described herein with respect to any suitable framework sequence, as well as other framework modifications that otherwise enhance the properties of the antibodies. As used herein, the term "derivative" when used to refer to a molecule or polypeptide related to a reference antibody or other binding protein, means a molecule or polypeptide that is capable of binding specifically to the same epitope as the reference antibody or other binding protein. The antibodies and antigen-binding fragments described herein are specific for PD-L1. In one embodiment, the antibodies and fragments are specific for human PD-L1. In another embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1 but not to PD-L1 of any other mammal. In a further embodiment, the antibodies and fragments do not bind to mouse PD-L1. The terms “human PD-L1,” “hPD-L1,” and “huPD-L1,” and similar terms, are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. “Specific for” means that the antibodies and fragments bind to PD-L1 with greater affinity than to any other target. As used herein, the term “EC50” refers to the effective concentration, or maximum 50% response, of the antibody.As used herein, the term “IC50” refers to the inhibitory concentration, the maximum 50% response of the antibody. Both EC50 and IC50 can be measured by ELISA or FACS assays or by any other method known to the art. In one modality, anti-PD-1 antibodies and fragments or variants thereof have a binding affinity (KD) for PD-L1 in the range of approximately 0.001 nM to approximately 100 nM, approximately 0.002 nM to approximately 50 nM, approximately 0.005 nM to approximately 5 nM, approximately 0.01 nM to approximately 1 nM, or approximately 0.005 nM to approximately 0.1 nM. In one modality, the antibodies and fragments thereof have a binding affinity (KD) for PD-L1 of approximately 50 nM or less, approximately 25 nM or less, approximately 20 nM or less, approximately 15 nM or less, approximately 10 nM or less, approximately 8 nM or less, approximately 6 nM or less, approximately 5 nM or less, approximately 4 nM or less, approximately 3 nM or less, approximately 2 nM or less, approximately 1 nM or less, approximately 0.9 nM or less, approximately 0.8 nM or less, approximately 0.7 nM or less, approximately 0.6 nM less, approximately 0.5 nM less, approximately 0.4 nM less, approximately 0.3 nM less, approximately 0.2 nM less, approximately 0.1 nM less, approximately 0.09 nM less, approximately 0.08 nM less, approximately 0.07 nM less, approximately 0.06 nM less, approximately 0.05 nM less, approximately 0.04 nM less, approximately 0.03 nM less, approximately 0.02 nM less, approximately 0.01 nM less, approximately 0.009 nM less, approximately 0.008 nM less, approximately 0.007 nM less, approximately 0.006 nM less, approximately 0.005 nM less, approximately 0.004 nM less, approximately 0.003 nM less, approximately 0.002 nM less or approximately 0.001 nM less.In one modality, the antibodies and fragments thereof have a binding affinity (KD) for PD-L1 of approximately 10 nM, approximately 9 nM, approximately 8 nM, approximately 7 nM, approximately 6 nM, approximately 5 nM, approximately 4 nM, approximately 3 nM, approximately 2 nM, approximately 1 nM, approximately 0.9 nM, approximately 0.8 nM, approximately 0.7 nM, approximately 0.6 nM, approximately 0.5 nM, approximately 0.4 nM, approximately 0.3 nM, approximately 0.2 nM, approximately 0.1 nM, approximately 0.09 nM, approximately 0.08 nM, approximately 0.07 nM, approximately 0.06 nM, approximately 0.05 nM, approximately 0.04 nM, approximately 0.03 nM, approx. 0.02 nM, approx. 0.01 nM, approx. 0.009 nM, approx. 0.008 nM, approx. 0.002 nM or approximately 0.001 nM. In one embodiment, the antibodies and fragments provided herein comprise a light chain and a heavy chain, each comprising three CDR regions. Example heavy chain CDR sequences (HCDR1, HCDR2, and HCDR3) for the PD-L1 antibodies of the invention are provided below in Table 1. Example light chain CDR sequences (LCDR1, LCDR2, and LCDR3) for the PD-L1 antibodies of the invention are provided below in Table 2. Example variable regions and full-length heavy and light chain sequences for the PD-L1 antibodies of the invention are provided below in Table 3. frQcznn / zznz / E / Yit TABLE 1 Heavy chain CDR sequences Number HCDR SEQ ID NO Secuencia 13C5 1 81 SYGMS 2 82 SISSGGSTYYPDSVKG 3 83 GYDSGFAY 5G9 1 87 SYGMS 2 88 SISSGGTTYYPDSVKG 3 89 GYDSGFAY 5G11 1 93 TYGVH 2 94 VIWRGVTTDYNAAFMS 3 95 LGFYAMDY 8C6 1 99 SYGVH 2 100 VIWSGGVTDYNAAFIS 3 101 LGFYAMDY 7B4 1 105 TYWMH 2 106 QINPDSTTINYAPSLKD 3 107 PGDYGYDFDC 4D1 1 111 SGYWN 2 112 YISYSGSTYYNPSLKS 3 113 SLLWFSTGFAY 4A8 1 117 SYGVH 2 118 VIWSGGLTDYNAAFKS 3 119 LGFYAMDY 8H4 1 123 SYGMS 2 124 SISSGGTTYYLGSVQG 3 125 GYDAGFAY 8H3 1 129 SGYWT 2 130 YISYTGSTYYNPSLKS 3 131 QRDWLGFAY 15F1 1 135 SYGMS 2 136 SISSGGSIYYPDSVKG 3 137 GYDAGFAF TABLA 2 Secuencias CDR de cadena ligera frQcznn / zznz / E / Yi Nombre LCDR SEQID NO Secuencia 13C5 1 84 ASQSVSTSSSSFMH 2 85 YASNLES 3 86 QHSWEIPYT 5G9 1 90 RASQSVSTSSSSYMH 2 91 YASNLES 3 92 QHSWEIPYT 5G11 1 96 KASQSVSNDVA 2 97 YAANRYT 3 98 QQDYTSPYT 8C6 1 102 KASQSVSNDVG 2 103 YASNRYS 3 104 QQDYTSPYT 7B4 1 108 RSSQIIVHSNANIYLE 2 109 KVSNRFS 3 110 FQGSHVPYT 4D1 1 114 SASSSVSSSYLY 2 115 NTSNLAS 3 116 HQWRSYPPT 4A8 1 120 SANSSVSYMH 2 121 DTSKLAS 3 122 QQWSSNPWT 8H4 1 126 RASQSVSTSSYSYMH 2 127 YASNLES 3 128 QNSWEIPYT 8H3 1 132 KSSQSLLYSSNQKNSLA 2 133 WASNRES 3 134 QQYYSYPLT 15F1 1 138 RASQSVSTSSYSYVH 2 139 YASNLES 3 140 QHSWEIPYT TABLA 3 Secuencias of the variable region of the cadena pesada and the cadena ligera and the long-standing amino acids that complete the cadena pesada and the ligera frocznn / zznz / E / Yii No. Región SEQ IP NO Secuencia 13C5 murino cadena variant pesada 2 EVKLVESGGGLVKPGGSLKLSCAASGFIFRSYGMSWVRQTPEKRLEWVASISSGGST YYPDSVKGRFTISRDNAR NILYLQM SSLRSEDTAMYDCARGYDSGFAYWGQGTLVTVSE 13C5 murino cadena variant ligera 4 DIVLTQSPASLAVSLGQRATISCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASN LESGVPARFSGSGSGTDFT LNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIKR 5G9 murino Variable type 6 EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWVRQTPEKRLEWVASISSGGT TYYPDSVKGRFIISRDNARNILYLQMSSLRSEDTAMYYCAKGYDSGFAYWGQGTLVI VSA 5G9 murino Variable version 8 DIVLTQSPPSLAVSLGQRATISCRASQSVSTSSSSYMHWYQQKPGQPPKLLIKYASN LESGVPARFSGSGSGTDFFLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK 5G11 murino Variable type 10 QVQLKQSGPGLVQPSQSLSrTCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWRGV TTDYNAAFMSRLTTTKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGT SVTVSS 5G11 murino Variable de cadena ligera 12 SIVMTQTPKFLLVSAGDRVTrrCKASQSVSNDVAWYQQKPGQSPKLLIYYAANRYT GVPDRFTGSGYGTDFTFTISIVQAEDLAVYFCQQDYTSPYTFGGGTKLEIK 8C6 murino Variable de cadenapesada 14 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGG VTDYNAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTS VTVSS 8C6 murino Variable de cadena ligera 16 SIVMTQTPKFLLVSAGDRVTrTCKASQSVSNDVGWYQQKPGQSPKLLIYYASNRYS GVPDRFTGSGYGTDFTFTISTVQAEDI-AVYFCQQDYTSPYTFGGGTKLEIK 7B4 murino Variable de cadena pesada 18 EVKLFESGGGLVQPGGSLKLSCVASGFDFSTYWMHWVRQAPGQGLEWIGQINPDS TTINYAPSLKDRFIISRDNAKNTLFLQMSKVRSEDTALYYCAKPGDYGYDFDCWGQ GTTLTVSS 7B4 murino variable number 20 DVLMTQTPLYLPVSLGDQASISCRSSQIIVHSNANTYLEWFLQKPGQSPKLLIYKVSN RFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK 4D1 murino Variable number 22 EVQLQESGPSLVKPSQTLSLTCSVTGDSrTSGYWNWIRKFPGNKLEYMGYISYSGST YYNPSLKSRISITRDTSKNQYYLQLNSVTTEDTATYYCARSLLWFSTGFAYWGQGTL VTVSA 4D1 murine Light chain variable 24 QIVLTQSPAIMSASPGEKVTLTCSASSSVSSSYLYWNQQKPGSSPKVWIYNTSNLAS GVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWRSYPPTLGAGTKLELK 4A8 murine Heavy chain variable 26 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGI TDYNAAFKSRLSISKDNSKSQVFFKMNSLQANDTAIYFCARLGFYAMDYWGQGTSV TVSS 4A8 murine Light chain variable QIVLTQSPAIMSASPGEKV™TCSANSSVSYMHWYQQKSGTSPKRWIYDTSKLASG VPARFSGSGSGTSYSLTISSMGAEDAATYYCQQWSSNPWTFGGGTKLEIK 8H4 murine Heavy chain variable 30 EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWARQIPEKRLEWVASISSGGTT YYLGSVQGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAYWGQGTLVS VSE 8H4 murine Light chain variable 32 DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYMHWYQQKPGQPPKLLIKYASN LESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQNSWEIPYTFGGGTKLEIK 8H3 murine Heavy chain variable 34 EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWTWIRKFPGNKLEYMGYISYTGST YYNPSLKSRISISRDTSKSQYYLQLNSVTTEDTATYYCARQRDWLGFAYWGQGTLV TVSA 8H3 murine Light chain variable 36DIVMTQTPSSLAVSLGEKVTMSCKSSQSLLYSSNQKNSLAWYQQKPGQSPKLLIYW ASNRESGVPDRFTGSSSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK 15F1 murino Variable type 38 EEKLVESGGGLVKPGGSLKLSCAASGFSFSSYGMSWVRQTPEKRLEWVASISSGGSI YYPDSVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAFWGQGTLVT ASA 15F1 murino Variable type 40 DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYVHWYQQKPGQPPKLLIKYASNL ESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK 5G11 humanizado Variable de cadena pesada 42 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTT DYNAAFMSRLTrTKDNSKNQWLTMNNMDPVDTAIYYCARLGFYAMDYWGQGTLV TVSS 5G11 humanizado Variable de cadena ligera 44 DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYT GVPDRFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIK 13C5 humanizado Variable de cadena pesada 46 48DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASN LESGVPARFSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIK 8C6-IgG4 chimeric (F234A / L235A) Full length heavy chain (IgG4) 50 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGV TDYNAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSV TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAP EAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVM H EALHN HYTQKSLSLSLG 8C6 Chimeric Full Length Light Chain 52 SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVGWYQQKPGQSPKLLIYYASNRYSG VPDRFTGSGYGTDFTFTISTVQAEDtAVYFCQQDYTSPYTFGGGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 8H4-IgG4 chimeric (F234A / L235A) Full length heavy chain (IgG4) 54EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWARQIPEKRLEWVASISSGGTT YYLGSVQGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAYWGQGTLVS VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPE AAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 8H4 chimeric Full-length light chain 56 DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYMHWYQQKPGQPPKLLIKYASN LESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQNSWEIPYTFGGGTKLEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC frQcznn / zznz / E / Yi Chimeric 5Gll-IgGl (D265A) Full-length heavy chain (IgGl) 58 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWRGVTTDYNAAF M SRLTITKDN SKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE VTCVWAVSHEDPEWKFNWYVDGVEVHNACTKPREEQYASTYRWSVLTVLHQDWLNGKEYKC KVSNCALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTPPPVLDSDGFFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPPGK 5Gll-IgG4 chimérico ( LF2345A) full length (IgG4) 60 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWRGVTTDYNAAF M SRLTITKDN SKSQVFFKM NSLQANDTAIYYCARLGFYAM DY WGQGTSVSTSVKFPSVKFPSV APCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VWDVSQEDPEWQFNWYVDGVEVHNACTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSIEKTISKKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 5G11 chimeric Full-length light chain 62 SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYAANRYTGVPDRFTG SGYGTDFTFTISIVQAEDLAVYFCQQDYTSPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA SWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC 13C5-IgGl chimeric (D265A) Full-length heavy chain (IgGl) 64 EVKLVESGGGLVKPGGSLKLSCAASGFIFRSYGMSWVRQTPEKRLEWVASISSGGSTYYPDSVK GRFTISRDNARNILYLQMSSLRSEDTAMYDCARGYDSGFAYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13C5-IgG4 chimeric (F234A / L235A) Full length heavy chain (IgG4) 66 EVKLVESGGGLVKPGGSLKLSCAASGFIFRSYGMSWVRQTPEKRLEWVASISSGGSTYYPDSVKGRFTISRDNARNILYLQMSSLRSEDTAMYDCARGYDSGFAYWGQGTLVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKKPDTLMISRTPEVTCV WDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 13C5 chimeric Full-length light chain 68 DIVLTQSPASLAVSLGQRATISCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLESGVPAR FSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIKRTRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVFEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC 5Gll-Humanized IgGl (D265A) Full Length Heavy Chain (IgGl) 70 QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGK ALEWLGVIWRGVTTDYN AAFM SRLTITKDN SKNQWLTMN NM DPVDTATYYCARLGFYAM DY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 5Gll-IgG4 humanizado (F234A / L235A) Cadena pesada de longitud completa (IgG4) 72 QITLKESGPTLVKPTQTLTLTCTVSGFSLSYTGVHWIRQPPGK ALEWLGVI WRGVTTDYN AAFM SRLTITKDN SKNQWLTMN NM DPVDTATYYCARLGGYAM DY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAGQPREPQVYTLPPSQEEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLG fracznn / zznz / B / Yii 5G11 humanizado Cadena ligera de longitud completa 74 DIQMTQSPSSLSASVGDRVTJTCKASQSVSNDVAWYQQKPGKAPCLLIYYAANRYTGVPDRFSG SGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA SWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC 13C5-IgGl humanizado (D265A) Cadena pesada de longitud completa (igGD 76 EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKGLEWVASISSGGSTYYPDSVK GRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13C5-Humanized IgG4 (F234A / L235A) Full-length heavy chain (IgG4) 78 EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKLEWVASISSGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV WDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 13C5 humanizado Cadena ligera de longitud completa 80 DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLESGVPAR FSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLK SGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC In one embodiment, the invention provides anti-PD-I antibodies comprising light chain CDRs and heavy chain CDRs of antibodies 13C5, 5G9, 5G11, 8C6, 7B4, 4D1, 4A8, 8H4, 8H3, and / or 15F1. Those skilled in the art shall understand that the heavy and light chain CDRs of the antibodies provided herein may be selected independently or mixed or paired to form an antibody or binding fragment thereof comprising any heavy chain CDR1, CDR2, and CDR3; and any light chain CDR1, CDR2, and CDR3 of the antibodies provided herein. Therefore, the invention provides anti-PD-L1 antibodies comprising a heavy-chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 81, 87, 93, 99, 105, 111, 117, 123, 129 and 135; a heavy-chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 82, 88, 94, 100, 106,112, 118, 124, 130 and 136; a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 83, 89, 95, 101, 107, 113, 119, 125, 131 and 137; a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 84, 90, 96, 102, 108, 114, 120, 126, 132 and 138; a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 85, 91, 97, 103, 109, 115, 121, 127, 133 and 139; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 86, 92, 98, 104, 110, 116, 122, 128, 134, and 140. In one embodiment, the present invention provides anti-PD-L1 antibodies comprising heavy chain and light chain CDR regions comprising amino acid sequences having at least 75%, at least 80%, at least 81%, at least 82%, at least 83%,at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology with respect to the corresponding light-chain or heavy-chain CDR1, CDR2, or CDR3 provided herein. In one embodiment, the present invention provides anti-PD-L1 antibodies comprising heavy-chain and light-chain CDR regions comprising amino acid sequences having 1, 2, 3, 4, 5, or 6 amino acid substitutions, deletions, or insertions with respect to the corresponding heavy-chain or light-chain CDR1, CDR2, or CDR3 provided herein. In one embodiment, the invention provides anti-PD-L1 antibodies comprising a variable heavy chain of an antibody selected from the group consisting of 13C5, 5G9, 5G11, 8C6, 7B4, 4D1, 4A8, 8H4, 8H3 and / or 15F1 and a variable light chain of an antibody selected from the group consisting of 13C5, 5G9, 5G11, 8C6, 7B4, 4D1, 4A8, 8H4, 8H3 and / or 15F1.In one embodiment, the antibodies and fragments provided herein comprise a heavy chain variable region comprising an amino acid sequence that is at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology to a heavy chain variable region selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46.In one embodiment, the antibodies and fragments provided herein comprise a variable heavy-chain region comprising an amino acid sequence according to SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46 or a variant thereof, wherein the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions, or a combination thereof. In a further embodiment, the amino acid substitutions are conservative substitutions. In one embodiment, the antibodies and fragments provided herein comprise a light chain variable region comprising an amino acid sequence that is at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology to a light chain variable region selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48.In one embodiment, the antibodies and fragments provided herein comprise a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 or a variant thereof, wherein the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions, insertions, or deletions, or a combination thereof. In a further