Biosynthetic glycoprotein population

Abstract

To provide antibodies having enhanced antibody-dependent cellular cytotoxicity and enhanced complement-dependent cytotoxicity.SOLUTION: A population of antibodies wherein less than 80% of the oligosaccharides covalently attached to the population of antibodies via their N297 residues comprise core fucose residues, and wherein the population of antibodies comprises K338A and T437R mutations or K248E and T437R mutations in their Fc region.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. patent application Ser. No. 63 / 011,959, filed April 17, 2020. , U.S. Patent Application No. 63 / 011,974, filed April 17, 2020 U.S. Patent Application No. 63 / 011,985, filed April 17, 2020 U.S. Patent Application No. 63 / 011,993 filed on April 17, 2020; No. 63 / 011,991 filed May 27, 2020; Application No. 63 / 030,765, filed May 27, 2020, and U.S. Patent Application No. 6 No. 3 / 030,787, filed May 27, 2020, U.S. Patent Application No. 63 / 030 ,808, and U.S. Patent Application No. 63 / 030,823, filed May 27, 2020. , U.S. Patent Application No. 63 / 030,829, filed May 27, 2020 U.S. Patent Application No. 63 / 058,354, filed July 29, 2020 U.S. Patent Application No. 63 / 058,332, filed on July 29, 2020; No. 63 / 058,369 filed July 29, 2020; Application No. 63 / 058,345, filed July 29, 2020, and U.S. Patent Application No. 6 No. 3 / 058,351, U.S. Patent Application No. 63 / 142 filed January 28, 2021 ,981, and U.S. Patent Application No. 63 / 142,982, filed January 28, 2021. , U.S. Patent Application No. 63 / 142,983, filed January 28, 2021, 2021 U.S. Patent Application No. 63 / 142,985, filed January 28, 2020, and January 2021 This application claims the benefit of U.S. Patent Application No. 63 / 142,987, filed on the 28th. , each of which is incorporated herein by reference in its entirety.

[0002] (Reference to electronically submitted sequence listing) This application has been submitted electronically via EFS-Web as a Sequence Listing in ASCII format. The file name is "14620-451-228_SEQ_LISTING" and it is 2021 It was created on April 3rd and contains a sequence table with a size of 343,588 bytes. The Sequence Listing submitted via ibm.com is incorporated herein by reference in its entirety. be incorporated into the book.

[0003] 1. Field As used herein, enhanced antibody-dependent cellular cytotoxicity (ADC) is a cytotoxicity inhibitor. ADCC and enhanced complement-dependent cytotoxicity Antibodies having a specificity (CDC) are provided. [Background technology]

[0004] 2.Background technology Therapeutic antibodies target natural killer (NK) cells and macrophages. which can bind to Fc receptors expressed on immune effector cells and Therapeutic antibodies also exert antitumor activity through complement-dependent cell cytotoxicity (ADCC). Antitumor effects can be achieved by activating ADCC (ADCC). Antibodies with both CDC effector function and CDC effector function have been described in the art. It is needed. Summary of the Invention

[0005] 3. Overview In one embodiment, a population of antibodies, wherein the N297 residue of the antibody is covalently linked to the population of antibodies. Fewer than 80% of the oligosaccharides present in the antibody contain a core fucose residue, and the antibody population is characterized by its Fc region. and K338A and T437R mutations, or K248E and T437R mutations (RE mutations). The numbering of amino acid residues is according to the EU numbering system. In some embodiments, a population of T437R mutation, or K248E mutation and T437R mutation (RE mutation), and its N2 Less than 80% of the oligosaccharides covalently attached to the antibody population via 97 residues are core fucose Provided herein are populations of antibodies comprising residues.

[0006] In some embodiments, an agonist covalently binds to the population of antibodies via its N297 residue. In some embodiments, less than 70% of the oligosaccharides contain a core fucose residue. Fewer than 60% of the oligosaccharides covalently attached to the antibody population via heptad residues contain the core fucose residue. In some embodiments, the N297 residue of the α-amino acid covalently binds to the population of antibodies. In some embodiments, less than 50% of the oligosaccharides contained therein contain a core fucose residue. Less than 40% of the oligosaccharides covalently attached to the antibody population via the N297 residue of the core fragment In some embodiments, the antibody is shared among a population of antibodies through its N297 residue. Fewer than 30% of the covalently linked oligosaccharides contain a core fucose residue. In this study, less than 20% of the oligosaccharides covalently attached to the antibody population via their N297 residues were In some embodiments, the antibody is linked via its N297 residue to the N297 amino acid residue. Less than 10% of the oligosaccharides covalently attached to the population contain a core fucose residue.

[0007] In some embodiments, the antibody comprises a fucose residue attached to the oligosaccharide attached to the antibody. The present invention relates to a method for expressing a polynucleotide encoding an antibody or a fragment thereof in a host cell lacking the antibody. It is produced by

[0008] In some embodiments, the host cell comprises a reduced GDP-mannose 4,6-dehydratase. GDP-mannose 4,6-dehydratase (GMD) activity or decreased α-1,6 fucosyltransferase activity It has transferase activity.

[0009] In some embodiments, the population of antibodies is a population of antibodies that exhibits enhanced antibody-dependent cellular cytotoxicity (ADCC). and enhanced complement dependent cytotoxicity (CDC). The antibody is IgG1.

[0010] In some embodiments, the antibody binds to HLA-G. The antibody binds to CD37. In some embodiments, the antibody binds to GPRC5D. In some embodiments, the antibody binds to KLK2. The antibody binds to PSMA. In some embodiments, the antibody binds to CD3. In some embodiments, the antibody binds to BCMA.

[0011] In some embodiments, the antibody is a monospecific antibody. , and multispecific antibodies (such as PSMA x CD3 bispecific antibodies).

[0012] In another embodiment, eight of the oligosaccharides are covalently attached to the population of antibodies via their N297 residues. Less than 0% of the antibody population contained a core fucose residue, increasing the CDC activity of the antibody. A population of antibodies is described herein, including antibodies with one or more mutations in their Fc region for the purpose of It is provided at.

[0013] In another embodiment, a first means for increasing the ADCC activity of an antibody and a second means for increasing the CDC activity of the antibody. and a second means for increasing the affinity of the antibody.

[0014] In yet another aspect, the population of antibodies provided herein and a pharmaceutically acceptable excipient are In another aspect, a pharmaceutical composition is provided herein, comprising a population of antibodies. and less than 80% of the oligosaccharides are covalently attached to the antibody population via their N297 residues. contains a core fucose residue, and a population of antibodies may utilize that to increase the CDC activity of the antibody. A population of antibodies, including antibodies with one or more mutations in the Fc region, and a pharmaceutically acceptable carrier. In another aspect, a pharmaceutical composition is provided herein, comprising: (a) a pharmaceutical composition comprising: A first means for increasing the ADCC activity of an antibody and a second means for increasing the CDC activity of an antibody and (b) a pharmaceutically acceptable excipient. Compositions are provided herein.

[0015] In yet another embodiment, a method of generating a population of antibodies comprises attaching a nucleotide to the antibody through the N297 residue. The antibody or its fragments can be synthesized in host cells that lack the addition of fucose residues to the attached oligosaccharides. and expressing a polynucleotide encoding the F fragment, wherein the population of antibodies is The c region has K338A and T437R mutations, or K248E and T437R mutations ( Methods are provided herein, including antibodies comprising a nucleotide sequence encoding a nucleotide sequence encoding a nucleotide sequence (RE mutation).

[0016] In some embodiments, the host cell has a reduced α-1,6 fucosyltransferase In some embodiments, the host cell has reduced GDP-mannose 4 In some embodiments, the α-1,6 fucosyltransferase has α-1,6-dehydratase activity. The gene encoding the enzyme is mutated or expressed at lower levels than normal. In some embodiments, the GD The gene encoding P-mannose 4,6-dehydratase is either mutated or is higher than normal. The gene is expressed at lower levels than or knocked out in the host cell.

[0017] In another embodiment, a method for producing a population of antibodies comprises: adding K338 to the Fc region of the population of antibodies; A and T437R mutations, or K248E and T437R mutations (RE mutations) were introduced and a step of isolating the core fucoprotein in the oligosaccharide bound to the antibody via the N297 residue. and producing a population of antibodies having a reduced amount of IgG1. It is provided at.

[0018] In another embodiment, a method of producing a population of antibodies comprises attaching the antibody through the N297 residue. The antibody or its fragment is produced in a host cell lacking the addition of fucose residues to the oligosaccharides that carry the antibody. and performing a step of expressing a polynucleotide encoding the antibody. The population has an Fc region containing a K338A mutation and a T437R mutation, or a K248E mutation and a T Methods are provided herein that involve antibodies that include a 437R mutation (RE mutation).

[0019] In another embodiment, a method for producing a population of antibodies comprises: adding K338 to the Fc region of the population of antibodies; A and T437R mutations, or K248E and T437R mutations (RE mutations) were introduced and an oligonucleotide attached to the antibody via the N297 residue. Steps for performing the function of producing a population of antibodies with reduced amounts of core fucose in the saccharide. A method is provided herein, comprising:

[0020] In yet another aspect, the method comprises administering to a subject a population of antibodies provided herein. Provided herein are methods for treating a disease or disorder in a subject, including: In some embodiments, the antibody binds to an antigen and the disease or disorder is associated with the antigen. In some embodiments, the antigen is HLA-G. In some embodiments, the antigen is GPRC5D. In some embodiments, the antigen is KLK2. In some embodiments, the antigen is PSMA. In some embodiments, the antigen is CD3. In some embodiments, the antigen is In some embodiments, the disease or disorder is a solid tumor cancer. In some embodiments, the disease or disorder is renal adenocarcinoma, pancreatic adenocarcinoma, or lung adenocarcinoma, non-small cell lung cancer, or pulmonary adenocarcinoma. and ovarian cancer.

