Bispecific Antibodies Anti-PD-L1 / Anti-4-1BB and Their Uses

Abstract

A bispecific anti-PD-L1 / anti-4-1BB antibody is provided that is capable of effectively blocking the interactions between PD-L1 and its PD-1 receptor and between 4-1BB and its ligand. The bispecific antibody can have high binding affinity for both PD-L1 and 4-1BB proteins.

Description

ANTI-PD-L1 / ANTI-4-1 BB BISPECIFIC ANTIBODIES AND THEIR USES BACKGROUND OF THE INVENTION Programmed death ligand 1 (PD-L1), also known as differentiation cluster 274 (CD274) or homolog 1B7 (B7-H1), is a 40 kDa type 1 transmembrane protein that is thought to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease, and other disease states such as hepatitis. The binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal that reduces the proliferation of CD8+ T cells in the lymph nodes and in addition to that PD-1 is also capable of controlling the accumulation of antigen-specific T cells foreign cells into lymph nodes via apoptosis which is further mediated by downregulation of the Bcl-2 gene. It has been shown that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of tumor samples from patients with renal cell carcinomas found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and increased risk of death. Many PD-L1 inhibitors are in development, immuno-oncology therapies, and are showing good results in clinical trials. 4-1 BB is a member of the TNF receptor superfamily (TNFRSF) and is a costimulatory molecule that is expressed upon activation of immune cells, both innate and adaptive immune cells. 4-1 BB plays an important role in modulating the activity of various immune cells. 4-1 BB agonists enhance immune cell proliferation, survival, cytokine secretion, and cytolytic activity of CD8 T cells. Many other studies showed that activation of 4-1 BB enhances the immune response to kill tumors in mice. Thus, this suggests that 4-1 BB is a promising target molecule in cancer immunology. Despite its antitumor efficacy, the anti-4-1BB antibody induced severe liver toxicity in clinical application. BRIEF DESCRIPTION OF THE INVENTION The present disclosure provides an anti-PD-L1 / anti-4-1 BB bispecific antibody capable of effectively blocking interactions between PD-L1 and its receptor PD-1 and between 4-1 BB and its ligand. The bispecific antibody can have high affinity binding to both a PD-L1 protein (eg, a human PD-L1 protein) and a 4-1 BB protein (eg, a human 4-1 BB protein). The anti-PD-L1 / anti-4-1 BB bispecific antibody may comprise an antiPD-L1 antibody or an antigen-binding fragment thereof as a PD-targeting moiety. R / cann / Lznz / E / YiAi L1, which is capable of specifically recognizing and / or binding to a PD-L1 protein, and an anti-4-1BB antibody or an antigen-binding fragment thereof as a 4-1BB targeting moiety, which is capable of specifically recognize and / or bind to a 41BB protein. The anti-PD-L1 / anti-4-1BB bispecific antibody may comprise an antiPD-L1 antibody or an antigen-binding fragment thereof as a PDL1-targeting moiety. In one embodiment, the anti-PD-L1 antibody or fragment thereof comprised in the bispecific antibody can specifically bind to an immunoglobulin C (IgC) domain of a PD-L1 protein (eg, human PD-L1). In some embodiments, the IgC domain consists of amino acid residues 133-225 of a human PD-L1 protein. In some embodiments, the anti-PD-L1 antibody or fragment thereof can bind to at least one of amino acid residues Y134, K162, and N183 of a human PD-L1 protein. In some embodiments, the anti-PD-L1 antibody or fragment thereof does not bind to an immunoglobulin V (IgV) domain of the PD-L1 protein, and for example, the IgV domain consists of amino acid residues 19-127. of a human PD-L1 protein. For example, the human PD-L1 protein can be selected from the group consisting of proteins represented by GenBank Accession No. NP 001254635.1 NP 001300958.1, NP 054862.1, etc., but may not be limited thereto. These anti-PD-L1 antibodies may be useful for therapeutic purposes such as treating various types of cancer etc., and may also be used for diagnostic and prognostic purposes. In one embodiment, the nti-PD-L1 antibody or fragment thereof is capable of specificity to a human PD-L1 protein. The anti-PD-L1 / anti-4-1BB bispecific antibody comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof and an anti-4-1BB antibody or an antigen-binding fragment thereof, in wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is capable of specifically binding to an immunoglobulin C (IgC) domain of a human Programmed Death Ligand 1 (PD-L1) protein, wherein the IgC domain consists of amino acid residues 133-225; the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4, 5, 262, 263, 264, 265, 266, and 267; a VL CDR1 having an amino acid sequence of SEQ ID NOS: 6, 268, and 269; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having an amino acid sequence of R / cann / Lznz / E / YiAi SEQ ID NOS: 8, 270, 271, and 272; and the anti-4-1BB antibody or antigen-binding fragment thereof comprises a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 10 and 11; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 12 and 13; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 15, 16 and 17; a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4 and 5; a VL CDR1 having an amino acid sequence of SEQ ID NO: 6; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof is capable of binding to at least one of amino acid residues Y134, K162, or N183 of the PD-L1 protein. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof is capable of binding to amino acid residues Y134, K162, and N183 of the PD-L1 protein. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof does not bind to an immunoglobulin V (IgV) domain of the PD-L1 protein, wherein the IgV domain consists of the amino acid residues 19-127. In one embodiment, the anti-PD-L1 / anti-4-1 BB bispecific antibody activates 4-1 BB signaling, or an immune response, depending on PD-L1 expressed on cell surfaces. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof and the anti-4-1BB antibody or antigen-binding fragment thereof are each independently a chimeric antibody, a humanized antibody, or a fully human antibody. The anti-PD-L1 / ant¡-4-1 BB bispecific antibody comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof and an anti-4-1BB antibody or an antigen-binding fragment thereof. , wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: R / cann / Lznz / E / YiAi (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4, 5, 262, 263, 264, 265, 266 and 267; (4) a VL CDR1 having an amino acid sequence of SEQ ID NOS: 6, 268, and 269; (5) a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and (6) a VL CDR3 having an amino acid sequence of SEQ ID NOS: 8, 270, 271, and 272, and the anti-4-1 BB antibody or antigen-binding fragment thereof comprising: (i) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 10 and 11; (ii) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 12 and 13; (iii) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 15, 16 and 17; (iv) a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; (v) a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and (vi) a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. The anti-PD-L1 antibody or fragment thereof may comprise (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4, 5, 262, 263, 264, 265, 266 and 267; (4) a VL CDR1 having an amino acid sequence of SEQ ID NOS: 6, 268 and 269; (5) a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and (6) a VL CDR3 having an amino acid sequence of SEQ ID NOS: 8, 270, 271 and 272. For example, the anti-PD-L1 antibody or fragment thereof may comprise a VH CDR1 having a sequence of amino acids from SEQ ID NO: 1; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2 or 3; (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 4, 5, 262, 263, 264, 265, 266, or 267; a VL CDR1 having an amino acid sequence of SEQ ID NO: 6, 268 or 269; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 8, 270, 271 or 272. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: R / cann / Lznz / E / YiAi 1; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4 and 5; a VL CDR1 having an amino acid sequence of SEQ ID NO: 6; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 8. The anti-PD-L1 / anti-4-1BB bispecific antibody may comprise an anti4-1BB antibody or an antigen-binding fragment thereof as a 41BB-targeting moiety. In one embodiment, the anti-4-1BB antibody or fragment thereof can specifically bind to 4-1 BB protein (eg, human 4-1 BB). The anti-4-1BB antibody or an antigen-binding fragment thereof is capable of enhancing the immune response and / or treating tumor (cancer) in a mammal. The anti-4-1BB antibody or an antigen-binding fragment thereof is characterized by localizing and / or activating only in the tumor microenvironment (TME) and / or considerably reducing liver toxicities compared to pre-existing anti-4 antibodies -1BB, with the maintenance of the efficiencies of improving the increase in the immune response and / or tumor treatment. For example, the human 4-1 BB protein can be selected from the group consisting of proteins represented by NCBI Accession No. NP_001552, etc., but cannot be limited thereto. These anti-4-1BB antibodies may be useful for therapeutic purposes such as treating various types of cancer, etc., and may also be used for diagnostic and prognostic purposes. In one embodiment, the anti-4-1 BB antibody or fragment thereof is capable of specificity to a human 4-1 BB protein. The anti-4-1 BB antibody or fragment thereof may comprise (i) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 10 and 11; (ii) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 12 and 13; (iii) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 15, 16 and 17; (iv) a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; (v) a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and (vi) a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. For example, the anti-4-1 BB antibody or fragment thereof may comprise a VH CDR1 having an amino acid sequence of SEQ ID NO : 10 or 11; a VH CDR2 having an amino acid sequence of SEQ ID NO: 12 or 13; a VH CDR3 having an amino acid sequence of SEQ ID NO: 14, 15, 16, or 17; a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. R / cann / Lznz / E / YiAi In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof and the anti-4-1BB antibody or antigen-binding fragment thereof are each independently a chimeric antibody, a humanized antibody, or a fully human antibody. In one embodiment, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the anti-4-1BB antibody or antigen-binding fragment thereof are humanized antibodies. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 103 and 104, or a polypeptide having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 103 and 104. In one embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 105 and 106, or a peptide having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 105 and 106. In one embodiment, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24, or a polypeptide having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24. In one embodiment, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 25 and 26, or a peptide having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 25 and 26. In one embodiment, the anti-PD-L1 / anti-4-1 BB bispecific antibody activates 4-1 BB signaling depending on the PD-L1 expressed on cell surfaces. In one embodiment, the anti-PD-L1 / ant¡-4-1 BB bispecific antibody is in the IgG-scFv form. The anti-PD-L1 / ant¡-4-1 BB bispecific antibody may comprise a heavy component comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 27, 29, 31, 33, 35, 37, 39 , 41 and 43; and a light component an amino acid sequence selected from the group consisting of SEQ ID NOS: 28, 30, 32, 34, 36, 38, 40, 42 and 44. Another embodiment to provide a pharmaceutical composition comprising R / cann / Lznz / E / YiAi the bispecific antibody as described above. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutical composition can be used to treat and / or prevent cancer. Another embodiment provides a method of treating and / or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the bispecific antibody or pharmaceutical composition. The method can be an additional step to identify the subject in need of treating and / or preventing a cancer, prior to the administration step. Another embodiment provides a use of the bispecific antibody or pharmaceutical composition in treating and / or preventing cancer. Another embodiment provides a use of the bispecific antibody in preparing a pharmaceutical composition in treating and / or preventing cancer. In the pharmaceutical compositions, methods and / or uses provided herein, the cancer may be a solid cancer or a blood cancer, preferably a solid cancer. Another embodiment provides a composition for the detection of PD-L1,41BB, or both simultaneously, in a biological sample, the composition comprising the bispecific antibody. Another embodiment provides a method of detecting PD-L1, 4-1BB, or both simultaneously, in a biological sample, the method comprising contacting the biological sample with the bispecific antibody; and detecting (measuring) an antigen-antibody reaction (binding) between the bispecific antibody and the PD-L1,4-1 BB, or both thereof. The detection method may further comprise, after the detection step, determining that PD-L1, 4-1 BB, or both of them are present in the biological sample when an antigen-antibody reaction is detected, and / or that PD-L1, 4-1 BB, or both of them are absent (not present) in the biological sample, when an antigen-antibody reaction is not detected. Another embodiment provides a pharmaceutical composition for diagnosing a disease associated with PD-L1, 4-1 BB, or both, the composition comprising the bispecific antibody. In another embodiment, a use of the bispecific antibody to diagnose a disease associated with PD-L1, 4-1 BB, or both thereof is provided. Another embodiment provides a method for diagnosing a disease associated with PD-L1,4-1 BB, or both, the method comprises contacting a biological sample obtained from a patient with the bispecific antibody, and detecting the reaction. of antigen-antibody or measure a level of the antigen-antibody reaction in the biological sample. In some embodiments, the method may further comprise R / cann / Lznz / E / YiAi contacting a normal sample with the bispecific antibody, and measuring a level of an antigen-antibody reaction in a normal sample. Furthermore, the method may further comprise comparing the level of the antigen-antibody reaction in the biological sample and the normal sample, after the measurement step. Furthermore, after the detection step or comparison step, the method may further comprise determining that the patient as a patient with a disease associated with PD-L1, 4-1BB, or both of them, when the antigen-antibody reaction is detected in the biological sample or the level of the antigen-antibody reaction in the biological sample is higher than that of the normal sample. The disease associated with PD-L1, 4-1 BB, or both thereof may be one associated with activation (eg, abnormal activation or over-activation) and / or overproduction (overexpression) of PD-L1, 4- 1 BB, or both of the same. For example, the disease may be cancer, as described above. One embodiment provides a polynucleotide encoding the bispecific antibody. In particular, one embodiment provides a polynucleotide encoding a bispecific antibody heavy chain in an IgG-scFv form comprising a full-length IgG and a scFv ligated to a C-terminus and / or N-terminus of the IgG of full length. Another embodiment provides a polynucleotide encoding a bispecific antibody light chain in an IgG-scFv form. Another embodiment provides a recombinant vector comprising the polynucleotide encoding a bispecific antibody heavy chain, the polynucleotide encoding a bispecific antibody light chain, or both. Another embodiment provides a recombinant cell transfected with the recombinant vector. Another embodiment provides a method for preparing the bispecific antibody, which comprises expressing the polynucleotide encoding a heavy chain of the bispecific antibody, the polynucleotide encoding a light chain of the bispecific antibody in a cell. The step of expressing the polynucleotide can be conducted by culturing the cell comprising the polynucleotide (eg, in a recombinant vector) under a condition that allows expression of the polynucleotide. The method may further comprise isolating and / or purifying the bispecific antibody from cell culture, after the expression or culture step. BRIEF DESCRIPTION OF THE DRAWINGS FIGURES 1A and 1B schematically illustrate an anti-PD-L1 / anti4-1 BB bispecific antibody according to one embodiment. FIGURE 2 schematically illustrates the mechanism of action of an anti-PD-L1 / ant¡-4-1 BB bispecific antibody according to one embodiment. FIGURE 3 outlines selection criteria shown for PD-L1 variants in order to R / cann / Lznz / E / YiAi identify the residues required for Hu1210-41 binding. FIGURE 4 illustrates the locations of Y134, K162, and N183, the residues (beads) involved in anti-PD-L1 antibody binding according to one embodiment. FIGURE 5 shows that anti-4-1BB antibodies according to the embodiments can bind human 4-1BB with high affinity. FIGURE 6 shows that anti-4-1BB antibodies according to the embodiments can efficiently bind to 4-1 BB expressed in mammalian cells. FIGURES 7A-7B show graphs illustrating anti-PD-L1 / anti-4-1BB bispecific antibody binding according to one embodiment to human PD-L1 and human 4-1 BB as measured by DACE ( double antigen capture ELISA). FIGURE 8 shows that anti-PD-L1 / anti-4-1 BB bispecific antibodies according to one embodiment are stable in human serum. FIGS. 9A-9F show that PD-L1x4-1BB bispecific antibodies according to one embodiment activate 4-1 BB signaling depending on the expression of PD-L1 in the target cells. FIGURES 10A and 10B show that the PBMC assay results in the anti-PD-L1 / anti-4-1 BB bispecific antibodies according to the embodiments. It also shows graphs illustrating the T cell promoting activities of the anti-PD-L1 / ant¡-4-1 BB bispecific antibodies according to the embodiments. FIGURE 11 shows a graph illustrating the tumor growth inhibition effect of anti-PD-L1 / anti-4-1 BB bispecific antibody according to one embodiment. DETAILED DESCRIPTION OF THE INVENTION Definitions It will be shown that the term "a" or "an / an" entity refers to one or more of that entity eg "an antibody" is understood to represent one or more antibodies. As such, the terms "a" (or "one / an"), "one or more", and "at least one" may be used interchangeably herein. As used herein, the term "polypeptide" is intended to encompass a singular "polypeptide" as well as plural "polypeptides," and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as polypeptides). of peptide). The term "polypeptide" refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product. In this way, peptides, dipeptides, tripeptides, oligopeptides, "protein", "amino acid chain", or any other term used to refer to a chain or chains of two or more amino acids, are included within the definition of "polypeptide". ”, and the term “polypeptide” can be used instead of, or interchangeably with any of those R / cann / Lznz / E / YiAi terms. The term "polypeptide" is also intended to refer to the products of post-expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, or modification by non-binding amino acids. natural origin. A polypeptide can be derived from a natural biological source or can be produced by recombinant technology, but is not necessarily translated from a designated nucleic acid sequence. It can be generated in any way, including by chemical synthesis. The term "isolated" as used herein with respect to cells, nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively, that are present in the natural source of the macromolecule. The term "isolated" as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when produced by recombinant DNA techniques. They are chemically synthesized. On the other hand, an "isolated nucleic acid" is intended to include nucleic acid fragments that are not naturally occurring as fragments and would not be found in the natural state. The term "isolated" is also used herein to refer to cells or polypeptides that are isolated from other proteins or cellular tissues. Isolated polypeptides are intended to encompass both purified and recombinant polypeptides. As used herein, the term "recombinant" as it refers to polypeptides or polynucleotides proposes a form of the polypeptide or polynucleotide that does not occur naturally, a non-limiting example of which can be created by combining polynucleotides or polypeptides that would not normally be present. together. "Homology" or "identity" or "similarity" refers to a sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that can be aligned for comparison purposes. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An "unrelated" or "non-homologous" sequence shares less than 40% identity, but preferably less than 25% identity, with one of the sequences of the present disclosure. A polynucleotide or region of polynucleotide (or a polypeptide or region of polypeptide) has a certain percentage (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) "sequence identity" to another sequence means that when aligned, the percentage of base (or amino acids) is the same when comparing the two sequences. This alignment and the percentage of homology or sequence identity can be determined using software programs known in the art, for example those described by A / cann / Lznz / E / YiAi Ausubel et al. eds. (2007) Current Protocols in Molecular Biology. Preferably, the default parameters are used for alignment. An alignment program is BLAST, which uses defaults. In particular, the programs are BLASTN and BLASTP, which use the following default parameters: Genetic code = standard; filter = none; strand = both; cut = 60; expected = 10; Array = BLOSUM62; Descriptions = 50 sequences; short by = STOP CODE; Database = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translations + SwissProtein + SPupdate + PIR. Biologically equivalent polynucleotides are those having the specified percentage homology noted above and encoding a polypeptide having the same or similar biological activity. The term "an equivalent nucleic acid or polynucleotide" refers to a nucleic acid having a nucleotide sequence that has a certain degree of homology, or sequence identity, with the nucleotide sequence of the nucleic acid or complement thereof. A homologue of a double-stranded nucleic acid is intended to include nucleic acids having a nucleotide sequence that has a certain degree of homology with or with the complement thereof. In one aspect, the nucleic acid homologues are capable of hybridizing to the nucleic acid or complement thereof. Similarly, "an equivalent polypeptide" refers to a polypeptide that has a certain degree of homology, or sequence identity, to the amino acid sequence of a reference polypeptide. In some aspects, the sequence identity is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%. In some aspects, the equivalent polypeptide or polynucleotide has one, two, three, four, or five additions, deletions, substitutions, and combinations thereof compared to the reference polypeptide or polynucleotide. In some aspects, the equivalent sequence retains the activity (eg, epitope binding) or structure (eg, salt bridge) of the reference sequence. Hybridization reactions can be carried out under conditions of different "stringency." In general, a low stringency hybridization reaction is carried out at about 40°C in about 10xSSC or an equivalent ionic strength / temperature solution. A moderate stringency hybridization is typically carried out at about 50°C at about 6xSSC, and a high stringency hybridization reaction is generally carried out at about 60°C at about 1xSSC. Hybridization reactions can also be carried out under "physiological conditions" which are well known to one of skill in the art. A non-limiting example of a physiological condition is the temperature, ionic strength, pH, and Mg2+ concentration normally found in a cell. A polynucleotide is made up of a specific sequence of four bases. R / cann / Lznz / E / YiAi nucleotides: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term "polynucleotide sequence" is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be entered into databases on a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology search. The term "polymorphism" refers to the coexistence of more than one form of a gene or portion thereof. A portion of a gene of which there are at least two different forms, ie, two different nucleotide sequences, is referred to as a "polymorphic region of a gene." A polymorphic region can be a single nucleotide, the identity of which differs on different alleles. The terms "polynucleotide" and "oligonucleotide" are used interchangeably and refer to a polymeric form of nucleotides of any length, whether deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and can carry out any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST, or SAGE tag), exons, introns, messenger RNA (mRNA), blot RNA, ribosomal RNA, ribozymes, cDNA , dsRNA, siRNA, miRNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, the modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The nucleotide sequence can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a tagging component. The term also refers to both double-stranded and single-stranded molecules. Unless otherwise specified or required, any embodiment of this disclosure that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to constitute the double-stranded form. strand. The term "encode" as applied to polynucleotides refers to a polynucleotide that is said to "encode" a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, it can be transcribed and / or translate to produce the mRNA for the polypeptide and / or a fragment thereof. The antisense strand is the complement of this nucleic acid, and the coding sequence can be reduced therefrom. As used herein, an "antibody" or "antigen-binding polypeptide" refers to a polypeptide or polypeptide complex that specifically recognizes and binds to R / cann / Lznz / E / YiAi an antigen. An antibody can be a complete antibody and any antigen-binding fragment or a single chain thereof. Thus the term "antibody" includes any molecule that contains a protein or peptide that comprises at least a portion of an immunoglobulin molecule that has biological antigen-binding activity. Examples of these include, but are not limited to, a heavy or light chain complementarity determining region (CDR) or ligand-binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, heavy or light chain, a framework region (FR), or any portion thereof, or at least a portion of a binding protein. The term "antibody fragment" or "antigen-binding fragment" as used herein is a portion of an antibody such as F(ab')2, F(ab)2, Fab', Fab, Fv , scFv and the like. Regardless of structure, an antibody fragment binds to the same antigen that is recognized by the intact antibody. The term "antibody fragment" includes aptamers, spiegelmers, and diabodies. The term "antibody fragment" also includes any synthetic or genetically modified protein that acts as an antibody by binding to a specific antigen to form a complex. A "single chain variable fragment" or "scFv" refers to a fusion protein of the variable regions of the immunoglobulin heavy (Vh) and light (Vl) chains. In some aspects, some regions are connected with a short linker peptide of ten to about 25 amino acids. The linker can be rich in lysine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of Vh to the C-terminus of Vl, or vice versa. This protein retains the specificity of the original immunoglobulin, despite the removal of the constant regions and the introduction of the linker. ScFv molecules are known in the art and are described, for example, in US Patent 5,892,019. The term antibody encompasses several broad classes of polypeptides that can be distinguished biochemically. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon (γ, μ, α, δ, ε) with some subclasses in between (eg, γΙ-γ4). It is the nature of this chain that determines the "class" of the antibody as IgG, IgM, IgA IgG, or IgE, respectively. Immunoglobulin subclasses (isotypes) eg, IgG1, IgG2, IgG3, IgG4, IgG5, etc., are well characterized and are known to confer functional specialization. Modified versions of each of these classes and isotypes are readily discernible to the skilled artisan in view of the present disclosure and are therefore within the scope of the present invention. All classes of immunoglobulins are clearly within the scope of the present disclosure, the following discussion will generally be directed to the IgG class of immunoglobulin molecules. With respect to IgG, a molecule of R / cann / Lznz / E / YiAi standard immunoglobulin comprises two identical light chain polypeptides of molecular weight about 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000. The four chains are typically joined by disulfide bonds in a "Y" configuration where the light chains surround the heavy chain starting at the head of the "Y" and continuing through the variable region. Antibodies, antigen-binding polypeptides, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, fragments of epitope binding, e.g. Fab, Fab' and F(ab')2, Fd, Fvs, single chain Fvs (scFv), single chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies (including, for example, anti-ld antibodies to the LIGHT antibodies described herein). The immunoglobulin or antibody molecules of the description can be of any type (for example, IgG, IgE, IgM, IgD, IgA, and IgY), class (for example, IgGI, IgG2, IgG3, IgG4, IgAl, and IgA2), or immunoglobulin molecule subclass. Light chains are classified as either kappa or lambda (K, λ). Each class of heavy chain can be linked with either a kappa or lambda light chain. In general, the light and heavy chains are covalently linked to each other, and the "tail" portions of the two heavy chains are linked to each other by covalent disulfide ligations or non-covalent ligations when the immunoglobulins are generated either by hybridomas, cells B or genetically modified host cells. In the heavy chain, the amino acid sequences run from an N-terminus of the hairpin ends of the Y configuration to the C-terminus of the bottom of each chain. Both the light and heavy chains are divided into regions of structural and functional homology. The terms "constant" and "variable" are used functionally. In this regard, it will be appreciated that the variable domains of both the light (VL) and heavy (VH) chain portions determine the region of antigen and specificity. Conversely, the light chain (CK) and heavy chain (CH1, CH2, or CH3) constant domains confer important biological properties such as secretion, transplacental motility, Fe receptor binding, complement binding, and the like. By convention, the numbering of constant region domains increases as they become more distant from the amino-terminal or antigen-binding site of the antibody. The N-terminal portion is a variable region and the C-terminal portion is a constant region; the CH3 and CK domains currently comprise the carboxy-terminus of the heavy and light chain, respectively. As indicated above, the variable region allows the antibody to selectively recognize and specifically bind epitopes on antigens. That is, the VL domain and A / cann / Lznz / E / YiAi the VH domain, or subset of the complementarity determining regions (CDRs), of an antibody combine to form the variable region that defines a three-dimensional antigen-binding site. This quaternary antibody structure forms the antigen-binding site present at the end of each arm of the Y. More specifically, the antigen-binding site is defined by three CDRs on each of the VH and VL chains (ie CDR -H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3). In some cases, for example, certain immunoglobulin molecules derived from camelid species or modified based on camelid immunoglobulins, the entire immunoglobulin molecule may consist of heavy chains only, without light chains. See, for example, HamersCasterman et al., Nature 363: 446-448 (1993). In naturally occurring antibodies, the six "complementarity determining regions" or "CDRs" present in each antigen-binding domain are short, non-contiguous sequences of amino acids that are positioned specifically to form the antigen-binding domain according to the antibody. assumes its three-dimensional configuration in an aqueous environment. The rest of the amino acids in the antigen-binding domains, referred to as "framework" regions, show less inter-molecular variability. The framework regions largely adopt a β-sheet conformation and the CDRs form loops that connect to, and in some cases form part of, the β-sheet structure. In this way, the framework regions act to form a scaffold that provides positioning of the CDRs in the correct orientation for non-covalent, interstrand interactions. The antigen-binding domain formed by the collated CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope. The amino acids comprising the CDRs and framework regions, respectively, can be readily identified for any heavy or light chain variable region by one of ordinary skill in the art, since they have been precisely defined (see www.bioinf.org .uk: Dr. Andrew C.R. Martin's Group, “Sequences of Proteins of Immunological Interest,” Kabat, E., et al., U.S. Department of Health and Human Services, (1983) and Chothia and Lesk, J. Mol. Biol. , 196: 901-917 (1987)). In the case where there are two or more definitions of a term that are used and / or accepted within the art, the definition of the term as used herein is intended to include all of these meanings unless otherwise explicitly stated. A specific example is the use of the term "complementarity determining region" ("CDR") to describe the non-congital antigen combining sites found within the variable region of both heavy and light chain polypeptides. This particular region has been described by Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” (1983) and by Chothia et al., J. R / cann / Lznz / E / YiAi Mol. Biol. 196: 901-917 (1987), which are incorporated herein by reference in their entireties. The CDR definitions according to Kabat and Chothia include overlapping or subsets of amino acid residues when compared to each other. However, the application of any definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The appropriate amino acid residues encompassed by the CDRs as defined by each of the references cited above are set forth in the following table as a comparison. The exact residue numbers encompassed by a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the antibody variable region amino acid sequence. R / cann / Lznz / E / YiAi Table 1 Kabat Chothia CDR-H1 31-35 26-32 CDR-H2 50-65 52-58 CDR-H3 95-102 95-102 CDR-L1 24-34 26-32 CDR-L2 50-56 50-52 CDR -L3 89-97 91-96 Kabat et al. also defined a numbering system for variable domain sequences that is applicable to any antibody. One of ordinary skill in the art can unambiguously assign this "Kabat numbering" system to any variable domain sequence, without reliance on any experimental beyond the sequence itself. As used herein, "Kabat numbering" refers to a numbering system disclosed by Kabat et al., U.S. Dept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). In addition to the table above, the Kabat numbering system describes the CDR regions as follows: CDR-H1 starts at about amino acid 31 (i.e., about 9 residues after the first cysteine ​​residue), includes about 5-7 amino acids, ending at the next tryptophan residue. CDR-H2 starts at the fifteenth residue after the end of CDR-H1, includes about 16-19 amino acids, and ends at the next arginine or lysine residue. CDR-H3 begins at about the thirty-third amino acid residue after the end of CDR-H2; includes 3-25 amino acids; and ends the sequence W-G-X-G, where X is any amino acid. CDR-L1 begins at around residue 24 (ie, after one cysteine ​​residue); includes about 10-17 residues; and ends at the next tryptophan residue. CDR-L2 starts at about the sixteenth residue after the end of CDR-L1 and includes is about 7 residues. CDRL3 begins at about the thirty-third residue after the end of CDR-L2 (ie, after one cysteine ​​residue); it includes about 7-11 residues and ends in the sequence F or W-G-X-G, where X is any amino acid. The antibodies described herein can be of any animal origin including birds and mammals. Preferably, the antibodies are human, murine, donkey, rabbit, goat, guinea pig, camel, llama, horse, or chicken antibodies. In another embodiment, the variable region may be chondritoid in origin (eg, from sharks). As used herein, the term "heavy chain constant region" includes amino acid sequences derived from an immunoglobulin heavy chain. A polypeptide comprising a heavy chain constant region comprises at least one of: a CH1 domain, a hinge domain (eg, upper, middle, and / or lower hinge region), a CH2 domain, a CH3 domain, or a variant or fragment of them. For example, an antigen-binding polypeptide for use in the disclosure may comprise a polypeptide chain comprising a CH1 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH2 domain; a polypeptide chain comprising a CH1 domain and a CH3 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH3 domain, or a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, a CH2 domain, and a CH3 domain. In another embodiment, a polypeptide of the disclosure comprises a polypeptide chain comprising a CH3 domain. Furthermore, an antibody for use in the disclosure may lack at least a portion of a CH2 domain (eg, all or part of a CH2 domain). As stated above, it will be understood by one of ordinary skill in the art that the heavy chain constant region can be modified in such a way that they vary in amino acid sequence from the naturally occurring immunoglobulin molecule. The heavy chain constant region of an antibody described herein can be derived from different immunoglobulin molecules. For example, a heavy chain constant region of a polypeptide may comprise a CH1 domain derived from an IgG1 molecule and a hinge region derived from an IgG3 molecule. In another example, a heavy chain constant region may comprise a hinge region derived in part from an IgG1 molecule, in part from an IgG3 molecule. In another example, a heavy chain portion may comprise a chimeric hinge derived in part from an IgG1 molecule and in part from an IgG4 molecule. As used herein, the term "light chain constant region" includes amino acid sequences derived from the antibody light chain. By way of A / cann / Lznz / E / YiAi Preferably, the light chain constant region comprises at least one of a constant kappa domain or a constant lambda domain. A "light chain-heavy chain pair" refers to the collection of a light chain and a heavy chain that can form a dimer through a disulfide bond between the CL domain of the light chain and the CH1 domain of the light chain. heavy. As previously indicated, the subunit structures and dimensional configuration of the constant regions of the various classes of immunoglobulin are well known. As used herein, the term "VH domain" includes the amino-terminal variable domain of an immunoglobulin heavy chain and the term "CH1 domain" includes the first (mainly amino-terminal) constant region domain of a heavy chain. of immunoglobulin. The CH1 domain is adjacent to the VH domain and is amino-terminal to the hinge region of an immunoglobulin heavy chain molecule. As used herein the term "CH2 domain" includes that portion of a heavy chain molecule that extends, for example, from about residue 244 to residue 360 ​​of an antibody using conventional numbering schemes (residues 244 to 360, Kabat numbering system, and residues 231-340, EU numbering, see Kabat et al, U.S. Dept. of Health and Human Services, "Sequences of Proteins of Immunological Interest" (1983).The CH2 domain is unique in that does not pair closely with another domain Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule It is also well documented that the CH3 domain extends from the CH2 domain to the C -terminal of the IgG molecule and comprises about 108 residues. As used herein, the term "hinge region" includes the portion of a heavy chain molecule that joins the CH1 domain to the CH2 domain. This hinge region comprises about 25 residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. The hinge regions can be subdivided into three distinct domains: upper, intermediate, and lower hinge domains (Roux et al., J. Immunol 161:4083 (1998)). As used herein the term "disulfide bond" includes the covalent bond formed between two sulfur atoms. The cisterna amino acid comprises a thiol group that can form a disulfide bond or bridge with a second thiol group. In most naturally occurring IgG molecules, the CH1 and CK regions are linked by a disulfide bond and the two heavy chains are linked by two disulfide bonds at positions corresponding to 239 and 242 using the Kabat numbering system. (position 226 or 229, EU numbering system). As used herein, the term "chimeric antibody" shall be retained to mean any antibody in which the immunoreactive region or site is obtained or derived R / cann / Lznz / E / YiAi from a first species and the constant region (which may be intact, partial or modified according to the present disclosure) is obtained from a second species. In certain embodiments, the target binding region or site will be from a non-human source (eg mouse or primate) and the constant region is human. As used herein, "percent humanization" is calculated by determining the number of structural amino acid differences (i.e., non-CDR difference) between the humanized domain and the germline domain, subtracting that number from the total number. of amino acids and then dividing that by the total number of amino acids and multiplying by 100. By "binds specifically" or "has specificity for", it is generally intended that an antibody binds to an epitope through its antigen-binding domain, and that the binding involves some complementarity between the antigen-binding domain and the antigen-binding domain. epitope. According to this definition, an antibody is said to "specifically bind" to an epitope when it binds to the epitope, through its antigen-binding domain more readily than it would bind to a random, unrelated epitope. The term "specificity" is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody "A" can be considered to have a higher specificity for an epitope since antibody "B", or antibody "A" can be said to bind epitope "C" with a higher specificity than it has. made for the related epitope "D". Preferably, the antibody binds to an antigen (or epitope) with "high affinity, particularly with a Kd of 1 χ 10'7Mo less, more preferably 5 χ 10-8M or less, most preferably 3 χ 10'8M or less, more preferably 1 χ 10-8M or less, more preferably 25 χ 10-9M or less or even more preferably 1 χ 10-9M or less. As used herein, the terms "treat" or "treatment" can refer to both therapeutic treatment and prophylactic or preventative measures, where the object is to prevent or slow down (reduce) an unwanted physiological change or disorder, such as progression Of cancer. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, decreased disease grade, stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, slowing or palliation of the disease state, and remission (either partial or total), whether detectable or undetectable. "Treatment" may also propose to prolong survival compared to the expected survival if you do not receive the treatment. Those in need of treatment include those already with the condition or disorder as well as those likely to have the condition or disorder or those in whom the condition or disorder is to be prevented. By “subject” or “individual” or “animal” or “patient” or “mammal”, they may refer to R / cann / Lznz / E / YiAi any subject, particularly a human subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and the like. As used herein, phrases such as "to a patient in need of treatment" or "a subject in need of treatment" include subjects, such as mammalian subjects, who will benefit from administration of an antibody or composition of the present description used, for example, for detection, for a diagnostic procedure and / or for a treatment. The present disclosure provides an anti-PD-L1 / anti-4-1BB bispecific antibody capable of effectively blocking interactions between PD-L1 and its receptor PD-1 and between 4-1 BB and its ligand. The bispecific antibody can have high affinity binding to both a PD-L1 protein (eg, a human PD-L1 protein) and a 4-1 BB protein (eg, a human 4-1 BB protein). The anti-PD-L1 / anti-4-1 BB bispecific antibody may comprise an anti-PD-L1 antibody or an antigen-binding fragment thereof as a PDL1-targeting moiety, which is capable of specifically recognizing and / or binding to a PD-L1 protein, and an anti-4-1 BB antibody or an antigen-binding fragment thereof as a 4-1 BB targeting moiety, which is capable of specifically recognizing and / or binding a 41BB protein. Anti-PD-L1 antibody The anti-PD-L1 / anti-4-1 BB bispecific antibody may comprise an antiPD-L1 antibody or an antigen-binding fragment thereof as a PDL1-targeting moiety. The anti-PD-L1 antibody or antigen-binding fragment thereof may show potent binding and inhibitory activities to PD-L1, and be useful for diagnostic and therapeutic uses. The PD-L1 protein is a 40 kDa type 1 transmembrane protein. The PD-L1 protein may be a human PD-L1 protein, and the human PD-L1 protein may be selected from the group consisting of proteins represented by GenBank Accession No. NP 001254635.1, NP 001300958.1, NP 054862.1, etc. , but cannot be limited to the same, the human PD-L1 protein includes an extracellular portion that includes an N-terminal immunoglobulin V (IgV) domain (amino acids 19-127) and a C-terminal immunoglobulin C (IgC) domain. ) (amino acids 133-225). Unlike pre-existing anti-PD-L1 antibodies, which bind to the IgV domain of PD-L1, thereby alternating binding between PD-1 and PDL1, the anti-PD-L1 antibody or fragment thereof comprised in the bispecific antibody cannot bind to an immunoglobulin V (IgV) domain of the PD-L1 protein but binds to the IgC domain of PD-L1, to effectively inhibit PD-L1, thereby improving the R / cann / Lznz / E / YiAi therapeutic effects. In particular, the anti-PD-L1 antibody or fragment thereof comprised in the bispecific antibody may specifically bind to an immunoglobulin C (IgC) domain of the PD-L1 protein. In the case of the human PD-L1 protein, the IgC domain comprises or consists essentially of amino acid residues 133-225 of the full-length human PD-L1 protein. More specifically, the anti-PD-L1 antibody or fragment thereof can bind to at least one selected from amino acid residues Y134, K162, and N183 of the human PD-L1 protein. In some embodiments, the anti-PD-L1 antibody or fragment thereof can bind to at least two amino acid residues Y134, K162, and N183 of the human PD-L1 protein. In some embodiments, the anti-PD-L1 antibody or fragment thereof does not bind to an immunoglobulin V (IgV) domain of the PD-L1 protein, where the IgV domain consists of amino acid residues 19-127. of the human PD-L1 protein. In one embodiment, the anti-PD-L1 antibody or fragment thereof is capable of specificity to a human PD-L1 protein. The anti-PD-L1 antibody or fragment thereof may comprise (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 3; (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4, 5, 262, 263, 264, 265, 266 and 267; (4) a VL CDR1 having an amino acid sequence of SEQ ID NO: 6, 268 and 269; (5) a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and (6) a VL CDR3 having an amino acid sequence of SEQ ID NO: 8, 270, 271 and 272. Table 2 CDRs of anti-PD-L1 antibodies Sequence Name SEQ ID NO: VH CDR1 SYDMS 1 R / cann / Lznz / E / YiAi VH CDR2 TISDAGGYIYYSDSVKG TISDAGGYIYYRDSVKG 2 3 VH CDR3 EFGKRYALDY 4 ELPWRYALDY 5 EFGKRYALDS 262 EIFNRYALDY 263 ELHFRYALDY 22 264 ELYFRYALDY 265 ELLHRYALDY 266 ELRGRYALDY 267 VL CDR1 KASQDVTPAVA 6 KAKQDVTPAVA 268 KASQDVWPAVA 269 VL CDR2 STSSRYT 7 VL CDR3 QQHYTTPLT 8 MQHYTTPLT 2 70 QQHSTTPLT 271 QQHSDAPLT 272 R / cann / Lznz / E / YiAi In some embodiments, an antibody or fragment thereof includes no more than one, no more than two, or no more than three of the above substitutions. In some embodiments, the antibody or fragment thereof includes a VH CDR1 of SEQ ID NO: 1, to VH CDR2 of SEQ ID NO: 2 or 3, to VH CDR3 of SEQ ID NO: 4, 5, 262, 263 , 264, 265, 266 or 267, to VL CDR1 of SEQ ID NO: 6, 268 or 269, a VL CDR2 of SEQ ID NO: 7, and a VL CDR3 of SEQ ID NO: 8, 270, 271 or 272. For example, the anti-PD-L1 antibody or fragment thereof may comprise a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2 or 3; a VH CDR3 having an amino acid sequence of SEQ ID NO: 4 or 5; a VL CDR1 having an amino acid sequence of SEQ ID NO: 6; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 8. Subsequent mutations may be useful in retaining certain features of anti-PD-L1 antibodies. In some embodiments, the anti-PD-L1 antibodies of the present disclosure, particularly human or humanized, may include one or more of the following mutations. In some embodiments, the subsequent mutation (ie, amino acid included at specified position) in a heavy chain variable region (VH) is one or more selected from (a) Ser at position 44, (b) Ala at position 49, (c) Ala at position 53, (d) He at position 91, (e) Glu at position 1, (f) Val at position 37, (g) Thr at position 40, (h) Val at position 53, (i) Glu at position 54, (j) Asn at position 77, (k) Arg at position 94, and (I) Thr at position 108, of the heavy chain variable region, according to Kabat numbering, and combinations thereof. In some embodiments, VH later mutations are selected from (a) Ser at position 44, (b) Ala at position 49, (c) Ala at position 53, and / or (d) lie at position 91, of the heavy chain variable region, according to Kabat numbering, and combinations thereof. In some embodiments, the subsequent mutation in a variable light chain (VL) region is one or more selected from (a) Ser at position 22, (b) Gln at position 42, (c) Ser at position 43, (d) Asp at position 60, and (e) Thr at position 63, of the light chain variable region, according to Kabat numbering, and combinations thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof further comprises a heavy chain constant region, a light chain constant region, an Fe region, or a combination thereof. In some embodiments, the light chain constant region may be a kappa or lambda chain constant region. In some embodiments, the antibody is of an IgG, IgM, IgA, IgE, or IgD isotype, eg, human IgG, human IgM, human IgA, human IgE, or human IgD. In some embodiments, the isotype can be IgG, for example human IgG, such as IgG1, IgG2, IgG3, or IgG4. In some embodiments, the fragment (anti-PD-L1 antibody antigen-binding) may be any fragment comprising heavy chain CDRs and / or antibody CDRs, and for example, may be selected from the group consisting of Fab, Fab', F(ab')2, Fd (comprising a heavy chain variable region and a CH1 domain), Fv (a heavy chain variable region and / or a light chain variable region), Fv chain single (scFv; comprising or consisting essentially of one heavy chain variable region and one light chain variable region, in any order, and a peptide linker between the heavy chain variable region and light chain variable region), single chain antibodies, disulfide-linked Fvs (sdFv), and the like. Without limitation, the anti-PD-L1 antibody or fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody. In one aspect, the antibody or fragment thereof is not naturally occurring, or is chemically or recombinantly synthesized. The binding of an antibody of the disclosure to PD-L1 can be assessed using one or more well-established techniques in the field. For example, in a preferred embodiment, an antibody can be tested by a flow cytometric assay in which the antibody is reacted with a cell line that expresses human PD-L1, such as CHO cells that have been transfected to express PD-L1, eg, PD-L1 A / cann / Lznz / E / YiAi human, or monkey PD-L1, eg, rhesus or cynomolgus monkey, or mouse PD-L1 on its cell surface. Other cells suitable for use in flow cytometric assays include anti-CD3 stimulated CD4+ activated T cells, which express native PD-L1. Still other suitable binding assays include ELISA assays, for example using a recombinant PD-L1 protein. Additionally, or alternatively, antibody binding, including binding kinetics (eg, KD value) can be tested in the Biacore assay. Preferred binding affinities of an antibody of the disclosure include those with a dissociation constant or KD of 4.25 x 10.9M or less. Since each of these antibodies can bind to PD-L1 just like human PD-L1, the CDR sequences or Vh and Vl sequences can be "mixed and matched" to create other anti-PD-L1 binding molecules of the same type. description. Preferably, when CDR sequences or Vh and Vl chains are mixed and matched, for example, a Vh sequence for a particular Vh / Vl pairing is replaced with a structurally similar Vh sequence. Similarly, preferably a Vl sequence from a particular Vh / Vl pairing is replaced with a structurally similar Vl sequence. Anti-4-1BB antibody The anti-PD-L1 / anti-4-1 BB bispecific antibody may comprise an anti-4-1 BB antibody or an antigen-binding fragment thereof as a 41BB targeting moiety. In one embodiment, the anti-4-1 BB antibody or fragment thereof can specifically bind 4-1 BB protein (eg, human 4-1 BB). For example, the human 4-1 BB protein may be selected from the group consisting of proteins represented by NCBI Accession No. NP_001552, etc., but may not be limited thereto, these anti-4-1BB antibodies or fragments of antigen binding thereof are capable of enhancing the immune response and / or treating tumor (cancer) in a mammal. The anti-4-1BB antibody or an antigen-binding fragment thereof is characterized by localization and / or activation only in the tumor microenvironment (TME) and / or considerably reduced liver toxicities compared with pre-41BB anti-41BB antibodies. existing ones, with the maintenance of the efficiencies to improve the increase of the immune response and / or tumor treatment. The term "4-1 BB" refers to CD137, or TNFRSF9 (TNF Receptor Superfamily 9 Member 25), is a member of the TNF receptor superfamily (TNFRSF) and is a costimulatory molecule that is expressed after activation of immune cells, both innate and adaptive immune cells. As used herein, 4-1 BB can originate from a mammal, eg, Homo sapiens (human) (NCBI Accession No. NP 001552). For example, the human 4-1 BB protein (NP_001552) can be represented by the amino acid sequence (SEQ ID NO: 9), as follows: R / cann / Lznz / E / YiAi mgnscyniva tlllvlnfer trslqdpcsn cpagtfcdnn rnqicspcpp nsfssaggqr tcdicrqckg vfrtrkecss tsnaecdctp gfhclgagcs mceqdckqgq eltkkgckdc 121 cfgtfndqkr gicrpwtncs Idgksvlvng tkerdvvcgp spadlspgas svtppapare 181 pghspqiisf flaltstall flllffltlrf svvkrgrkkl lyifkqpfmr pvqttqeedg 241 cscrfpeeee ggcel As described herein, the term "4-1 BB" includes variants, isoforms, homologs, orthologs, and paralogs. For example, antibodies specific for a human 4-1 BB protein can, in certain cases, cross-react with a 41BB protein from a non-human species. In other embodiments, antibodies specific for a human 4-1 BB protein may be completely specific for the human 4-1 BB protein and may show species or other types of cross-reactivity, or may cross-react with 4-1. BBs from certain other species but not all other species (eg, they cross-react with monkey 4-1 BB, but not mouse 4-1 BB). The term "human 4-1 BB" refers to a human 4-1 BB sequence, such as the complete amino acid sequence of human 4-1 BB having NCBI Accession No. NP_001552. The term "mouse 4-1 BB" refers to the mouse 4-1 BB sequence, such as the complete amino acid sequence of mouse 4-1 BB having NCBI Accession No. NP 033430.1. 4-1 BB may also be known in the art as, for example, CD137. The sequence of human 4-1 BB in the disclosure may differ from human 4-1 BB in NCBI Accession No. NP 001552 by having, for example, conserved mutations or mutations in non-conserved regions and 4-1 BB in the description has substantially the same biological function as 4-1 BB in NCBI Accession No. NP_001552. As shown in the experimental examples, the anti-4-1BB antibodies described herein show binding abilities to 4-1 BB, binding abilities to 41BB which is expressed on the cell surface, and binding affinities to 4-1 high BBs. Furthermore, as shown in the experimental example, the anti-4-1BB antibody described herein, particularly when combined with the anti-PD-L1 antibody described herein, is capable of T cell activation. Furthermore, as shown in the experimental example, the anti-4-1BB antibody described herein has increased in vivo antitumor effect. These anti-4-1 BB antibodies may be useful for therapeutic purposes such as treating various types of cancer, etc., and may also be used for diagnostic and prognostic purposes. In one embodiment, the anti-4-1 BB antibody or fragment thereof is capable of specificity to a human 4-1 BB protein. The anti-4-1 BB antibody or fragment thereof may comprise (i) a VH CDR1 having an amino acid sequence R / cann / Lznz / E / YiAi selected from the group consisting of SEQ ID NOS: 10 and 11; (ii) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 12 and 13; (iii) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 15, 16 and 17; (iv) a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; (v) a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and (vi) a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. For example, the anti-4-1 BB antibody or fragment thereof may comprise a VH CDR1 having an amino acid sequence of SEQ ID NO : 10 or 11; a VH CDR2 having an amino acid sequence of SEQ ID NO: 12 or 13; a VH CDR3 having an amino acid sequence of SEQ ID NO: 14, 15, 16, or 17; a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 20. R / cann / Lznz / E / YiAi Table 3 CDRs of anti-4-1 BB antibodies SEQ ID NO Sequence Name VH CDR1 SYDMS 10 GYDMS 11 VH CDR2 WISYSGGSIYYADSVKG 12 VIYPDDGNTYYADSVKG 13 VH CDR3 DGQRNSMREFDY 14 HGGQKPTTKSSSAYGMDG 15 DAQRNSMREFD Y 16 DAQRQSMREFDY 17 VL CDR1 SGSSSNIGNNYVT 18 VL CDR2 ADSHRPS 19 VL CDR3 ATWDYSLSGYV 20 In non-limiting examples of the anti-4-1 BB antibody or fragment thereof, (1) the heavy chain variable region may comprise or consist essentially of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24, or a polypeptide having a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% to the amino acid sequences described above; and / or (2) the light chain variable region may comprise or consist essentially of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOS: 25 and 26, or a polypeptide having sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% to the amino acid sequences described above. Non-limiting examples of the anti-4-1BB antibody or fragment thereof may comprise a heavy chain variable region comprising or consisting essentially of the amino acid sequence of SEQ ID NO: 21, 22, 23 or 24. EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVSWISYSG GSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGQRNSMREFDYWGQGTL VTVSS (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAASGFTFSGYDMSWVRQAPGKCLEWVSVIYPDDG NTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDAAVYYCAKHGGQKPTTKSSSAYGMDGW GQGTLVTVSS (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVSWISYSG GSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAQRNSMREFDYWGQGTLV TVSS (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVSWISYSG GSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAQRQSMREFDYWGQGTL VTVSS (SEQ ID NO: 24) Non-limiting examples of the anti-4-1BB antibody or fragment thereof may comprise a light chain variable region comprising or consisting essentially of the amino acid sequence of SEQ ID NO: 25 or 26. QSVLTQPPSASGTPGRRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYADSHRPSG VPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTKLTVL (SEQ ID NO: 25) QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYADSHRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTKLTVL (SEQ ID NO: 26) The antibodies of the disclosure are characterized by particular functional aspects or properties of the antibodies. For example, antibodies specifically bind to human 4-1BB and can bind to 4-1BB of certain other species, e.g. R / cann / Lznz / E / YiAi eg 4-1 BB from monkey eg cynomolgus monkey, rhesus monkeys, but do not substantially bind to 4-1 BB from certain other species eg 4-1 BB from mouse. Preferably, an antibody of the disclosure binds human 4-1 BB with high affinity. In addition, the antibody of the disclosure, particularly as the bispecific antibody comprising an anti-PD-L1 antibody of the disclosure herein, has the ability to enhance immune cell proliferation, survival, cytokine secretion, and cytolytic activity. of CD8 T cells. In certain embodiments, an antibody of the disclosure, particularly as the bispecific antibody comprising an anti-PD-L1 antibody, binds to human 4-1 BB and exhibits an ability to activate T cells. Other means by which to assess the ability of the antibody to stimulate an immune response include the ability of the antibody to inhibit tumor growth, such as in an in vivo tumor graft model. Binding of the antibody of the disclosure to 4-1 BB can be assessed using one or more techniques well established in the field. For example, in a preferred embodiment, an antibody can be tested by a flow cytometric assay in which the antibody is reacted with a cell line expressing human 4-1 BB, such as CHO cells that have been transfected to express 4-1 BB, eg, human 4-1 BB, or monkey 41BB, eg, rhesus or cynomolgus monkey, or mouse 4-1 BB on its cell surface. Other cells suitable for use in flow cytometric assays include anti-CD3 stimulated CD4+ activated T cells, expressing native 4-1 BB. Still other suitable binding assays include ELISA assays, for example using a recombinant 41BB protein. Additionally or alternatively, antibody binding, including binding kinetics (eg, KD value) can be tested in Octet analysis. Preferred binding affinities of an antibody of the disclosure include those with a dissociation constant or KD of 1.80 x 10'10M or less. In some embodiments, the anti-4-1BB antibody or fragment thereof further comprises a heavy chain constant region, a light chain constant region, an Fe region, or a combination thereof. In some embodiments, the light chain constant region may be a kappa or lambda chain constant region. In some embodiments, the antibody is of an IgG, IgM, IgA, IgE, or IgD isotype, eg, human IgG, human IgM, human IgA, human IgE, or human IgD. In some embodiments, the isotype can be IgG, for example human IgG, such as IgG1, IgG2, IgG3, or IgG4. In some embodiments, the fragment (anti-PD-L1 antibody antigen-binding fragment) may be any fragment comprising the heavy chain CDRs and / or the light chain CDRs of the antibody, and for example, may be selected from the group consisting of Fab, Fab', F(ab')2, Fd (comprising a chain variable region R / cann / Lznz / E / YiAi heavy and a CH1 domain), Fv (a heavy chain variable region and / or a light chain variable region), single chain Fv (scFv; comprising or consisting essentially of a region heavy chain variable and a light chain variable region, in any order, and a peptide linker between the heavy chain variable region and the light chain variable region), single chain antibodies, disulfide-linked Fvs (sdFv), and the like. Without limitation, the anti-4-1BB antibody or fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody, in one aspect, the antibody or fragment thereof is not naturally occurring, or is chemically or recombinantly. Since each of these antibodies can bind to 4-1 BB such as human 4-1 BB, the CDR sequences or the Vh and Vl sequences can be "mixed and matched" to create other antibody-binding molecules. 4-1 BB of the description. Preferably, when CDRs or Vh and Vl chains are mixed and matched, for example, a Vh sequence from a particular Vh / Vl pairing is replaced with a structurally similar Vh sequence. Similarly, preferably a Vl sequence from a particular Vh / Vl pairing is replaced with a structurally similar Vl sequence. Anti-PD-L1 / anti-4-1BB bispecific antibody In the bispecific antibody comprising the PD-L1 targeting portion and the 4-1 BB targeting portion, one of the PD-L1 targeting portion and the 4-1 BB targeting portion may be an antibody of full length, and the other may be an antigen-binding fragment (eg, scFv) comprising the heavy chain CDRs, the light chain CDRs, or a combination thereof. The full-length antibody that targets one of the PD-L1 and 4-1 BB proteins, and the antigen-binding fragment that targets the other protein can be chemically ligated (eg, covalently ligated) directly through of a peptide linker. The antigen-binding fragment (eg, scFv) can be ligated directly or via a peptide linker to the N-terminus of the full-length antibody (eg, the N-terminus of a light chain or heavy chain of the antibody). full length), C-terminus of the full length antibody (eg, C-terminus of a heavy chain (or Fe or CHS domain) of the full length antibody), or both (see FIGS. 1A and 1B ) . In one embodiment, the bispecific antibody may comprise a full-length anti-PD-L1 antibody, an antigen-binding fragment (eg, scFv) of an anti-4-1BB antibody, and a peptide linker between the two. themselves. In another embodiment, the bispecific antibody may comprise a full-length anti-4-1BB antibody, an antigen-binding fragment (eg, scFv) of an anti-PD-L1 antibody, and a peptide linker between the two. themselves R / cann / Lznz / E / YiAi In one embodiment, the scFv contained in the bispecific antibody may comprise a heavy chain variable region and a light chain variable region in any order. For example, the scFv contained in the bispecific antibody may comprise a heavy chain variable region and a light chain variable region, in an N-terminal to C-terminal direction, and optionally a peptide linker between them, or alternatively, the scFv contained in the bispecific antibody may comprise a light chain variable region and a heavy chain variable region, in an N-terminal to C-terminal direction, and optionally a peptide therebetween. In one embodiment, the anti-PD-L1 / anti-4-1 BB bispecific antibody activates 4-1 BB signaling, and as a result an immune response, depending on the PD-L1 expressed on cell surfaces. The use of a peptide linker for the bispecific antibody can lead to high purity of the antibody. As used herein, the term "peptide linker" may be those including any of amino acids 1 to 100, particularly 2 to 50, and any of the kinds of amino acids may be included without restriction. The peptide linker can include, for example, Gly, Asn and / or Ser residues, and also includes neutral amino acids such as Thr and / or Ala. Suitable amino acid sequences for the peptide linker may be those known in the relevant art. Meanwhile, a peptide linker length can be variously determined within this limit that the functions of the fusion protein will not be affected. For example, the peptide linker can be formed by including a total of about 1 to about 100, about 2 to about 50, or about 5 to about 25 of one or more selected from the group consisting of Gly, Asn, Ser, Thr, and Ala. In one embodiment, the peptide linker may be represented as (GmSi)n (m, I, and n, are independently an integer from about 1 to about 10, particularly an integer from about 2 to about 5 ). For example, examples of peptide coatings are summarized as follows: R / cann / Lznz / E / YiAi Linker Function Examples Fusion Protein Type Linker Sequence3 Ref. scFv flexible (GGGGS)s