embodiment, the amino acid substitutions are conservative substitutions. The anti-PD-L1 antibodies described herein that have one or more amino acid substitutions, insertions, or deletions, or a combination thereof, in the CDR or light or heavy chain variable region maintain the biological activity of the corresponding anti-PD-L1 antibody that does not have such a substitution, insertion, or deletion. Therefore, the anti-PD-L1 antibody variants provided herein maintain PD-L1 binding. Percent homology, as used herein, refers to the number of identical amino acid sequences shared by two reference sequences, divided by the total number of amino acid positions, multiplied by 100. In some embodiments, the anti-PD-L1 antibodies provided herein comprise conservative amino acid substitutions. Those skilled in the art will recognize that a conservative amino acid substitution is a substitution of one amino acid with another amino acid having similar structural or chemical properties, such as, for example, a similar side chain. Examples of conservative substitutions are described in the art, for example, in Watson et al., Molecular Biology of the Gene, The Benjamin / Cummings Publication Company, 4th ed. (1987). A person skilled in the art will understand that the variable light and heavy chains can be selected independently, or mixed and paired, from the antibodies provided herein. Therefore, the present invention provides anti-PD-L1 antibodies comprising a variable heavy chain region having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ IDs 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46; and a variable light chain region having at least 80% homology to an amino acid sequence selected from the group consisting of SEQ IDs 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. In one embodiment, the present invention provides antibodies that bind to the same epitope as any of the example antibodies described herein. Therefore, in one embodiment, the present invention provides antibodies that compete for binding to PD-L1 with the example antibodies provided herein. The anti-PD-1 antibodies and fragments thereof provided herein may further comprise modifications to the Fe region to alter effector functions. Modifications to Fe may be insertions, deletions, or substitutions of amino acids, or they may be chemical modifications. For example, modifications to the Fe region may be made to increase or decrease complementary binding, to increase or decrease antibody-dependent cellular cytotoxicity, or to increase or decrease the antibody half-life. Some Fe modifications increase or decrease the antibody's affinity for an Fcy receptor, such as FcyRI, FcyRII, FcyRIII, or FcRn. Several Fe modifications have been described in the art, for example, in Shields et al., J Biol Chem 276; 6591 (2001); Tai et al. Blood 119; 2074 (2012); Spiekermann et al., J Exp Med 196; 303 (2002); Moore et al.mAbs 2:2; 181 (2010); Medzihradsky Methods in Molecular Biology 446; 293 (2008); Mannan et al. Drug Metabolism and Disposition 35; 86 (2007); and Idusogie et al. J Immunol 164; 4178 (2000). In some modalities, the glycosylation patterns of the Fe region are altered. In other modalities, the Fe region is modified by pegylation (e.g., by reacting the antibody or an antibody fragment with polyethylene glycol (PEG)). In one modality, the antibodies or antibody fragments provided herein are immunoconjugates comprising an anti-PD-L1 antibody or a fragment thereof and further comprising an agent selected from the group that includes an additional therapeutic agent, a cytotoxic agent, an immunoadhesion molecule, and an imaging agent. In some modalities, the imaging agent is selected from the group consisting of a radiolabel, an enzyme, a fluorescent marker, a luminescent marker, a bioluminescent marker, a magnetic marker, and biotin. In some modalities, the imaging agent is a radiolabel selected from the group consisting of: 3H, 14C, 35S, 62Cu, 64Cu, 89Zr, 90Y, 99Tc, U1ln, 125I, 131I, 177Lu, 166Ho, and 153Sm.In some formulations, the therapeutic or cytotoxic agent is selected from a group that includes a chemotherapeutic agent, an immunosuppressant, an immunostimulatory agent, an antimetabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an antiangiogenic agent, an antimitotic agent, an anthracycline, a toxin, and an apoptotic agent. In some formulations, the binding protein is conjugated directly to the agent. In other formulations, the binding protein is conjugated to the agent via a linker. Suitable linkers include, but are not limited to, the amino acid and polypeptide linkers described herein. Linkers may be scintiphils or non-scintiphils. In one embodiment, the present invention provides single- or multi-specific antibodies specific for PD-L1 and at least one other antigen or epitope. The anti-PD-L1 antibodies and fragments thereof provided herein can be analyzed to determine their binding to PD-L1 using the binding assays provided herein or any other binding assay known in the art. Unless otherwise indicated, the practice of the present invention employs conventional molecular biology, cell biology, biochemistry, and immunology techniques known in the art and described, for example, in Methods in Molecular Biology, Humana Press; Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989); Current Protocols in Immunology (E. Coliganet et al., eds., 1991); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000). Phage display: a laboratory manual (C. Barbas III et al, Coid Spring Harbor Laboratory Press, 2001); and Using antibodies: a laboratory manual (E. Harlow and D. Lañe (Coid Spring Harbor Laboratory Press, 1999). In one aspect, the present invention provides methods for treating a subject for a disease or condition that responds to the enhancement, stimulation, or elicitation of an immune response. As used herein, the terms "treatment" or "treat" refer to therapeutic treatment and to prophylactic or preventive measures. Subjects requiring treatment include those who already have the disease or condition, as well as those who may develop the disease or condition and in whom the objective is to prevent, delay, or lessen the disease or condition. As used herein, the term "subject" denotes a mammal, such as a rodent, feline, canine, or primate. Preferably, a subject according to the invention is a human being. The expression "therapeutically effective amount", as used herein, refers to the amount of a compound or composition necessary to provide a therapeutic and / or preventive benefit to the subject. In one aspect, antibodies and antigen-binding fragments thereof are useful in the treatment of solid or non-solid tumors. Therefore, in one aspect, the present invention provides methods for the treatment of cancer. "Cancer," as used herein, refers to the physiological condition in mammals typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma (including liposarcoma, osteogenic sarcoma, angiosarcoma, endotheliosarcoma, leiomyosarcoma, chordoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma, myxosarcoma, chondrosarcoma), neuroendocrine tumors, mesothelioma, synovioma, schwannoma, meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid neoplasms. The most particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer),Hodgkin lymphoma; non-Hodgkin lymphomas (Burkitt lymphoma, small lymphocytic lymphoma / chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, hairy cell lymphoma, and lymphoplasmacytic leukemia), lymphocyte precursor cell tumors, including B-cell acute lymphoblastic lymphoma / leukemia and T-cell acute lymphoblastic lymphoma / leukemia, thymoma, mature T-cell and NK-cell tumors, including peripheral T-cell leukemias, adult T-cell leukemia / T-cell lymphomas, and large granular lymphocytic leukemia, Langerhans cell histiocytosis, myeloid neoplasms such as acute myeloid leukemias, including AML with maturation, undifferentiated AML, acute promyelocytic leukemia, acute myelomonocytic leukemia and acute monocytic leukemias, myelodysplastic syndromes and chronic myeloproliferative disorders,including chronic myelogenous leukemia, B-cell acute lymphoblastic lymphoma / leukemia, T-cell acute lymphoblastic lymphoma / leukemia, lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung, small cell carcinoma of the lung, cancer of the peritoneal cavity, hepatocellular carcinoma, gastric or stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, biliary tract tumors, Ewing sarcoma, basal cell carcinoma, adenocarcinoma,carcinoma of the sweat glands, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, testicular tumor, lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, myelodysplastic disease, heavy chain disease, neuroendocrine tumors, schwannoma and other