[0021] In another aspect, a method of treating a disease or disorder in a subject includes administering a population of antibodies to the subject. and administering to a subject an oligonucleotide covalently linked to the population of antibodies via its N297 residue. Less than 80% of the sugars contain a core fucose residue, and the antibody population is enriched to increase the CDC activity of the antibody. The method includes an antibody having one or more mutations in its Fc region to enhance the provided in the document.

[0022] In another aspect, there is provided a method of treating a disease or disorder in a subject, comprising administering to the subject: (a) an anti-cancer agent; First, to increase the ADCC activity of the body, and second, to increase the CDC activity of antibodies. and (b) a pharmaceutically acceptable excipient. A method is provided herein, comprising:

[0023] In yet another aspect, a method for treating a cancer includes administering to a host a population of antibodies provided herein. Provided herein are methods for modulating immunity in a host, including: A method of modulating immunity in a host, comprising administering to the host a population of antibodies, Less than 80% of the oligosaccharides covalently attached to the antibody population via the N297 residue of the core fragment A population of antibodies containing covalent residues in their Fc region to increase the CDC activity of the antibody. Methods are provided herein that include antibodies with one or more mutations. In one embodiment, a method for modulating immunity in a host includes increasing ADCC activity of an antibody. and a second means for increasing the CDC activity of the antibody. Provided herein are methods comprising administering a population of [Brief explanation of the drawings]

[0024] [Figure 1A]Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1B] Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1C]Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1D] Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1E]Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1F] Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1G]Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 1H] Figure 1 shows the CDC activity of different types of anti-CD37 antibodies with hypofucosylation (Figures 1A and 1B), Xencor mutations (Figures 1C and 1D), RE mutations (Figures 1E and 1F), and hypofucosylation and RE mutations (Figures 1G and 1H) on target cells expressing high levels of CD37 (CARNAVAL, Figures 1A, 1C, 1E, and 1G) and low levels of CD37 (JEKO-1, Figures 1B, 1D, 1F, and 1H). Target cells were incubated with titrated concentrations of antibody as indicated for 30 min. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, and is reported in relative luminescence units (RLU). [Figure 2]Figure 1 shows the CDC activity of anti-GPRC5D antibodies with wild-type hypofucosylation and RE mutations on H929 target cells. Target cells were incubated with titrated concentrations of antibody as indicated for 30 minutes. Baby rabbit serum was then added to the mixture to a final concentration of 10% to provide a source of complement components. After a 4-hour incubation, cell viability was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence, reported in relative luminescence units (RLU). [Figure 3A] This figure shows the in vitro ADCC kinetics of VcaP cells mediated by KLK2 antibody with PBMCs. Briefly, VcaP cells stably transfected with Nuclight Red (Incucyte®, Essen Bioscience) were seeded at 10,000 cells per well in clear medium (RPMI 1641 + 10% FBS, Thermo Fisher Scientific) in a 384-well plate (Perkin Elmer ViewPlate) and allowed to adhere overnight. The ADCC assay was performed using freshly thawed PBMCs (Hemcare, PB009C-3). The effector to target cell ratio per well was 34:1 with PBMCs as effector cells. KLK2 antibody was tested at final concentrations ranging from 100 nM to 0.01 nM. After adding the effector cells and antibody to the target cells, real-time imaging was performed using an Incucyte® S3 instrument (Essen BioScience). The total intergraded red signal per well was quantified using Incucyte® software. Data analysis was performed using Incucyte® software and Prism (GraphPad Software) based on quadruplicate values. The percentage of cell death was calculated as (1-KLK2mAb / no mAb control) × 100%. [Figure 3B]This figure shows the in vitro ADCC kinetics of VcaP cells mediated by KLK2 antibody with PBMCs. Briefly, VcaP cells stably transfected with Nuclight Red (Incucyte®, Essen Bioscience) were seeded at 10,000 cells per well in clear medium (RPMI 1641 + 10% FBS, Thermo Fisher Scientific) in a 384-well plate (Perkin Elmer ViewPlate) and allowed to adhere overnight. The ADCC assay was performed using freshly thawed PBMCs (Hemcare, PB009C-3). The effector to target cell ratio per well was 34:1 with PBMCs as effector cells. KLK2 antibody was tested at final concentrations ranging from 100 nM to 0.01 nM. After adding the effector cells and antibody to the target cells, real-time imaging was performed using an Incucyte® S3 instrument (Essen BioScience). The total intergraded red signal per well was quantified using Incucyte® software. Data analysis was performed using Incucyte® software and Prism (GraphPad Software) based on quadruplicate values. The percentage of cell death was calculated as (1-KLK2mAb / no mAb control) × 100%. [Figure 3C]This figure shows the in vitro ADCC kinetics of VcaP cells mediated by KLK2 antibody with PBMCs. Briefly, VcaP cells stably transfected with Nuclight Red (Incucyte®, Essen Bioscience) were seeded at 10,000 cells per well in clear medium (RPMI 1641 + 10% FBS, Thermo Fisher Scientific) in a 384-well plate (Perkin Elmer ViewPlate) and allowed to adhere overnight. The ADCC assay was performed using freshly thawed PBMCs (Hemcare, PB009C-3). The effector to target cell ratio per well was 34:1 with PBMCs as effector cells. KLK2 antibody was tested at final concentrations ranging from 100 nM to 0.01 nM. After adding the effector cells and antibody to the target cells, real-time imaging was performed using an Incucyte® S3 instrument (Essen BioScience). The total intergraded red signal per well was quantified using Incucyte® software. Data analysis was performed using Incucyte® software and Prism (GraphPad Software) based on quadruplicate values. The percentage of cell death was calculated as (1-KLK2mAb / no mAb control) × 100%. [Figure 3D]This figure shows the in vitro ADCC kinetics of VcaP cells mediated by KLK2 antibody with PBMCs. Briefly, VcaP cells stably transfected with Nuclight Red (Incucyte®, Essen Bioscience) were seeded at 10,000 cells per well in clear medium (RPMI 1641 + 10% FBS, Thermo Fisher Scientific) in a 384-well plate (Perkin Elmer ViewPlate) and allowed to adhere overnight. The ADCC assay was performed using freshly thawed PBMCs (Hemcare, PB009C-3). The effector to target cell ratio per well was 34:1 with PBMCs as effector cells. KLK2 antibody was tested at final concentrations ranging from 100 nM to 0.01 nM. After adding the effector cells and antibody to the target cells, real-time imaging was performed using an Incucyte® S3 instrument (Essen BioScience). The total intergraded red signal per well was quantified using Incucyte® software. Data analysis was performed using Incucyte® software and Prism (GraphPad Software) based on quadruplicate values. The percentage of cell death was calculated as (1-KLK2mAb / no mAb control) × 100%. [Figure 3E]This figure shows the in vitro ADCC kinetics of VcaP cells mediated by KLK2 antibody with PBMCs. Briefly, VcaP cells stably transfected with Nuclight Red (Incucyte®, Essen Bioscience) were seeded at 10,000 cells per well in clear medium (RPMI 1641 + 10% FBS, Thermo Fisher Scientific) in a 384-well plate (Perkin Elmer ViewPlate) and allowed to adhere overnight. The ADCC assay was performed using freshly thawed PBMCs (Hemcare, PB009C-3). The effector to target cell ratio per well was 34:1 with PBMCs as effector cells. KLK2 antibody was tested at final concentrations ranging from 100 nM to 0.01 nM. After adding the effector cells and antibody to the target cells, real-time imaging was performed using an Incucyte® S3 instrument (Essen BioScience). The total intergraded red signal per well was quantified using Incucyte® software. Data analysis was performed using Incucyte® software and Prism (GraphPad Software) based on quadruplicate values. The percentage of cell death was calculated as (1-KLK2mAb / no mAb control) × 100%. [Figure 4] Figure 1 shows in vitro ADCC dose-response killing of VcaP cells by PBMCs at 48 hours. Dose-response curves were generated 48 hours after addition of effector cells and antibody to target cells. [Figure 5A] Figure 1 shows the ADCC activity of anti-HLA-G antibodies MHGB732 and MHGB738, and their respective counterparts with hypofucosylation, RE mutation, and hypofucosylation and RE mutation, against JEG-3 and RERF-LC-Ad-1 cells. Percent lysis was compared to the maximum lysis of JEG-3 or RERF-LC-Ad-1 cells by Triton-X100 detergent and calculated as (sample value - target only value) / (maximum value - target only value) x 100%. [Figure 5B] Figure 1 shows the ADCC activity of anti-HLA-G antibodies MHGB732 and MHGB738, and their respective counterparts with hypofucosylation, RE mutation, and hypofucosylation and RE mutation, against JEG-3 and RERF-LC-Ad-1 cells. Percent lysis was compared to the maximum lysis of JEG-3 or RERF-LC-Ad-1 cells by Triton-X100 detergent and calculated as (sample value - target only value) / (maximum value - target only value) x 100%. [Figure 5C] Figure 1 shows the CDC activity of anti-HLA-G antibodies MHGB732 and MHGB738 and their respective counterparts with hypofucosylation, RE mutation, and hypofucosylation and RE mutation. Target cells were incubated with the indicated antibodies for 30 min at 37°C. 15–20% (stock concentration) rabbit complement and heat-inactivated complement were added to the wells to a volume of 25 μL / well, respectively. The mixtures were incubated at 37°C for 4–12 h. Target cell lysis was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence and is reported in relative luminescence units (RLU). [Figure 5D] Figure 1 shows the CDC activity of anti-HLA-G antibodies MHGB732 and MHGB738 and their respective counterparts with hypofucosylation, RE mutation, and hypofucosylation and RE mutation. Target cells were incubated with the indicated antibodies for 30 min at 37°C. 15–20% (stock concentration) rabbit complement and heat-inactivated complement were added to the wells to a volume of 25 μL / well, respectively. The mixtures were incubated at 37°C for 4–12 h. Target cell lysis was measured by adding Cell Titer-Glo reagent (Promega) and measuring the resulting luminescence and is reported in relative luminescence units (RLU). [Figure 6A]Figure 6 shows in vitro ADCC dose-response killing of C42B and LNCap cells mediated by the hypofucosylated and RE-mutated anti-PSMA antibodies PSMB896 and PSMB898. Specifically, Figure 6A shows the in vitro ADCC dose-response killing of C42B cells by PBMCs at 6 hours, Figure 6B shows the in vitro ADCC dose-response killing of LNCap cells by PBMCs at 6 hours, Figure 6C shows the in vitro ADCC dose-response killing of C42B cells by NK cells at 24 hours, and Figure 6D shows the in vitro ADCC dose-response killing of LNCap cells by NK cells at 24 hours. Dose-response curves were generated 6 or 24 hours after the addition of effector cells and antibodies to target cells. [Figure 6B] Figure 6 shows in vitro ADCC dose-response killing of C42B and LNCap cells mediated by the hypofucosylated and RE-mutated anti-PSMA antibodies PSMB896 and PSMB898. Specifically, Figure 6A shows the in vitro ADCC dose-response killing of C42B cells by PBMCs at 6 hours, Figure 6B shows the in vitro ADCC dose-response killing of LNCap cells by PBMCs at 6 hours, Figure 6C shows the in vitro ADCC dose-response killing of C42B cells by NK cells at 24 hours, and Figure 6D shows the in vitro ADCC dose-response killing of LNCap cells by NK cells at 24 hours. Dose-response curves were generated 6 or 24 hours after the addition of effector cells and antibodies to target cells. [Figure 6C]Figure 6 shows in vitro ADCC dose-response killing of C42B and LNCap cells mediated by the hypofucosylated and RE-mutated anti-PSMA antibodies PSMB896 and PSMB898. Specifically, Figure 6A shows the in vitro ADCC dose-response killing of C42B cells by PBMCs at 6 hours, Figure 6B shows the in vitro ADCC dose-response killing of LNCap cells by PBMCs at 6 hours, Figure 6C shows the in vitro ADCC dose-response killing of C42B cells by NK cells at 24 hours, and Figure 6D shows the in vitro ADCC dose-response killing of LNCap cells by NK cells at 24 hours. Dose-response curves were generated 6 or 24 hours after the addition of effector cells and antibodies to target cells. [Figure 6D] Figure 6 shows in vitro ADCC dose-response killing of C42B and LNCap cells mediated by the hypofucosylated and RE-mutated anti-PSMA antibodies PSMB896 and PSMB898. Specifically, Figure 6A shows the in vitro ADCC dose-response killing of C42B cells by PBMCs at 6 hours, Figure 6B shows the in vitro ADCC dose-response killing of LNCap cells by PBMCs at 6 hours, Figure 6C shows the in vitro ADCC dose-response killing of C42B cells by NK cells at 24 hours, and Figure 6D shows the in vitro ADCC dose-response killing of LNCap cells by NK cells at 24 hours. Dose-response curves were generated 6 or 24 hours after the addition of effector cells and antibodies to target cells. DETAILED DESCRIPTION OF THE INVENTION