[46] G-CSF-Tf flexible (GGGGSjs

[20] hbSaG PREs1 flexible (GGGGS)3

[85] Increase stability / flexibility Myc-Est2p flexible (Gly)8

[30] albumin-ANF virus coat protein detaglucanasexylanase flexible rigid rigid (Gly)6 (EAAAK)3 (EAAAK)n (n=1-3)

[31]

[50]

[52] Increase hGH-Tf and Tf-rigid A (EAAAK)4ALEA(EAAAK)4A

[18] hGH expression G-CSF-Tf Y rigid A(EAAAK)4ALEA(EAAAK)4A

[18] Tf-G-CSF G-CSF-Tf flexible (GGGGS)3

[20] G-CSF-Tf rigid A(EAAAK)4ALEA(EAAAK)4A

[20] hGH-Tf rigid A(EAAAK)4ALEA(EAAAK)4A

[40] HSA-IFN-a2b flexible GGGGS

[17] Enhance HSA-IFN activity -a2b rigid PAPAP

[17] biological HSA-IFN-a2b rigid AEAAAKEAAAAKA

[17] PGA-rTHS flexible (GGGGS)n (N=1,2,4)

[55] interferon- - rigid (Ala-Pro)n (10 -34 aa)

[54] gp120 GSF-S-S-Tf disulfide cleavable

[39] IFN-a2b-HSA disulfide cleavable

[42] FlX-albumin VSQTSKLTR AETVFPDVb

[59] LAP-IFN- PLG LWA c

[64] MazE- MazF cleavable RVL AEA: EDVVCC SMSY;

[68] GGIEGR GSC Allow targeting Cleavable immunotoxins TRHRQPR GWE;