carcinomas, as well as head and neck cancer. In one instance, the antibodies and antibody fragments provided herein are useful in the treatment of diseases caused by infectious agents. Infectious agents include, but are not limited to, bacterial, fungal, parasitic, and viral agents. Examples of such infectious agents include the following: staphylococcus, methicillin-resistant staphylococcus aureus, Escherichia coli, streptococcaceae, neisseriaaceae, cocci, enterobacteriaceae, enterococcus, vancomycin-resistant enterococcus, cryptococcus, histoplasmosis, aspergillus, pseudomonadaceae, vibrionaceae, campylobacter, pasteurellaceae, bordetella, francisella, brucella, legionellaceae, bacteroidaceae, gram negative bacilli, clostridium, corynebacterium, propionibacterium, gram positive bacilli, anthrax, actinomyces, nocardia, fracznn / zznz / E / Yii mycobacteria, treponema, borrelia, leptospira, mycoplasma, ureaplasma, rickettsia, chlamydiae, candida, systemic mycoses,opportunistic fungi, protozoa, nematodes, trematodes, cestodes, adenovirus, herpesvirus (including, for example, herpes simplex virus, Epstein-Barr virus, and herpes zoster virus), poxvirus, papovavirus, hepatitis virus (including, for example, hepatitis B virus and hepatitis C virus), papillomavirus, orthomyxovirus (including, for example, influenza A, influenza B, and influenza C), paramyxovirus, coronavirus, picornavirus, reovirus, togavirus, flavivirus, bunyaviridae, rhabdovirus, rotavirus, respiratory syncytial virus, human immunodeficiency virus, and retrovirus. Some examples of infectious diseases include, but are not limited to, candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal infections, gram-negative sepsis, tuberculosis, mononucleosis, influenza, respiratory syncytial virus (RSV) disease, malaria, schistosomiasis, and trypanosomiasis. In one modality, the antibodies and fragments thereof provided herein are useful in the treatment of diseases mediated by type 2 helper T lymphocytes (Th2), such as, for example, asthma, allergies, or graft-versus-host disease. In one embodiment, the antibodies and antibody fragments provided herein are useful in stimulating an immune response in a subject in need. For example, in one embodiment, anti-PD-L1 antibodies and antibody fragments herein can be administered together with an antigen of interest to elicit an immune response to that antigen. An antigen of interest can be an antigen associated with a pathogen such as a virus or bacteria. Therefore, in one embodiment, the present invention provides a vaccine comprising an anti-PD-L1 antibody and an antigen, wherein the vaccine elicits an immune response specific to the antigen. In one embodiment, the anti-PD-L1 antibodies provided herein modulate the function of regulatory T lymphocytes. CD4+ CD25+ regulatory T lymphocytes are lymphocytes that suppress or reduce the effects of effector T lymphocyte functions. The terms "regulatory T lymphocyte" and "Treg" are used interchangeably herein. In one embodiment, the anti-PD-L1 antibodies provided herein prevent or reverse the inhibitory effects of regulatory T lymphocytes on cytokine production by effector T lymphocytes. For example, in one embodiment, the anti-PD-L1 antibodies provided herein restore the ability of effector T lymphocytes to produce IFNγ upon contact with regulatory T lymphocytes. In one modality, the antibodies and fragments thereof described herein may be administered to the subject through at least one route selected from the parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intra-abdominal, intracapsular, intracartilaginous, intracavity, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intratympanic, intrauterine, intravesical, intravitreal, bolus, subconjunctival, vaginal, rectal, buccal, sublingual, intranasal, intratumoral, and transdermal routes. In one modality, the antibodies and antibody fragments described herein may be administered to a subject in need along with one or more additional therapeutic agents. In another modality, the antibodies and antibody fragments may be administered to a subject before, during, and / or after the administration of the additional therapeutic agent. In one modality, the additional therapeutic agent is a chemotherapeutic agent, a radiotherapeutic agent, a cytokine, an antibody or antibody fragment, or any other additional therapeutic agent indicated for the disease to be treated. In one modality, the anti-PD-L1 antibody and the additional therapeutic agent exhibit therapeutic synergy when administered together, either simultaneously or sequentially. In another modality, the anti-PD-L1 antibody and the additional therapeutic agent are administered in separate formulations.In another embodiment, the anti-PD-L1 antibody and the additional therapeutic agent are administered in the same formulation. In one embodiment, the anti-PD-L1 antibodies and fragments provided herein enhance the immune-modulating effect of one or more additional therapeutic agents. In another embodiment, one or more additional therapeutic agents enhance the effect of the anti-PD-L1 antibody or fragment thereof. The present invention provides isolated antibodies and antigen-binding fragments thereof, nucleic acids encoding such antibodies and fragments, and compositions comprising such isolated antibodies, fragments, and nucleic acids. The term "isolated" refers to a compound of interest (e.g., an antibody or nucleic acid) that has been separated from its natural environment. The present invention further provides pharmaceutical compositions comprising the isolated antibodies or fragments thereof, or nucleic acids encoding such antibodies or fragments, and further comprising one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other agents. The use of the singular form includes the plural unless specifically stated otherwise. The words "a" or "an" mean "at least one" unless specifically stated otherwise. The use of "or" means "and / or" unless stated otherwise. The meaning of the phrase "at least one" is equivalent to the meaning of the phrase "one or more." Likewise, the use of the term "inclusive," as well as other forms such as "includes" and "included," is not exhaustive. Furthermore, terms such as "element" or "component" include both elements and components comprising one unit and elements and components comprising more than one unit, unless specifically stated otherwise. Although the preceding invention has been described in some detail for illustrative and exemplary purposes to aid understanding, it will readily become apparent to those skilled in the art, based on the indications of the present invention, that certain changes and modifications may be made to it without departing from the spirit or scope of the appended claims. The following examples are provided for illustrative purposes only and are not exhaustive. Those skilled in the art will readily recognize a variety of non-essential parameters that could be changed or modified to produce essentially similar results. EXAMPLES EXAMPLE 1 Generation of hPD-Ll monoclonal antibodies Immunization of mice with hPD-Ll-HisTaq v hPD-Ll-mFc To generate antibodies against human PD-L1, cDNAs encoding the open reading frame of the extracellular domain of hPD-Ll fused with a histidine marker (hPD-Ll-HisTag, SEQ ID NO: 143 and 144), mouse Fe (hPD-Ll-mFc, SEQ ID NO: 145 and 146), and human Fe (hPD-Ll-hFc, SEQ ID NO: 147 and 148) were obtained by PCR and subcloned into the pcDNA3.1 expression vector (Invitrogen CAT#:V-790), respectively. After transient expression in Freestyle 293 cells, hPD-Ll-HisTag was purified using an NTA column (GE Healthcare), and hPD-Ll-mFc and hPD-Ll-hFc were purified using a protein G column (GE Healthcare). BALB / cJ mice were immunized subcutaneously every 2 weeks for 6 weeks with recombinant hPD-Ll-HisTag protein (100pg / mouse) or hPD-Ll-mFc emulsified with an equivalent volume of complete / incomplete Freund's adjuvant. Three days prior to fusion, mice were stimulated with intravenous injection of the antigen without adjuvant. Spleen cells (1 x 108) from immunized mice were fused with SP2 / 0 myeloma cells (1.5 x 107) using PEG HybriMax (Sigma Inc., CAT#:7181). After fusion, the cells were distributed into 96-well plates at 0.1 ml per well and incubated at 37 °C in a 5% CO2 incubator. On day 1, cells were nourished by adding 0.1 ml per well with medium containing serum and HAT plus 2x methotrexate. On day 3 and day 7, 0.1 ml of medium in each well was replaced with 0.1 ml of fresh HT medium.The analysis normally occurred between days 9-14 and the supernatant fracznn / zznz / E / Yii of the culture was analyzed to determine the reaction of the antibodies with hPD-Ll-hFc by ELISA. To clone the selected hybridoma cell, a four-fold