[0025] 5. Detailed Description The present disclosure provides antibodies wherein less than 80% of the oligosaccharides covalently attached to a population of antibodies contain a fucose residue. When the Fc region of the antibody contains the K248E mutation and the T437R mutation (RE mutation), The surprising finding is that the population has both enhanced ADCC activity and enhanced CDC activity. In addition, as demonstrated in Section 7 below, Fucosylation does not interfere with the effect of RE mutations on enhanced CDC, and RE mutations are associated with hypofucosylated In one embodiment, the Fc region does not interfere with the enhanced ADCC activity conferred by RE. The oligosaccharides containing the mutation and covalently attached to the Fc region of the antibody contain a core fucose residue. In another embodiment, an antibody comprising an RE mutation in the Fc region, and an antibody that does not contain a core fucose residue in the oligosaccharide covalently bound to the Fc region of the antibody. In some embodiments, a population of antibodies comprising the K248E mutation is provided herein. A group of antibodies containing the T437R mutation (RE mutation) and the T437R mutation (RE mutation) through the N297 residue. wherein less than 80% of the oligosaccharides covalently attached to the antibody population contain a core fucose residue. In some embodiments, a population of Fewer than 70% of the oligosaccharides covalently attached to the antibody population via In some embodiments, an agonist is covalently attached to the population of antibodies via its N297 residue. In some embodiments, less than 60% of the oligosaccharides contain a core fucose residue. Fewer than 50% of the oligosaccharides covalently attached to the antibody population via heptad residues contain a core fucose residue. In some embodiments, the N297 residue of the α-amino acid covalently binds to the population of antibodies. In some embodiments, less than 40% of the oligosaccharides contained therein contain a core fucose residue. Less than 30% of the oligosaccharides covalently attached to the antibody population via the N297 residue of the core fragment In some embodiments, the antibody is shared among a population of antibodies through its N297 residue. Fewer than 20% of the covalently linked oligosaccharides contain a core fucose residue. In this study, less than 10% of the oligosaccharides covalently attached to the antibody population via their N297 residues were In some embodiments, the antibody is linked via its N297 residue to the N297 amino acid residue. Less than 5% of the oligosaccharides covalently attached to the population contain a core fucose residue.

[0026] In certain embodiments, the antibody may have any antigen binding structure, as long as it has an Fc region. or any antibody targeting any antigen is included in the present disclosure. Pharmaceutical compositions comprising the antibody , methods of making, and uses thereof are also included in this disclosure.

[0027] 5.1 Definition The techniques and procedures described or referenced herein are generally well understood by those skilled in the art. and / or those commonly employed by those skilled in the art using conventional techniques, e.g., Mol ecular Cloning:A Laboratory Manual(Sambr ook, et al., 3d ed.2001), Current Protocols in Molecular Biology(Ausubel, et al. eds. ,2003), Therapeutic Monoclonal Antibodies :From Bench to Clinic(An,ed.2009), Monocl onal Antibodies:Methods and Protocols(Al bitar, ed. 2010), and Antibody Engineering Vo ls 1 and 2(Kontermann and Dubel, eds.,2d These include widely used methods described in (ed. 2010).

[0028] Unless otherwise defined herein, the technical and scientific terms used herein Terms have the meanings commonly understood by those skilled in the art. The explanation of terms below applies and, where appropriate, terms used in the singular also include the plural; Any explanation of a term described is incorporated herein by reference. In the event of a conflict with any document contained herein, the explanations of terms set forth below shall prevail.

[0029] The terms "antibody," "immunoglobulin," or "Ig" are used interchangeably herein. is used in the broadest sense, and specifically refers to, for example, monochrome, as described below. Monoclonal antibodies (agonist, antagonist, neutralizing antibodies, full-length or intact monoclonal antibodies) antibody compositions with polyepitopic or monoepitopic specificity, polyclonal antibodies, monovalent or monovalent antibodies, polyvalent antibodies, and antibodies formed from at least two intact antibodies Multispecific antibodies (e.g., bispecific antibodies) can be used to express the desired biological activity. Antibodies may be human, humanized, chimeric, and / or affinity matured, and may be The antibodies may be from other species, such as mice and rabbits. It is capable of binding to specific molecular antigens and consists of two identical paired polypeptide chains. It is intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides. Each pair consists of one heavy chain (approximately 50-70 kDa) and one light chain (approximately 25 kDa). ), and each amino-terminal portion of each chain has a variable region of about 100 to about 130 or more amino acids. The carboxy-terminal portion of each chain contains a constant region. engineering (Borrebaeck, ed., 2d ed.1995), and See Kuby, Immunology (3rd ed. 1997). In embodiments, the specific molecular antigen comprises a polypeptide or epitope, as defined herein. The antibodies provided may be synthetic antibodies, recombinantly produced antibodies, or any combination thereof. Camelized antibodies or their humanized variants, intracellular antibodies, and anti-idiotypic (anti-Id) antibodies ) antibodies. As used herein, the term "antibody" Also, the Fc region and any of the above functional fragments (e.g., antigen-binding fragments) A functional fragment includes any binding molecule having a functional fragment (e.g., a fragment from which the fragment originates). A portion of the antibody heavy or light chain polypeptide that retains some or all of the binding activity of the resulting antibody. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include: Single-chain Fvs (scFv) (including, for example, monospecific, bispecific, etc.), Fab flags ment, F(ab') fragment, F(ab)2 fragment, F(ab')2 fragment ment, disulfide-linked Fvs (dsFv), Fd fragment, Fv fragment, These include diabodies, triabodies, tetrabodies, and minibodies. The antibodies provided herein are immunoglobulin molecules and immunologically related to immunoglobulin molecules. an antigen-binding site (e.g., one or more amino acid sequences of an antibody) that binds to an antigen. Such antibody fragments include antigen-binding domains or molecules comprising the CDRs (above). For example, Harlow and Lane, Antibodies: A Laboratory ory Manual(1989);Mol.Biology and Biotech nology:A Comprehensive Desk Reference(My ers, ed., 1995); Huston, et al., 1993, Cell Bi ophysics 22:189-224;Pluckthun and Skerra ,1989,Meth.Enzymol.178:497-515;and Day,A Advanced Immunochemistry (2nd ed. 1990) The antibodies provided herein can be any class of immunoglobulin molecule ( For example, IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., , IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). The antibody may be an agonist antibody or an antagonist antibody.