[72] AGNRVRR SVG; RRRRRRR R Rd Cleavable immunotoxin GFLG c

[77] dipeptide LE Alter PK G-CSF-Tf and rigid A(EAAAK)4ALEA(EAAAK)4A

[79] hGH-Tf Disulfide cleavage κ / ραηη / ίζηζ / Ε / γίΛΐ In another embodiment, both the PD-L1 targeting portion and the 4-1 BB targeting portion may be a full-length antibody or an antigen-binding fragment comprising the heavy chain CDRs, the light chain, or a combination thereof. In another embodiment, the bispecific antibody may be in a heterodimeric form, comprising a first arm that includes a first heavy chain and a first light chain pair that targets one of PD-L1 and 4-1 BB, and a second arm including a pair of a second heavy chain and a second light chain that are mutually oriented. In one embodiment, the full-length antibody may be in a full-length immunoglobulin form (for example, IgG, IgM, IgA, IgE, or IgD, such as, IgG, human IgM, human IgA, human IgE, or human IgD), and the antigen-binding fragment may be selected from the group consisting of Fab, Fab', F(ab')2, Fd, Fv, scFv, single chain antibodies, sdFv, and the like, as described in the above. For example, the full-length antibody can be in a full-length human IgG (human IgG1, human IgG2, human IgG3, or human IgG4) form, and the antigen-binding fragment can be scFv. For example, an antibody described herein may comprise a flexible linker sequence, or may be modified to add a functional portion (eg, PEG, drug, toxin, or tag). The antibodies or variants described herein may comprise derivatives that are modified, for example, by the covalent attachment of any type of molecule to the antibody in such a way that the covalent attachment does not prevent the antibody from binding to the antigen (eg, a epitope). For example, but not by way of limitation, antibodies can be modified, eg, by at least one selected from the group consisting of glycosylation, acetylation, pegylation, phosphorylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, ligation to a cellular ligand or other protein, and the like. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the antibodies may contain one or more non-classical amino acids. Antibodies or fragments thereof can be detectably labeled by labeling (coupling) with a conventional labeling material selected from chemiluminescent compounds, fluorescent compounds (eg, fluorescent-emitting metals), radioisotopes, dyes, etc. The presence of the labeled antibodies or fragments thereof can be detected by measuring a signal that arises during a R / cann / Lznz / E / YiAi chemical reaction between the antibody (or fragment thereof) and the labeled material. Examples of particularly useful labeled material may be at least one selected from the group consisting of luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt, oxalate ester, fluorescent-emitting metals, and the like. For example, the fluorescent emitting metals can be 152 Eu, or others of the lanthanide series. These metals can be attached to the antibody using these metal chelating groups such as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). In certain embodiments, the bispecific antibodies prepared will not induce a deleterious immune response in the animal to be treated, eg, in a human. In one embodiment, the bispecific antibody can be modified to reduce its immunogenicity using any of the conventional techniques. For example, the bispecific antibody can be a humanized, primatized, deimmunized, or chimeric antibody. These types of antibody are derived from a non-human antibody, typically a murine or primate antibody, that retains or substantially retains the antigen-binding properties of the parent antibody, but is less immunogenic in humans. This can be accomplished by several methods, including (a) grafting the entire non-human variable domains onto the human constant regions to generate chimeric antibodies; (b) grafting at least a portion of one or more of the non-human complementarity determining regions (CDRs) into a human framework and constant regions with or without retention of critical framework residues; or (c) transplanting the entire non-human variable domains, but "hiding" them with a human-like section by replacement of surface residues. De-immunization can also be used to decrease the immunogenicity of an antibody. As used herein, the term "de-immunization" can include the alteration of an antibody to modify T cell epitopes (see, for example, International Application Publication Nos.: WO / 9852976 A1 and WO / 0034317 A2 ). For example, the variable heavy chain and variable light chain sequences of the starting antibody are made and a human T cell epitope "map" of each V (variable) region is created showing the location of the epitopes relative to the complementarity determining regions (CDRs) and other key residues within the sequence. Individual T cell epitopes from the T cell epitope map are analyzed to identify alternative amino acid substitutions with a low risk of altering the activity of the final antibody. A range of alternative variable heavy and variable light sequences comprising combinations of amino acid substitutions are designed and these sequences are subsequently incorporated into a range of binding polypeptides. Typically, between 12 and 24 variant antibodies are generated and tested for binding and / or function. The complete heavy and light chain genes comprising regions Variable constants and modified human R / cann / Lznz / E / YiAi are then cloned into the expression vectors and subsequent plasmids are introduced into the cell lines for full-length antibody production. The antibodies are then compared in appropriate biochemical and biological assays, and the optimal variant is identified. The binding specificity and / or affinity of the bispecific antibody to each target protein can be determined by any conventional assay, for example, in vitro assays such as immunoprecipitation, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA), but not is limited to them. Alternatively, the techniques described for the production of single chain units (US Patent No. 4,694,778, etc.) can be adapted to produce single chain units of the present disclosure. Single chain units are formed by ligating the heavy and light chain fragments of the Fv region through an amino acid bridge (peptide linker), resulting in a single chain fusion peptide (scFv). Techniques for the assembly of functional Fv fragments in E. col i can also be used. Examples of techniques that can be used to produce single chain Fvs (scFvs) and antibodies include those described in US Patent Nos. 4,946,778, 5,258,498, etc.). For some uses, including in vivo use of the antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies that have a variable region derived from a murine monoclonal antibody and a constant region from human immunoglobulin. Methods for producing chimeric antibodies are known in the art. See, for example, US Patent Nos. 5,807,715, 4,816,567, and 4,816,397, which are incorporated herein by reference in their entireties. Humanized antibodies are antibody molecules derived from a non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and framework regions from a human immunoglobulin molecule. Frequently, framework residues in human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably enhance, antigen binding. These framework substitutions are identified by methods well known in the art, for example, by modeling the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify residues. of unusual structure at the particular positions (See, eg, Queen et al., US Patent No. 5,585,089, which are incorporated herein by reference in their entireties). Antibodies can be R / cann / Lznz / E / YiAi humanize using a variety of techniques known in the art including, for example, CDR grafting (US Patent Nos. 5,225,539, 5,530,101, 5,585,089, etc., each of which is incorporated by reference in its entirety), restoration or resurfacing (EP 592,106; EP 519,596, each of which is incorporated by reference in its entirety), and chain transposition (U.S. Patent No. 5,565,332, which is incorporated by reference in its entirety). . Fully human antibodies are particularly desirable for the therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. See also, US Patent Nos. 4,444,887, 4,716,111, etc., each of which is incorporated herein by reference in its entirety. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but can express human immunoglobulin genes. For example, human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region can be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. Mouse heavy and light chain immunoglobulin genes can be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin sites by homologous recombination. In particular, the homozygous deletion of the JH region prevents the production of endogenous antibodies. The modified embryonic stem cells are expanded and microinjected into blasts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring that express human antibodies. Transgenic mice are immunized in the normal manner with a selected antigen, eg, all or a portion of a desired target polypeptide. Monoclonal antibodies directed against the antigen can be obtained from immunized transgenic mice using standard hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice are rearranged during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using this technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. Fully human antibodies that recognize a selected epitope can also be generated using a technique referred to as "guided selection." In this procedure, a selected non-human monoclonal antibody, for example, a mouse antibody, is used to guide the selection of a completely Human R / cann / Lznz / E / YiAi recognizing the same epitope. In another embodiment, the DNA encoding desired monoclonal antibodies can be readily isolated and sequenced using standard procedures (for example, using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of antibodies). murine). Isolated and subcloned hybridoma cells serve as a preferred source of this DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into prokaryotic or eukaryotic host cells such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or CHO cells. myeloma that do not otherwise produce immunoglobulins. More particularly, the isolated DNA (which may be synthetic as described herein) can be used to clone constant and variable region sequences for the preparation of antibodies as described by Newman et al., US Patent No. 5,658,570, which is issued. incorporated by reference herein. Essentially, this involves RNA extraction from selected cells, conversion to cDNA, and PCR amplification using Ig-specific primers. Primers suitable for this purpose are also described in US Patent No. 5,658,570. As will be discussed in more detail below, transformed cells expressing the desired antibody can be grown in relatively large numbers to provide clinical and commercial supplies of the immunoglobulin. Additionally, using routine recombinant DNA techniques, one or more of the CDRs of the bispecific antibody can be inserted into framework regions, eg, into human framework regions to humanize a non-human antibody. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, for example, Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing. of human framework regions). For example, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds at least one epitope of a desired polypeptide, eg, LIGHT. Preferably, one or more amino acid substitutions can be made within the framework regions, and preferably, the amino acid substitutions enhance the binding of the antibody to its antigen (or epitope). Additionally, these methods can be used to make amino acid substitutions or deletions of one or more variable region cysteine ​​residues that participate in an intrachain disulfide bond to generate antibody molecules that lack one or more intrachain disulfide bonds. Other alterations to the polynucleotide are encompassed by the present disclosure and within the skill of the art. In addition, the techniques developed for the production of "chimeric antibodies" by R / cann / Lznz / E / YiAi splicing genes from a mouse antibody molecule, of appropriate antigen specificity, together with genes from a human antibody molecule of appropriate biological activity can be used. As used herein, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a constant region from human immunoglobulin. Alternatively, antibody-producing cell lines can be selected and cultivated using techniques well known to the skilled artisan. These techniques are described in a variety of laboratory manuals and primary publications. Additionally, standard techniques known to those of skill in the art can be used to introduce mutations into the nucleotide sequence encoding an antibody of the present disclosure, including, but not limited to, site-directed mutagenesis and cell-mediated mutagenesis. POR that result in amino acid substitutions. Preferably, the variants (including derivatives) encode less than 50 amino acid substitutions, less than 40 amino acid substitutions, less than 30 amino acid substitutions, less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, amino acids, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the reference variable heavy chain region, CDR-H1 , CDR-H2, CDR-H3, variable light chain region, CDR-L1, CDR-L2, or CDR-L3. Alternatively, mutations can be randomly introduced along all or part of the coding sequence, such as by saturation mutagenesis, and the resulting mutants screened for biological activity to identify mutants that retain activity. Non-limiting examples of Anti-PD-L1 / ant¡-4-1 BB bispecific antibody are provided in Table 4 below. As used herein, "Heavy Component" means a component of an anti-PD-L1 / anti-4-1 BB bispecific antibody of the present disclosure, comprising (1) anti-PD-L1 antibody heavy chain and (2) heavy chain and light chain of the anti-4-1BB antibody. As used herein, "Light Component" means a component of the anti-PD-L1 / ant¡-4-1 BB bispecific antibody of the present disclosure, comprising an anti-PD-L1 antibody light chain. A / cann / Lznz / E / YiAi Table 4 Examples of Anti-PD-L1 / ant¡-4-1 BB bispecific antibody ABLPNB.01 Heavy Component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYSDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICAREFGKRYALDYWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAFPGCLVKDY EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVV SVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSASGTPGRRVTISCSGSSSNIG NNYVT WYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVS WISYSGGSIYYADSVKGRFTISRDNS KNTLYLQMNSLRA EDTAVYYCARDGQRNSMREFDYWGQGTLVTVSS SEQ ID NO: 27 Light component DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTFGQGTKLEIKRT VAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 28 ABLPNB.02 Heavy component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQ APGKSLEWVATISDAGGYIYYSDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICAREFGKRYALDYWGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVE VHNAKTKPREEQYASTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE SEQ ID NO: 29 R / cann / Lznz / E / YiAi WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDY SLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVS WISYSGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDAQRNSMREFDYWGQGTLVTVSS Light component DIQMT QSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 30 ABLPNB.03 Heavy component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYSDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICAREFGKRYALDY WGQGTT VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWY VDGVEVHNAKTKPREEQYASTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGS GG GGSGGGGSQSVLTQPPSASGTPGRRVTISCSGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSGY DMSWVRQAPGKCLEWVS VIYPDDGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDAAVYYCAKHGGQKPTTKSSSAYGMDGWGQGTLVT VSS SEQ ID NO : 31 Compo- DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ SEQ κ / ραηη / ίζηζ / Ε / γίΛΐ light nenie KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPV TKSFNRGEC ID NO: 32 ABLPNB.04 Heavy component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV VSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSASGTPGRRVTISC SGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVS WISYSGGSIYYA DSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDGQRNSMREFDYWGQGTLVTVSS SEQ ID NO: 33 Light component DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTF GQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 34 ABLPNB.05 Heavy component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC SEQ ID NO: 35 κ / ραηη / ίζηζ / Ε / γίΛΐ Ppcpapellggpsvflfpppkpkdtlmisrtpevtcvvvd vshedpevkfnwyvdgvevhnakpreeqyastyrv vsvltvlhqdwlngkeykckckvsnkalpapiektiskkgg qprepqvytlppsreemtknqvsltclvkfypsd Iave wesngqpennykttppvldsdgsfflyyskltvdksrw qqgnvfScSvmhealhnhytqkslslSPgKGGGGGGGGGGgggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggg Ggsgggggggggs RPSGVPDRFSGSKS GTSASLAISGLERSEDYYCATWDYSGYVFGCGTK LTVLGGGGGGGGGGGGGGGGGGGSEVQLLLLESGGGGL DNSKNTLYLQMNSLRA EDTAVYYCARDAQRNSMREFDYWGQGTLVTVSS Light component diqmtqmtqSSSLSASVGDRVTITCKASQDVTPAVAVAWYQQ KPGKAPKLLIYSTSSSRYTGVPSGSGSGSGSGSGTDFTFTFTFTFTFTISSL QgtkleikRTVAAPSVFIF PPSDEQLKSGTASVVCllNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 36 LscaasgftfsSyDMSWV rqapgkslewvatisdaggyiyryrdsvkgrftisrdnak nslylqmnslrdedtavyicarelpwryaldywgqgt tvtvssastkgpsvfplapskstsggtaalgclvkdyf pepvtvSwnsgsgvhtfpa VLQSSGLYSSSVVTV PSSSLGTQTYICNVNHKPSNKVDKKVPKSCDKTHTC PPCPAPLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD YKCKVSNKALPAPIKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQpenNYKTTPPVLDSDGSFSFLYSKLTVDKSRW QQGGNVFSCSVMHEALHNHYTQKSLSPGKGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG SQSVLTQPPSASGTPGRRVTISSGSSNIG NNYVTWyQQLPGTAPKLIYADSHRPSGVPDRFSGSKS GTSASLAISGLERSEDYYCATWDYSLSGYVFGCGTK LTVLGGGGGGGGGGGGGGGGGGGGGGSGGGGGGSEVQLLLLASGGGGL SLRLSCAASGFTFSYDMSWVRQAPGKCLEWVS SEQ ID NOT: 37 R / cann / Lznz / E / YiAi WISYSGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDAQRQSMREFDYWGQGTLVTVSS Light component DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHY TTPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 38 ABLPNB.07 Heavy component EVQLVESGGGLVQPGGSLRLSCA ASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSE DEADYYCATWDYSLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVS WISYSGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDAQRNSMREFDYWGQGTLVTV SS SEQ ID NO: 39 Light component DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTFGQGTKLEIKRTVAAPSVFIF SEQ ID NO: κ / ραηη / ίζηζ / Ε / γίΛΐ PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC 40 ABLPNB.08 Heavy component EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAG GYIYYRDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTK LTVLG GGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSSYDMSWVRQAPGKCLEWVS WISYSGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARDAQRQSMREFDYWGQGTLVTVSS SEQ ID NO: 41 Light component DIQMTQSPSSLSAS VGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQHYTTPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 42 ABLPNB.09 Component heavy EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAK NSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV SEQ ID NO: 43 κ / ραηη / ίζηζ / Ε / γίΛΐ VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGG GGSGGGGSQSVLTQPPSAS GTPGRRVTISCSGSSSNIG NNYVTWYQQLPGTAPKLLIYADSHRPSGVPDRFSGSKS GTSASLAISGLRSEDEADYYCATWDYSLSGYVFGCGTK LTVLGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLV QPGGSLRLSCAASGFTFSGYDMSWVRQAPGKCLEWVS VIYPD DGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDAAVYYCAKHGGQKPTTKSSSAYGMDGWGQGTLVT VSS Light Component DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQ KPGKAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIATYYCQQH YTTPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC SEQ ID NO: 44 R / cann / Lznz / E / YiAi Therapeutic use of the bispecific antibody The bispecific antibody provided herein is capable of simultaneously blocking the activities of PD-L1 and 4-1 BB, thus showing enhanced effects in immunotherapies and / or anticancer therapies, for example, by activating an immune response ( see FIGURE 2). Given the ability of the bispecific antibodies of the disclosure to inhibit the binding of PD-L1 to PD-1 molecules and to stimulate antigen-specific T cell responses, the disclosure also provides composition or in vitro and in vivo methods. to use the antibodies of the disclosure to stimulate, enhance, or upregulate antigen-specific T cell responses. One embodiment provides a pharmaceutical composition comprising the bispecific antibody as described above. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutical composition can be used to stimulate an immune response (eg, an antigen-specific T cell response) and / or treat and / or prevent a disease associated with PD-L1,4-1 BB, or both thereof . Another embodiment provides a method of stimulating an immune response (eg, an antigen-specific T cell response) and / or treating and / or preventing a disease associated with PD-L1, 4-1 BB, or both of the themselves, in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the bispecific antibody or pharmaceutical composition. The method may be an additional step to identify the subject in need to treat and / or prevent a disease associated with PD-L1,4-1 BB, or both, prior to the administration step. The disease associated with PD-L1, 4-1 BB, or both thereof, may be selected from cancers (or tumors), infectious diseases, autoimmune reactions, nervous system disorders, and the like. In one embodiment, the subject may be selected from mammals including humans, eg, a mammal (eg, a human) afflicted with mammalian cancer cells. In another embodiment, the subject may be a detached (isolated) cell from a mammal, eg, a mammal afflicted with disease selected from cancers, infectious diseases, autoimmune reactions, nervous system disorders, and the like (eg , a cancer cell or a cell detached from (isolated) from an infectious region in the mammal, or a T cell, such as a tumor-infiltrating T lymphocyte, a CD4+ T cell, a CD8+ T cell, or combination thereof ). Another embodiment provides a use of the bispecific antibody or pharmaceutical composition in treating and / or preventing cancer. Another embodiment provides a use of the bispecific antibody in preparing a pharmaceutical composition for treating and / or preventing cancer. In the pharmaceutical compositions, methods, and / or uses provided herein, the disease associated with PD-L1, 4-1 BB, or both may be one associated with activation (eg, abnormal activation or overactivation) and / or overproduction (overexpression) of PD-L1, 4-1 BB, or both. For example, the disease may be cancer. The cancer may be a solid cancer or a blood cancer, preferably a solid cancer. Administration of the bispecific antibody can be conducted by one or more well-established techniques in the field. A "therapeutically effective dosage" of the antibody of the disclosure preferentially results in a decrease in the severity of disease symptoms, an increase in the infrequency and duration of symptom-free periods of disease, or a prevention of deterioration. or disability due to the affliction of the disease. For example, for the treatment of tumor-bearing subjects, a "therapeutically effective dosage" preferentially inhibits tumor growth for at least R / cann / Lznz / E / YiAi about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% compared to untreated subjects. A therapeutically effective amount of a therapeutic compound can reduce tumor size, or otherwise ameliorate symptoms in a subject, which is typically a human or may be another mammal. Pharmaceutical compositions may comprise an effective amount of the bispecific antibody, and an acceptable carrier. In some embodiments, the composition further includes a second anticancer agent (eg, an immune checkpoint inhibitor). In a specific embodiment, the term "pharmaceutically acceptable" may refer to one approved by a Federal or state government regulatory agency or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. In addition, a "pharmaceutically acceptable carrier" will generally be a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid of any type. The composition comprising the antibody or antigen-binding fragment thereof of the present disclosure may further comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is that used conventionally in preparing a formulation. Bispecific Antibody Diagnostic Use Overexpression and / or overactivation of PD-L1 and / or 4-1 BB is observed in a biological sample (eg, cells, tissues, blood, serum, etc.) from a patient suffering from a certain cancer (eg, tumor cell) and / or patients who have cells that overexpress PD-L1 and / or 4-1 BB that are likely to be sensitive to bispecific antibody treatments. Accordingly, the bispecific antibody of the present disclosure can also be used for diagnostic and prognostic purposes. One embodiment provides a pharmaceutical composition for diagnosing a disease associated with PD-L1, 4-1 BB, or both, the composition comprising the bispecific antibody. In another embodiment, a use of the bispecific antibody to diagnose a disease associated with PD-L1, 4-1 BB, or both thereof is provided. Another embodiment provides a method for diagnosing a disease associated with PD-L1,4-1 BB, or both, the method comprises contacting a biological sample obtained from a patient with the bispecific antibody, and detecting the reaction. of the antigen-antibody or measure a level of the antigen-antibody response in the biological sample. In this method, when the antigen-antibody reaction is detected in the biological sample or the level of the antigen-antibody reaction in the biological sample R / cann / Lznz / E / YiAi is higher than that of a normal sample, the patient from whom the biological sample is obtained can be determined as a patient with a disease associated with PD-L1, 41BB, or both of the same . Therefore, in some embodiments, the method may further comprise contacting a normal sample with the bispecific antibody, and measuring a level of an antigen-antibody reaction in the normal sample. Furthermore, the method may further comprise comparing the level of the antigen-antibody reaction in the biological sample and the normal sample, after the measurement step. Furthermore, after the detection step or comparison step, the method may further comprise determining the patient as a patient with a disease associated with PD-L1, 4-1BB, or both of them, when the antigen-antibody reaction is detected in the biological sample or the level of the antigen-antibody reaction in the biological sample is higher than that of the normal sample. The disease associated with PD-L1, 4-1 BB, or both thereof, may be one associated with activation (eg, abnormal activation or overactivation) and / or overproduction (overexpression) of PD-L1, 4-1 BB, or both of the same. For example, the disease may be cancer, as described above. In the composition and diagnostic method, the biological sample may be at least one selected from the group consisting of a cell, a tissue, body fluid (for example, blood, serum, lymph, etc.) and the like, obtained (separated) of a patient being diagnosed. The normal sample may be at least one selected from the group consisting of a cell, a tissue, body fluid (for example, blood, serum, lymph, urine, etc.) and the like, obtained (separated) from a patient who is not associated with disease with PD-L1, 4-1 BB, or both. The patient can be selected from a mammal, such as a human. Following optional sample pretreatment, the sample can be incubated with the bispecific antibody of the present disclosure under conditions that allow the antibody to interact with a PD-L1 and / or 4-1 BB protein potentially present in the sample. The presence and / or level (concentration) of PD-L1 and / or 4-1 BB protein in the sample can be used to identify a patient who is suitable for treatment with the bispecific antibody, or a patient who is sensitive or susceptible to treatment with the bispecific antibody. One embodiment provides a pharmaceutical composition that identifies a patient who is suitable for treatment with the bispecific antibody, or a patient who is sensitive or susceptible to treatment with the bispecific antibody, the composition comprising the bispecific antibody. In another embodiment, a use of the bispecific antibody to identify a patient who is suitable for treatment with the bispecific antibody, or a patient who is sensitive or susceptible to treatment with the bispecific antibody is provided. Another embodiment provides a method for R / cann / Lznz / E / YiAi to identify a patient who is suitable for treatment with the bispecific antibody, or a patient who is sensitive or susceptible to treatment with the bispecific antibody, the method comprises contacting a biological sample obtained from a patient with the bispecific antibody, and detecting the antigen-antibody response or measuring a level of the antigen-antibody response in the biological sample. One embodiment provides a composition for detection of PD-L1, 41BB, or both simultaneously, in a biological sample, the composition comprising the bispecific antibody. Another embodiment provides a method of detecting PD-L1, 4-1 BB, or both simultaneously, in a biological sample, the method comprising contacting the biological sample with the bispecific antibody; and detecting (measuring) an antigen-antibody reaction (binding) between the bispecific antibody and PD-L1,4-1 BB, or both thereof. In detection composition and detection method, the term "detection of POLI, 4-1 BB, or both thereof" may refer to, but is not limited to, detection of the presence (and / or absence) and / or level of PD-L1, 4-1 BB, or both of the same in the biological sample. In the detection method, when an antigen-antibody reaction is detected, it can be determined that PD-L1, 4-1 BB, or both of them are present in the biological sample, and when an antigen-antibody reaction is not is detected, it can be determined that PD-L1, 4-1 BB, or both of them are absent (not present) in the biological sample. Therefore, the detection method may further comprise, after the detection step, determining that PD-L1,4-1 BB, or both of them are present in the biological sample when an antigen-antibody reaction is detected, and / or that PD L1, 4-1 BB, or both of them are absent (not present) in the biological sample, when an antigen-antibody reaction is not detected. In the detection method, the level of PD-L1, 4-1 BB, or both of them can be determined according to the degree of the antigen-antibody reaction (for example, the amount of the antigen-antibody complex formed by the antigen-antibody reaction, the intensity of any signal obtained by the antigen-antibody reaction, and the like, which can be measured by any conventional means). The biological sample may comprise at least one selected from the group consisting of a cell (for example, a tumor cell), a tissue (for example, a tumor tissue), body fluid (for example, blood, serum, etc.), and the like, obtained or isolated from a mammal such as a human. The detection method steps can be conducted in vitro. In the diagnostic method and / or detection method, the step of detecting the antigen-antibody reaction or measuring a level of the antigen-antibody reaction is R / cann / Lznz / E / YiAi can be formed by any general method known to the relevant art, such as general enzymatic reactions, fluorescent reactions, luminescent reactions, and / or radiation detection. For example, the step can be carried out by a method selected from, but not limited to, the group consisting of immunochromatography, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), enzyme immunoassay ( EIA), fluorescence immunoassay (FIA), luminescence immunoassay (LIA), western blot analysis, microarray, flow cytometry, surface plasmon resonance (SPR), and the like, but are not limited thereto. Polynucleotides Encoding the Antibodies and Methods for Preparing the Antibodies One embodiment provides a polynucleotide encoding the bispecific antibody. In particular, one embodiment provides a polynucleotide encoding a bispecific antibody heavy chain in an IgG-scFv form. Another embodiment provides a polynucleotide encoding a bispecific antibody light chain in the IgG-scFv form. The IgG-scFv form may refer to a class of a bispecific antibody comprising a full-length IgG antibody that targets (binds) one of the PD-L1 and 4-1 BB proteins and a scFv fragment that targets to (binds to) the other, wherein the scFv ligates to a C-terminus and / or N-terminus of the full-length IgG antibody directly (without a peptide linker) or via a peptide linker. In one embodiment, where the bispecific antibody in an IgG-scFv form comprises a full-length IgG antibody against PD-L1 and a scFv fragment against 4-1 BB, the polynucleotide encoding a heavy chain of the bispecific antibody may encode a heavy chain of the full-length IgG antibody against PD-L1 and a scFv fragment against 4-1 BB that ligates to a C-terminus and / or N-terminus of the full-length IgG antibody directly or via a peptide linker; and the polynucleotide encoding a bispecific antibody light chain may encode a full length IgG antibody light chain against PD-L1. In another embodiment, when the bispecific antibody in an IgG-scFv form comprises a full-length IgG antibody against 4-1 BB and a scFv fragment against PD-L1, the polynucleotide encoding a heavy chain of the bispecific antibody may encode a heavy chain of the full-length IgG antibody against 4-1 BB and an anti-PD-L1 scFv fragment that ligates to a C-terminus and / or N-terminus of the full-length IgG antibody directly or via a peptide linker; and the polynucleotide encoding a bispecific antibody light chain may encode a full length IgG antibody light chain against 4-1 BB. Another embodiment provides a recombinant vector comprising the polynucleotide encoding a bispecific antibody heavy chain, the polynucleotide R / cann / Lznz / E / YiAi encoding a bispecific antibody light chain, or both. Another embodiment provides a recombinant cell transfected with the recombinant vector. Another embodiment provides a method for preparing the bispecific antibody, which comprises expressing the polynucleotide encoding a heavy chain of the bispecific antibody, the polynucleotide encoding a light chain of the bispecific antibody in a cell. The step of expressing the polynucleotide can be conducted by culturing the cell comprising the polynucleotide (eg, in a recombinant vector) under a condition that allows expression of the polynucleotide. The method may further comprise isolating and / or purifying the bispecific antibody from cell culture, after the expression or culture step. examples Hereinafter, the present invention will be described in detail by examples. The following examples are intended merely to illustrate the invention and are not intended to restrict the invention. Example 1: Preparation of anti-PD-L1 monoclonal antibodies 1.1. Preparation of Anti-human-PD-L1 mouse monoclonal antibodies and analysis thereof Mouse anti-human-PD-L1 monoclonal antibodies were generated using hybridoma technology, as described in International Application Publication WO2017-215590. The amino acid and polynucleotide sequences of the variable regions of the hybridoma supernatants, named Hybridoma HL1210-3, are provided in Table 5 below. Table 5 HL1210-3 variable sequences A / cann / Lznz / E / YiAi Sequence Name SEQ ID NO: HL1210-3 VH GAAGTGAAACTGGTGGAGTCTGGGGGAGACTTAGTGAA GCCTGGAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTG GATTCACTTTCAGTAGCTATGACATGTCTTGGGTTCGCC AGACTCCGGAGAAGAGTCTGGAGTGGGTCGCAACCATT AGT GATGGTGGTGGTTACATCTACTATTCAGACAGTGTG AAGGGGCGATTTACCATTCTCCAGAGACAATGCCAAGAA CAACCTGTACCTGCAAATGAGCAGTCTGAGGTCTGAGG ACACGGCCTTGTATATTTGTGCAAGAGAATTTGGTAAGC GCTATGCTTTGGACTACTGGGGTCAAGGAACCTCAGTC ACCGTCTC TCCA 45 HL1210-3 51 EVKLVESGGDLVKPGGSLKLSCAASGFTFSSYDMSWVRQ 46 VH TPEKSLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNNLY LQMSSLRSEDTALYICAREFGKRYALDYWGQGTSVT HL1210-3 GACATTGTGATGACCCAGTCTC ACAAATTCATGTCCACA 47 VL TCGGTAGGAGACAGGGTCAGCATCTCCTGCAAGGCCA GTCAGGATGTGACTCCTGCTGTCGCCTGGTATCAACAG AAGCCAGGACAATCTCCTAAACTACTGATTTACTCCACA TCCTCCCGGTACACTGGAGTCCCTGATCGCTTCACTGG CAGTGGATCTGGGACGGATTTCACTTTCACC ATCAGCA GTGTG C AG G CTG AAG ACCTGG C AGTTTATTACTGTC AG CAACATTATACTACTCCGCTCACGTTCGGTGCTGGGAC CAAGCTGGAGCTGAAA HL1210-3 DIVMTQSHKFMSTSVGDRVSISCKASQDVTPAVAWYQQK 48 VL PGQSPKLLIYSTSSRYTGVPDRFTGS GSGTDFTFTISSVQA EDLAVYYCQQHYTTPLTFGAGTKLELK R / cann / Lznz / E / YiAi 1.2. Humanization of mouse mAb HL1210-3 Variable region genes mAb HL1210-3 were used to create a humanized Mab, according to methods commonly used in the art and as described in International Application Publication WO 2017-215590. The nucleotide and amino acid sequences of some of the resulting humanized antibodies are listed in Table 6 below. Table 6 Humanized antibody sequences (bold indicates GDR) Name Amino acid sequence SEQ ID NO: HL1210-VH EVKLVESGGDLVKPGGSLKLSCAASGFTFSSYDMSWVRQTP EKSLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNNLYLQM 49 SSLRSEDTALYICAREFGKRYALDYWGQGTSVTVSS Hu1210 VH.1 EVQL VESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVSTISDGGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 50 MNSLRAEDTAVYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.1a EVQLVESGGGLVKPGGSLRLSCAASGFTFSSY DMSWVRQA PGKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 51 MNSLRAEDTAVYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.1b EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQA 52 PGKSLEWVATISDGGG YIYYSDSVKGRFTISRDNAKNSLYLQ 52 MNSLRAEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.2 EVQLVESGGGLVKPGGSLRLSCAASGFFTFSSYDMSWIRQAP GKGLEWVSTISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQM 53 NSLRAEDTAVYYCAREFGKRYALDY WGQGTTVTVSS Hu1210 VH.2a EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWIRQAP GKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQM 54 NSLRAEDTAVYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.2b EVQL VESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 55 MNSLRAEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.3 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVR QA PGKGLEWVSTISDGGGGYIYYSDSVKGRFTISRDNSKNTLYLQ 56 MNSLRAEDTAVYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.3a EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDGGGYIYYSDSV KGRFTISRDNSKNTLYLQ 57 MNSLRAEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVSTISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 58 MNSLRDEDTA VYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4a EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 59 MNSLRDEDTAVYYCAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4b EVQLVESGGGL VQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 60 MNSLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4c EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PG KSLEWVATISEGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 61 MNSLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4d EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSYDMSWVRQA (H12 VH) PGKSLEWVATISDAGGYIYYSDSVKGRFTISRDNAKNSLYLQ 62 MNSLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS Hu1210 VH.4e EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDVGGYIY YSDSVKGRFTISRDNAKNSLYLQ 63 MNSLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS A / cann / Lznz / E / YiAi Hu1210 VH.5 53 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 64 MNSLRAEDTAVYYCAREFGKRYALDYWGQGTLVTVSS HU1210 VH.5a EVQLVESG GGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 65 MNSLRAEDTAVYICAREFGKRYALDYWGQGTLVTVSS HU1210 VH.5b EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVR QA PGKGLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNSLYLQ 66 MNSLRAEDTAVYICAREFGKRYALDYWGQGTTVTVSS HU1210 VH.5C EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKGLEWVATISDGGGYIYYSDSV KGRFTISRDNAKNNLYLQ 67 MNSLRAEDTAVYICAREFGKRYALDYWGQGTLVTVSS HU1210 VH.5d EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQT PEKSLEWVATISDGGGYIYYSDSVKGRFTISRDNAKNNLYLQ 68 MNSLRAEDTA VYICAREFGKRYALDYWGQGTLVTVSS HL1210-VK DIVMTQSHKFMSTSVGDRVSISCKASQDVTPAVAWYQQKP GQSPKLLIYSTSSRYTGVPDRFTGSGSGTDFTFTISSVQAED 69 LAVYYCQQHYTTPLTFGAGTKLELK R / cann / Lznz / E / YiAi Hu1210 VK.1 DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG (H12 VL) KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 70 TYYCQQHYTTPLTFGQGTKLEIK Hu1210 VL.1a DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KSPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSL QPEDIA 71 TYYCQQHYTTPLTFGQGTKLEIK Hu1210 VK.2 DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTLTISSLQPEDFA 72 TYYCQQHYTTPLTFGQGTKLEIKR Hu1210 VK .2a DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPDRFTGSGSGTDFTLTISSLQPEDFA 73 TYYCQQHYTTPLTFGQGTKLEIKR Hu1210 VK.2b DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG QSPKLLIYSTSSRYTGVPDRFTGSGSGTDFTLTISSLQPEDFA 74 TYYCQQHYTTPLTFGQGTKLEIKR Hu1210 VK.2c DIQMTQSPSSLSASVGDRVTISCKASQDVTPAVAWYQQKPG 75 54 QSPKLLIYSTSSRYTGVPDRFTGSGSGTDFTLTISSLQPEDFA TYYCQQHYTTPLTFGQGTKLEIKR Name Amino Acid Sequence SEQ ID NO: HL1210 VH GAGGTGAAGCTGGTGGAGAGCGGCGGAGATCTGGTGAA GCCTGGCGGCAGCCTGAAGCTGAGCTGTGCCGCCAGCG GCTTCACCTTCAGCAGCTACGACATGAGCTGGGTGAGGC AGACCCCCGAGAAGAGCCTGGAGTGGGTGGCCACCATCA GCGATGGCGGCGGCTACATCTACTACAGCGACAGCGTGA 76 AGGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACA ACCTGTACCTGCAGATGAGCAGCCTGAGGAGCGAG GACA CCGCCCTGTACATCTGCGCCAGGGAGTTCGGCAAGAGGT ACGCCCTGGACTACTGGGGACAGGGCACCAGCGTGACCG TGAGCAGC Hu1210 VH.1 GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA GCCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCTTCAGCA GCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGAGCACCATTCC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 77 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACAC CGCC GTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.1a GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA GCCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCGGCTTCACCTTCAGCAGCTACGA CATGAGCTGGGTGAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGGCCACCATCTC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 78 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACAC CGCCGTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.1b GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA 79 GCCCG GAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG κ / ραηη / ίζηζ / Ε / γίΛΐ 55 GCTTCACCTTCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTCCGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGCC GAGGACAC CGCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.2 GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA GCCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCAC CTTCAGCAGCTACGACATGAGCTGGATCAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGAGCACCATTCC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 80 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGGCCGAGGACAC CGCCGTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.2a GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA GCCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCTTCAGCAG CTACGACATGAGCTGGATCAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGGCCACCATCTC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 81 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACAC CGCCGT GTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.2b GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGAA GCCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCGGCTTCACCTTCAGCAGCTACGACAT GAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC 82 CG ATG GCG G CGG CTAC ATCTATT ACTCCG AC AG CG TG AA GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACAC κ / ραηη / ίζηζ / Ε / γίΛΐ 56 CGCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.3 GAGGTGCAGCTGCTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCTTC AGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGAGCACCATTCC CG ATG GCG G CGG CTAC ATCTATT ACTCCG AC AG CG TG AA 83 GGGCAGGTTCACCATCAGCAGGGACAACAGCAAGAACAC CCTGTACCTGCAGATGAACAGCCTGAGGGCC GAGGACAC CGCCGTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.3a GAGGTGCAGCTGCTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCT TCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 84 GGGCAGGTTCACCATCAGCAGGGACAACAGCAAGAACAC CCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACAC CGCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4 GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCTTCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGAGCACCATCTC CGATGGCGGCGGCTACATCTATTACTCCGACAG CGTGAA 85 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGATGAGGACAC CGCCGTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4a GAGG TGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA 86 ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG κ / ραηη / ίζηζ / Ε / γίΛΐ 57 GCTTCACCTTCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAGGCCTGGAGTGGGTGGCCACCATCTCCGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGG ATGAGGACAC CGCCGTGTACTACTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4b GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTC ACCTTCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC CGATGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 87 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGATGAGGACA C CGCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4c GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCACCTTCAG CAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC CGAAGGCGGCGGCTACATCTATTACTCCGACAGCGTGAA 88 GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGATGAGGACAC CGCCG TGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4d GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCGGCTTCACCTTCAGCAGCTACGA CATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC 89 CG ATG CG G G CGG CTAC ATCTATT ACTCCG AC AG CG TG AA GGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAG CCTGTACCTGCAGATGAACAGCCTGAGGGATGAGGACAC κ / ραηη / ίζηζ / Ε / γίΛΐ 58 CGCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTA CGCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGT GAGCAGC Hu1210 VH.4e GAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCA ACCCGGAGGCAGCCTGAGACTGAGCTGCGCTGCCAGCG GCTTCAC CTTCAGCAGCTACGACATGAGCTGGGTGAGACA GGCCCCTGGCAAAAGCCTGGAGTGGGTGGCCACCATCTC CGATGTTGGCGGCTACATCTATTACTCCGACAGCGTGAAG 90 GGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACAGC CTGTACCTGCAGATGAACAGCCTGAGGGATGAGGACACC GCCGTGTACATCTGCGCCAGGGAGTTCGGCAAAAGGTAC GCCCTGGACTACTGGGGCCAGGGCACAACCGTGACCGTG AGCAGC Hu1210 VH.5 GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCA ACCTGGAGGCTCCCTGAGGCTGTCCTGTGCCGCTTCCGG CTTCACCTTC AGCTCCTACGATATGAGCTGGGTGAGGCAG GCTCCTGGAAAGGGCCTGGAGTGGGTGGCCACCATCTCC GACGGAGGCGGCTACATCTACTACTCCGACTCCGTGAAG 91 GGCAGGTTCACCATCTCCCGGGACAACGCCAAGAACTCC CTGTACCTGCAGATGAACTCTCTCAGGGCTGAGGACACC GCCGTG TATTACTGCGCCAGGGAGTTTGGCAAGAGGTAC GCCCTGGATTACTGGGGCCAGGGCACACTGGTGACAGTG AGCTCC Hu1210 VH.5a GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCA ACCTGGAGGCTCCCTGAGGCTGTCCTGTGCCGCTTCCGG CTTCACCTTCAGCTCCTA CGATATGAGCTGGGTGAGGCAG GCTCCTGGAAAGGGCCTGGAGTGGGTGGCCACCATCTCC GACGGAGGCGGCTACATCTACTACTCCGACTCCGTGAAG 92 GGCAGGTTCACCATCTCCCGGGACAACGCCAAGAACTCC CTGTACCTGCAGATGAACTCTCTCAGGGCTGAGGACACC GCCGTGTATATCT GCGCCAGGGAGTTTGGCAAGAGGTAC GCCCTGGATTACTGGGGCCAGGGCACACTGGTGACAGTG AGCTCC Hu1210 VH.5b GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCA 93 ACCTGGAGGCTCCCTGAGGCTGTCCTGTGCCGCTTCCGG κ / ραηη / ίζηζ / Ε / γίΛΐ 59 CTTCACCTTCAGCTCCTACGATATGAGCTGGGTGAGGCAG GCTCCTGGAAAGGGCCTGGAGTGGGTGGCCACCATCTCC GACGGAGGCGGCTACATCTACTACTCCGACTCCGTGAAG GGCAGGTTCACCATCTCCCGGGACAACGCCAAGAACAAC CTGTACCTGCAGATGAACTCTCTCAGGGCTGAG GACACC GCCGTGTATATCTGCGCCAGGGAGTTTGGCAAGAGGTAC GCCCTGGATTACTGGGGCCAGGGCACACTGGTGACAGTG AGCTCC Hu1210 VH.5c GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCA ACCTGGAGGCTCCCTGAGGCTGTCCTGTGCCGCTTCCGG CTTCACCTTCAGCTCCTACGATATGAGCTGGGTGAGGCAG ACCCCTGAGAAGAGCCTGGAGTGGGTGGCCACCATTCCC GACGGAGGCGGCTACATCTACTACTCCGACTCCGTGAAG 94 GGCAGGTTCACCATCTCCCGGGACAACGCCAAGAACAAC CTGTACCTGCAGATGAACTCTCTCAGGGCTGAGGACACC GCC GTGTATATCTGCGCCAGGGAGTTTGGCAAGAGGTAC GCCCTGGATTACTGGGGCCAGGGCACACTGGTGACAGTG AGCTCC Hu1210 VH.5d GAGGTGCAGCTGGTGGAGTCCGGAGGAGCCTGGTGCA ACCTGGAGGCTCCCTGAGGCTGTCCTGTGCCGCTTCCGG CTTCACCTTC AGCTCCTACGATATGAGCTGGGTGAGGCAG GCTCCTGGAAAGGGCCTGGAGTGGGTGGCCACCATCTCC GACGGAGGCGGCTACATCTACTACTCCGACTCCGTGAAG 95 GGCAGGTTCACCATCTCCCGGGACAACGCCAAGAACTCC CTGTACCTGCAGATGAACTCTCTCAGGGCTGAGGACACC GCCGTG TATATCTGCGCCAGGGAGTTTGGCAAGAGGTAC GCCCTGGATTACTGGGGCCAGGGCACAACCGTGACAGTG AGCTCC HL1210 VK GACATCGTGATGACCCAGAGCCACAAGTTCATGAGCACCA GCGTGGGCGATAGGGTGAGCATCAGCTGCAAGGCCAGCC AGGATGTGACCCCTGCCGTGG CCTGGTACCAGCAGAAGC CCGGCCAGAGCCCCAAGCTGCTGATCTACAGCACCAGCA 96 GCAGGTACACCGGCGTGCCCGACAGGTTCACAGGAAGCGGCAGCGGCACCGACTTCACCTTCACCATCAGCAGCGTGC AGGCCGAGGACCTGGCCGTGTACTACTGCCAGCAGCACT κ / ραηη / ίζηζ / Ε / γίΛΐ 60 ACACCACCCCTCTGACCTTCGGCGCCGGCACCAAGCTGG AGCTGAAG Hu1210 VK.1 GACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCT AGCGTGGGCGACAGGGTGACCATCACCTGCAAGGCCAGC CAGGATGTGACCCCTGCCGTGGCCTGGTACCAGCAGAAG CCCGGCAAGGCCCC CAAGCTGCTGATCTACAGCACCAGC AGCAGGTACACCGGCGTGCCCAGCAGGTTTAGCGGAAGC 97 GGCAGCGGCACCGACTTCACCTTCACCATCAGCAGCCTG CAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGCAC TACACCACCCCTCTGACCTTCGGCCAGGGCACCAAGCTG GAGATCAAG Hu1210 VK. 1a GACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCT AGCGTGGGCGACAGGGTGACCATCACCTGCAAGGCCAGC CAGGATGTGACCCCTGCCGTGGCCTGGTACCAGCAGAAG CCCGGCAAGTCCCCCAAGCTGCTGATCTACAGCACCAGC AGCAGGTACACCGGCGTGCCCAGCAGGTTTAGCGGAAG C 98 GGCAGCGGCACCGACTTCACCTTCACCATCAGCAGCCTG CAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGCAC TACACCACCCCTCTGACCTTCGGCCAGGGCACCAAGCTG GAGATCAAG Hu1210 VK.2 GACATTCAGATGACCCAGTCCCCTAGCAGCCTGTCCGCTT CCGTGGGCGACAGGGTGACCAT CACCTGCAAGGCCAGCC AGGACGTGACACCTGCTGTGGCCTGGTATCAACAGAAGC CTGGCAAGGCTCCTAAGCTCCTGATCTACAGCACATCCTC CCGGTACACCGGAGTGCCCTCCAGGTTTAGCGGCAGCGG 99 CTCCGGCACCGATTTCACCCTGACCATTTCCTCCTGCAG CCCGAGGACTTCGCCACCTACTACT GCCAGCAGCACTACA CCACACCCCTGACCTTCGGCCAGGGCACCAAGCTGGAGA TCAAGCGG Hu1210 VK.2a GACATTCAGATGACCCAGTCCCCTAGCAGCCTGTCCGCTT CCGTGGGCGACAGGGTGACCATCACCTGCAAGGCCAGCC AGGACGTGACACCTGCTGTGGCCTGGTATCAACAGAAGC 100 CTGGCAAGGCTCCTAAGCTCCTGATCTACAGCACATCCTC CCGGTACACCGGAGTGCCCGACAGGTTTACCGGCAGCGG CTCCGGCACCGATTTCACCCTGACCATTTCTC CCTGCAG κ / ραηη / ίζηζ / Ε / γίΛΐ CCCGAGGACTTCGCCACCTACTACTGCCAGCAGCACTACA CCACACCCCTGACCTTCGGCCAGGGCACCAAGCTGGAGA TCAAGCGG Hu1210 VK.2b GACATTCAGATGACCCAGTCCCCTAGCAGCCTGTCCGCTT CCGTGGGCGACAGGGTGACCATCACCTGCAAGGCCAGCC AGGACGTGACACCTGCTGTGGCCTGGTATCAACAGAAGC CTGGCCAGAGCCCTAAGCTCCTGATCTACAGCACATCCTC CCGGTACACCGGAGTGCCCGAC AGGTTTACCGGCAGCGG 101 CTCCGGCACCGATTTCACCCTGACCATTTCCTCCCTGCAG CCCGAGGACTTCGCCACCTACTACTGCCAGCAGCACTACA CCACACCCCTGACCTTCGGCCAGGGCACCAAGCTGGAGA TCAAGCGG Hu1210 VK.2c GACATTCAGATGACCCAGTCCCCTAGCAGCCTGTCCGCTT CCGTGGGCGACAGGGTGACCATCAGCTGCAAGGCCAGCC AGGACGTGACACCTGCTGTGGCCTGGTATCAACAGAAGC CTGGCCAGAGCCCTAAGCTCCTGATCTACAGCACATCCTC CCGGTACACCGGAGTGCCCGAC AGGTTTACCGGCAGCGG 102 CTCCGGCACCGATTTCACCCTGACCATTTCCTCCTGCAG CCCGAGGACTTCGCCACCTACTACTGCCAGCAGCACTACA CCACACCCCTGACCTTCGGCCAGGGCACCAAGCTGGAGA TCAAGCGG The humanized VH and VK genes were produced synthetically and then respectively cloned into vectors containing the human gamma 1 and human kappa constant domains. Pairing of human VH and human VK created all 40 humanized antibodies (see Table 7). R / cann / Lznz / E / YiAi Table 7 Humanized antibodies with their VH and VL regions VH VK HU1210 VH.1 HU1210 VH.1a Hu1210 VH.1b Hu1210 VH.2 Hu1210 VH.2a Hu1210 VH 2.b Hu1210 VH Hu1210 VK.1 Hu1210-1 Hu1210-2 Hu1210-3 Hu1210-4 Hu1210-5 Hu1210 V k .1a Hu1210-7 Hu1210-8 Hu1210-9 Hu1210-10 Hu1210-11 Hu1210 VK Chimera H1210 VH VK Hu1210 VH.3 Hu1210 VH.3a Hu1210 VH.4 Hu1210 VH.4a Hu1210 VH.4b Hu1210 VK.1 Hu1210-13 Hu1210-14 Hu1210-15 Hu1210-16 Hu1210-17 Hu1210 VK.1a Hu1210-18 Hu12 10- 19 Hu1210-20 Hu1210-21 Hu1210-22 R / cann / Lznz / E / YiAi VH VK Hu1210 VH.5 HU1210 VH.5a HU1210 VH.5b HU1210 VH.5C HU1210 VH.5d Hu1210 VK.2 Hu1210-23 Hu1210-27 Hu1210-31 Hu1210-32 Hu1210-36 Hu1210 VK.2a Hu1210- 24 Hu1210- 28 Hu1210-33 Hu1210-37 Hu1210 VK.2b Hu1210-25 Hu1210-29 Hu1210-34 Hu1210-38 Hu1210 VK.2c Hu1210-26 Hu1210-30 Hu1210-35 Hu1210-39 VH VK Hu1210 VH.4c Hu1210 VH.4d Hu1210 VH.4e Hu1210 VK.1 Hu1210-40 Hu1210-41 Hu1210-42 1.3. Identification of the PD-L1 epitope This study was conducted to identify the amino acid residues involved in the binding of PD-L1 to the antibodies of the present disclosure. A PD-L1 alanine scanning library was constructed. Briefly, 217 PD-L1 mutant clones were generated on Integral Molecular's protein engineering platform. Hu1210-41 Fab binding to each variant in the PD-L1 mutation library was determined, in duplicate, by high-throughput flow cytometry. Each raw data point had background fluorescence subtracted and normalized to reactivity with wild-type (WT) PD-L1. For each PD-L1 variant, the mean binding value is plotted as a function of expression. To identify preliminary critical clones (circles with enlargements), thresholds (dotted lines) of >70% WT binding to control MAb (MIH1 Mab, lab-prepared) and <30%WT reactivity to Hu1210-41 Fab were applied. (FIGURE 3). PD-L1 Y134, K162 and N183 were identified as required from the residues for Hu1210-41 binding. The low reactivity of clone N183A with Hu1210-41 Fab suggests that it is the major energetic contributor for Hu1210-41 binding, with minor contributions by Y134 and K162. Critical residues (spheres) were identified in a 3D PD-L1 structure, as illustrated in FIGURE 4. These residues, Y134, K162, and N183, therefore constitute epitopes of PD-L1 responsible for binding to the antibodies of various embodiments of the present disclosure. It is interesting to note that Y134, K162 and N183 are located within the IgG domain of the PD-L1 protein. The extracellular portions of both PD-1 and PD-L1 have an IgV domain and an IgC domain. It is commonly known that PD-L1 binds PD-1 through the junctions between its IgV domains. Unlike these conventional antibodies, however, Hu1210-41 binds to the IgC domain, which would have been expected to be ineffective in inhibiting PD-1 / PD-L1 binding. This different epitope from Hu1210-41 surprisingly contributes in the same way to the excellent activities of Hu1210-41. 1.4. Antibody Engineering of the Anti-PD-L1 Antibody Examples 1.4 attempted to identify additional improved antibodies based on Hu1210-41 using mutagenesis. Four sub-libraries for antibody modification of the anti-PD-L1 monoclonal antibody were constructed using any of the following strategies. In strategy 1, mutagenesis of the VH CDR3 or VL-CDR3 heavy chain variable domain was carried out by highly random mutation. In strategy 2, two CDR pooling libraries composed of (VH-CDR3, VL-CDR3, and VL-CDR1) or (VH-CDR1, VH-CDR2, and VL-CDR2) were generated by CDR walking with controlled mutation rates. Bio-immunoplating: Phage immunoplating methods were adapted by shortening the incubation / binding time before the stringent wash condition. Briefly, 100 pL of magnetic streptavidin beads (Invitrogen, USA) were blocked with 1 mL of MPBS for 1 hr at room temperature. In another tube, phage from the library (5 x 10Λ11~12 for each round) were pre-incubated with 100 pL of magnetic streptavidin beads in 1 mL of MPBS to remove unwanted binders. Biotinylated PD-L1 protein was added to the phage and incubated 2h at room temperature, and mixed gently using an overhead shaker. The phage-bearing pellets in the solution were separated on the magnetic particle concentrator and the supernatant was discarded. The pellets were washed with fresh wash buffer, ten times with PBST, and ten times with PBS (pH7.4). 0.8mL, 0.25% Trypsin in PBS (Sigma, USA) was added and incubated for 20 min at 37°C to elute phage. The output phage were titered and rescued for the next round panning, decreasing the antigen concentration round by round. ELISA sorting and on / off frequency sorting Clones were selected and induced for the desired immunoplating yield; phage ELISA was conducted for primary sorting; positive clones are R / cann / Lznz / E / YiAi analyzed by sequencing; unique access points were found. Table 8 shows the identified mutations. As shown below, the hotspot mutation residues and / or their surrogates are underlined. Table 8 Mutations in the CDRs R / cann / Lznz / E / YiAi CDR-H1 (SEQ ID No.) CDR-H2(SEQ ID No.) CDR-H3(SEQIDNo.) WT (H12) SYDMS(107) TISDAGGYIYYSDSVKG (117) EFGKRYALDY(127) B3 SYDMS(108) TISDAGGYIYYRDSVKG (118) EFGKRYALDY(128) C4 SYDMS(109) TISDAGGYIYYRDSVKG (119) EFGKRYALDS(129) B1 SYDMS(110) TISDAGGYIYYRDSVKG (120) EIFNRYALDY(130) B6 SYDMS(111) TISDAGGYIYYRDSVKG (121) ELPWRYALDY(131) C3 SYDMS(112) TISDAGGYIYYRDSVKG ( 122) ELHFRYALDY(132) C6 SYDMS(113) TISDAGGYIYYRDSVKG (123) ELYFRYALDY(133) A1 SYDMS(114) TISDAGGYIYYRDSVKG (124) ELLHRYALDY(134) A2 SYDMS(115) TISDAGGYIYYRDSVK G (125) ELRGRYALDY(135) A3 SYDMS(116) TISDAGGYIYYRDSVKG (126) EFGKRYALDY(136) CDR-L1 (SEQIDNo.) CDR-L2 (SEQ ID No.) CDR-L3(SEQIDNo.) WT KASQDVTPAVA(137) STSSRYT(147) QQHYTTPLT(157) B3 KAKQDVTPAVA(138) S TSSRYT (148) MQHYTTPLT(158) C4 KASQDVWPAVA(139) STSSRYT(149) QQHSTTPLT(159) B1 KASQDVTPAVA(140) STSSRYT(150) QQHYTTPLT(160) B6 KASQDVTPAVA(141) STSSRYT(151) QQHYTTPLT (161) C3 KASQDVTPAVA(142 ) STSSRYT(152) QQHYTTPLT(162) C6 KASQDVTPAVA(143) STSSRYT(153) QQHYTTPLT(163) A1 KASQDVTPAVA(144) STSSRYT(154) QQHYTTPLT(164) A2 KASQDVTPAVA(145) STSSRYT(155) ) QQHYTTPLT(165) A3 KASQDVTPAVA (146) STSSRYT(156) QQHSDAPLT(166) The amino acid sequences of the variable regions of these antibodies are shown in Table 9 below. Table 9 Antibody sequences Sequence Name SEQ ID NO: WT-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAP 167 GKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQMN SLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS WT-VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPGK 168 APKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATY YCQQHYTTPLTFGQGTKLEIK B3-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAP 169 GKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQMN SLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS B3-VK DIQMTQSPSSLSASVGDRVTITCKAKQDVTPAVAWYQQKPGK 170 APKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATY YCMQHYTTPLTFGQGTKLEIK C4-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAP 171 GKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQMN SLRDEDTAVYICAREFGKRYALDSWGQGTTVTVSS C4-VK DIQMTQSPSSLSASVGDRVTITCKASQDVWPAVAWYQQKPGK APKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATY 172 YCQQHSTTPLTFGQGTKLEIK B1 -VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 173 MNSLRDEDTAVYICAREIFNRYALDYWGQGTTVTVSS B1 -VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 174 TYYCQQHYTTPLTFGQGTKLEIK B6-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 175 MNSLRDEDTAVYICARELPWRYALDYWGQGTTVTVSS B6-VK ​​DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 176 TYYCQQHYTTPLTFGQGTKLEIK C3-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 177 MNSLRDEDTAVYICARELHFRYALDYWGQGTTVTVSS C3-VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 178 TYYCQQHYTTPLTFGQGTKLEIK C6-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA 179 R / cann / Lznz / E / YiAi PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ MNSLRDEDTAVYICARELYFRYALDYWGQGTTVTVSS C6-VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 180 TYYCQQHYTTPLTFGQGTKLEIK A1 -VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 181 MNSLRDEDTAVYICARELLHRYALDYWGQGTTVTVSS A1 -VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 182 TYYCQQHYTTPLTFGQGTKLEIK A2-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 183 MNSLRDEDTAVYICARELRGRYALDYWGQGTTVTVSS A2-VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 184 TYYCQQHYTTPLTFGQGTKLEIK A3-VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQA PGKSLEWVATISDAGGYIYYRDSVKGRFTISRDNAKNSLYLQ 185 MNSLRDEDTAVYICAREFGKRYALDYWGQGTTVTVSS A3-VK DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPG KAPKLLIYSTSSRYTGVPSRFSGSGSGTDFTFTISSLQPEDIA 186 TYYCQQHSDAPLTFGQGTKLEIK R / cann / Lznz / E / YiAi Table 10 Heavy chain variable regions for clones H12 and B6 Antibody VH SEQ ID NO: H12 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKSLEWVATISDAG GYIYYSDSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYICAREFGKRYALDYWGQ GTTVTVSS 103 B6 EVQLVESGGGLVQPGGSLRLS CAASGFTFSSYDMSWVRQAPGKSLEWVATISDAG GYIYYRDSVKGRFT1SRDNAKNSLYLQMNSLRDEDTAVYICARELPWRYALDYWGQ GTTVTVSS 104 Table 11 Light chain variable regions for clones H12 and B6 VL SEQ ID No. antibody NO: H12 DIQMTQSPSSLSASVGDRVTITCKASQDVTPAVAWYQQKPGKAPKLLr / STSSRYTG VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYTTPLTFGQGTKLEIK 105 B6 DIQMTQSPSSLSASVGDRVTrTCKASQDVTPAVAWYQQKPGKAPKLL lYSTSSRYTG VPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYTTPLTFGQGTKLEIK 106 R / cann / Lznz / E / YiAi 1.5. Protein kinetics for PD-L1 To explore the binding kinetics for the humanized antibody, this example performed affinity sorting using Biacore. As shown in the following Table 12, H12 and B6. Table 12 Antibody KD (M) kon(1 / Ms) kdis(1 / s) Chi H12 6.122E-09 7.124E+04 4.361 E-04 0.0415 B6 4.248E-09 9.827E+04 4.175E-04 0.0766 As shown in Table 12, the tested anti-PD-L1 antibodies show high binding affinities to PD-L1. Example 2. Preparation of anti-4-1BB monoclonal antibodies 2.1. Sorting Whole Human Monoclonal Antibodies Against 4-1 BB Phage Library Immunoplatter Immunoplotting Against 4-1 BB For panning of the library against the target molecules, four rounds of panning were carried out in total using 4-1 BB coated immunotubes. Bacterial colonies from the 3 rounds of immunoplating yield were grown in SB-Carbenicillin in a 96-well deep plate until turbid, at which point 1011 pfu of VCSM13 helper phage was added to each well. After 1 h of infection at 37°C with gentle shaking (80 rpm), 70 pg / mL kanamycin was added and cells were grown overnight at 30°C with 200 rpm shaking. The next day, the plates were centrifuged and the supernatants containing the phage added to 3% BSA blocked 4-1 BB antigen-coated ELISA plates in PBST. After 1 h of incubation at room temperature, the plates were washed three times with PBST and the anti-M13 antibody was added. Plates were incubated for 1 h, washed three times with PBST, and binding activity was measured using tetramethylbenzidine (TMB). The 4-1 BB specific binders were amplified for plasmid DNA sequencing. Ig light chain (VL) V genes and VH sequences were analyzed to identify unique sequences and determine sequence diversity. Table 13 Heavy Chain Variable Regions Antibody VH SEQID NO: 41B01 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSWISYSGGS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGQRNSMREFDYWGQGT LVTVSS 187 41B01.01 EVQ LLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEVWSWISYSGGS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAQRNSMREFDYWGQGT LVTVSS 188 41B01.02 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSW VRQAPGKGLEWVSWISYSGGS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAQRQSMREFDYWGQGT LVTVSS 189 41B01.03 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSWISYSGGS IYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAQRNSMREFDYWGQGT LVTVSS 190 41B01.04 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSWISYSGGS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARDAQRQSMREFDYWGQGT LVTVSS 191 41B02 EVQLLESGGGLVQPGGSLRLSCAASGFTFSGYDMSWVRQAPGKGLEWVSVIYPDDGN TYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDAAVYYCAKHGGQKPTTKSSSAYGMD GWGQGTLVTVSS 192 Table 14 Heavy Chain CDRs Antibody No. CDRH1 SEQID NO: CDRH2 SEQID NO: CDRH3 SEQID NO: 41B01 SYDMS 10 WISYSGGSIYYADSVKG 12 DGQRNSMREFDY 14 41B01.01 SYDMS 10 WISYSGGSIYYADSVKG 12 DAQRNSMREFDY 16 41B 01.02 SYDMS 10 WISYSGGSIYYADSVKG 12 DAQRQSMREFDY 17 41B01.03 SYDMS 10 WISYSGGSIYYADSVKG 12 DAQRNSMREFDY 16 41B01.04 SYDMS 10 WISYSGGSIYYADSVKG 12 DAQRQSMREFDY 17 41B02 GYDMS 11 VIYPDDGNTYYADSVKG 13 HGGQKPTTKSSSAYGMD G 15 Table 15 Light chain variable regions No. of VL SEQID R / cann / Lznz / E / YiAi antibody NO: 41B01 QSVLTQPPSASGTPGRRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGGGTKLTVL 193 41B01.01 QSVLTQPPSASGTPGRRVTISCSGSSSNIGNNYVT WYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGGGTKLTVL 194 41B01.02 QSVLTQPPSASGTPGRRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSEDE ADYYCATWDYSLSGYVFGGGTKLTVL 195 41B01.03 QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLUYADSHR PSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGGGTKLTVL 196 41B01.04 QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGGGTKLTVL 197 41B02 QSVLTQPPSASGTPGRRVTISCSGSSSNIGNNYVTWYQQLPGTAPKLLIYA DSHR PSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDYSLSGYVFGGGTKLTVL 198 R / cann / Lznz / E / YiAi Table 16 light chain CDRs Antibody No. 41B01 CDRL1 SGSSSNIGNNYVT SEQ ID NO: 18 CDRL2 ADSHRPS SEQ ID NO: 19 CDRL3 ATWDYSLSGYV SEQ ID NO: 20 41B01.01 SGSSSNIGNNYVT 18 ADSHRPS 19 ATWDYSLSGYV 20 41B01.02 SGSSSNIGNNYVT 1 8 ADSHRPS 19 ATWDYSLSGYV 20 41B01.03 SGSSSNIGNNYVT 18 ADSHRPS 19 ATWDYSLSGYV 20 41B01.04 SGSSSNIGNNYVT 18 ADSHRPS 19 ATWDYSLSGYV 20 41B02 SGSSSNIGNNYVT 18 ADSHRPS 19 ATWDYSLSGYV 20 2.2. Antigen-Binding Capabilities of Anti-4-1 BB to Human 4-1 BB Antibodies (1) Antigen binding measured by ELISA To assess antigen-binding activity, antibody candidates were subjected to ELISA. Briefly, microtiter plates were coated with human 4-1BB-Fc protein at 0.1pg / mL in PBS, 100 pL / well at 4°C overnight, then blocked with 100 pL / well 5% BSA. . Five-fold dilutions of the humanized antibodies {41B01 and 41B02} starting at 10 pg / mL were added to each well and incubated for 1-2 hours at RT. Plates were washed with PBS / Tween and then incubated with Horseradish Peroxidase (HRP)-conjugated goat anti-human IgG antibody for 1 hour at RT. After washing, plates were developed with TMB substrate and analyzed by spectrophotometer at OD 450-630nm. As shown in FIGURE 5, the tested anti-4-1 BB antibodies show binding capabilities to 4-1 BB. (2) Cell binding measured by FACS To assess antigen-binding property, antibody candidates were analyzed for their binding to mammalian expressed 4-1 BB by FACS. Briefly, 41BB-Jurkat cells were incubated with the antibodies (41B01 and 41B02). After washing by FACS buffer (1% BSA in PBS), FITC anti-human IgG antibody was added to each well and incubated at 4°C for 1 hour. FITC MFI was assessed using a FACS Calibrator. As shown in FIGURE 6, the anti-4-1BB antibodies tested show binding abilities to 4-1 BB that was expressed on the cell surface and can efficiently bind 4-1 BB expressed in mammalian cells. (3) Protein kinetics for 4-1 BB To explore the binding kinetics of the humanized antibody, affinity sorting was performed in this example using Octet Red 96. As shown in Table 17 below, 41B01 and 41B02. Table 17 R / cann / Lznz / E / YiAi Antibody KD (M) kon(1 / Ms) kdis(1 / s) Chi R2 41B01 1.80E-10 6.58E+05 1.19E-04 0.0392 0.9987 41B02 1.01E-09 5.95E+05 6.03E-04 0.0525 0.9973 As shown in Table 17, the tested anti-4-1BB antibodies show high binding affinities to 4-1BB. Example 3. Preparation of anti-PD-L1 / anti-4-1BB bispecific antibodies Clones Hu1210-41 (Hu1210 VH.4dxHu1210 VK.1, see Table 6; hereafter "H12") and B6 (see Table 12) among the anti-PD-L1 clones prepared in Example 1 and clones 41B01 , 41B01.01, 41B01.02, 41B01.03, 41B01.04, and 41B02 among the anti-4-1BB clones prepared in Example 2 were exemplarily selected, to prepare the anti-PD-L1 / anti-4 bispecific antibodies. -1BB in a full length IgG X scFv form. When PD-L1 was placed in the complete IgG part, lgG1 with the ADCC reduced mutant backbone (N297A mutation; US Patent No. 7332581, 8219149, etc.) was used, and when 4-1 BB was placed in the IgG part complete, lgG4 was used. A DNA segment 1 having a nucleotide sequence encoding a heavy chain of an anti-PD-L1 / anti-4-1 BB bispecific antibody IgG antibody was inserted into pcDNA 3.4 (Invitrogen, A14697; plasmid 1), and a DNA segment 2 having a nucleotide sequence encoding a light chain of an anti-PD-L1 / anti-4-1BB bispecific antibody IgG antibody was inserted into pcDNA 3.4 (Invitrogen, A14697; plasmid 2). Therefore, a DNA segment 3 encoding a scFv was fused into a part of DNA segment 1 that corresponds to the G-terminus of the Fe region of the IgG antibody inserted into plasmid 1, using a DNA segment 4 that encodes a linker peptide having 10 amino acid lengths consisting of (GGGGS)2, to construct vectors for the expression of the bispecific antibodies. In addition, in order to stabilize scFv, additional modification was applied to generate the disulfide bridge that fuses VL103-VH44 to the C-terminus of the light chain and C-terminus of the heavy chain, respectively. The sequences of the heavy chain, light chain, scFv segments, and DNA are summarized in Table 18: Table 18 Bispecific antibody comprising the anti-PD-L1 clone in the IgG form and the anti-4-1 BB