limiting dilution was performed. Hybridoma cells were cultured in Dulbecco's modified Eagle medium (GIBCO; Invitrogen Corporation, Carlsbad, Calif.) containing 10% fetal bovine serum, 1% penicillin / streptomycin, 2% L-glutamine, and 1% adjusted NaHCO3 solution. Selected hybridoma cells were then adapted to serum-free culture medium, and the antibody was purified from the supernatant using a protein G column (GE Healthcare). After washing with PBS, the bound antibodies were eluted using 0.1 M glycine, pH 3.0, followed by pH neutralization using 2.0 M Tris. Ultra-15 centrifugal concentrators (Amicon) were used for buffer exchange and antibody concentration. EXAMPLE 2 Cloning and humanization of cDNA sequences of Anti-PD-1 antibodies. Immunoglobulin cDNA cloning. Total RNA isolated from the hybridoma cell line producing the hPD-L1 antibody was used as a template to synthesize first-strand cDNA with SuperScript® II Reverse Transcriptase (Life Technology, CAT#:18064-14) according to the manufacturer's instructions. The cDNA product was then subjected to PCR in a 50 lp reaction volume mix using degenerated mouse IgG primers (Kettleborough CA, et al, European Journal of Immunology 23: 206-211 (1993), Strebe N, et al, Antibody Engineering 1:3-14 (2010)). The reaction was carried out in an S1000™ thermal cycler (Bio-Rad, CAT#:184-2000) with 30 cycles of: 94 °C, 1.5 minutes for denaturation; 50 °C, 1 minute for hybridization; and 72 °C, 1 minute for synthesis. At the end of the 30th cycle, the reaction mixture was incubated for another 7 minutes at 72 °C for extension. The PCR mixture was electrophoresis-treated on a 1% agarose / Tris-Borate gel containing 0.5 pg / ml ethidium bromide. DNA fragments of the expected size (approximately 450 bp for both the heavy and light chains) were cleaved from the gel and purified. Three microliters of purified PCR product were cloned into the pMD-18T vector (Takara, CAT#:D101A) and transformed into chemically competent E. coli using One Shot® TOP10 (Invitrogen, CAT#:C4040-03). Clones were analyzed by colony PCR using universal M13 forward and reverse primers, and 10 positive clones from each reaction were selected for bidirectional DNA sequencing using M13 forward and reverse primers. The heavy and light chain variable region sequences of the antibodies m4A8 (SEQ ID NO: 25-28), m4Dl (SEQ ID NO: 21-24), m5G9 (SEQ ID NO: 5-8), m5Gll (SEQ ID NO: 9-12), m8C6 (SEQ ID NO: 13-16), m8H3 (SEQ ID NO: 33-36), m8H4 (SEQ ID NO: 29-32), m7B4 (SEQ ID NO: 17-20), ml3C5 (SEQ ID NO: 1-4), and ml5Fl (SEQ ID NO: 37-40) were amplified from the corresponding hybridoma clones. These antibodies exhibited the desired functions, such as blocking PD-L1 binding to PD-1 and enhancing T-cell activation and cytokine release. Creation and expression of chimeric 5G11 and 13C5 antibodies The chimeric light chains 8C6, 8H4, 5G11, and 13C5 (SEQ ID NO: 52, 56, 62, and 68, respectively) were created by linking PCR-cloned cDNAs from mouse VL regions to a human kappa chain constant region, respectively. The chimeric heavy chains 8C6, 8H4, 5G11, and 13C5 (SEQ ID NO: 50 (8C6-IgG4), 54 (8H4-IgG4), 58 (5G11IgG1), 60 (5G11-IgG4), 64 (13C5-IgG1), and 66 (13C5-IgG4)) were created by linking PCR-cloned cDNAs from mouse VH regions to human IgG1 and IgG4 constant regions. The 5' ends of mouse cDNA sequences were modified using PCR primers designed to add a leader sequence to both the light and heavy chains. Freestyle 293 cells (200 mL at 10⁶ / mL) were transfected with 100 pg of each of the chimeric heavy and light chain expression plasmids and cultured for 6 days. The chimeric antibody was then purified from the supernatant using a protein G column (GE healthcare). The binding of the chimeric antibody to PD-L1 was measured by ELISA and Biacore and was shown to bind to PD-L1 with an affinity comparable to that of the original murine antibody. Antibody humanization design The antibodies 5G11 and 13C5 were humanized using the CDR grafting approach (see, for example, U.S. Patent No. 5,225,539). The light-chain and heavy-chain variable-chain sequences of the murine antibodies 5G11 and 13C5 were compared with those available in the protein database of the Research Collaborative for Structural Bioinformatics (RCSB) (http: / / www.ncbi.nlm.nih.gov / iqblast / iqblast.cqi). Models of 5G11 and 13C5 were generated, respectively, based on the VH and VL structures with the highest sequence homology. Human template antibodies to be grafted with the complementarity-determining regions (CDRs) in VH and VL of mouse antibodies 5G11 and 13C5 were selected from human antibody germlines that have high sequence homology with mouse antibodies 5G11 and 13C5 by searching the International Immunogenetics Information System website (http: / / www.imqt.org / 3Dstructure- DB / cqi / DomainGaDAliqn.cqi'). For 5G11, the selected template human VH was a combination of IGHV2-5*10 and IGHJ4*01, and the selected template human VL was a combination of IGKV1-33*O1 and IGKJ2*01. For 13C5, the selected template human VH was a combination of IGHV3-21*04 and IGHJ4*01, and the selected template human VL was a combination of IGKV7-3*01 and IGKJ2*01. The amino acid sequences of the CDRs of the aforementioned human template antibodies were replaced with CDRs from the hybridoma (mouse) antibodies 5G11 (SEQ ID NO 9398) and 13C5 (SEQ ID NO 81-86). The VH and VL frameworks of the aforementioned human template antibody were grafted with the necessary amino acid sequences from the VH and VL of the 5G11 and 13C5 mouse antibodies to provide a functional humanized antibody. For the 5G11 and 13C5 VH and VL, several amino acid sites of the aforementioned human template antibody framework were backmutated to the corresponding amino acid sequences in the 5G11 and 13C5 mouse antibodies.For the light chain variable region of the humanized 5G11 antibody, the amino acid at position 60 mutates from Ser (S) to Asp (D) and the amino acid at position 67 mutates from Ser (S) to Tyr (Y); and for the heavy chain variable region of the humanized 5G11 antibody, the amino acid at position 24 mutates from Phe (F) to Val (V), the amino acid at position 49 mutates from Ala (A) to Gly (G), the amino acid at position 73 mutates from Thr (T) to Asn (N), and the amino acid at position 83 mutates from Thr (T) to Asn (N). For the light chain variable region of humanized 13C5, the amino acid at position 53 mutates from Tyr (Y) to Lys (K). and for the humanized 13C5 heavy chain variable region, the amino acid at position 28 mutates from Thr (T) to He (I), the amino acid at position 30 mutates from Ser (S) to Arg (R), the amino acid at position 49 mutates from Ser (S) to Ala (A) and the amino acid at position 94 mutates from Tyr (Y) to Asp (D).The amino acid sequences of VH and VL of humanized 5G11 are provided as SEQ ID NO: 42 and 44, respectively; the DNA sequences encoding VH and VL of humanized 5G11 are provided as SEQ ID NO: 41 and 43, respectively. The amino acid sequences of VH and VL of humanized 13C5 are provided as SEQ ID NO: 46 and 48, respectively; the DNA sequences encoding VH and VL of humanized 13C5 are provided as SEQ ID NO: 45 and 47, respectively. The full-chain amino acid sequences for the humanized antibodies 5G11 and 13C5 are provided as SEQ IDs 74 and 80, respectively. The full-length DNA sequences encoding the humanized 5G11 and 13C5 are provided as SEQ IDs 73 and 79, respectively. IgG1 and IgG4 versions of the humanized antibodies 5G11 and 13C5 were produced. The constant region of IgG1 carries the D265A mutation (Clynes R, et al., Nature Medicine 6: 443–446 (2000)), while the constant region of IgG4 has a double mutation, F234A and L235A (Xu D, et al., Cellular Immunology 200: 16–26 (2000)). The DNA and amino acid sequences for the full-length heavy chain of humanized IgG1 antibody 5G1-hIgG1 are provided as SEQ ID NO: 69 and 70, respectively.The DNA and amino acid sequences for the full-length IgG4 heavy chain of the humanized antibody 5G11-hIgG4 are provided as SEQ ID NO: 71 and 72, respectively. The DNA and amino acid sequences for the full-length IgG1 heavy chain of the humanized antibody 13C5-hIgG1 are provided as SEQ ID NO: 75 and 76, respectively. The DNA and amino acid sequences for the full-length IgG4 heavy chain of the humanized antibody 13C5-hIgG4 are provided as SEQ ID NO: 77 and 78, respectively. Creation and expression of humanized 5G11 and 13C5 antibodies DNA encoding the light and heavy chains of the humanized antibodies 5G11 and 13C5 was synthesized and cloned into the pcDNA3.1 expression vector (Invitrogen, CAT: #V-790). Freestyle 293 cells (200 mL at 10⁶ / mL) were transfected with 100pg of each of the humanized heavy and light chain expression plasmids and cultured for 6 days. The humanized antibody was then