[0030] An "antigen" is a structure to which an antibody can selectively bind. peptides, carbohydrates, nucleic acids, lipids, haptens, or other naturally occurring or synthetic compounds In some embodiments, the target antigen is a polypeptide. In embodiments, the antigen is associated with a cell, eg, present on or within a cell.

[0031] An "intact" antibody is one that contains an antigen-binding site as well as constant domains (C L) and at least heavy chain constant regions CH1, CH2 and CH3. The region may include a human constant region or a variant of its amino acid sequence. Intact antibodies have one or more effector functions.

[0032] The term "binds" or "binding" refers to, for example, the binding of a complex to a Interactions between molecules include the formation of hydrogen bonds, ionic bonds, etc. In this case, non-covalent interactions include hydrophobic interactions and / or van der Waals interactions. A complex may contain molecules held together by covalent or non-covalent bonds, interactions, or forces. This also includes the binding of two or more molecules held together by a single antigen-binding site on an antibody and a target such as an antigen. The strength of the total non-covalent interactions between a single epitope on a target molecule determines the affinity of the target molecule to that epitope. The affinity of an antibody or functional fragment to a monovalent antigen. Dissociation rate (k off ) and association rate (k on ) and the ratio (k off / k on ) is the solution separation constant K D and has an inverse relationship with affinity. D The lower the value, the higher the affinity of the antibody. It becomes. K D The value of k varies for different complexes of antibody and antigen. on and k of f The dissociation constant K of the antibodies provided herein depends on both D is presented herein. The method may be determined using any of the methods provided herein, or any other method known to those skilled in the art. Affinity at one binding site does not necessarily represent the true extent of the interaction between antibody and antigen. It does not reflect the strength of the antigen. When an antigen comes into contact with an antibody that contains multiple binding sites, the antibody interacts with the antigen at one site. This will increase the probability of reaction at the second site. The strength of multiple interactions is called affinity.

[0033] "binds to" and "specifically binds to" in reference to the antibodies described herein and similar terms are also used interchangeably herein, and refer to antigens such as polypeptides. It refers to an antibody whose antigen-binding domain specifically binds to an antigen. Specifically binding antibodies or antigen-binding domains may cross-react with related antigens. In the form, an antibody or antigen-binding domain that binds to or specifically binds to an antigen is Antibodies or antibodies that bind to or specifically bind to an antigen and do not cross-react with other antigens. Antigen-binding domains can be used in immunoassays, e.g., Octet®, Biacor e®, or other techniques known to those skilled in the art. In some embodiments, the antibody or antigen-binding domain is used in a radioimmunoassay. RIA and enzyme-linked immunosorbent assay higher than any cross-reactive antigen determined using laboratory techniques such as ELISA When an antibody binds to an antigen with affinity, it binds to the antigen or specifically binds to the antigen. In this case, a specific or selective reaction is one that is at least as high as the background signal or noise. 2-fold and may exceed background levels by 10-fold. For more information, see, for example, Fundamental Immunology 332-36 (P aul, ed., 2d ed. 1989). In certain embodiments, "non-standard" The degree of binding of the antibody or antigen-binding domain to the "target" protein can be determined, for example, by fluorescence activated by fluorescence activated cell sorting (FACS) analysis or RIA The binding of the antibody or antigen-binding domain to its specific target antigen is determined as follows: Terms such as "specific binding," "specifically binds to," or "specific for" In this context, binding means binding that is measurably different from non-specific interactions. In this case, the binding activity may be compared with that of a control molecule, which is a molecule of similar structure that generally does not have binding activity. Specific binding can be measured by determining the binding of the molecule to the target molecule. For example, specific binding can be measured by This can be determined by competition with a control molecule similar to the target, e.g., excess unlabeled target. In this case, binding of the labeled target to the probe is competitively inhibited by excess unlabeled target. Inhibition indicates specific binding. The antibody is sufficiently characterized so that it is useful, for example, as a diagnostic or therapeutic agent targeting the antigen. In certain embodiments, the antigen is capable of binding to the antibody with sufficient affinity. The binding antibodies or antigen-binding domains are at 1000 nM, 800 nM, 500 nM, 250 nM, nM, 100nM, 50nM, 10nM, 5nM, 4nM, 3nM, 2nM, 1nM, 0 .9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM , 0.2 nM, or a dissociation constant (K D In certain embodiments, Antibodies or antigen-binding domains may be used to differentiate between antigens from different species (e.g., human and cynomolgus monkey). It binds to epitopes on antigens that are conserved across species.

[0034] "Binding affinity" generally refers to the binding affinity of a single binding site on a molecule (e.g., a binding protein such as an antibody). The strength of the sum of non-covalent interactions between a protein (e.g., a protein) and its binding partner (e.g., an antigen) is Unless otherwise specified, as used herein, "binding affinity" refers to the ability of a binding pair to bind to a molecule. Intrinsic binding affinity, which reflects a 1:1 interaction between members (e.g., antibody and antigen) The affinity of a binding molecule X for its binding partner Y is roughly determined by the dissociation constant (K D )in Affinity can be expressed in any manner known in the art, including those described herein. Low affinity antibodies generally bind to antigens slowly. High affinity antibodies generally bind antigens faster and have a better affinity for the antigen. Various methods for measuring binding affinity are known in the art. Any of these may be used for the purposes of this disclosure. In one embodiment, "K D " or "K D value " can be measured by assays known in the art, for example, by binding assays. It can be determined. D For example, a Fab version of an antibody of interest and its antigen can be used. It can be measured by RIA performed with a 2000-kJ / kg / day antibody (Chen, et al., J. Mol. Biol., 1999,293:865-81). Also, K D or K D The values ​​are based on biolayer interferometry (bi layer interferometry (BLI), or for example Octet® Red 96 by Octet® using the stem or by e.g. Biacore® Biacore® 2000 or Biacore® 3000 Surface plasmon resonance (SPR) assay using Fluorescence Spectroscopy (FPS) It can also be measured by using the "on rate" or "rate of association." degree" or "association rate" or "k on " is, for example, Octet (registered trademark) Red 96, Biacore® 2000 or Biacore® 3000 system Using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, This can be determined using PR (Protein Reaction) techniques.

[0035] In certain embodiments, an antibody is one in which a portion of the heavy and / or light chain is derived from a particular species or or sequences identical or homologous to the corresponding sequences of antibodies belonging to a particular antibody class or subclass. while the remainder of the chain is from a different species or belongs to a different antibody class or subclass. The antibody may contain "chimeric" sequences that are identical or homologous to corresponding sequences of antibodies belonging to the same class. can be used, but only if they exhibit the desired biological activity (U.S. Pat. No. 4,816,567, and Morrison, et al., Proc. Natl. Acad. Sci. USA ,1984,81:6851-55).

[0036] In certain embodiments, antibodies are prepared such that the native CDR residues provide the desired specificity, affinity, and Non-human species such as mice, rats, rabbits, or non-human primates (e.g., donors) that are competent human immunoglobulin (e.g., a human immunoglobulin) in which residues from the corresponding CDRs of a human immunoglobulin (e.g., a human antibody) are substituted. forms of non-human (e.g., murine) antibodies that are chimeric antibodies containing the recipient antibody In some cases, the antibody may contain portions of one or two "humanized" forms of human immunoglobulins. In addition, humanized antibodies have one or more FR region residues replaced by corresponding non-human residues. These modifications may include residues that are not found in the recipient antibody or the donor antibody. Humanization is performed to further improve antibody performance. The heavy or light chain of a humanized antibody may have CDRs all or substantially all of the FRs correspond to those of a non-human immunoglobulin, and all or substantially all of the FRs correspond to those of a non-human immunoglobulin May contain one or more variable regions, all of which are human immunoglobulin sequences. In certain embodiments, humanized antibodies contain an immunoglobulin constant region (Fc), typically contains at least a portion of a human immunoglobulin. s,et al.,Nature,1986,321:522-25;Riechman n,et al.,Nature,1988,332:323-29;Presta,C urr.Op.Struct.Biol.,1992,2:593-96;Carter ,et al.,Proc.Natl.Acad.Sci.USA,1992,89:4 285-89; U.S. Patent Nos. 6,800,738, 6,719,971, and 6, See US Pat. Nos. 6,407,213, and 6,054,297. I want to be.