clone in the scFv form (PD-L1 x4-1 BB) ABLPNB.01 (bispecific antibody comprising the anti-PD-L1 H12 clone in IgG form and the anti-4-1 BB 41B01 clone in scFv form) Sequence of Nucleotide Sequence (5’^3’) (Seq ID No.) Amino Acids (N’^C’) (Seq ID No.) Heavy chain compo- EVQLVESGGGLVQPG GAGGTGCAGCTGGTGGAGAGCGGAGGAGG nente H12 GSLRLSCAASGFTFSS ACTGGTGCAACCCGGAGGCAGCCTGAGAC Heavy YDMSWVRQAPGKSLE TGAGCTGCGCTGCCAGCGGCTTCACCTTCA WVAT1SDAGGYIYYSD GCAGCTACGACATGAGCTGGGTGAGACAG SVKGRFTISRDNAKNSGCCCCTGGCAAAAGCCTGGAGTGGGTGGC LYLQMNSLRDEDTAVYCACCATCTCCGATGCGGGCGGCTACATCTA ICAREFG KRYALDYW TTACTCCGACAGCGTGAAGGGCAGG TTCAC GQGTTVTVSSASTKG CATCAGCAGGGACAACGCCAAGAACAGCCT PSVFPLAPSSKSSGG GTACCTGCAGATGAACAGCCTGAGGGATGA TAALGCLVKDYFPEPV GGACACCGCCGTGTACATCTGCGCCAGGG TVSWNSGALTSGVHT AGTTCGGCAAAAGGTACGCCCTGGACTACT FPAVLQ SSGLYSLSSV GGGGCCAGGGCACAACCGTGACCGTGAGC VTVPSSSLGTQTYICN AGCgctAgcAccAAgGGCCCCTCTGTGTTCCCT VNHKPSNTKVDKKVEPCTGGCCCCTTCCTTAAAATCCACCTCTGGC KSCDKTHTCPPCPAPEGGAACCGCTGCTCTGGGCTGTCTGGTCAAG LLGGPSVFLFPPKPKD GACTACTTCCCTGAGCCCGTGACCGTGTCT TLMISRTPEVTCVVVD TGGAATTCTGGCGCTCTGACCAGCGGAGTG VSHEDPEVKFNWYVD CACACCTTTCCAGCTGTGCTGCAGTCCTCC GVEVHNAKTKPREEQ GGCCTGTACTCTCTGTCCTCTGTCGTGACA YASTYRVVSVLTVLHQ GTGCCTTCCAGCTCTCTGGGCACCCAGACC DWLNG KEYKCKVSNK TACATCTGCAACGTGAACCACAAGCCCTCC R / cann / Lznz / E / YiAi 72 ALPAPIEKTISKAKGQP AACACCAAGGTGGACAAGAAGGTGGAACCC REPQVYTLPPSREEMTAAGTCCTGCGACAAGACCCACACCTGTCCT KNQVSLTCLVKGFYPSCCATGTCCTGCTCCAGAACTGCTGGGCGGA DIAVEWESNGQPENN CCCTCCGTGTTCCTGTTCCCTCCAAAGCCTA YKTT PPVLDSDGSFFL AGGACACCCTGATGATCTCCCGGACCCCTG YSKLTVDKSRWQQGN AAGTGACCTGCGTGGTGGTGGATGTGTCCC VFSCSVMHEALHNHY ACGAGGATCCCGAAGTGAAGTTCAATTGGT TQKSLSLSPGK ACGTGGACGGCGTGGAAGTGCACAACGCC (199) AAG AC CAAGCCTAGAG AGG AACAGTACgccT Ligator GGGGSGGGGSGGGGCCACCTACCGGGTGGTGTCCGTGCTGACC S (200) GTTCTGCACCAGGATTGGCTGAACGGCAAA VL scFv GAGTACAAGTGCAAGGTGTCCAACAAGGCC 41B01 QSVLTQPPSASGTPG CTGCCT GCCCCTATCGAAAAGACCATCTCTA RRVTISCSGSSSNIGN AGGCCAAGGGCCAGCCCCGGGAACCTCAA NYVTWYQQLPGTAPK GTGTACACCTTGCCTCCCAGCCGGGAAGAG LLIYADSHRPSGVPDR ATGACCAAGAACCAGGTGTCCCTGACCTGC FSGSKSGTSASLAISG CTGGl lAAGGG Cl ICTACCCCTCCGATATO LRSEDEADYYCATWD GGCGTGGAATGGGAGTCTAACGGCCAGCG YSLSG YVFGCGTKLTV CG AGAACAACT ACAAGACCACCCCTCCTGT L (201) GCTGGACTCCGACGGCTCATTCTTCCTGTA Ligator GGGGSGGGGSGGGG CTCCAAGCTGACCGTGGACAAGTCTCGGTG SGGGGS (202) GCAGCAGGGCAACGTGTTCTCCTGCTCTGT VH EVQLLESGGGLVQPG GAT GCACGAGGCCCTGCACAACCACTACAC GSLRLSCAASGFTFSS CCAGAAGTCCCTGTCCCTGTCTCCCGGCAA YDMSWVRQAPGKCLEAGGTGGGGGGGGATCTGGTGGTGGTGGAT wvswisysggsiyyadCagggggtggggggtctcaaagcgtactc SVKGRFTISRDNSKNT A CCCAACCTCCATCTGCATCCGGTACACCT LYLQM NSLRAEDTAVY GGT CGGCG AGT AACCAT CT CCTGCTCTGGG ycardgqrnsmrefdagctcttctaatattggtaacaactatgtca YWGQGTLVTVSS CCTGGTATCAGCAGTTGCCTGGGACAGCAC (203) CCAAACTTCTTATATATG CCGATAGCCATCGGCCTTCCGGCGTACCCGATCGCTTCTCCGG GTCAAAATCTGGAACATCTGCCTCACTCGCA ATTAGTGGATTGCGATCTGAGGATGAAGCA GATTATTATTGCGCTACCTGGGATTCAC TTTCTGGCTACGTCTTTGGTtgtggaACAAAAC A / cann / Lznz / E / YiAi TTACCGTGTTGGGCGGCGGAGGAAGCGGA GGCGGCGGTTCTGGTGGTGGCGGTAGCGG AGGTGGTGGATCTGAAGTACAGCTTCTTGA GTCTGGCGGAGGATTGGTCCAGCCAGGCG GTTCCCTCCGCCTGTCATGTGCCGCATCCG GCTTTACTTTCTCTAGTTATGATATGAGCTG GGTTCGCCAAGC TCCTGGCAAAtgcCTGGAG TGGGTCTCCTGGATTTCATACTCAGGTGGC AGCATCTATTATGCTGACAGTGTGAAAGGTC GCTTTACAATCTCCCGAGATAACAGCAAAAA CACCTTGTACCTGCAAATGAACAGCCTTCG CGCAGAGGACACAGCCGTATATTATTGCGC TCGCGATGGACAACGTAATTCTATGCGTGA GTTTGACTACTGGGGACAGGGGACATTGGT CACTGTATCTTCCtga (204) Compo- DIQMTQSPSSLSASVG G ACATCCAGATGACCCAG AGCCCTAGCAGC light chain nente H12 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light chain VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREA GCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV (28) TGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGTGACCAAGTCCTT R / cann / Lznz / E / YiAi CAACAGAGGCGAGTGCTGA (205) ABLPNB.02 (bispecific antibody comprising anti-PD-L1 H12 clone in IgG form and anti-4-1 BB clone 41B01.03 in scFv form) Sequence of Nucleotide Sequence (5’^3’) (Seq ID No.) Amino Acids (N’^C’) (Seq ID No.) Heavy chain compo- EVQLVESGGGLVQPG GAGGTGCAGCTGGTGGAGAGCGGAGGAGG nente H12 GSLRLSCAASGFTFSS ACTGGTGCAACCCGGAGGCAGCCTGAGAC Heavy YDMSWVRQAPGKSLE TGAGCTGCGCTGCCAGCGGCTTCACCTTCA WVATISDAGGYIYYSD GCAGCTACGACATGAGCTGGGTGAGACAG SVKGRFTISRDNAKNSGCCCCTGGCAAAAGCCTGGAGTGGGTGGC LYLQMNSLRDEDTAVYCACCATCTCCGATGCGGGCGGCTACATCTA ICAREFG KRYALDYW TTACTCCGACAGCGTGAAGGGCAGGTT CAC GQGTTVTVSSASTKG CATCAGCAGGGACAACGCCAAGAACAGCCT PSVFPLAPSSKSSGG GTACCTGCAGATGAACAGCCTGAGGGATGA TAALGCLVKDYFPEPV GGACACCGCCGTGTACATCTGCGCCAGGG TVSWNSGALTSGVHT AGTTCGGCAAAAGGTACGCCCTGGACTACT FPAVLQSS GLYSLSSV GGGGCCAGGGCACAACCGTGACCGTGAGC VTVPSSSLGTQTYICN AGCgctAgcAccAAgGGCCCCTCTGTGTTCCCT VNHKPSNTKVDKKVEPCTGGCCCCTTCCTTAAAATCCACCTCTGGC KSCDKTHTCPPCPAPEGGAACCGCTGCTCTGGGCTGTCTGGTCAAG LL GGPSVFLFPPKPKD GACTACTTCCCTGAGCCCGTGACCGTGTCT TLMISRTPEVTCVVVD TGGAATTCTGGCGCTCTGACCAGCGGAGTG VSHEDPEVKFNWYVD CACACCTTTCCAGCTGTGCTGCAGTCCTCC GVEVHNAKTKPREEQ GGCCTGTACTCTCTGTCCTCTGTCGTGACA YASTYRV VSVLTVLHQ GTGCCTTCCAGCTCTCTGGGCACCCAGACC DWLNGKEYKCKVSNKTACATCTGCAACGTGAACCACAAGCCCTCC ALPAPIEKTISKAKGQP AACACCAAGGTGGACAAGAAGGTGGAACCC REPQVYTLPPSREEMTAAGTCCTGCGACAAGACCCACACCTGTCCT KNQVSLTCLVKGF YPS CCATGTCCTGCTCCAGAACTGCTGGGCGGA DIAVEWESNGQPENN CCCTCCGTGTTCCTGTTCCCTCCAAAGCCTA YKTTPPVLDSDGSFFL AGGACACCCTGATGATCTCCCGGACCCCTG YSKLTVDKSRWQQGN AAGTGACCTGCGTGGTGGTGGATGTGTCCC VFSCSVMHEALHNHY ACGAG GATCCAGAAGTGAAGTTCAATTGGT R / cann / Lznz / E / YiAi 75 TQKSLSLSPGK (206) ACGTGGACGGCGTGGAAGTGCACAATGCC Ligator GGGGSGGGGSGGGGAAGACCAAGCCTAGAGAGGAACAGTACGCC S (207) TCCACCTACAGAGTGGTGTCCGTGCTGACT scFv de VL QSVLTQPPSASGTPG GTGCTGCACCAGGATTGGCTGAAC GGCAAA 41B01.03 QRVTISCSGSSSNIGN GAGTACAAGTGCAAGGTGTCCAACAAGGCC NYVTWYQQLPGTAPK CTGCCTGCTCCTATCGAAAAGACCATCAGC LLIYADSHRPSGVPDR AAGGCCAAGGGCCAGCCTAGGGAACCCCA FSGSKSGTSASLAISG GGTTTACACCCTGCCTCCA AGCCGGGAAGA LRSEDEADYYCATWD GATGACCAAGAACCAGGTGTCCCTGACCTG YSLSGYVFGCGTKLTVCCTCGTGAAGGGCTTCTACCCTTCCGATAT L (208) CGCCGTGGAATGGGAGAGCAATGGCCAGG Ligator GGGGSGGGGSGGGGCTGAGAACAACTACAAGACAACCCCTCCTG S GGGGS (209) TGCTGGACTCCGACGGCTCATTCTTCCTGT VH EVQLLESGGGLVQPG ACTCCAAGCTGACCGTGGACAAGTCCAGAT gslrlscaasgftfssggcagcagggcaacgtgttctcctgctccg YDMSWVRQAPGKCLE TG ATGCACG AGGCCCTGGACAATCACTACA WVSWISYSGGSIYYADCCCAGAAGTCCCTGTCTCTGAGCCCTGGAA SVKG RFTISRDNSKNT AAGGCGGCGGAGGATCTGGCGGAGGTGGT LYLQMNSLRAEDTAVY AGCGGAGGCGGTGGATCTCAGTCTGTTCTG YCARDAQRNSMREFD ACCCAGCCTCCTTCCGCTTCTGGCACCCCT YWGQGTL VTVSS GGAcAGAGAGTGACCATTCTCTTGCTCCGGC (210) TCCTCCTCCAACATCGGCAACAACTACGTG ACCTGGTATCAGCAGCTGCCCGGCACAGCT CCCAAACTGCTGATCTACGCCGACTCTCAC AGACCTTCCGGCGTGCCCGATAGATTCTCC GGCTCTAAGTCTGGCACCTCTGCCAGCCTG GCTATCAGCGGCCTGAGATCTGAGGACGAG GCCGACTACTACTGCGCCACCTGGGATTAT TCCCTGTCCGGCTACGTGTTCGGCTGCGGC ACAAAACTGACAGTGCTCGGAGGCGGAGG AAGTGGTGGCGGAGGTTCAGGTGGTGGTG GTAGTGGCGGAGGCGGATCAGAAGTTCAG CTGTTGGAGTCAGGTGGCGGCTTGGTGCAA CCAGGTGGAAGTCTGAGACTCAGCTGTGCT GCCAGCGGCTTTACCTTCAGCTCCTACGAC ATGAGCTGGGTTCGACAAGCTCCCGGAAAG R / cann / Lznz / E / YiAi TGCTTGGAGTGGGTTTCCTGGATCTCCTACT CCGGCGGCAGCATCTATTACGCCGACAGC GTGAAAGGCCGGTTTACCATCTCTCGGGAT AACAGCAAGAATACCCTCTACCTCCAAATGA ACTCTCTGAGAGCCGAGGACACTGCTGTGT ACTATTGCGCCAGAGATGccCAGCGGAACTC CATGAGAGAGTTCGACTACTGGGGA CAAGG CACCCTGGTCACCGTGTCTAGTTGA (211) Compo- DIQMTQSPSSLSASVG light chain GACATCCAGATGACCCAGAGCCCTAGCAGC nente H12 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGA C. YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV CGTGGCCGCTCCCTCCGTGTTCATCTTCCC YACEVTHQGLSSPVTKACCATCTGACGAGCAGCTGAAGTCCGGCAC SFNRGEC (30) CGCTTCTGTCGTGTGCCTGCTGAACAACTT CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CCAAGAGTCTGTGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTCTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGT GACCAAGTCCTT CAACAGAGGCGAGTGCTGA (212) ABLPNB.03 (bispecific antibody comprising anti-PD-L1 H12 clone in IgG form and anti-4-1 BB 41B02 clone in scFv form Sequence of Nucleotide Sequence (5’—>3’) (Seq ID No.) Amino Acids (N’^C’) (Seq ID No.) A / cann / Lznz / E / YiAi Heavy chain compo- EVQLVESGGGLVQPG GAGGTGCAGCTGGTGGAGAGCGGAGGAGG nente H12 GSLRLSCAASGFTFSS ACTGGTGCAACCCGGAGGCAGCCTGAGAC Heavy YDMSWVRQAPGKSLE TGAGCTGCGCTGCCAGCGGCTTCACCTTCA WVATISDAGGYIYYSD GCAGCTACGACATGAGCTGGGTGAGACAG SVKGRFTISRDNAKNS GCCCCTGGCAAAAGCCTGGAGTGGGTGGC LYLQMNSLRDEDTAVYCACCATCTCCGATGCGGGCGGCTACATCTA ICAREFG KRYALDYW TTACTCCGACAGCGTGAAGGGCAGGTT CAC GQGTTVTVSSASTKG CATCAGCAGGGACAACGCCAAGAACAGCCT PSVFPLAPSSKSSGG GTACCTGCAGATGAACAGCCTGAGGGATGA TAALGCLVKDYFPEPV GGACACCGCCGTGTACATCTGCGCCAGGG TVSWNSGALTSGVHT AGTTCGGCAAAAGGTACGCCCTGGACTACT FPAVLQSS GLYSLSSV GGGGCCAGGGCACAACCGTGACCGTGAGC VTVPSSSLGTQTYICN AGCgctAgcAccAAgGGCCCCTCTGTGTTCCCT VNHKPSNTKVDKKVEPCTGGCCCCTTCCTTAAAATCCACCTCTGGC KSCDKTHTCPPCPAPEGGAACCGCTGCTCTGGGCTGTCTGGTCAAG LL GGPSVFLFPPKPKD G ACTACTTCCCTGAGCCCGTGACCGTGTCT TLMISRTPEVTCVVVD TGGAATTCTGGCGCTCTGACCAGCGGAGTG VSHEDPEVKFNWYVD CACACCTTTCCAGCTGTGCTGCAGTCCTCC GVEVHNAKTKPREEQ GGCCTGTACTCTCTGTCCTCTGTCGTGACA YASTY RVVSVLTVLHQ GTGCCTTCCAGCTCTCTGGGCACCCAGACC DWLNGKEYKCKVSNK TACATCTGCAACGTGAACCACAAGCCCTCC ALPAPIEKTISKAKGQP AACACCAAGGTGGACAAGAAGGTGGAACCC REPQVYTLPPSREEMTAAGTCCTGCGACAAGACCCACACCTGTCCT KNQVSLTCLVKG FYPS CCATGTCCTGCTCCAGAACTGCTGGGCGGA DIAVEWESNGQPENN CCCTCCGTGTTCCTGTTCCCTCCAAAGCCTA YKTTPPVLDSDGSFFL AGGACACCCTGATGATCTCCCGGACCCCTG YSKLTVDKSRWQQGNAAGTGACCTGCGTGGTGGTGGATGTGTCCC VFSCSVMHEALHNHY ACGA GGATCCCGAAGTGAAGTTCAATTGGT TQKSLSLSPGK (213 ) ACGTGGACGGCGTGGAAGTGCACAACGCC Ligator GGGGSGGGGSGGGG AAG ACCAAGCCTAGAG AGGAACAGTACgccT S (214) CCACCTACCGGGTGGTGTCCGTGCTGACC scFvde VL QSVLTQPPSASGTPG GTTCTGCACCAGGATTGGCTGAACGGCAAA 41B02 RRVTISCSGSSSNIGN GAGTACAAGTGCAAGGTGTCCAACAAGGCC NYVTWYQQLPGTAPK CTGCCTGCCCCTATCGAAAAGACCATCTCTA LLIYADSHRPSGVPDR AGGCCAAGGGCCAGCCCCGGGAACCTCAA FSGSKSGTSASLAISG GTGTACACCTTGCCTCCCAGCCGGGAAGAG R / cann / Lznz / E / YiAi LRSEDEADYYCATWD ATGACCAAGAACCAGGTGTCCCTGACCTGC YSLSGYVFGCGTKLTVCTGGTTAAGGGCTTCTACCCTCTCCGATATC L (215) GCCGTGGAATGGGAGTCTAACGGCCAGCC Ligator GGGGSGGGGSGGGG CG AG AACAACTACAAG ACCACCCCTCCTGT SGGGGS (216) GCTGGACTCCGACGGCTCATTCTTCCTGTA VH EVQLLESGGGLVQPG CTCCAAGCTGACCGTGGACAAGTCTCGGTG GSLRLSCAASGFTFSGGCAGCAGGGCAACGTGTTCTCCTGCTCTGT YDMSWVRQAPGKCLE G ATGCACGAGGCCCTGCACAACCACT ACAC WVSVIYPDDGNTYYA CCAGAAGTCCCTGTCCCTGTCTCCCGG CAA DSVKGRFTISRDNSKN AGGTGGGGGGGGATCTGGTGGTGGTGGAT TLYLQMNSLRAEDAAVCAGGGGGGTGGGGGGTCTCAAAGCGTACTG YYCAKHGGQKPTTKS ACCCAACCTCCATCTGCATCCGGTACACCT SSAYGMDGWGQGTL GGTCGGCGAGTAAC CATCTCCTGCTCTGGG VTVSS (217) AGCTCTTCTAATATTGGTAACAACTATGTCA CCTGGTATCAGCAGTTGCCTGGGACAGCAC CCAAACTTCTTATATATGCCGATAGCCATCG GCCTTCCGGCGTACCCGATCGCTTTCTCCGG GTCAAAATCTGGAACATCTGCCTCACTCGCA ATTAGTGGATTGCGATCTGAGGATGAAGCA GATTATTATTGCGCTACCTGGGATTTCAC TTTCTGGCTACGTCTTTGGTtgt GGAACAAAA CTTACCGTGTTGGGCGGCGGAGGAAGCGG AGGCGGCGGTTCTGGTGGTGGCGGTAGCG GAGGTGGTGGATCTGAGGTTCAACTGTTGG AGTCAGGTGGCGGACTTGTCCAGCCTGGC GGGTCTCTGAGGCTGAGTTGCGCTGCTTCT GGGTTTACTTTTTCAGGATATGAC ATGAGTT GGGTACGTCAGGCTCCAGGTAAGtgcCTCGA ATGGGTCTCCGTTATCTATCCCGATGATGGA AATACTTACTACGCTGACAGTGTGAAAGGCA GGTTCACAATCAGTAGGGACAATTCTAAAAA TACACTCTACCTCCAGATGAACTCACTTCGA GCCGAGGACGCCGCCGTATATTACTGTGCC AAACACGGCGGGCAAA AACCCACTACTAAA TCCAGTAGTGCTTACGGGATGGATGGCTGG GGACAGGGGACATTGGTCACTGTATCTTCCt R / cann / Lznz / E / YiAi ga (218) Compo- Light chain DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC nente H12 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV (32) TGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGTGACCAAGTCCTT CAACAGAGGCGAGTGCTGA (219) R / cann / Lznz / E / YiAi ABLPNB.04 (bispecific antibody comprising the anti-PD-L1 B6 clone in IgG form and the anti-4-1 BB 41B01 clone in scFv form) Nucleotide Sequence (5’—>3’) (Seq ID No.) Amino Acid Sequence (N’->C’) (Seq ID No.) Compo- heavy chain of EVQLVESGGGLVQPG GAAGTGCAGCTGGTTGAATCTGGCGGCGG nente B6 GSLRLSCAASGFTFSS ATTGGTTCAGCCTGGCGGATCTCTGAGACT heavy YDMSWVRQAPGKSLE GTCTTGTGCCGCCTCCGGCTTCACCTTCTC WVAT1SDAGGYIYYRD CAGCTACGATATGTCCTGGGTCCGACAGGC SVKGRFTISRDNAKNS CCCTGGCAAGTCTTTGGAATGGGTCGCCAC LYLQMNSLRDEDTAVYCATCTCTGACGCTGGCGGCTACATCTACTA ICARELPWRYALDYW CCGGGACTCTGTGAAGGGCAGATTCACCAT GQGTTVTVSSASTKG CAGCCGGGACAACGCCAAGAACTCCCTGTA PSVFPLAPSSKSTSGG CCTGCAGATGAACAGCCTGCGCGACGAGG TAALGCLVKDYFPEPV ATACCGCCGTGTACATCTGTGCTAGAGAGC TVSWNS GALTSGVHT TGCCTTGGAGATACGCCCTGGATTATTGGG FPAVLQSSGLYSLSSV GCCAGGGCACCACAGTGACCGTGTCCTCTG VTVPSSSLGTQTYICN CTTCTACCAAGGGACCCAGCGTGTTCCCTC VNHKPSNTKVDKKVEPTGGCTCCTTCCAGCAAGTCTACCTCTGGCG KSCDKTHTCPPCP APEGAACAGCTGCTCTGGGCTGCCTGGTCAAGG LLGGPSVFLFPPKPKD ACTACTTTCCTGAGCCTGTGACAGTGTCCTG TLMISRTPEVTCVVVD GAACTCTGGCGCTCTGACATCTGGCGTGCA R / cann / Lznz / E / YiAi VSHEDPEVKFNWYVD CACCTTTTCCAGCAGTGCTGCAGTCCTCCGG GVEVHNAKTKPREEQ CCTGTACTCTCTGTCCTCTGTCGTGACCGT YASTYRVVSVLTVLHQ GCCTTCCAGCTCTCTGGGAACCCAGACCTA VL scFv ligator DWLNGKEYKCKVSNK CATCTGCAATGTGAAC CACAAGCCTTCCAAC ALPAPIEKTISKAKGQP ACGAAGGTGGACAAGAAGGTGGAACCCAAG REPQVYTLPPSREEMTTCGTGCGACAAGACGGACACCTGTCCTCCA KNQVSLTCLVKGFYPSTGTCCTGCTCCAGAACTGCTCGGCGGACCT DIAVEWESNGQPENN TCCGTGTTCCTGTTTCCTCCAAAGCC TAAGG YKTTPPVLDSDGSFFL ACACCCTGATGATCTCTCGGACCCCTGAAG YSKLTVDKSRWQQGN TGACCTGCGTGGTGGTGGATGTGTCCCACG VFSCSVMHEALHNHY AGGATCCAGAAGTGAAGTTCAATTGGTACG TQKSLSLSPGK (220) TGGACGGCGTGGAAGTGCACAATGCC AAGA GGGGSGGGGSGGGGCCAAGCCTAGAGAGGAACAGTACGCCTCCA S (221) CCTACAGAGTGGTGTCCGTGCTGACTGTGC QSVLTQPPSASGTPG TGCACCAGGATTGGCTGAACGGCAAAGAGT 41B01 VH ligator RRVTISCSGSSSNIGN ACAAGTGCAAGGTGTCCAACAAGGCC CTGC NYVTWYQQLPGTAPK CTGCTCCTATCGAAAAGACCATCAGCAAGG LLIYADSHRPSGVPDR CCAAGGGCCAGCCTAGGGAACCCCAGGTTT FSGSKSGTSASLAISG ACACCCTGCCTCCAAGCCGGGAAGATGA LRSEDEADYYCATWD CCAAGAACCAGGTGTCCCTGACCTGCCTCG YSLSG YVFGCGTKLTV TG AAGGGCTT CT ACCCTT CCG ATAT CGCCG L (222) TGGAATGGGAGAGCAATGGCCAGCCTGAG GGGGSGGGGSGGGGAACAACTACAAGACAACCCTCCCTGTGCTG SGGGGS (223) GACTCCGACGGCTCATTCTTCCTGTACTCCA EVQLLESG GGLVQPG AGCTGACCGTGGACAAGTCCAGATGGCAGC GSLRLSCAASGFTFSS AGGGCAACGTGTTCTCCTGCTCCGTGATGC YDMSWVRQAPGKCLEACGAGGCCCTGCACAATCACTACACCCAGA WVSWISYSGGSIYYADAGTCCCTGTCTCTGAGCCCTGGAAAAGGCG SVKGRFTISRDNSKNT GCGGAGGATCTGGCGGAGGTGGTAGCGGA LYLQMNSLRAEDTAVYGGCGGTGGATCTCAGTCTGTTCTGACCCAG YCAR DGQRNSMREFDCCTCCTTCCGCTTCTGGCACCCCTGGAAGA YWGQGTLVTVSS AGAGTGACCATTCCTTGCTCCGGCTCCTCC (224) TCCAACATCGGCAACAACTACGTGACCTGG TATCAGCAGCTGCCCGGCACAGCTCCCAAA CTGCTGATCTACGCCGACTCTCACAGACCT TGCGGCGTGCCCGATAGATTCTCCGGCTCT AAGTCTGGCACCTCTGCCAGCCTGGCTATC AGCGGCCTGAGATCTGAGGACGAGGCCGA CTACTACTGCGCCACCTGGGGATTATTCCCT GTCCGGCTACGTGTTCGGCTG CGGCACAAA ACTGACAGTGCTCGGAGGCGGAGGAAGTG GTGGCGGAGGTTCAGGTGGTGGTGGTAGT GGCGGAGGCGGATCAGAAGTTCAGCTGTT GGAGTCAGGTGGCGGCTTGGTGCAACCAG GTGGAAGTCTGAGACTCAGCTGTGCTGCCA GCGGCTTTACCTTCAGCTCCTACGACATGA GCT GGGTTCGACAAGCTCCCGGAAAGTGCT TGGAGTGGGTTTCCTGGATCTCCTACTCCG GCGGCAGCATCTATTACGCCGACAGCGTGA AAGGCCGGTTTACCATCTCTCGGGATAACA GCAAGAATACCCTCTACCTCCAAATGAACTC TCTGAGAGCCGAGGACACTGCTGTGTACTA TTGCGCCAGAGATGGCCAGCGGAACTCC AT GAGAGAGTTCGACTACTGGGGACAAGGCAC CCTGGTCACCGTGTCTAGTTGA (225) Compo- Light chain of DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC nenie B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC R / cann / Lznz / E / YiAi TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDS KDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV CGTGGCCGCTCCCTCCGTGTTCATCTTCCC YACEVTHQGLSSPVTKACCATCTGACGAGCAGCTGAAGTCCGGCAC SFNRGEC (34) CGCTTCTGTCGTGTGCCTGCTGAACAACTT CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CGAAGAGTCTGTGACGGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTCTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGT GACCAAGTCCTT CAACAGAGGCGAGTGCTGA (226) ABLPNB.05 (bispecific antibody comprising the anti-PD-L1 B6 clone in IgG form and the anti-4-1 BB clone 41B01.01 in scFv form) Sequence of Nucleotide Sequence (5’^3’) (Seq ID No.) Amino Acids (N’^C’) (Seq ID No.) Compo- heavy chain of EVQLVESGGGLVQPG GAAGTGCAGCTGGTTGAATCTGGCGGCGG nente B6 GSLRLSCAASGFTFSS ATTGGTTCAGCCTGGCGGATCTCTGAGACT heavy YDMSWVRQAPGKSLE GTCTTGTGCCGCCTCCGGCTTCACCTTCTC WVATISDAGGYIYYRD CAGCTACGATATGTCCTGGGTCCGACAGGC SVKGRFTISRDNAKNS CCCTGGCAAGTCTTTGGAATGGGTCGCCAC LYLQMNSLRDEDTAVYCATCTCTGACGCTGGCGGCTACATCTACTA ICARELPWRYALDYW CCGGGACTCTGTGAAGGGCAGATTCACCAT GQGT TVTVSSASTKG CAGCCGGGACAACGCCAAGAACTCCCTGTA PSVFPLAPSSKSSGG CCTGCAGATGAACAGCCTGCGCGACGAGG TAALGCLVKDYFPEPV ATACCGCCGTGTACATCTGTGCTAGAGC TVSWNSGALTSGVHT TGCCTTGGAGATACGCCCTGGATTATTGGG FPAVLQSSGLY SLSSV GCCAGGGCACCACAGTGACCGTGTCCTCTG VTVPSSSLGTQTYICN CTTCTACCAAGGGACCCAGCGTGTTCCCTC VNHKPSNTKVDKKVEPTGGCTCCTTCCAGCAAGTCTACCTCTGGCG R / cann / Lznz / E / YiAi 83 KSCDKTHTCPPCPAPEGAACAGCTGCTCTGGGCTGCCTGGTCAAGG LLGGPSVFLFPPKPKD ACTACTTTCCTGAGCCTGTGACAGTGTCCTG TLMISRTPEVTCVVVD GAACTCTGGCGCTCTGACATCTGGCGTGCA VSHEDPEVKFNWYVD CACCTTTTCCAGCAGTGCTGCAG TCCTCCGG GVEVHNAKTKPREEQ CCTGTACTCTCTGTCCTCTGTCGTGACCGT YASTYRVVSVLTVLHQ GCCTTCCAGCTCTCTGGGAACCCAGACCTA DWLNGKEYKCKVSNK CATCTGCAATGTGAACCACAAGCCTTCCAAC ALPAPIEKTISKAKGQP ACCAAGGTGGACAAGAAGGTGGAACC CAAG REPQVYTLPPSREEMTTCCTGCGACAAGACCCACCTGTCCTCCA KNQVSLTCLVKGFYPSTGTCCTGCTCCAGAACTGCTCGGCGGACCT DIAVEWESNGQPENN TGCGTGTTCCTGTTTGGTCCAAAGCCTAAGG YKTTPPVLDSDGSFFL ACACCCTGATGATCTCTCGGACCCCTGAAG YSKLTVD KSRWQQGN TGACCTGCGTGGTGGTGGATGTGTCCCACG VFSCSVMHEALHNHY AGGATCCAGAAGTGAAGTTCAATTGGTACG TQKSLSLSPGK (227) TGGACGGCGTGGAAGTGCACAATGCCAAGA Ligator GGGGSGGGGSGGGGCCAAGCCTAGAGAGGAACAGTACGCCTCCA S (22 8) CCTACAGAGTGGTGTCCGTGCTGACTGTGC scFv of VL QSVLTQPPSASGTPG TGCACCAGGATTGGCTGAACGGCAAAGAGT 41B01.01 RRVTISCSGSSSNIGN ACAAGTGCAAGGTGTCCAACAAGGCCCTGC NYVTWYQQLPGTAPK CTGCTCCTATCGAAAAGAC CATCAGCAAGG LLIYADSHRPSGVPDR CCAAGGGCCAGCCTAGGGAACCCCAGGTTT FSGSKSGTSASLAISG ACACCCTGCCTCCAAGCCGGGAAGAGATGA LRSEDEADYYCATWD CCAAGAACCAGGTGTCCCTGACCTGCCTCG YSLSGYVFGCGTKLTVTGAAGGGCTTCTACCCTTCCGATATCGCCG L (229 ) TGGAATGGGAGAGCAATGGCCAGCCTGAG Ligator GGGGSGGGGSGGGGAACAACTACAAGACAACCCTCCCTGTGCTG SGGGGS (230) GACTCCGACGGCTCATTCTTCCTGTACTCCA VH EVQLLESGGGLVQPG AGCTGACCGTGGACAAGTCCAGATGGCAGC GSLRLSCAASGFTFSS AGGGCAACGTGTTCTCCTGCTCCGTGATGC YDMSWVRQAPGKCLE ACG AGGCCCTGCACAATCACTACACCCAG A WVSWISYSGGSIYYAD AGTCCCT GT CTCTG AGCCCT GGAAAAGGCG SVKGRFTISRDNSKNT GCGGAGGATCTGGCGGAGGTGGTAGCGGA lylqm ns lraedt avy ggcggt gg at ct cagt ctgtt ct g acccag YCARDAQRNSMREFD CCTCCTTCCGCTTCTGGCACCCCTGGAAGA YWGQGTLVTVSS AGAGTGACCATTCCTTGCTCCGGCTCCTCC (231) TCCAACATCGGCAACAACTACGTGACCTGG κ / ραηη / ίζηζ / Ε / γίΛΐ TATCAGCAGCTGCCCGGCACAGCTCCCAAA CTGCTGATCTACGCCGACTCTCACAGACCT TCCGGCGTGCCCGATAGATTCTCCGGCTCT AAGTCTGGCACCTCTGCCAGCCTGGCTATC AGCGGCCTGAGATCTGAGGACGAGGCCGA CTACTGCGCCACCTGGGATTATTCCCT GTCCGGCTACGTGTTCGGCTGCGGCACAAA ACTGACAGTGCTCGGAGGCG T GGAGTGGGTTTCCTGGATCTCCTACTCCG GGGGCAGCATCTATTACGGCGACAGCGTGA AAGGCCGGTTTACCATCTCTCGGGATAACA GCAAGAATACCCTCTACCTCCAAATGAACTC TCTGAGAGCCGAGGACACTGCTGTGTACTA TTGCGCCAGAGATGccCAGCGGAACTCCAT GAGAGATTCGACTACTGGGGACAAGGCA C CCTGGTCACCGTGTCTAGTTGA (232) Compo- DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC light chain nente B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREA GCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV CGTGGCCGCTCCCTCCGTGTTCATCTTCCC YACEVTHQGLSSPVTKACCATCTGACGAGCAGCTGAAGTCCGGCAC SFNRGEC (36) CGCTTCTGTCGTGTGCCTGCTGAACAACTT R / cann / Lznz / E / YiAi CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CCAAGAGTCTGTGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTCTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGT GACCAAGTCCTT CAACAGAGGCGAGTGCTGA (233) ABLPNB.06 (bispecific antibody comprising anti-PD-L1 B6 clone in IgG form and anti-4-1 BB clone 41B01.02 in scFv form) Sequence of Nucleotide Sequence (5’^3’) (Seq ID No.) Amino Acids (N’->C’) (Seq ID No.) Heavy chain compo- EVQLVESGGGLVQPG GTGCAGCTGGTTGAATCTGGCGGCGGATTG nente B6 GSLRLSCAASGFTFSS GTTCAGCCTGGCGGATCTCTGAGACTGTCT Heavy YDMSWVRQAPGKSLE TGTGCCGCCTCCGGCTTCACCTTCTCCAGC WVATISDAGGYIYYRD TACGATATGTCCTGGGTCCGACAGGCCCCT SVKGRFTISRDNAKNS GGCAAGTCTTTGGAATGGGTCGCCACCATC LYLQMNSLRDEDTAVYTCTGACGCTGGCGGCTACATCTACTACCGG ICARELPWRYALDYW GACTCTGTGAAGGGCAGATTCACCATCAGC GQGT TVTVSSASTKG CGGGACAACGCCAAGAACTCCCTGTACCTG PSVFPLAPSSKSSGG CAGATGAACAGCCTGCGCGACGAGGATACC TAALGCLVKDYFPEPV GCCGTGTACATCTGTGCTAGAGAGCTGCCT TVSWNSGALTSGVHT TGGAGATACGCCCTGGATTATTGGGGCCAG FPAVLQSSGLY SLSSV GGCACCACAGTGACCGTGTCCTCTGCTTCT VTVPSSSLGTQTYICN ACCAAGGGACCCAGCGTGTTCCCTCTGGCT VNHKPSNTKVDKKVEPCCTTCCAGCAAGTCTACCTCTGGCGGAACA KSCDKTHTCPPCPAPEGCTGCTCTGGGCTGCCTGGTCAAGGACTAC LLGGPSVFLFPPKPKD TTTCCTGAGCCTGTGACAGTGTCCTGGAAC TLMISRTPEVTCVVVD TCTGGCGCTCTGACATCTGGCGTGCACACC VSHEDPEVKFNWYVD TTTCCAGCAGTGCTGCAGTCCTCCGGCCTG GVEVHNAKTKPREEQ TACTCTCTGTCCTCTGTCGTGACCGTGCCTT YASTYRVVSVLTVLH Q CCAGCTCTCTGGGAACCCAGACCTACATCT DWLNGKEYKCKVSNK GCAATGTGAACCACAAGCCTTCCAACACCA ALPAPIEKTISKAKGQP AGGTGGACAAGAAGGTGGAACCCAAGTCCT A / cann / Lznz / E / YiAi 86 REPQVYTLPPSREEMTGCGACAAGACCCACACCTGTCCTCCATGTC KNQVSLTCLVKGFYPS CTGCTCCAGAACTGCTCGGCGGACCTTCCG DIAVEWESNGQPENN TGTTCCTGTTTCCTCCAAAGCCTAAGGACAC YKTTPPVLDSDGSFFL CCTGATGATCTCTCGGACCCCTGAAGTGAC YSKLTVD KSRWQQGN CTGCGTGGTGGTGGATGTGTCCCACGAGG VFSCSVMHEALHNHY ATCCAGAAGTGAAGTTCAATTGGTACGTGG TQKSLSLSPGK (234) ACGGCGTGGAAGTGCACAATGCCAAGACCA Ligator GGGGSGGGGSGGGGAGCCTAGAGAGGAACAGTACGCCTCCACCT S (2 35) ACAGAGTGGTGTCCGTGCTGACTGTGCTGC scFv de VL QSVLTQPPSASGTPG ACCAGGATTGGCTGAACGGCAAAGAGTACA 41B01.02 RRVTISCSGSSSNIGN AGTGCAAGGTGTCCAACAAGGCCCTGCCTG NYVTWYQQLPGTAPK CCTCCTATCGAAAAGACCA TCAGCAAGGCCA LLIYADSHRPSGVPDR AGGGCCAGCCTAGGGAACCCCAGGTTTACA FSGSKSGTSASLAISG CCCTGCCTCCAAGCCGGGAAGAGATGACCA LRSEDEADYYCATWD AGAACCAGGTGTCCCTGACCTGCCTCGTGA YSLSGYVFGCGTKLTVAGGGCTTCTACCCTTCCGATATCGCCG TGG L (236) AATGGGAGAGCAATGGCCAGCCTGAGAACA Linker ggggsggggsggggactacaagacaacccctcctgtgctggact SGGGGS (237) CCGACGGCTCATTCTTCCTGTACTCCAAGCT VH EVQLLESGGGLVQPG GACCGTGGACAAGTCCAGATGGCAGCAGG gslrlscaasgftfssgcaacgtgttctcctgctccgtgatgcacg YDMSWVRQAPGKCLEAGGCCCTGCACAATCACTACACCCCAGAAG T WVSWISYSGGSIYYADCCCTGTCTCTGAGCCCTGGAAAAGGCGGC SVKGRFTISRDNSKNT GGAGGATCTGGCGGAGGTGGTAGCGGAGG LYLQMNSLRAEDTAVYCGGTGGATCTCAGTCTGTTCTGACCCAGCC ycardaqrqsmrefdtccttccgcttctggcacccctggaagaa g YWGQGTLVTVSS AGTGACCATTCCTTGCTCCGGCTCCTCCTC (238) CAACATCGGCAACAACTACGTGACCTGGTA TCAGCAGCTGCCCGGCACAGCTCCCAAACT GCTGATCTACGCCGACTCTCACAGACCTTC CGGCGTGCCCGATAGATTCTCCGGCTCTAA GTCTGGCACCTCTGCCAGCCTGGCTATCAG CGGCCTGAGATCTGAGGACGAGGCCGACT ACTACTGCGCCACCTGGGATTATTCCCTGT CCGGCTACGTGTTCGGCTGCGGCACAAAAC TGACAGTGCTCGGAGGCGGAGGAAGTGGT A / cann / Lznz / E / YiAi light component GGCGGAGGTTCAGGTGGTGGTGGTAGTGG CGGAGGCGGATCAGAAGTTCAGCTGTTGGA GTCAGGTGGCGGCTTGGTGCAACCAGGTG GAAGTCTGAGACTCAGCTGTGCTGCCAGCG GCTTTACCTTCAGCTCCTACGACATGAGCTG GGTTCGACAAGCTCCCGGAAAGTGCTTGGA GTG GGTTTCCTGGATCTCCTACTCCGGCGG CAGCATCTATTACGCCGACAGCGTGAAAGG CCGGTTTACCATCTCTCGGGATAACAGCAA GAATACCCTCTACCTCCAAATGAACTCTCTG AGAGCCGAGGACACTGCTGTGTACTATTGC GCCAGAGATGccCAGCGGCAATCCATGAGA GAGTTCGACTACTGGGGACAAGGCACCCTG GTCA CCGTGTCTAGTTGA (239) DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light chain DIQMTQSPSSLSASVG VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDS TYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV CGTGGCCGCTCCCTCCGTGTTCATCTTCCC YACEVTHQGLSSPVTKACCATCTGACGAGCAGCTGAAGTCCGGCAC SFNRGEC (38) CGCTTCTGTCGTGTGCCTGCTGAACAACTT CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CCAAGAGTCTGTGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTCTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGT GACCAAGTCCTT CAACAGAGGCGAGTGCTGA (240) R / cann / Lznz / E / YiAi ABLPNB.07 (bispecific antibody comprising anti-PD-L1 B6 clone in IgG form and anti-4-1 BB clone 41B01.03 in scFv form) Sequence of Nucleotide Sequence (5’^3’) (Seq ID No.) Amino