purified from the supernatant using a protein G column (GE healthcare). The binding kinetics between PD-L1 and PD-L1 antibodies were measured using Biacore assays, performed at 25 °C on a Biacore3000 instrument and recorded at a data acquisition rate of 1 Hz. Polyclonal rabbit anti-mouse IgG (GE, BR-1008-38) was diluted with 10 mM sodium acetate, pH 5.0, and immobilized in reference and experimental flow cells of a CM5 biosensor chip at approximately 5000 RU using an amine coupling kit (GE, BR10050). At the beginning of each cycle, the diluted test antibody (1.5 pg / mL) was injected into the experimental flow cell for 1 minute for capture. PD-L1 analyte series were prepared by diluting the stock solutions with buffer to 100 nM followed by two-fold serial dilution in the same buffer to 0.78 nM. Analytes were injected serially into the reference and experimental flow cells for 3 minutes at a flow rate of 30 pL / minute.The buffer (PBS with 0.05% P2O) was allowed to flow for 10 minutes at a flow rate of 30 pL / minute. At the end of each cycle, the biosensor surface was regenerated with a 3-minute injection of 10 mM pH 1.7 glycine-HCl buffer at a flow rate of 10 pL / minute. For each analyte sample injection (i.e., each cycle), the binding responses obtained from the experimental biosensor surface were double-referenced by simultaneously removing the recorded responses from the reference surface, followed by further removal of responses from a single-reference buffer sample. The association and dissociation constants (ka and kd) were simultaneously determined by fitting the double-referenced sensograms of the entire titration series to the Langmuir (1:1) model using Biaevaluation 4.0 software.The dissociation constant, KD, was calculated from the rate constants determined using the relationship KD = kd / ka. The binding affinity of anti-PD-L1 antibodies to human PD-L1 and crab-eating macaque PD-L1 (cyno-PD-L1) is summarized in Table 4. TABLE 4 Binding affinity to PD-L1 of anti-PD-L1 antibodies Selected Antibody Antigen KD(M) m4A8 Human PD-L1 2.33E-9 m4Dl Human PD-L1 4.39E-9 m5G9 Human PD-L1 4.78E-9 m5Gll Human PD-L1 1.90E-10 m7B4 Human PD-L1 6.01E-9 m8H3 Human PD-L1 6.60E-9 m8H4 Human PD-L1 4.56E-9 m8C6 Human PD-L1 1.53E-9 ml3C5 Human PD-L1 1.35E-9 ml5Fl Human PD-L1 3.59E-9 ch5Gll Human PD-L1 2.86E-10 chl3C5 Human PD-L1 2.28E-09 hu5Gll Human PD-L1 2.25E-10 hul3C5 Human PD-L1 1.74E-09 hu5Gll Cyno- PD-L1 2.75E-10 hul3C5 Cyno- PD-L1 2.43E-09 EXAMPLE 3 ELISA binding analysis of anti-PD-Ll antibodies ELISA binding assays were performed using human PD-Ll-mFc proteins (for the detection of chimeric and humanized antibodies) and PD-Ll-hFc proteins (for the detection of hybridoma antibodies). 96-well plates (Costar, Cat No.: 9018) were coated with 100 pL of 2 pg / ml PD-Ll-mFc (Crownbio) in PBS coating buffer (Hyclone, Cat No.: SH30256.01B) overnight at 4°C. The wells were aspirated and nonspecific binding sites were blocked by adding 200 pL of blocking buffer (PBS with 1% (w / v) bovine serum albumin (BSA, Roche, Cat No.: 738328)) and incubated for 1 hour at 37°C. After the plates were washed three times with wash buffer (PBS with 0.05% (v / v) Tween20 (Sigma, Cat No.:P1379)), 100 pL / well of serial 1:10 dilutions of anti-PD-L1 hybridoma (Figure 1A to ID), chimeric (Figure 2A to 2C), or humanized (Figure 3A to 3B) antibodies were added in blocking buffer (starting from 20 pg / mL) and incubated at room temperature for 1 hour. The plates were washed and incubated with 100 pL / well of goat anti-mouse (H+L) IgG (Thermo, Cat No.: 31432) in blocking buffer for 60 min. After washing, 100 pL / well of TMB substrate solution (eBioscience, Cat No.: 00-4201-56) was added and the plates were incubated for 2 min at room temperature. 100 pL / well of stop solution (2N H2SO4) was added to stop the reaction. Colorimetric signals were developed and read at 450 nm using a SpectraMax Plus autoplate (Supplier: Molecular Devices; Model: MNR0643; Software: SoftMax Pro v5.4).Data were analyzed using GraphPad Prism 5 and the EC50 was calculated (Figures 1A to 3B; Tables 5 to 7). These data demonstrated that anti-PD-L1 antibodies (hybridoma, chimeric, and humanized) bind to PD-L1, as measured by ELISA. frocznn / zznz / E / Yii TABLE 5 EC50 ELISA-based binding of anti-PD-L1 hybridoma monoclonal antibodies Hybridoma Ab m5Gll m7B4 m4Dl m8H4 ml3C5 EC50 ng / ml 45.9 31.42 7.14 29.04 65.1 Hybridoma Ab m8C6 m5G9 m4A8 m8H3 ml5Fl EC50 ng / ml 18.2 31.2 57.6 48.7 48.7 TABLE 6 EC50 ELISA-based binding of chimeric anti-PD-L1 antibodies to PD-L1 Chimeric Ab ch5Gll hlgGl ch5Gll h!gG4 ch8C6 h!gG4 ch8H4-h!gG4 chl3C5 hlgGl chl3C5 h!gG4 EC50 ng / ml 82.1 90 76 133.6 72.1 118 TABLE 7 EC50 ELISA-based binding of humanized anti-PD-L1 antibodies to PD-L1 Ab humanized hul3C5-h!gGl hul3C5-h!gG4 hu5Gll-h!gGl hu5Gll-h!gG4 EC50 (ng / ml) 85.6 126.82 49.5 69.9 Ligand-blocking assays were performed based on ELISA by blocking the binding of biotinylated human PD-I-mFc to human PD-I-hFc. The PD-I-hFc antigen (Crownbio) was suspended in PBS buffer (2 µg / ml, 100 µg / well) and coated onto a 96-well plate (Costar, Cat No. 9018) at 4 °C overnight. The wells were aspirated and nonspecific binding sites were blocked by adding 200 pL of blocking buffer (PBS with 1% (w / v) bovine serum albumin (BSA, Roche, Cat No.:738328)) and incubated for 1 hour at 37°C. After washing the plate three times with wash buffer (PBS with 0.05% (v / v) Tween20 (Sigma, Cat No.:P1379)), 100 pL / well of serial 1:3 dilutions of hybridoma (Figure 4A to 4C), chimeric (Figure 5A to 5C) or humanized (Figure 6A to 6B) anti-PD-L1 antibodies were added in blocking buffer (starting from 20 pg / mL) and incubated at 37°C for 1 hour.Then, 100 pL of PDL-l-mFc-biotin (0.1 pg / ml) were added to each well and incubated at 37 °C for 2 h. After washing the plate three times, the secondary antibody (Avidin HRP eBioscience cat No.: E07418-1632, 1:500, 100 pL / well) was added and incubated at 37 °C for 0.5 h. After washing the plate, 100 pL / well of TMB substrate solution (eBioscience, Cat No.: 00-4201-56) was added and the plate was incubated for 3 min at room temperature. Finally, 100 pL / well of stop solution (2N H₂SO₄) was added to stop the reaction. Colorimetric signals were developed and read at 450 nm using a SpectraMax Plus autoplate (Supplier: Molecular Devices; Model: MNR0643; Software: SoftMax Pro v5.4). Data were analyzed using GraphPad Prism 5 and the IC50 was calculated (Figures 4A to 6B; Tables 8-10).These data showed that anti-PD-L1 antibodies (hybridoma, chimeric, and humanized) can block the binding of PD-1 to PD-L1 on the cell surface, as measured by ELISA. TABLE 8 IC50 of hybridoma anti-PD-L1 monoclonal antibodies that inhibit the binding of PD-1 to PD-L1 on the solid surface Hybridoma Ab m5Gll m7B4 m4Pl m8H4 ml3C5 m8C6 m5G9 m4A8 m8H3 ml5Fl IC50 (ng / ml) 710.2 892.0 332.2 787.8 871.7 343.7 613.2 867.8 647.4 655.3 TABLE 9 IC50 of chimeric anti-PD-L1 antibodies that inhibit the binding of PD-1 to PD-L1 on the solid surface Chimeric Ab ch5GllhlgGl ch5Gllh!gG4 ch8C6- h!gG4 ch8H4- h!gG4 ch!3C5hlgGl chl3C5h!gG4 IC50 (ng / mL) 1006 926.1 476.6 848.1 805.2 375.3 TABLE 10 IC50 of humanized anti-PD-L1 antibodies that inhibit the binding of PD-1 to PDL1 on the solid surface frocznn / zznz / E / Yii Humanized Ab hu5Gll-h!gGl hu5Gll-h!gG4 hul3C5-h!gGl hul3C5-h!gG4 IC50 (ng / ml) 793.6 822.5 1202.6 1192.4 EXAMPLE 4 Cell-based binding analysis of anti-PD-Ll antibodies Cell binding assays of anti-PD-L1 antibodies were performed based on binding to a 293T cell line stably expressing PD-L1 (PD-L1-293T). 