[0037] In certain embodiments, the antibody may comprise a "fully human antibody" or a portion of a "human antibody." These terms are used interchangeably herein to refer to human variable regions and, e.g., human In a specific embodiment, these terms refer to antibodies of human origin that contain a human constant region. A "fully human" antibody refers to an antibody comprising variable and constant regions. peptides and naturally occurring somatic mutations in human germline immunoglobulin nucleic acid sequences. It also encompasses antibodies encoded by nucleic acid sequences that are variants of the antibody. The term "human germline immunoglobulin" includes human germline immunoglobulins as described by Kabat et al. Antibodies having variable and constant regions corresponding to the phospho-phosphoryl sequences are included (Kabat, et al. al. (1991) Sequences of Proteins of Immuno logical interest,Fifth Edition,USDepar tment of Health and Human Services,NIH P (See Publication No. 91-3242.) A "human antibody" is an antibody produced by a human and / or These have been produced using any of the techniques for producing human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art. Among these are phage display libraries (Hoogenboom and Wi ter,J.Mol.Biol.,1991,227:381;Marks,et a l., 1991, J. Mol. Biol., 1991, 222:581) and yeast disc Play library (Chao, et al., Nature Protocols, 20 06,1:755-68). In addition, the preparation of human monoclonal antibodies includes Co le, et al., Monoclonal Antibodies and Canc. er Therapy 77(1985);Boerner,et al.,J.Imm unol., 1991, 147(1):86-95; and van Dijk and v an de Winkel,Curr.Opin.Pharmacol.,2001,5 :368-74. Human antibodies can be produced in response to antigen challenge. modified to produce such antibodies in response, but whose endogenous locus is ineffective The antigen is prepared by administering the antigen to a transgenic animal, such as a mouse, which has been engineered to be a virion. (See, e.g., Jakobovits, Curr. Opin. Biote chnol.,1995,6(5):561-66;Bruggemann and T. aussing,Curr.Opin.Biotechnol.,1997,8(4): 455-58; and U.S. Patent No. 6,075,115 relating to XENO Mouse™ technology. 81 and 6,150,584). Also, see, for example, Li, et al. ,Proc.Natl.Acad.Sci.USA,2006,103:3557-62 See also (regarding human antibodies generated via human B-cell hybridoma technology) .

[0038] In certain embodiments, the antibody may comprise portions of a "recombinant human antibody," a term The phrase also includes human antibodies prepared, expressed, created, or isolated by recombinant means, e.g., , an antibody expressed using a recombinant expression vector transfected into a host cell; Antibodies, human immunoglobulins isolated from a recombinant combinatorial human antibody library Animals that are transgenic and / or transchromosomal for the gene (e.g., mice or Bovine) (e.g., Taylor, LD, et al., Nucl Acids Res., 1992 20:6287-6295), or human immunoglobulin or by any other means involving splicing the purine gene sequence to another DNA sequence. Such recombinant human antibodies include antibodies prepared, expressed, engineered, or isolated using recombinant human antibodies. The antibody has variable and constant regions derived from human germline immunoglobulin sequences. (Kabat, EA, et al. (1991) Sequences f Proteins of Immunological Interest,Fif th Edition,USDepartment of Health and Human Services,NIH Publication No.91-324 2). However, in certain embodiments, such recombinant human antibodies The method involves in vitro mutagenesis (or the use of animals transgenic for human Ig sequences). If present, the VH and VH fragments of the recombinant antibody have been subjected to in vivo somatic mutagenesis (in vivo mutagenesis). The amino acid sequences of the VH and VL regions are derived from and related to human germline VH and VL sequences. However, they may not naturally occur within the human antibody germline repertoire in vivo. It is an array.

[0039] In certain embodiments, the antibody may comprise a portion of a "monoclonal antibody," As used herein, the term refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., For example, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in trace amounts. are identical, and each monoclonal antibody typically recognizes a single epitope on the antigen. In a specific embodiment, as used herein, a "monoclonal antibody" refers to a single An antibody produced by a hybridoma or other cell. The term is not limited to a particular method for making an antibody. For example, Useful monoclonal antibodies are described by Kohler et al., 1975, Nature 256:495, or by the hybridoma method first described by can be produced using recombinant DNA methods in bacteria or eukaryotic animal or plant cells ( See, e.g., U.S. Patent No. 4,816,567. Also, "monoclonal antibodies" " is, for example, Clackson, et al., Nature, 1991, 352:6 24-28 and Marks, et al., J. Mol. Biol., 1991, 222:581-97, a single antibody was isolated from a phage antibody library. To prepare clonal cell lines and the monoclonal antibodies expressed by them, Other methods for this purpose are well known in the art. in Molecular Biology(Ausubel et al. eds. ,5th ed.2002).

[0040] A typical four-chain antibody unit consists of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, the four chain units are roughly 50,000 daltons. Each light chain is linked by a heavy chain with one covalent disulfide bond. The two H chains are bonded together by one or more disulfide bonds depending on the H chain isotype. Each H chain and L chain is linked to each other by regularly spaced intrachain disulfides. Each H chain has a variable domain (VH) at the N-terminus followed by Each of the α and γ chains has three constant domains (CH), as well as μ and ε Each L chain has four CH domains. At the other end is a constant domain (CL). L aligns with VH, and CL aligns with the first constant domain of the heavy chain (CH1). Particular amino acid residues form an interface between the light- and heavy-chain variable domains. The pairing of VH and VL together forms a single antigen-binding site. The structure and properties of classes of antibodies are described in, for example, Basic and Clinical l Immunology 71(Stites,et al.eds.,8th ed. .1994);and Immunobiology(Janeway,et al.e ds., 5th ed. 2001).

[0041] As used herein, "core fucose," "core fucose residue," "fucose," or The "fucose residue" is the α1,6-glycosylation site of the first GlcNAc of the Asn297-linked N-oligosaccharide. -refers to the fucose residue in the linkage. Ferrara et al., Proc Natl Acad Sci USA, 2011, 108:12669-74. "Core Fucose ", "core fucose residue", "fucose", and "fucose residue" are used interchangeably in this disclosure. Used interchangeably.

[0042] The term "Fab" or "Fab region" refers to the region of an antibody that binds to an antigen. IgG typically contains two Fab regions, each of which is one of the two arms of the Y-shaped IgG structure. Each Fab region typically contains one variable region of each of the heavy and light chains. and one constant region. More specifically, the variable region of the heavy chain in the Fab region The variable and constant regions are the VH and CH1 regions, the variable and constant regions of the light chain in the Fab region. The constant regions are the VL and CL regions. The VH, CH1, VL, and CLs can be arranged in a variety of ways to confer antigen binding capacity in accordance with the present disclosure. For example, a VH region and a CH1 region may be on one polypeptide, and a VL region and a CH2 region may be on the same polypeptide. The L region may be on a separate polypeptide, similar to the Fab region of conventional IgG. Generally, the VH, CH1, VL, and CL domains are all present on the same polypeptide. , which can be oriented in different orders, as described in more detail in the following sections. .

[0043] The terms "variable region," "variable domain," "V region," or "V domain" refer to Located approximately at the amino terminus of the heavy or heavy chain, approximately 120-130 amino acids in the heavy chain and approximately 140-150 amino acids in the light chain. It refers to a portion of the light or heavy chain of an antibody having a length of 100 to 110 amino acids, and is used for each specific antibody The variable region of the heavy chain is designated "VH" and is used for the binding and specificity of the antibody to its particular antigen. The variable region of the light chain may be referred to as "VL." The term "variable" refers to the variable region. The V region is a specific segment of the antibody that binds to the antigen. The variable region mediates the binding of the antibody and determines the specificity of a particular antibody for a particular antigen. The variability is not uniform across the 110 amino acid span of the V region. Instead, the V region , and more variable regions called "hypervariable regions" ( For example, fragments of about 15-30 amino acids separated by shorter regions of extreme variability The framework region (FR) is a region with less variability (e.g., The variable regions of the heavy and light chains each contain four FRs, with the largest stretch consisting of a single FR. The β-sheet structure is connected by three hypervariable regions, which connect the β-sheet structure. The hypervariable regions within each chain form loops that connect the two strands and may form part of a beta sheet structure. are held together in close proximity by the FRs and, together with the hypervariable regions of the other chains, form the antigen-binding portion of the antibody. contributes to the formation of the nucleotide sequence (e.g., Kabat et al., Sequences of f Proteins of Immunological Interest(5th ed. 1991). The constant region is not directly responsible for binding the antibody to the antigen. Although not involved in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), The variable regions exhibit various effector functions, including the involvement of antibodies. In a specific embodiment, the variable region is a human variable region.

[0044] "Kabat variable region residue numbering" or "amino acid positions as in Kabat" The term "sequence numbering" and variations thereof refer to the heavy chain of the antibody compilation of Kabat et al. (supra). This numbering system refers to the numbering system used for the variable region or light chain variable region. The actual linear amino acid sequence may be determined by truncating or deleting the FR or CDR of the variable domain. may contain fewer or additional amino acids corresponding to insertions therein. For example, The variable domain contains a single amino acid insertion after residue 52 (residue 52a according to Kabat) , three inserted residues after residue 82 (e.g., residues 82a, 82b according to Kabat The Kabat numbering of residues may be, for a given antibody, Aligning the antibody sequence with the "standard" Kabat numbered sequence at the homologous regions The Kabat numbering system is used to number the residues in the variable domain ( Generally used to refer to approximately residues 1-107 of the light chain and approximately residues 1-113 of the heavy chain (e.g. (See, for example, Kabat et al., supra.) The "EU numbering system" or "EU index" refers to Generally used when referring to residues within an immunoglobulin heavy chain constant region (e.g., K (EU index as reported in Kabat et al.). "A" refers to the residue numbering of a human IgG1 EU antibody. Other numbering systems include For example, AbM, Chothia, Contact, IMGT, and AHon It is listed.