Acids (N’^C) (Seq ID No.) R / cann / Lznz / E / YiAi Compo- Heavy Chain of EVQLVESGGGLVQPG GAAGTGCAGCTGGTTGAATCTGGCGGCGG nente B6 GSLRLSCAASGFTFSS ATTGGTTCAGCCTGGCGGATCTCTGAGACT heavy YDMSWVRQAPGKSLEGTCTTGTGCCGCCTCCGGCTTCACCTTCTC WVATISDAGGYIYYRD CAGCTACGATATGTCCTGGGTCCGACAGGC SVKGRFTISRDNAKNS CCCTGGCAAGTCTTTGGAATGGGTCGCCAC LYLQMNSLRDEDTAVYCATCTCTGACGCTGGCGGCTACATCTACTA ICARELPWRYALDYW CCGGGACTCTGTGAAGGGCAGATTCACCAT GQGTTVTVSSASTKG CAGCCGGGACAACGCCAAGAACTCCCTGTA PSVFPLAPSSKSTSGG CCTGCAGATGAACAGCCTGCGCGACGAGG TAALGCLVKD YFPEPV ATACCGCCGTGTACATCTGTGCTAGAGAGC TVSWNSGALTSGVHT TGCCTTGGAGATACGCCCTGGATTATTGGG FPAVLQSSGLYSLSSV GCCAGGGCACCACAGTGACCGTGTCCTCTG VTVPSSSLGTQTYICN CTCTACCAAGGGACCCAGCGTGTTCCCTC VNHKPSNTKVDK KVEPTGGCTCCTTCCAGCAAGTCTACCTCTGGCG KSCDKTHTCPPCPAPEGAACAGCTGCTCTGGGCTGCCTGGTCAAGG LLGGPSVFLFPPKPKD ACTACTTTCCTGAGCCTGTGACAGTGTCCTG TLMISRTPEVTCVVVD GAACTCTGGCGCTCTGACATCTGGCGTGCA VSHEDPEVKFNWY VD CACCTTTCCAGCAGTGCTGCAGTCCTCCGG GVEVHNAKTKPREEQ CCTGTACTCTCTGTCCTCTGTCGTGACCGT YASTYRVVSVLTVLHQ GCCTTCCAGCTCTCTGGGAACCCAGACCTA DWLNGKEYKCKVSNK CATCTGCAATGTGAACCACAAGCCTTCCAAC ALPAPIEKTISKAKGQP AC CAAGGTGGACAAGAAGGTGGAACCCAAG REPQVYTLPPSREEMTTCCTGCGACAAGACCCACACCTGTCCTCCA KNQVSLTCLVKGFYPSTGTCCTGCTCCAGAACTGCTCGGCGGACCT DIAVEWESNGQPENN TCCGTGTTCCTGTTTCCTCCAAAGCCTAAGG YKTTPPVLDSDGSFFL ACACCCTGATGATCTC TCGGACCCCTGAAG YSKLTVDKSRWQGNTGACCTGCGTGGTGGTGGATGTGTCCCACG VFSCSVMHEALHNHY AGGATCCAGAAGTGAAGTTCAATTGGTACG TQKSLSLSPGK (241) TGGACGGCGTGGAAGTGCACAATGCCAAGA Linker GGGGSGGGGSGGGGCCAAGCCTAGAGAGGAACAGTACGCCTCCA S (242) CCTACAGAGTGGTGTCCGTGCTGACTGTGC scFvde VL QSVLTQPPSASGTPG TGCACCAGGATTGGCTGAACGGCAAAGAGT 41B01.03 QRVTISCSGSSSNIGN ACAAGTGCAAGGTGTCCAACAAGGCCCTGC NYVTWYQQLPGTAPK CTGCTCCTATCGAAAAGACCATCAGCAAGG LLIYADSHRPSGVPDR CCAAGGGCCAGCCTAGGGAACCCCAGGTTT FSGSKSGTSASLAISG ACACCCTGCCTCCAAGCCGGGAAGAGATGA LRSEDEADYYCATWD CCAAGAACCAGGTGTCCCTGACCTGCCTCG YSLSG YVFGCGTKLTV T G AAGGGCTT CT ACCCTT CCG ATAT CGCCG L (243) TGGAATGGGAGAGCAATGGCCAGCCTGAG Ligator GGGGSGGGGSGGGG AACAACTACAAGACAACCCTCCCTGTGCTG SGGGGS (244) GACTCCGAGGGCTCATTCTTCCTGTACTCGA VH EVQLLESGGGLVQPG AGCTGACCGTGGACAAGTCCAGATGGCAGC GSLRLSCAASGFTFSS AGGGCAACGTGTTCTCCTGCTCCGTGATGC YDMSWVRQAPGKCLEACGAGGCCCTGCACAATCACTACACCCAGA WVSWISYSGGSIYYADAGTCCCTGTCTCTGAGCCCTGGAAA AGGCG SVKGRFTISRDNSKNT GGGGAGGATCTGGCGGAGGTGGTAGCGGA LYLQM NSLRAEDTAVY GGCGGTGG AT CT CAGT CTGTT CT G ACCCAG YCARDAQRNSMREFD CCTCCTTCCGCTTCTGGCACCCCTGGAcAG YWGQGTLVTVSS AG AGTGACCAT CT CTTGCT CCG GCT CCT CC (245) TCCAACATCGGCAACAACTACGTGACCTGG TATCAGCAGCTGCCCGGCACAGCTCCCAAA CTGCTGATCTACGCCGACTCTCACAGACCT TCCGGCGTGCCCGATAGATTCTCCGGCTCT AAGTCTGGCACCTCTGCCAGCCTGGCTATC AGCGGCCTGAGATCTGAGGACGAGGCCGA CTACTACTGCGCCACCTGGGGATTATTCCCT GTCCGGCTACGTGTTCGGCTG CGGCACAAA ACTGACAGTGCTCGGAGGCGGAGGAAGTG GTGGCGGAGGTTCAGGTGGTGGTGGTAGT GGCGGAGGCGGATCAGAAGTTCAGCTGTT GGAGTCAGGTGGCGGCTTGGTGCAACCAG GTGGAAGTCTGAGACTCAGCTGTGCTGCCA GCGGCTTTACCTTCAGCTCCTACGACATGA GCT GGGTTCGACAAGCTCCCGGAAAGTGCT TGGAGTGGGTTTCCTGGATCTCCTACTCCG GCGGCAGCATCTATTACGCCGACAGCGTGA R / cann / Lznz / E / YiAi AAGGCCGGTTTACCATCTCTCGGGATAACA GCAAGAATACCCTCTACCTCCAAATGAACTC TCTGAGAGCCGAGGACACTGCTGTGTACTA TTGCGCCAGAGATGccCAGCGGAACTCCATGAGAGAGTTCGACTACTGGGGACAAGGCAC CCTGGTCACCGTGTCTAGTTGA (246) Compo- DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC light chain nente B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV CGTGGCCGCTCCCTCCGTGTTCATCTTCCC YACEVTHQGLSSPVTKACCATCTGACGAGCAGCTGAAGTCCGGCAC SFNRGEC (40) CGCTTCTGTCGTGTGCCTGCTGAACAACTT CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CCAAGAGTCTG TGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGTGACCAAGTCCTT CAACAGAGGCGAGTGCTGA (247) ABLPNB.08 (bispecific antibody comprising anti-PD-L1 B6 clone in IgG form and anti-4-1 BB clone 41B01.04 in scFv form) Sequence of Nucleotide sequence (5'—>3') (Seq ID No.) amino acids (N'^C') (Seq ID No.) Compo- Heavy Chain of EVQLVESGGGLVQPG GAAGTGCAGCTGGTTGAATCTGGCGGCGG nente B6 GSLRLSCAASGFTFSS ATTGGTTCAGCCTGGCGGATCTCTGAGACT R / cann / Lznz / E / YiAi heavy 91 YDMSWVRQAPGKSLEGTCTTGTGCCGCCTCCGGCTTCACCTTCTC WVAT1SDAGGYIYYRD CAGCTACGATATGTCCTGGGTCCGACAGGC SVKGRFTISRDNAKNS CCCTGGCAAGTCTTTGGAATGGGTCGCCAC LYLQMNSLRDEDTAVYCATCTCTGACGCTGGCGGCTACATCTACTA ICARELPWRYALDYW CCGGGACTCTGTGAAGGGCAGATTCACCAT GQGTTVTVSSASTKG CAGCCGGGACAACGCCAAGAACTCCCTGTA PSVFPLAPSSKSTSGG CCTGCAGATGAACAGCCTGCGCGACGAGG TAALGCLVKDYFPEPV ATACCGCCGTGTACATCTGTGCTAGAGAGC TVSWNSG ALTSGVHT TGCCTTGGAGATACGCCCTGGATTATTGGG FPAVLQSSGLYSLSSV GCCAGGGCACCACAGTGACCGTGTCCTCTG VTVPSSSLGTQTYICN CTTCTACCAAGGGACCCAGCGTGTTCCCTC VNHKPSNTKVDKKVEPTGGCTCCTTCCAGCAAGTCTACCTCTGGCG KSCDKTHTCPPCPA PEGAACAGCTGCTCTGGGCTGCCTGGTCAAGG LLGGPSVFLFPPKPKD ACTACTTTCCTGAGCCTGTGACAGTGTCCTG TLMISRTPEVTCVVVD GAACTCTGGCGCTCTGACATCTGGCGTGCA VSHEDPEVKFNWYVD CACCTTTCCAGCAGTGCTGCAGTCCTCCGG GVEVHNAKTK PREEQ CCTGTACTCTCTGTCCTCTGTCGTGACCGT YASTYRVVSVLTVLHQ GCCTTCCAGCTCTCTGGGAACCCAGACCTA DWLNGKEYKCKVSNK CATCTGCAATGTGAACCACAAGCCTTCCAAC ALPAPIEKTISKAKGQP ACCAAGGTGGACAAGAAGGTGGAACCCAAG REPQVYTLPPSREEMTTC CTGCGACAAGACCCACACCTGTCCTCCA KNQVSLTCLVKGFYPSTGTCCTGCTCCAGAACTGCTCGGCGGACCT DIAVEWESNGQPENN TCCGTGTTCCTGTTTCCTCCAAAGCCTAAGG YKTTPPVLDSDGSFFL ACACCCTGATGATCTCTCGGACCCCTGAAG YSKLTVDKSRWQQGN TGACCTGCGTGG TGGTGGATGTGTCCCACG VFSCSVMHEALHNHY AGGATCCAGAAGTGAAGTTCAATTGGTACG TQKSLSLSPGK ( 248) TGGACGGCGTGGAAGTGCACAATGCCAAGA Ligator GGGGSGGGGSGGGGCCAAGCCTAGAGAGGAACAGTACGCCTCCA S (249) CCTACAGAGTGGTGTCCGTGCTGACTGTGC scFv of VL QSVLTQPPSASGTPG TGCACCAGGATTGGCTGAACGGCAAAGAGT 41 B01.04 QRVTISCSGSSSNIGN ACAAGTGCAAGGTGTCCAACAAGGCCCTGC NYVTWYQQLPGTAPK CTGCTCCTATCGAAAAGACCATCAGCAAGG LLIYADSHRPSGVPDR CCAAGGGCCAGCCTAGGGAACCCCAGGTTT FSGSKSGTSASLAISG ACACCCTGCCTCCAAGCCGGGAAGATGA LRSEDEADYYCATWD CCAAGAACCAGGTGTCCCTGACCTGCCTCG YSLSG YVFGCGTKLTV TG AAGGGCTT CT ACCCTT CCG ATAT CGCCG κ / ραηη / ίζηζ / Ε / γίΛΐ L (250) TGGAATGGGAGAGCAATGGCCAGCCTGAG GGGGSGGGGSGGGGAACAACTACAAGACAACCCTCCCTGTGCTG Ligator SGGGGS (251) GACTCCGACGGCTCATTCTTCCTGTACTCCA VH EVQLLESGGGLVQPG AGCTGACCGTGGACAAGTCCAGATGGCAGC GSLRLSCAASGFTFSS AGGGCAACGTGTTCTCCTGCTCCGTGATGC YDMSWVRQAPGKCLE ACG AGGCCCTGCACAAT CACT ACACCCAG A WVSWISYSGGSIYYADAGTCCCTGTCTCTGAGCCCTG GAAAAGGCG SVKGRFTISRDNSKNT GCGGAGGATCTGGCGGAGGTGGTAGCGGA LYLQM NSLRAEDTAVY GGCGGTGG AT CT CAGT CTGTT CT G ACCCAG YCARDAQRQSMREFDCCTCCTTCCGCTTCTGGCACCCCTGGAcAG YWGQGTLVTVSS AG AGTGACCAT CT CTTGCT CCGGCT CCT CC (252) TCCAACATCGGCAACAACTACGTGACCTGG TATCAGCAGCTGCCCGGCACAGCTCCCAAA CTGCTGATCTACGCCGACTCTCACAGACCT TCCGGCGTGCCCGATAGATTCTCCGGCTCT AAGTCTGGCACCTCTGCCAGCCTGGCTATC AGCGGCCTGAGATCTGAGGACGAGGCCGA CTACTACTGCGCCACCTGGGGATTATTCCCT GTCCGGCTACGTGTTCGGCTG CGGCACAAA ACTGACAGTGCTCGGAGGCGGAGGAAGTG GTGGCGGAGGTTCAGGTGGTGGTGGTAGT GGCGGAGGCGGATCAGAAGTTCAGCTGTT GGAGTCAGGTGGCGGCTTGGTGCAACCAG GTGGAAGTCTGAGACTCAGCTGTGCTGCCA GCGGCTTTACCTTCAGCTCCTACGACATGA GCT GGGTTCGACAAGCTCCCGGAAAGTGCT TGGAGTGGGTTTCCTGGATCTCCTACTCCG GCGGCAGCATCTATTACGCCGACAGCGTGA AAGGCCGGTTTACCATCTCTCGGGATAACA GCAAGAATACCCTCTACCTCCAAATGAACTC TCTGAGAGCCGAGGACACTGCTGTGTACTA TTGCGCCAGAGATGccCAGCGGCAAT CCAT GAGAGAGTTCGACTACTGGGGACAAGGCAC CCTGGTCACCGTGTCTAGTTGA (253) R / cann / Lznz / E / YiAi Compo- DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC light chain nente B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCCGTGGCCTGGTACCAGCAGAAGC SGSGTDFTFTISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCTTCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA KVQWKVDNALQSGNSGCAGCACTACACCACCCCTCTGACCTTCGG QESVTEQDSKDSTYSLCCAGGGCACCAAGCTGGAGATCAAGAGAAC SSTLTLSKADYEKHKV (42) TGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCTGCGAAGTGACCCACCA GGGACTGTCTAGCCCCGTGACCAAGTCCTT CAACAGAGGCGAGTGCTGA (254) ABLPNB.09 (bispecific antibody comprising the anti-PD-L1 B6 clone in IgG form and the anti-4-1 BB 41B02 clone in scFv form) Nucleotide Sequence (5’—>3’) (Seq ID No.) Amino Acid Sequence (Ν’—>C’) (Seq ID No.) Compo- heavy chain of EVQLVESGGGLVQPG GAAGTGCAGCTGGTTGAATCTGGCGGCGG nente B6 GSLRLSCAASGFTFSS ATTGGTTCAGCCTGGCGGATCTCTGAGACT heavy YDMSWVRQAPGKSLE GTCTTGTGCCGCCTCCGGCTTCACCTTCTC WVATISDAGGYIYYRD CAGCTACGATATGTCCTGGGTCCGACAGGC SVKGRFTISRDNAKNS CCCTGGCAAGTCTTTGGAATGGGTCGCCAC LYLQMNSLRDEDTAVYCATCTCTGACGCTGGCGGCTACATCTACTA ICARELPWRYALDYW CCGGGACTCTGTGAAGGGCAGATTCACCAT GQGT TVTVSSASTKG CAGCCGGGACAACGCCAAGAACTCCCTGTA PSVFPLAPSSKSTSGG CCTGCAGATGAACAGCCTGCGCGACGAGG TAALGCLVKDYFPEPV ATACCGCCGTGTACATCTGTGCTAGAGAGC scFv linker of 41B02 TVSWNSGALTSGVHT TGCCTTGGAGATACGCCCTGGATTATTGGG FPAVLQSSGLYSLSSV GCCAGGGCACCACAGTGACCGTGTCCTCTG VTVPSSSLGTQTYICN CTTCTACCAAGGGACCCAGCGTGTTCCCTC VNHKPSNTKVDKKVEPTGGCTCCTTCCAGCAAGTCTACCTCTGGCG KSCDKTHTCPPCPPAPEGAACAGCTGCTCTGGGCTGCCTGGTCAAGG LL Y ASTYRVVSVLTVLHQ GCCTTCCAGCTCTCTGGGCACCCAGACCTA DWLNG KEYKCKVSNK CATCTGCAACGTGAACCACAAGCCCTCCAA ALPAPIEKTISKAKGQP CACCAAGGTGGACAAGAAGGTGGAACCCAA REPQVYTLPPSREEMTGTCCTGCGACAAGACCCACACCTGTCCTCC KNQVSLTCLV KGFYPSATGTCCTGCTCCAGAACTGCTGGGCGGACC DIAVEWESNGQPENN CTCCGTGTTCCTGTTCCCTCCAAAGCCTAAG YKTTPPVLDSDGSFFL GACACCCTGATGATCTCCCGGACCCCTGAA YSKLTVDKSRWQQGNGTGACCTGCGTGGTGGTGGATGTGTCCCAC VFSCSVMHEALHNHY GAGGATCCCGAAGTGAAGTTCAATTGGTAC TQKSLSLSPGK (255) GTGGACGGCGTGGAAGTGCACAACGCCAA GGGGSGGGGSGGGGGACCAAGCCTAGAGAGGAACAGTACgccTCC S (256) ACCTACCGGGTGGTGTCCGTGCTGACCGTT VL QSVLTQPPSASGTPG CTGCACCAGGATTGGCTGAACGGCAAAGAG RRVTISCSGSSSNIGN TACAAGTGCAAGGTGTCCAACAAGGCCCTG NYVTWYQQLPGTAPK CCTGCCCCTATCGAAAAGACCATCTCTAAG LLIYADSHRPSGVPDR GCCAAGGGCCAGCCCCGGGAACCTCAAGT FSGS KSGTSASLAISG GTACACCTTGCCTCCCAGCCGGGAAGAT LRSEDEADYYCATWD GACCAAGAACCAGGTGTCCCTGACCTGCCT YSLSGYVFGCGTKLTVGGTTAAGGGCTTCTACCCTCCCGATATCGC L (257) CGTGGAATGGGAGTCTAACGGCCAGCCCG Ligator GGGGSGGGGSGGGG AGAACAACTACAAGACCACCCCTCCTGTGC SGGGGS (258) TGGACTCCGACGGCTCATTCTTCCTGTACTC VH EVQLLESGGGLVQPG CAAGCTGACCGTGGACAAGTCTCGGTGGCA GSLRLSCAASGFTFSGGCAGGGCAACGTGTTCTCCTGCTCTGTGAT YDMSWVRQAPGKCLE GCACGAGGCCCTGCACAACCACT ACACCCA WVSVIYPDDGNTYYA GAAGTCCCTGTCCCTGTCTCCCGGCAA AGG DSVKGRFTISRDNSKN TGGGGGGGGATCTGGTGGTGGTGGATCAG R / cann / Lznz / E / YiAi TLYLQMNSLRAEDAAVGGGGTGGGGGGTCTCAAAGCGTACTCACC YYCAKHGGQKPTTKS CAACCTCCATCTGCATCCGGTACACCTGGT SSAYGMDGWGQGTL CGGCGAGTAACCATCTCCTGCTCTGGGAGC VTVSS (259) TCTTCTAATATTGGTAACAACTATGTCACCT GGTATCAGCAGTTGCCTGGGACAGCACCCA AACTTCTTATATATGCCGATAGCCATCGGCC TTCCGGCGTACCCGATCGCTTTCTCCGGGTC AAAATCTGGAACATCTGCCTCACTCGCAATT AGTGGATTGCGATCTGAGGATGAAGCAGAT TATTATTGCGCTACCTGGGATTATTCACTTT CTGGCTACGTCTTTGGTtgt GGAACAAAACTT ACCGTGTTGGGCGGCGGAGGAAGCGGAGG CGGCGGTTCTGGTGGTGGCGGTAGCGGAG GTGGTGGATCTGAGGTTCAACTGTTGGAGT R / cann / Lznz / E / YiAi CAGGTGGCGGACTTGTCCAGCCTGGCGGG TCTCTGAGGCTGAGTTGCGCTGCTTCTGGG TTTACTTTTTCAGGATATGACATGAGTTGGG TACGTCAGGCTCCAGGTAAGtgcCTCGAATG GGTCTCCGTTATCTATCCCGATGATGGAAAT ACTTACTACGCTGACAGTGTGAAAGGCAGG TTCACAATCAGTAGGGACAATTCTAAAAAATA CACTCTACCTCCAGATGAACTCACTTCGAGC CGAGGACGCCGCCGTATATTACTGTGCCAA ACACGGCGGGCAAAAACCCACTACTAAATC CAGTAGTGCTTACGGGATGGATGGCTGGG GACAGGGGACATTGGTCACTGTATCTTCCtg a (260) Compo- Light chain DIQMTQSPSSLSASVG GACATCCAGATGACCCAGAGCCCTAGCAGC nente B6 DRVTITCKASQDVTPA CTGAGCGCTAGCGTGGGCGACAGGGTGAC light VAWYQQKPGKAPKLLICATCACCTGCAAGGCCAGCCAGGATGTGAC YSTSSRYTGVPSRFSGCCCTGCC GTGGCCTGGTACCAGCAGAAGC SGSGTDFIF IISSLQP CCGGCAAGGCCCCCAAGCTGCTGATCTACA EDIATYYCQQHYTTPL GCACCAGCAGCAGGTACACCGGCGTGCCC TFGQGTKLEIKRTVAA AGCAGGTTTAGCGGAAGCGGCAGCGGCAC PSVFIFPPSDEQLKSG CGACTTCACCT TCACCATCAGCAGCCTGCA TASVVCLLNNFYPREAGCCCGAGGACATCGCCACCTACTACTGCCA 4 4) CGCTTCTGTCGTGTGCCTGCTGAACAACTT CTACCCTCGGGAAGCCAAGGTGCAGTGGAA GGTGGACAATGCCCTGCAGTCCGGCAACTC CCAAGAGTCTGTGACCGAGCAGGACTCCAA GGACAGCACCTACTCCCTGTCCTTCTACCCT GACCCTGTCCAAGGCCGACTACGAGAAGCA CAAGGTGTACGCCT GGGAAGTGACCCACGAGGGACTGTCTAGCCCCGTGACCAAGTCCTT CAACAGAGGCGAGTGCTGA (261) The constructed vectors were transiently expressed in Exp¡CHO-SMR cells (Thermo Fisher, A29127) using (ExpiFectamineMRCHO Kit, Thermo, A29129), grown in Exp¡CHOMR (Thermo, A29100-01) expression medium under the conditions of 30 to 37°C for 7 to 15 days in a CO2 incubator equipped with a rotary shaker. Plasmid DNA (250 pg) and ExpiFectamin CHO Reagent (800 pL) were mixed with Opti-MEMMRI medium (20 mL final volume) and allowed to stand at room temperature for 5 min. The mixed solution was added to 6 x 106 ExpiCHO cells grown in ExpiCHO Expression Medium and mixed gently in a shaker incubator at 37°C with a humidified atmosphere of 8% CO2 in air. At 18 hours post-transfection, 1.5 mL of ExpiFectamin CHO 1 Transfection Enhancer and 60 mL of ExpiFectamin CHO Transfection Feed were added to each flask. Each BsAb was purified from cell culture supernatant by recombinant protein A affinity chromatography (Hitrap Mabselect Sure, GE Healthcare, 28-4082-55) and gel filtration chromatography with a HiLoad 26 / 200 Superdex200 preparation grade column ( GE Healthcare, 28-9893-36). SDS-PAGE analysis (4-12% Bis-Tris NuPage gel, NP0321) and size exclusion HPLC (Agilent, 1200 series) with SEHPLC column (SWXL SE-HPLC column, TOSOH, G3000SWXL) were carried out. to detect and confirm the size and purity of each BsAb. Purified proteins were concentrated in PBS by ultrafiltration using an Amicon Ultra 15 30K device (Merck, UFC903096), and protein concentrations were estimated using a nanodroplet (Thermo, Nanodrop One). When a two vector system was applied, the ratio of light to heavy chain could be 1:1 to 1:3 by weight. Alternatively, a one-vector system containing R / cann / Lznz / E / YiAi both strings in a single vector can also be used. Anti-PD-L1 / anti-4-1 BB bispecific antibodies prepared with calls like H12x41BO1(ABLPNB.O1), B6x41 B01 (ABLPNB.04), B6x41 B01,O3(ABLPNB.O7), H12x41 B01,O3(ABLPNB.O2), B6x41B01.01(ABLPNB.05), B6x41 B01,O4(ABLPNB.O8), H12x41BO2(ABLPNB.O3) B6x41B01.01 (ABLPNB.06) and B6x41BO2 (ABLPNB.O9) A / cann / Lznz / E / YiAi respectively, where the former refers to the clone in the IgG form and the latter refers to the clone in the scFv form. Example 4. Characterization of bispecific antibodies PD-L1x4-1BB 4.1. Binding of bispecific antibodies To evaluate the PD-L1 and 4-1 BB binding activity of the bispecific antibodies prepared in Example 3, the BsAbs (ABLPNB.O1, ABLPNB.03, ABLPNB.04 and ABLPNB.07), were tested. DACE (double antigen captured ELISA). Briefly, microtiter plates were coated with 100 ng / well of human PD-L1-Fc protein (Sinobio, 10084-H02H) in PBS at 4°C overnight, then blocked with 100 µL / well BSA at 1% for 2 hours at 37°C. Three-fold dilutions of each of the BsAbs starting at 100 nM were added to each well and incubated for 2 hours at 37°C. Plates were washed with PBS / Tween and then incubated with 50 ng / well of human 4-1BB-His protein (Sinobio, 16498-H08H) in 1% BSA for 1 hour at 37°C. The plates were washed with PBS / Tween and then incubated with Anti-His HRP (Roche, Cat: 11965085001) for 1 hour at 37°C. After washing, the plates were developed with the TMB substrate and analyzed by spectrophotometer at OD 450-650nm. The results are shown in FIGS. 7A and 7B. As shown in FIGS. 7A and 7B, all BsAbs tested can bind to both the human PD-L1 and human 4-1 BB proteins with high activities. 4.2 Serum stability of the bispecific antibody To evaluate the stability of PD-L1 and 4-1 BB serum of the BsAb (ABLPNB.05, ABLPNB.06, ABLPNB.07 and ABLPNB.08), the BsAb was incubated in human serum for 3, 7, 14 days at 37°C. Binding activity was analyzed by the DACE test (dual antigen captured ELISA). Briefly, microtiter plates were coated with 100 ng / well of human PD-L1-Fc protein (Sinobio, 10084-H02H) in PBS at 4°C overnight, then blocked with 100 µL / well BSA at 1% for 2 hours at 37°C. Three-fold dilutions of each of the BsAbs starting at 100 nM were added to each well and incubated for 2 hours at 37°C. Plates were washed with PBS / Tween and then incubated with 50 ng / well of human 4-1BB-His protein (Sinobio, 16498-H08H) in 1% BSA for 1 hour at 37°C. The plates were washed with PBS / Tween and then incubated with Anti-His HRP (Roche, Cat: 11965085001) for 1 hour at 37°C. After washing, plates were developed with TMB substrate and analyzed by spectrophotometer at OD 450-650 nm. The binding activity of each of the BsAbs (ABLPNB.05 to ABLPNB.08) to both antigens was comparable for each sample. This means that BsAbs are stable in human serum for 2 weeks at 37°C. Representative data is as shown in FIGURE 8. 4.3. Development capacity of bispecific antibodies The developability was evaluated with respect to the physicochemical properties of PD-L1 and 4-1 BB of the BsAbs (ABLPNB.02 and ABLPNB.07). The quality attributes for the BsAbs were evaluated by various analytical methods. Briefly the purity was measured by size exclusion high performance liquid chromatography (SE-HPCL) and both of the BsAbs showed high purity over 99%. Thermal stability was analyzed by protein thermal shift (PTS) with fluorescence-tagged real-time polymerase chain reaction (RT-PCR). Its melting temperature was observed to be above 67°C which indicated that the test articles have stable structural integrity. To assess the solubility of the molecules, the proteins were concentrated to 20 mg / mL using ultrafiltration (Amicon Ultra-15 rotating concentrator). As a result, visible particles were not observed by visual inspection and no increments of aggregates were confirmed by SE-HPLC. The Isoelectric point (pl) of ABLPNB.02 and ABLPNB.07 measured by capillary isoelectric focusing (clEF) were 8.26 and 8.35, respectively. This pl range is appropriate for proceeding downstream processing and formulation development. In general, as shown in Table 19. It showed that the BsAbs (ABLPNB.O2 and ABLPNB.07) tested have appropriate physicochemical properties for successful development. Table 19 R / cann / Lznz / E / YiAi Content Method ABLPNB.07 ABLPNB.02 Purity SEC 99.6 99.8 Thermal Stability PTS 67.0 67.1 76.8 80.5 Solubility Visual inspection Easy to concentrate to 20 mg / mL, clear Easy to concentrate to 20 mg / mL, clear pi clEF 8.26 8.35 4.4. Activity of bispecific antibodies to promote the 4-1 BB signal To test the ability of the bispecific antibodies (ABLPNB.01, ABLPNB.03, ABLPNB.07 and ABLPNB.08) to promote the 4-1 BB signal, the cell-based 4-1 BB assay was used. In this assay, the Jurkat GloResponseMRNFkB99 luc2 / 4-1BB cell line (Promega, cai# CS196004) was used as the elector cells and the PD-L1 expressing or non-cancer expressing cell line as the target cells. The Jurkat GloResponseMRNFkB-Iuc2 / 4-1 BB cell line is genetically engineered to stably express 4-1 BB and low chain luciferase response element A. Luciferase expression is induced upon antibody binding to the 4-1 BB receptor. Briefly, plate HCC1954 (PD-L1 expressing) or BT474 or NCI-N87 (PD-L1 non-expressing) at 2.5x104 cells per well in a white 96-well assay plate in 100 pL culture medium (RPMI1640 + 10% FBS). Overnight culture in a humidified incubator at 37°C + 5% CO2. After overnight culture, 100 pL of culture medium is removed and 25 pL of Assay Medium (RPMI1640 + 1% FBS) is dispensed to the preplated target cells. 25 µL of bispecific antibodies (starting at 15 nM 8-fold diluted or 1.5 nM 4-fold diluted) and BMUR or monoclonal antibody 41B01 (starting at 20 nM 10-fold or 133 nM 6-fold) were added to the plate. The Jurkat GloResponseMRNFkB-Iuc2 / 4-1 BB Jurkat cell line were resuspended with Assay Medium. Dispense 25 pL of Jurkat GloResponseMRNFkB-Iuc2 / 4-1 BB Jurkat cell line per well to prepare 2.5x104 cells per aisle for plating. Culture for 6 hrs in a humidified incubator at 37°C + 5% CO2. During the incubation time, reconstitute the Bio-Glo™ reagent according to the manufacturer's instructions. After 6 hours of incubation, add 75 per well of Bio-GloMRa reagent to the assay plate. Wait 5 min and measure the luminescence using the microplate reader. Four-parameter logistic curve analysis was carried out with GraphPad software. The results are shown in FIGS. 9A-9F. As shown in FIGS. 9A-9B, the anti-4-1BB antibody showed very limited 4-1 BB signal activation as compared to BUMR. "41 B01 (assayed in the cross-Fe-linked form) showed only weak activation of the 4-1 BB signal (FIGURE 9B). In case of the bispecific antibody, co-cultured with PD-L1 negative cancer cells (FIGURE 9C and 9D), the PD-L1x4-1BB bispecific antibody did not show activation of signal 4-1 BB (FIGURE 9C) and signal 4 -1 BB weak after cross-Fe ligation as presented in FIGS. 9C and 9D, respectively. In the presence of PD-L1, that is, when co-cultured with PD-L1-positive target cells (FIGS. 9E and 9F), the PD-L1x4-1BB bispecific antibody showed 4-1 BB signal activation that was dependent on PD-L1. the presence of the tumor antigen (PD-L1). 4.5. Activity of Bispecific Antibodies in Promoting the Human T-Cell Immune Response To test the ability of bispecific antibodies for the response of stimulated human PBMCs, the cytokine production assay was used. Human PBMCs stimulated with the anti-human CD3 antibody were used as the cells. R / cann / Lznz / E / YiAi 100 voters. HCC1954 cells expressing PD-L1 were used as the target cells. In this system, PBMCs (3x104) were co-cultured with HCC1954 (1x104) in the presence of the anti-human CD3 antibody. The bispecific antibodies (ABLPNB.01 and ABLPNB.04) (starting at 20 nM (=4 ug / mL) diluted for 10 doses) and their counterpart monoclonal antibodies (41B01 and H12) (starting at 26.67 nM (=4 ug / mL ) diluted for 10 doses) were added to the mixed culture. As shown in FIGS. 10A and 10B, only the bispecific antibody can activate the T cell in the presence of the PD-L1-expressing tumor cells (see FIG. 10A). On the other hand, bispecific antibodies activated the T cell in a dose-dependent manner (see FIGURE 10B). 4.6. Inhibition of tumor growth by bispecific antibodies (In vivo assay) Humanized mice expressing the extracellular domain of human 4-1 BB were used. Mouse colon adenocarcinoma cells (MC38) were engineered to express human PD-L1. Humanized mice (h4-1BB) were implanted subcutaneously with MC38-hPD-L1 cells. Mice were intraperitoneally administered Q3D for 5 times (5 times injection of antibody every three days) with the following antibodies: isotype control (10 mg / kg), anti-PD-L1 antibody (H12, 10 mg / kg) , anti-4-1BB antibody (41B01, 10 mg / kg), combination of anti-PD-L1 (H12, 10 mg / kg) and anti-4-1BB (41B01, 10 mg / kg), and PD- bispecific antibody L1x4-1BB (BsAb) {BLPNB.01, 13.3 mg / kg}. Tumor volumes were monitored by caliper measurement twice weekly for the duration of the experiment. The inhibition of tumor growth induced by ABLPNB.01 was significantly greater than that observed with the combination of each of the targeting monoclonal antibodies (See FIGURE 11). The scope of this description is not to be limited to the specific embodiments described which are intended to be sole illustrations of individual aspects of the description, and any compositions or methods that are functionally equivalent are within the scope of this description. It will be apparent to those skilled in the art that various modifications and variations may be made to the methods and compositions herein without departing from the spirit or scope of the disclosure. Therefore, it is intended that the present description cover the modifications and variations of this description provided they come within the scope of the appended claims and their equivalents. All publications and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