2 × 10⁵ 293T-PD-L1 cells were added to each well of 96-well culture plates and incubated with the specified antibody (20 pg / ml at a 1:5 dilution) at 4 °C for 1 h. After washing the cells three times with FACS buffer, the secondary antibody (goat anti-mouse PE: 1:200; mouse anti-human PE: 1:10) was added to the cells at 10⁻¹µ / well and incubated at 4 °C for 40 min. The cells were washed three times with FACS buffer and analyzed using FACS Array. The binding of hybridoma antibodies is shown in Figure 7A and 7B. The binding of chimeric antibodies is shown in Figure 8. The binding of humanized antibodies is shown in Figure 9.The calculated EC50 values ​​for hybridoma, chimeric, and humanized antibodies are shown below in Tables 11, 12, and 13, respectively. These data demonstrated that anti-PD-L1 antibodies (from hybridoma, chimeric, and humanized cells) bind to PD-L1, as measured by FACS analysis. TABLE 11 EC50 of anti-PD-L1 hybridoma monoclonal antibodies with PD-L1 on the cell surface Hybridoma Ab m4Pl m4A8 m5Gll m8H4 m8H3 EC50 ng / ml 36.07 67.83 35.94 43.49 50.81 Hybridoma Ab m8C6 m9G9 m7B4 ml3C5 ml5Fl EC50 ng / ml 40.97 33.7 47.41 45.29 47.8 TABLE 12 E C50 of chimeric anti-PD-L1 antibodies with PD-L1 on the cell surface frQcznn / zznz / E / Yi Ab chimeric chl3C5 hlgGl ch5Gll hlgGl ch5Gll h!gG4 EC50 ng / ml 75.75 58.26 89.68 TABLE 13 EC50 of humanized anti-PD-L1 antibodies with PD-L1 on the cell surface Humanized Ab hu5Gll-h!gGl hu5Gll-h!gG4 hul3C5-h!gGl hul3C5-h!gG4 EC50 ng / ml 47.93 54.33 80.01 80.39 The effect of anti-PD-L1 antibodies on PD-1 binding to PD-L1 on the cell surface was also investigated. Briefly, PD-L1-293T cells were suspended in FACS buffer (PBS with 3% fetal bovine serum). Various concentrations of hybridoma (Figure 10A to 10B), chimeric (Figure 11), or humanized (Figure 12) anti-PD-L1 antibodies were added to the cell suspension and incubated at 4°C for 60 minutes in 96-well plates. Biotin-labeled PD-L1 protein was then added to the wells and incubated at 4°C for 60 minutes. The cells were washed three times with PBS and incubated with mouse PE antibiotin (Biolegend, cat# 409004). Fluorescence associated with the cells was then detected by flow cytometry analysis using a FACS array. The effects of anti-PD-L1 antibodies on the binding of PD-1 to PD-L1-293T were measured by mean fluorescent intensity (MFI) of staining.The inhibition of PD-1 binding by hybridoma anti-PD-L1 antibodies is shown in Figures 10A and 10B. The inhibition of PD-1 binding by chimeric anti-PD-L1 antibodies is shown in Figure 11. The inhibition of PD-1 binding by humanized anti-PD-L1 antibodies is shown in Figure 12. The calculated IC50 values ​​for hybridoma (Table 14), chimeric (Table 15), and humanized (Table 16) antibodies are shown in the tables below. These data demonstrated that anti-PD-L1 antibodies (hybridoma, chimeric, and humanized) can block the binding of PD-1 to PD-L1 on the cell surface, as measured by FACS assay. TABLE 14 IC50 of anti-PD-L1 hybridoma monoclonal antibodies that inhibit the binding of PD-1 with PD-L1 on the cell surface frqcznn / zznz / E / Yii Hybridoma Ab mlgGl m4Dl m5Gll ml3C5 m7B4 m8H4 IC50 ng / ml NA 27.3 16.3 28.9 38.1 30. 6 Hybridoma Ab m4A8 m5G9 m8C6 m8H3 ml5Fl IC50 ng / ml 29.1 49.1 8.2 33.6 21.1 TABLE 15 IC50 of chimeric anti-PD-L1 antibodies that inhibit the binding of PD-1 to PD-L1 on the cell surface Humanized Ab ch5GllhlgGl ch5Gllh!gG4 ch8C6h!gG4 ch8H4h!gG4 chl3C5hlgGl chl3C5h!gG4 IC50 ng / ml 40.36 33.18 34.91 42.02 42.71 35.78 TABLE 16 IC50 of humanized anti-PD-L1 antibodies that inhibit the binding of PD-1 to PD-L1 on the cell surface Humanized Ab h!gG4 hul3C5-h!gGl hul3C5-h!gG4 hu5Gll-hIgGl hu5Gll-h!gG4 IC50 ng / ml NA 18.5 49.9 16.5 9.6 EXAMPLE 5 Effect of anti-PD-L1 antibodies on T lymphocyte activation in a mixed lymphocyte reaction A mixed lymphocyte reaction was used to demonstrate the effect of murine (Figure 13A, 13B), chimeric (Figure 14A, 14B), or humanized (Figure 15A, 15B) anti-PD-L1 antibodies on blocking the PD-L1 / PD-1 pathway in effector lymphocytes. T lymphocytes were analyzed in the assay to determine IFN-γ and IL-2 secretion in the presence or absence of the humanized anti-PD-L1 antibody. Human CD4+ T lymphocytes were purified from human PBMCs using a CD4+ negative selection isolation kit (Mitenyi Biotech, cat# 130-091-155). Immature dendritic cells (DCs) were derived from monocytes isolated from human PBMCs using a Mo-DC generation toolkit (Miltenyi, Cat# 130-093-568). The cells were cultured in Mo-DC differentiation medium for 7 days and then induced to mature DCs in Mo-DC maturation medium for 2 days. To establish the MLR, for each reaction, 10⁵ purified T lymphocytes and 10⁴ allogeneic mature DCs were added to a total volume of 200 µL. The test antibody was analyzed at different concentrations as shown in Figures 13A, 13B, 14A, 14B, 15A, and 15B (i.e., 20 pg / mL, 2 pg / mL, 0.2 pg / mL, 0.02 pg / mL, and 0.002 pg / mL). No antibody was used, or a control isotype antibody was used as a negative control. Cells were cultured for 5 days at 37 °C.On day 6, IFN-γ and IL-2 levels were measured in the culture medium using the IL-2 ELISA kit (eBioscience) and the hIFN-γ ELISA kit (R&D, cat#DY285). The results are shown in Figures 13A, 14A, and 15A for IL-2 secretion and in Figures 13B, 14B, and 15B for IFN-γ secretion. The study results showed that anti-PD-1 antibodies from hybridoma, chimeric, and humanized cells promoted IFN-γ and IL-2 secretion from T lymphocytes in a concentration-dependent manner. In contrast, cultures containing the control isotype antibody did not show an increase in IFN-γ and IL-2 secretion. EXAMPLE 6 Effect of anti-PD-L1 antibody on regulatory T lymphocyte function Regulatory T lymphocytes (CD4+, CD25+) are lymphocytes that suppress the immune response. The effect of regulatory T lymphocytes on cytokine secretion by effector T lymphocytes in MLR was analyzed in the presence or absence of chimeric or humanized anti-PD-11 antibodies. Regulatory T lymphocytes (CD4+, CD25+) were purified from PBMCs using a regulatory T lymphocyte isolation kit (Miltenyi Biotec, cat#130-091-301). Immature dendritic cells (DCs) were derived from monocytes isolated from human PBMCs using a Mo-DC generation toolkit (Miltenyi, cat#130-093-568). The cells were cultured with Mo-DC differentiation medium for 7 days and then induced to mature DCs with Mo-DC maturation medium for 2 days.Regulatory T lymphocytes were added to a mixed lymphocyte reaction containing purified CD4+CD25- T lymphocytes and allogeneic dendritic cells in a 4:1 ratio of CD4+CD25- T lymphocytes to regulatory T lymphocytes. For example, the reaction was added with 1 × 10⁻⁵ cells / well of CD4+CD25- T lymphocytes, 1 × 10⁻⁴ cells / well of mDCs, and 0.25 × 10⁻⁵ cells / well of CD4+CD25- T lymphocytes. Antibody was added to each reaction at a concentration of 10 pg / ml. No antibody or a control isotype antibody was used as a negative control. Cells were cultured for 5 days at 37°C. On day 5, 50 µL of medium were taken to detect IL-2 and IFN-gamma concentrations. After supplementing each well with 50 µL of culture medium, the cells were cultured for another 2 days before being analyzed for cell proliferation using CTG (Promega, G7573). IFN-γ and IL-2 levels were measured in the culture medium using a high IFN-γ ELISA kit (R&D, cat#DY285) and an IL-2 ELISA kit (eBioscience). As shown in Figure 16, the chimeric and humanized anti-PD-Ll antibodies, ch-13C5-hIgGl, ch-13C5-hIgG4, hu-13C5IgGl, hu-13C5-IgG4, ch-5Gll-IgGl, ch-5Gll-IgG4, hu-5Gll-IgGl and hu-5Gll-IgG4, can reduce the inhibitory effect of Treg lymphocytes on IFN-γ secretion by CD4+CD25' effector T lymphocytes, indicating that anti-PD-Ll antibodies can modulate the immune suppression function of regulatory T lymphocytes. EXAMPLE 7 Effect of humanized anti-PD-L1 antibody on the activation of autologous T lymphocytes In this example, the effect of PD-1 / PD-L1 pathway blockade with anti-PD-L1 antibody on T cell activation was examined. Purified human CD4+ T cells (Mitenyi Biotech, cat# 130-091-155) were activated with 1 pg / ml of soluble anti-CD3 antibody (R&D, cat# MAB100) in the presence of autologous monocyte-derived dendritic cells (DCs). After three days of activation in the presence or absence of the titrated anti-PD-L1 antibody, the culture medium was harvested and IFNγ concentration was measured by ELISA. The results, shown in Figure 17, indicate that PD-L1 blockade using humanized anti-PD-L1 antibodies enhanced IFNγ secretion from T cells. EXAMPLE 8 The response of human memory T lymphocytes to tetanus toxoid exposure is enhanced by the humanized anti-PD-L1 antibody To investigate whether the activated antigen-specific T-cell receptor was modulated by blocking the PD-1 / PD-L1 pathway with anti-PD-L1 antibodies, the human T-cell memory assay was employed using tetanus toxoid (TT) antigen to stimulate pre-existing memory T cells in the blood of healthy TT-immunized donors. For this purpose, fresh PBMCs from recently [<1 year] immunized donors were placed in 96-well round-bottom plates (Costar, cat#3799) at 4 x 10⁻⁵ cells / well using RPMI1640 (Invitrogen, cat# A10491-01) supplemented with 80 U / ml of penicillin, 80 µg / ml of streptomycin, and 30% autologous serum, with added humanized 5G11 or 13C5 at various concentrations and stimulated with 0.1 µg / ml of SEB and 1 pg / ml of TT (Astarte Biologies). After co-culture for 7 days at 37 °C, 5% CO2, the supernatant was harvested and the IFN-γ concentration was measured.Figures 18A and 18B show the results of the assay using PBMCs from two different donors. The study results demonstrate that, compared with TT antigen alone, PD-L1 blockade with anti-PD-L1 antibodies resulted in improved IFN-γ secretion from memory T cells. In summary, the humanized antibodies 5G11 and 13C5 maintained the functional activity of their original antibodies during the humanization process.