[0045] The term "heavy chain" when used in reference to an antibody refers to a polypeptide of approximately 50-70 kDa. a peptide chain, the amino terminal portion of which contains a variable region of about 120 to 130 amino acids or more The carboxy-terminal portion of the heavy chain constant region includes the amino acid sequence of the heavy chain constant region. Based on the amino acid sequence, they are classified as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), of five distinct types (e.g., isotypes) The distinct heavy chains vary in size, with α, δ, and γ having approximately 450 When combined with the light chain, the α- and ε-chains contain approximately 550 amino acids, and the α- and ε-chains contain approximately 550 amino acids. These distinct types of heavy chains are each divided into five well-known classes (e.g., isotypes). ) antibodies, IgA, IgD, IgE, IgG, and IgM (four subclasses of IgG, i.e., IgG1, IgG2, IgG3, and IgG4 are also included.

[0046] The term "light chain" when used in reference to an antibody refers to a polypeptide chain of approximately 25 kDa. wherein the amino terminal portion contains a variable region of about 100 to about 110 amino acids or more, The carboxy-terminal portion of the light chain contains the constant region. The approximate length of the light chain is 21 to 21 Based on the amino acid sequence of the constant domain, they are classified as kappa (κ) or lambda ( There are two different types called λ.

[0047] As used herein, "hypervariable region," "HVR," The terms "complementarity determining region" and "Complementarity Determining Region, CDR" are used interchangeably. , are used interchangeably. "CDR" refers to a CDR that is a sequence of an immunoglobulin (Ig or antibody) VH β-seq sequence. One of the three hypervariable regions (H1, H2) in the non-framework region of the ATP framework 2, or H3), or non-framework regions of the antibody VL β-sheet framework The term "L1" refers to one of the three hypervariable regions (L1, L2, or L3) in the CDRs are variable region sequences interspersed within framework region sequences.

[0048] CDR regions are well known to those skilled in the art and are defined by well-known numbering systems. For example, Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most Commonly used (see, e.g., Kabat et al., supra). Instead, it refers to the position of the structural loop (see, e.g., Chothia and Lesk, J (See Mol. Biol., 1987, 196:901-17). Kabat no. Ends of the Chothia CDR-H1 loop as numbered using the numbering convention varies from H32 to H34 depending on the length of the loop (this is in accordance with the Kabat numbering The scheme is to place the insertion at H35A and H35B, and neither 35A nor 35B exists. If not present, the loop ends at 32, and if only 35A is present, the loop ends at 33. (If both 35A and 35B are present, the loop ends at 34). AbM hypervariable region represents a compromise between the Kabat CDR and the Chothia structural loop, while Oxford d Used by AbM antibody modeling software from Molecular ( For example, Antibody Engineering Vol.2 (Kontermann and Dubel, eds., 2d ed. 2010). The "act" hypervariable regions are based on the analysis of available complex crystal structures. Another universal numbering system that is used worldwide is ImMunoGeneTics (IMGT ) Information System (registered trademark) (Lafranc, et al.,Dev.Comp.Immunol.,2003,27(1):55-77). IMGT is a system of immunoglobulins (IG), T cell receptors (TCRs), and r, TCR), and the major histocompatibility complex (MHC) of humans and other vertebrates. The MHC (Multi-Healthcare Computing Center) is a specialized integrated information system. The immunoglobulins are referred to in terms of both amino acid sequence and position within the light or heavy chain. The "positions" of the CDRs within the structure of globin variable domains are conserved among species and are called loops. Since the variable domain sequences are present in different structures, it is necessary to align them according to their structural features. By using the nomenclature system, CDR and framework residues are easily identified. This information is used to identify CDR residues from immunoglobulins of one species, typically from human antibodies. It can be used to port and replace existing acceptor frameworks. gger and Pluckthun, J. Mol. Biol., 2001, 309: 657-70, an additional numbering system (AHon) was developed. For example, Contrast between numbering systems, including Kaba numbering and the IMGT specific numbering system Reaction relationships are well known to those skilled in the art (see, e.g., Kabat, supra; Chothia and Les See k, supra; Martin, supra; Lefranc, et al., supra. ) The residues from each of these hypervariable regions or CDRs are shown below.

[0049] [Table 1]

[0050] The boundaries of a given CDR may vary depending on the scheme used to identify it. Unless otherwise specified, the "CDRs" and "complementary domains" of a given antibody or regions thereof, such as variable regions, The term "CDR-H" as well as the individual CDRs of an antibody or regions thereof (e.g., "CDR-H"). 1, CDR-H2) by any of the known schemes described herein above. It should be understood that the term "Kab" encompasses the complementary determining regions defined therein. specific CDRs or CDRs defined in the At, Chothia, or Contact Acts In some cases, schemes for identifying multiple CDRs are specified. The amino acid sequence is:

[0051] The hypervariable region may comprise an "extended hypervariable region" such as: 24-36 or 2 within VL; 4-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3), and 26-35 or 26-35A (H1), 50-65 or 49- 65 (H2), and 93-102, 94-102, or 95-102 (H3).

[0052] The term "constant region" or "constant domain" refers to the region of the antibody that is directly involved in binding to an antigen. However, the light and heavy chains exhibit various effector functions, such as interaction with Fc receptors. The term refers to the carboxy-terminal portion of the immunoglobulin, which is the variable region that contains the antigen-binding site. a portion of an immunoglobulin molecule that has a more conserved amino acid sequence than other portions of the molecule The constant region refers to the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain. may include:

[0053] The term "framework" or "FR" refers to the variable region residues that flank the CDRs. FR residues are used in, for example, chimeric antibodies, humanized antibodies, human antibodies, domain antibodies, and diabodies. FR residues are present in di-, linear, and bispecific antibodies. These are variable domain residues other than the DR residues. Typically, there are four of each of the VH and VL regions. The FR regions in VH are VH FR1, VH FR2, and VH F R3, and VH FR4 (or FR H1, FR H2, FR H3, and FR H4) The FR regions in VL are VL FR1, VL FR2, VL FR3 and VL FR4 (or FR L1, FR L2, FR L3 and FR L4).

[0054] As used herein, the term "Fc region" refers to, for example, a native sequence Fc region, a recombinant Fc region, or a recombinant Fc region. To define the C-terminal region of an immunoglobulin heavy chain, including the Fc region and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, human IgG heavy chains are The Fc region of the chain is composed of the amino acid residues at positions Cys226 and Pro230. The Fc region is often defined as extending from the C-terminal lysine (EU) to the carboxyl terminus. Residue 447 according to the numbering system of It can be removed by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody. A composition of intact antibodies includes a population of antibodies in which all K447 residues have been removed, and a mixture of antibodies with and without the K447 residue. A "functional Fc region" may comprise an antibody population that possesses the "effector functions" of a native sequence Fc region. Exemplary "effector functions" include C1q binding, CDC, Fc receptor binding, , ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors) Such effector functions are generally achieved by the Fc region acting as a binding region or It is necessary to combine it with a binding domain (e.g., an antibody variable region or domain). The Fc variants can be assessed using a variety of assays known to those skilled in the art. A "region" is a region that has been modified by at least one amino acid modification (e.g., substitution, addition, or deletion) to In certain embodiments, the variant comprises an amino acid sequence that differs from the amino acid sequence of a native sequence Fc region. The variant Fc region has at least one Fc region that is at least as distinct from a native sequence Fc region or the Fc region of a parent polypeptide. The Fc region of the parent polypeptide also has one or more amino acid substitutions, e.g., a native sequence Fc region or Fc region of the parent polypeptide. c region, having about 1 to about 10 amino acid substitutions, or about 1 to about 5 amino acid substitutions The variant Fc regions herein are native sequence Fc regions and / or Fc regions of a parent polypeptide. At least about 80% homology to the region, or at least about 90% homology thereto, e.g., It may have at least about 95% homology thereto.

[0055] When used in reference to an antigen or antibody, the term "variant" refers to a naturally occurring or unmodified sequence. Compared to the row, one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15 , about 1 to about 10, or about 1 to about 5 amino acid sequence substitutions, deletions, and / or additions. For example, a CD37 variant may refer to a peptide or polypeptide that is an amino acid sequence of a native CD37. One or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15) amino acid sequences , about 1 to about 10, or about 1 to about 5). The variants include one or more modifications to the amino acid sequence of a native or previously unmodified anti-CD37 antibody. Two or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about Variants can arise from alterations of about 1 to about 5. Variants can be allelic variants or splicing variants. Polypeptide variants can be naturally occurring, such as variants, or can be artificially constructed. The variants can be prepared from corresponding nucleic acid molecules encoding the variants. The variants or anti-CD37 antibody variants may be used to inhibit the functional activity of CD37 or anti-CD37 antibodies, respectively. In a specific embodiment, the anti-CD37 antibody variant retains at least In certain embodiments, the variant inhibits and / or antagonizes CD37 activity. or an anti-CD37 antibody VH or VL region or subregion, e.g., one or more C Single nucleotide polymorphism (SNP) mutations in the nucleic acid molecule encoding DR Encoded by variants.

[0056] The term "identity" is determined by aligning and comparing sequences. refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules. "Percent amino acid sequence identity" for peptide sequences is the maximum sequence identity percentage. The sequence identity is determined without considering any conservative substitutions as part of the sequence identity. the reference polypeptide after aligning the sequences and introducing gaps if necessary. It is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the sequence. Alignment for purposes of determining percent amino acid sequence identity is well known in the art. Various methods within the skill of the art, e.g., BLAST, BLAST-2, ALI GN or MEGALIGN (DNAStar, Inc.) software, etc. This can be accomplished using available computer software. Any algorithm needed to achieve maximal alignment over the entire length of the sequences being Appropriate parameters for aligning sequences can be determined, including the algorithm .