Claims

NOVELTY OF THE INVENTION Having described the present invention, the following are considered novel and are therefore claimed as property: CLAIMS 1. A bispecific anti-PD-L1 / anti-4-1 BB antibody, comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and an anti-4-1 BB antibody or an antigen-binding fragment thereof, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 and 3; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 4, 5, 262, 263, 264, 265, 266 and 267; a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 6, 268 and 269; a VL CDR2 having an amino acid sequence of SEQ ID NO: 7;and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 8, 270, 271 and 272; and the anti-4-1 BB antibody or its antigen-binding fragment comprises a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 10 and 11; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 12 and 13; a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOS: 14, 15, 16 and 17; a VL CDR1 having an amino acid sequence of SEQ ID NO: 18; a VL CDR2 having an amino acid sequence of SEQ ID NO: 19; and a VL CDR3 having an amino acid sequence of SEQ ID NO:

20.

2. The bispecific anti-PD-L1 / anti-4-1 BB antibody of claim 1, wherein the anti-PD-L1 antibody or its antigen-binding fragment is capable of specifically binding to an immunoglobulin C (Ig C) domain of a human programmed death ligand 1 (PD-L1) protein, wherein the Ig C domain consists of amino acid residues 133225.

3. The bispecific anti-PD-L1 / anti-4-1 BB antibody of claim 1, wherein the anti-PD-L1 antibody or its antigen-binding fragment does not bind to an immunoglobulin V (IgV) domain of the PD-L1 protein, wherein the IgV domain consists of amino acid residues 19-127. R / cann / Lznz / E / YiAi 102 4. The bispecific anti-PD-L1 / anti-4-1BB antibody of claim 1, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy-chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 103 and 104, or a polypeptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOS: 103 and 104.

5. The bispecific anti-PD-L1 / anti-4-1BB antibody of claim 1, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 105 and 106, or a peptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOS: 105 and 106.

6. The bispecific anti-PD-L1 / anti-4-1BB antibody of claim 1, wherein the anti-4-1BB antibody or its antigen-binding fragment comprises a heavy-chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24, or a polypeptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOS: 21, 22, 23 and 24.

7. The bispecific anti-PD-L1 / anti-4-1BB antibody of claim 1, wherein the anti-4-1BB antibody or its antigen-binding fragment comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 25 and 26, or a peptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOS: 25 and 26.

8. The bispecific anti-PD-L1 / anti-4-1 BB antibody of claim 1, which is in the form of IgG-scFv.

9. A pharmaceutical composition for treating or preventing a disease associated with PD-L1, 4-1 BB, or both, the composition comprising the bispecific anti-PD-L1 / anti-4-1 BB antibody of any of claims 1-8 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, wherein the disease associated with PD-L1,4-1 BB or both is cancer.