Claims

1. An isolated antibody or fragment thereof that binds to PD-L1, characterized in that the antibody or fragment thereof comprises (i) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 87, 88, and 89, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 90, 91, and 92, respectively; (ii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 105, 106, and 107, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 108, 109, and 110, respectively; (iii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 117, 118, and 119, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 120, 121, and 122, respectively;(iv) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 129, 130, and 131, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 132, 133, and 134, respectively; or (v) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 135, 136, and 137, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NOs: 138, 139, and 140, respectively.

2. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 87, 88, and 89, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 90, 91, and 92, respectively.

3. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 105, 106, and 107, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 108, 109, and 110, respectively.

4. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 117, 118, and 119, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 120, 121, and 122, respectively.

5. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 129, 130, and 131, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 132, 133, and 134, respectively.

6. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 135, 136, and 137, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID Nos: 138, 139, and 140, respectively.

7. The isolated antibody or fragment thereof according to any of claims 1 to 6, further characterized in that the antibody or fragment thereof is chimeric or humanized.

8. The isolated antibody or fragment thereof according to claim 1, further characterized in that the antibody or fragment thereof comprises: (i) a heavy chain variable region having at least 80% homology with SEQ ID NO: 6 and a light chain variable region having at least 80% homology with SEQ ID NO: 8; (ii) a heavy chain variable region having at least 80% homology with SEQ ID NO: 18 and a light chain variable region having at least 80% homology with SEQ ID NO: 20; (iii) a heavy chain variable region having at least 80% homology with SEQ ID NO: 26 and a light chain variable region having at least 80% homology with SEQ ID NO: 28; (iv) a heavy chain variable region having at least 80% homology with SEQ ID NO: 34 and a light chain variable region having at least 80% homology with SEQ ID NO: 36;or (v) a heavy chain variable region having at least 80% homology with SEQ ID NO: 38 and a light chain variable region having at least 80% homology with fracznn / zznz / E / Yii SEQ ID NO: 40.; 9. The isolated antibody or fragment thereof according to claim 8, further characterized in that the antibody or fragment thereof comprises (i) a variable heavy chain region comprising SEQ ID NO: 6 and a variable light chain region comprising SEQ ID NO: 8; (ii) a variable heavy chain region comprising SEQ ID NO: 18 and a variable light chain region comprising SEQ ID NO: 20; (iii) a variable heavy chain region comprising SEQ ID NO: 26 and a variable light chain region comprising SEQ ID NO: 28; (iv) a variable heavy chain region comprising SEQ ID NO: 34 and a variable light chain region comprising SEQ ID NO: 36; or (v) a variable heavy chain region comprising SEQ ID NO: 38 and a variable light chain region comprising SEQ ID NO:

40.

10. The isolated antibody or fragment thereof according to any of claims 1 to 9, further characterized in that the antibody or fragment thereof is selected from the group consisting of a monoclonal antibody, an scFv, a Fab fragment, a Fab' fragment, and an F(ab)' fragment.

11. The isolated antibody or fragment thereof in accordance with any of claims 1 to 9, further characterized in that the antibody or fragment thereof is bound or conjugated to a therapeutic agent.

12. The isolated antibody or fragment thereof according to claim 11, further characterized in that the therapeutic agent is a cytotoxic drug, a radioactive isotope, an immunomodulator, or an antibody.

13. The isolated antibody or fragment thereof according to any of claims 1 to 9, further characterized in that the antibody or fragment thereof has an affinity for PD-L1 of approximately 10 nM to approximately 0.01 nM.

14. The isolated antibody or fragment thereof according to claim 13, further characterized in that the antibody or fragment thereof has an affinity for PD-L1 of approximately 10 nM or less.

15. The isolated antibody or fragment thereof according to claim 13, further characterized in that the antibody or fragment thereof has an affinity for PD-L1 of approximately 1.0 nM or less.

16. The isolated antibody or fragment thereof according to any of claims 1 to 9, further characterized in that the antibody has a binding EC50 of approximately 5 ng / mL to approximately 1000 ng / mL.

17. The isolated antibody or fragment thereof in accordance with any of claims 1 to 9, further characterized in that the antibody blocks the binding of PD-L1 to PD-1.

18. The isolated antibody or fragment thereof according to claim 17, further characterized in that the antibody or fragment thereof blocks the binding of PD-L1 to PD-1 at an IC50 of approximately 5 ng / mL to approximately 1000 ng / mL.

19. The isolated antibody or fragment thereof according to any of claims 1 to 9, further characterized in that the antibody or fragment increases T lymphocyte activation as measured by inflammatory cytokine production.

20. The isolated antibody or fragment thereof according to claim 19, further characterized in that the antibody or fragment thereof increases the production of IL-2 and IFNγ by T lymphocytes.

21. A composition characterized in that it comprises the antibody or fragment thereof as claimed in any of claims 1 to 20 and a pharmaceutically acceptable carrier.

22. An isolated polynucleotide characterized in that it encodes the antibody or a fragment thereof as claimed in any of claims 1 to 20.

23. An expression vector characterized in that it comprises the isolated polynucleotide as claimed in claim 22.

24. A host cell characterized in that it comprises the expression vector as claimed in claim 23.

25. The use of an isolated antibody or fragment thereof as claimed in any of claims 1 to 20 for the manufacture of a medicament for increasing the activation of T lymphocytes in a subject.

26. The isolated antibody or fragment thereof in accordance with any of claims 1 to 20 for use in enhancing T lymphocyte activation in a subject.

27. The use of an isolated antibody or fragment thereof as claimed in any of claims 1 to 20 for the manufacture of a medicament for reducing tumors or inhibiting the growth of tumor cells in a subject.

28. The use of an isolated antibody or fragment thereof as claimed in any of claims 1 to 20 for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

29. The use as claimed in claim 28, wherein the cancer is selected from the group consisting of lymphoma, leukemia, melanoma, glioma, breast cancer, lung cancer, colon cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer, stomach cancer, rectal cancer, testicular cancer, salivary gland cancer, thyroid cancer, thymus cancer, epithelial cancer, head or neck cancer, gastric cancer, pancreatic cancer, or a combination thereof.

30. The use of an isolated antibody or fragment thereof as claimed in any of claims 1 to 20 for the manufacture of a medicament for the treatment of an infectious disease in a subject in need thereof.

31. The use as claimed in claim 30, wherein the infectious disease is selected from the group consisting of candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal cutaneous and oropharyngeal conditions, gram-negative sepsis, tuberculosis, mononucleosis, influenza, respiratory disease caused by Respiratory Syncytial Virus, malaria, schistosomiasis, and trypanosomiasis.

32. The isolated antibody or fragment thereof in accordance with any of claims 1 to 20 for use in tumor reduction or in inhibiting the growth of tumor cells in a subject.

33. The isolated antibody or fragment thereof in accordance with any of claims 1 to 20 for use in the treatment of cancer in a subject in need thereof.

34. The isolated antibody or a fragment thereof for use in accordance with claim 33, wherein the cancer is selected from the group consisting of lymphoma, leukemia, melanoma, glioma, breast cancer, lung cancer, colon cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer, stomach cancer, rectal cancer, testicular cancer, salivary gland cancer, thyroid cancer, thymus cancer, epithelial cancer, head or neck cancer, gastric cancer, pancreatic cancer, or a combination thereof.

35. The isolated antibody or fragment thereof in accordance with any of claims 1 to 20 for use in the treatment of an infectious disease in a subject in need thereof.

36. The isolated antibody or a fragment thereof for use in accordance with claim 35, wherein the infectious disease is selected from the group consisting of candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal cutaneous and oropharyngeal conditions, gram-negative sepsis, tuberculosis, mononucleosis, influenza, respiratory disease caused by Respiratory Syncytial Virus, malaria, schistosomiasis, and trypanosomiasis.