[0057] A "modification" of an amino acid residue / position refers to a change in the primary amino acid sequence compared to the starting amino acid sequence. The term "alteration" refers to a change in the sequence of the amino acid residue / position. Conservative modifications include substitution of a residue with another amino acid (e.g., conservative or non-conservative substitution). , one or more (e.g., typically 5, 4, or 3) adjacent residues / positions This includes insertion of amino acids (less than 100) and / or deletion of said residues / positions.

[0058] As used herein, "epitope" is a term of art and is used to describe an antibody An epitope is a localized region of an antigen to which a specific antigen can bind. Alternatively, the epitope may be a conformational epitope, a non-linear epitope, or a discontinuous epitope. In the case of a peptide antigen, for example, an epitope can be defined as a sequence of consecutive amino acids ("linear") of a polypeptide. epitopes), or the epitope may consist of two or more non-contiguous regions of a polypeptide. These amino acids may be present in a "conformational," "non-linear," or "discontinuous" epitope. Linear epitopes may or may not depend on secondary, tertiary, or quaternary structure. It will be appreciated by those skilled in the art that in some embodiments, Antibodies are made of amino acids that are either folded into a native three-dimensional protein structure or not. In other embodiments, the antibody recognizes and binds to an epitope. To achieve this, the amino acid residues that make up the epitope must be able to take on specific conformations (e.g., bends, twists, etc.). It is necessary to show the shape (i.e., the shape being folded, rotated, or folded).

[0059] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein. It is commonly used to refer to polymers of amino acids of any length. Polymers can be linear or branched. may contain modified amino acids and may be interrupted by non-amino acids The term also refers to amino acid polypeptides that are naturally modified or modified by intervention. Examples of interventions include disulfide bond formation, glycosylation, Lipidation, acetylation, phosphorylation, or any other manipulation or modification. can be, for example, one or more amino acids, including, but not limited to, unnatural amino acids. Also included are polypeptides containing analogs of the above, as well as other modifications known in the art. The polypeptides of the present disclosure may bind to antibodies or other members of the immunoglobulin superfamily. In certain embodiments, a "polypeptide" may be present as a single chain or as two or more chains. It is understood that the above may occur as related chains.

[0060] The term "vector" refers to a vector used to introduce a nucleic acid sequence into a host cell, e.g., as used herein. used to carry or contain nucleic acid sequences such as nucleic acid sequences encoding the antibodies described in Vectors applicable for use include, for example, expression vectors, plasmids, These include phage vectors, viral vectors, episomes, and artificial chromosomes. The vector may contain selection sequences or markers that are capable of stably integrating into the host cell chromosome. In addition, the vector may contain one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included include, for example, genes that encode antibiotics or toxins. provide tolerance to, complement auxotrophic deficiencies, or supply important nutrients missing from the culture medium Expression control sequences include constitutive and inducible promoters, which are well known in the art. The nucleic acid sequence may include a transcriptional promoter, a transcription enhancer, a transcription terminator, etc. When expressed (e.g., both the heavy and light chains of an antibody, or antibody VH and VL), both The nucleic acid molecules can be inserted, for example, into a single expression vector or into separate expression vectors. For expression in a vector, the encoding nucleic acids are operably linked to one common expression control sequence. or different expression promoters, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into host cells can be carried out using methods well known in the art. Such methods include, for example, Northern blot analysis. mRNA by polymerase chain reaction (PCR) Nucleic acid analysis such as amplification, immunoblotting for expression of gene products, or transfected nucleic acids Suitable analytical methods for testing the expression of a sequence or its corresponding gene product include: Those skilled in the art will understand that the nucleic acid molecule is expressed in sufficient amounts to produce the desired product. Furthermore, expression levels can be adjusted to obtain sufficient expression using methods well known to those skilled in the art. I understand that it can be optimized.

[0061] As used herein, the term "host" refers to an animal, such as a mammal (e.g., a human). vinegar.

[0062] As used herein, the term "host cell" refers to a cell that has been transfected with a nucleic acid molecule. refers to the particular subject cell that may be cultured, and the progeny or potential progeny of such a cell. The progeny of the cell differ from the parent cell transfected with the nucleic acid molecule in that the nucleic acid molecule has been incorporated into the host cell genome. Not identical due to mutations or environmental influences that may occur in subsequent generations or accumulations. There is a saying.

[0063] An "isolated nucleic acid" is a nucleic acid, e.g., RNA, DNA, or mixed nucleic acid, that is not present in other genomic DNA. DNA sequences and proteins, such as ribosomes and polymerases, that are naturally associated with the natural sequences An "isolated" nucleic acid molecule is one that is substantially separated from other proteins or complexes. It is separated from other nucleic acid molecules present in natural sources. Any "isolated" nucleic acid molecule, if produced by recombinant techniques, may be free from other cellular material or It may be substantially free of culture medium and, if chemically synthesized, may contain chemical precursors or other chemicals. In a specific embodiment, the antibodies described herein may be coated One or more nucleic acid molecules that encode the nucleic acid are isolated or purified. recombinant or cloned DNA isolates, including nucleic acid sequences removed from the environment; and chemically synthesized analogues or biologically synthesized analogues in heterologous systems. A substantially pure molecule can include isolated forms of the molecule.

[0064] "Polynucleotide," "nucleotide," or "nucleic acid" are used interchangeably herein. When used herein, nucleotides refer to polymers of nucleotides of any length, including DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases. and / or their analogs, or by DNA or RNA polymerases, or by synthetic reactions The polynucleotide may be any substrate that can be incorporated into a polymer by reaction. , modified nucleotides, such as methylated nucleotides and their analogs. The "oligonucleotides" used are generally less than about 200 nucleotides in length. "Oligonuclease" refers to a short, mostly single-stranded synthetic polynucleotide that is not necessarily required for the synthesis of a nucleic acid. The terms "nucleotide" and "polynucleotide" are not mutually exclusive. The above discussion of oligonucleotides is equally fully applicable to oligonucleotides. The cells that produce the antibodies of the present disclosure include the parent hybridoma cells as well as the nucleic acid encoding the antibody. Examples include bacterial and eukaryotic host cells into which the acid has been introduced. The left-hand end of any disclosed single-stranded polynucleotide sequence is the 5' end. The leftward direction of a nucleotide sequence is referred to as the 5' direction. The direction of addition of the RNA to the 5' end of the RNA transcript is called the transcription direction. The sequence region on the DNA strand that has the same sequence as the transcript is called the "upstream sequence" and is the sequence that is used to encode the RNA transcript. The region of sequence on the DNA strand that has the same sequence as the RNA transcript at the 3' to 3' end of the This is referred to as the "downstream sequence."

[0065] As used herein, the term "pharmaceutically acceptable" refers to a compound that is pharmaceutically acceptable for use in animals. and more specifically, for use in humans, by a federal or state regulatory agency. approved or in accordance with the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized It means that it is listed in the Pharmacopoeia.

[0066] "Excipient" refers to a pharmaceutical ingredient, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients refer to substances, compositions, or vehicles that are physiologically acceptable. Examples of excipients include absorption enhancers. agents, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers agents, extenders, fillers, flavoring agents, wetting agents, lubricants, fragrances, preservatives, propellants, release agents, disinfectants Examples of suitable encapsulating materials or additives include encapsulants, sweeteners, solubilizers, humectants, and mixtures thereof. The term "excipient" also includes diluents, adjuvants (e.g., Freund's It can refer to an adjuvant (complete or incomplete) or a vehicle.

[0067] In some embodiments, the excipient is a pharmaceutically acceptable excipient. Examples of excipients that may be used include buffers such as phosphates, citrates, and other organic acids; Antioxidants, including ascorbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polypeptides; peptides; proteins such as serum albumin, gelatin, or immunoglobulins; polyvinyl Hydrophilic polymers such as pyrrolidone; glycine, glutamine, asparagine, arginine, or amino acids such as lysine; monosaccharides, disaccharides, and sugars such as glucose, mannose, or dextran; Other carbohydrates containing thiamin; chelating agents such as EDTA; mannitol or sorbitol a sugar alcohol such as ethanol; a salt-forming counterion such as sodium; and / or TWEEN ( trademark), polyethylene glycol (PEG), and PLURON Pharmaceutically acceptable excipients include non-ionic surfactants such as ICS™. Other examples include Remington and Gennaro, Remington's P Described in Harmaceutical Sciences (18th ed. 1990) It is being done.

[0068] In one embodiment, each component is "pharmaceutical compatible" in the sense of being compatible with the other components of the pharmaceutical formulation. and are "reasonably acceptable" and do not cause excessive toxicity, irritation, allergic reaction, immunogenicity, or other adverse reactions. human and animal tissues or tissues without other problems or complications and with a reasonable benefit / risk ratio Suitable for use in contact with organs. ams & Wilkins:Philadelphia,PA,2005;Handb ook of Pharmaceutical Excipients,6th ed. ;Rowe et al.,Eds.;The Pharmaceutical Pre ss and the American Pharmaceutical Assoc. iation:2009;Handbook of Pharmaceutical A dditives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2007;Pharmaceutical P reformulation and formulation,2nd ed.;Gi bson Ed.;CRC Press LLC:Boca Raton,FL,200 See, e.g., U.S. Pat. No. 6,299,149. In some embodiments, pharmaceutically acceptable excipients are employed. At dosages and concentrations, they are non-toxic to cells or mammals exposed to them. In embodiments, the pharmaceutically acceptable excipient is an aqueous pH buffered solution.

[0069] In some embodiments, the excipients include water and those derived from petroleum, animal, plant, or synthetic sources. The oil may be a sterile liquid such as peanut oil, soybean oil, mineral oil, sesame oil, or the like. Water is an exemplary excipient when the composition (eg, a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are also suitable liquid excipients, particularly for injectable solutions. The excipients may be starch, glucose, lactose, sucrose, etc. cereals, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate , Glyceryl Monostearate, Talc, Sodium Chloride, Dried Skim Milk, Glyceryl Stearate Examples of the solvent include propylene, glycol, water, and ethanol. The composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. It may take the form of a solution, suspension, emulsion, tablet, pill, capsule, powder, sustained-release formulation, or the like. Oral compositions containing the formulation contain pharmaceutical grade mannitol, lactose, starch, stearate, and sorbitol. Magnesium phosphate, sodium saccharin, cellulose, magnesium carbonate, etc. The composition may contain suitable excipients.

[0070] Compositions containing pharmaceutical compounds may be prepared, for example, by incorporating an antibody in isolated or purified form in a suitable amount of excipient. It may be included together with the agent.

[0071] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount that produces a desired result. "Amount of an antibody or pharmaceutical composition provided herein sufficient to prevent or reduce the risk of inflammatory bowel disease."

[0072] The terms "subject" and "patient" can be used interchangeably herein. As used herein, in certain embodiments, a subject is a non-primate (e.g., bovine, porcine, mammals such as mammals (e.g., horses, cats, dogs, rats, etc.) or primates (e.g., monkeys and humans) In a specific embodiment, the subject is a human. In one embodiment, the subject is a patient suffering from a disease state or In another embodiment, the subject is a mammal, e.g., a human, diagnosed with a disorder. is a mammal, eg, a human, at risk of developing the disorder.

[0073] "Administering" or "administration" means administering a substance to a subject or a group of subjects as described herein or known in the art. Mucosal, intradermal, intravenous, intramuscular, subcutaneous delivery, and / or any other physical delivery method known in the art. The act of injecting or otherwise physically delivering an extracorporeal substance into a patient, such as by a method Refers to the purpose.

[0074] As used herein, "treat," "treatment," and "treatment" refer to The term "to treat" refers to the treatment of a disease or condition resulting from the administration of one or more therapies. Treatment refers to the reduction or remission of the progression, severity, and / or duration of a disease or condition. Improvements are observed in patients, even though they may still have underlying conditions. whether there was a decrease, relief, and / or alleviation of one or more symptoms associated with the underlying disease; The term "treating" refers to a disease. This includes both the management and remission of The term refers to the beneficial effect that a subject derives from a treatment, and does not necessarily result in a cure of the disease. Not possible.

[0075] The terms "prevent," "preventing," and "prevention" refer to the prevention of a disease, disorder, condition, or refers to reducing the likelihood of the onset (or recurrence) of the associated condition.

[0076] The terms "about" and "approximately" mean within 20%, 15%, or 20% of a given value or range. Within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3% , within 2%, within 1%, or less.

[0077] As used in this disclosure and claims, the singular forms "a," "an," and "the" " includes the plural unless the context clearly indicates otherwise.

[0078] Whenever an embodiment is described herein with the term "comprising," it is understood that the term "comprises" is not intended to be limiting unless otherwise specified. Other similar embodiments described with respect to "consisting of" and / or "consisting essentially of" may also be used. It is understood that the phrase "consisting essentially of" is used herein to describe an embodiment. Whenever "consisting of" is described, the same applies to the similar embodiments described above. It is also understood that embodiments are also provided.

[0079] The term "between" used in phrases such as "between A and B" or "between A and B" refers to A and A refers to the range that includes both A and B.

[0080] The term "and / or" as used herein in phrases such as "A and / or B" means It is intended to include both A and B, A or B; A (alone); and B (alone). Similarly, the term "and / or" when used in phrases such as "A, B, and / or C" Each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; It includes A and C; A and B; B and C; A (alone); B (alone); and C (alone). This is the intention.

[0081] 5.2 Hypofucosylation Antibody glycosylation can be linked to asparagine residues (N-oligosaccharides) or serine / threosaccharides. Attachment of oligosaccharides to antibodies via two types of covalent bonds: attachment to nucleotide residues (O-oligosaccharides) This is a type of post-translational modification that can occur through addition (Alter, G., et al., S emin Immunol.,2018,39:102-10), which has a significant impact on the therapeutic function of antibodies. (Walsh, G. and Jefferis, R., Nat. Biot echnol.,2006,24:1241-52;Jefferis, R., Nat. Rev.Drug Discov.,2009,8(3):226-34;Dalzie l,M.,et al.,Science,2014,343(6166):12356 81) In particular, all IgG antibodies share the conserved Asn-297 residue in their Fc regions. It is glycosylated (Alter G., et al., supra).

[0082] Asn-297 linked N-oligosaccharides consist of two covalently linked N-acetylglucosamines ( A conserved biantennary core structure consisting of a 2-membered mannose-binding domain (GlcNAc) and a 2-membered mannose-binding domain (GlcNAc). (Liu, L., J Pharm Sci., 2015, 104(6):18 66-84), which is linked to two other mannose residues in a 1,3-branched and 1,6-branched manner. (Alter, G., et al., supra). A monosaccharide, fucose, a bisecting GlcNAc, and two sialic acids (Alter, G ., et al., supra), the core structure may be extended, resulting in significant structural and functional changes. This causes heterogeneity (Jefferis, R., Biochem J., 1990, 268(3):529-37;Rudd,PM,Science,2001,291 (5512):2370-6; Liu, L., supra). At least 30 structures (glycoforms) of oligosaccharides have been reported (Alter, G .,et al., supra).

[0083] Antibodies expressed in mammalian cells are typically greater than 80% fucosylated (Kamo da,S.,et al.,J Chromatogr A.,2004,1050(2 ):211-6;Shinkawa, T., et al., J Biol Chem., 2003,278(5):3466-73). For example, normal Chinese hamster eggs Chinese Hamster Ovary (CHO) cells and HEK293 cells are used to bind fucose to IgG. Addition of Asn-297-linked N-oligosaccharides to antibodies occurs in 80–98% of cases (Shields, RLet al., J Biol Chem.,2002,277(30):267 33-40).

[0084] In one embodiment, the Fc region does not have fucose in the oligosaccharides attached thereto; and Provided herein are antibodies with RE mutations in the Fc region. The oligosaccharides bound to the Fc region of the Provided herein are populations of antibodies comprising antibodies with mutations. , less than 80% of the oligosaccharides covalently attached to the antibody population contain fucose residues, and these A population of antibodies whose Fc regions contain K248E and T437R mutations (RE mutations) , provided herein.

[0085] In some embodiments, less than 70% of the oligosaccharides covalently attached to the population of antibodies are In some embodiments, the oligosaccharides covalently attached to the population of antibodies include cos residues. In some embodiments, less than 60% of the covalently attached antibodies comprise a fucose residue. In some embodiments, less than 50% of the oligosaccharides of the antibody comprise a fucose residue. Fewer than 40% of the oligosaccharides covalently attached to the population contain fucose residues. In this form, less than 30% of the oligosaccharides covalently attached to the antibody population contain a fucose residue. In yet other embodiments, less than 20% of the oligosaccharides covalently attached to the population of antibodies are fucosaccharides. In yet another embodiment, 10 of the oligosaccharides covalently attached to the population of antibodies comprise saccharide residues. Less than % contain fucose residues.

[0086] The Asn297 linker on the antibody can be determined using standard techniques known to those skilled in the art, for example, mass spectrometry. The N-oligosaccharides can be characterized (Pereira, N.A., et al., (See Shields, RLet et al., supra). For example, matrix-assisted laser Matrix-assisted laser desorption / ionization time-of-flight mass spectrometry ion time-of-flight mass spectral (MALDI-TOF-MS) analysis, 50 mg IgG antibodies were placed in a MultiScreen 96-well IP plate (Millipore). The antibody was immobilized on a polyvinylidene fluoride membrane using a 1000-μL PBS solution. 50 mL of a 0.1 M solution of DTT in 360 mM EDTA, 360 mM Tris, and 8 M urea The protein was reduced using HCl. The free sulfhydryls resulting from the reduction step were then To carboxymethylate the groups, they were placed in RCM buffer containing 0.1 M iodoacetic acid. The membrane-bound proteins were then incubated in the buffer at 25°C for 30 minutes in the dark. Incubate in a 1% solution of polyvinylpyrrolidone 360 ​​(Sigma) in water at 25°C for 1 hour. The oligosaccharides were then cleaved from the protein by a three-step process: 32 units of Peptide:N-Glycosidase F (New England Biolabs) in 25 mL of pH 8.4 Tris-acetate buffer containing HCl (Beverly, MA). Incubate at 37°C for 3 hours and then add 1.5 M acetic acid (2.5 mL) to lower the pH. and incubate at 25°C for 3 hours (Shields, RR, Let al., JB iol Chem., 2001, 276(9):6591-604).

[0087] In some embodiments, the antibodies provided herein comprise an antibody that binds to the antibody. The antibody or fragment thereof can be encoded in a host cell lacking the addition of fucose to the oligosaccharide. The gene is produced by expressing a polynucleotide containing the gene.

[0088] In mammalian cells, FUT8 is core fucosylated (GDP- The only enzyme that catalyzes the transfer of a fucose residue to the innermost GlcNAc is α-1,6-fucosyltransferase (α-1,6-fucosyltransferase). Encoding cosyltransferase (Imai-Nishiya, H., et al ., BMC Biotechnol., 2007, 7:84). Oligosaccharide fucosylation Intracellular GDP-fucose is required as a substrate, which is essential for the synthesis of nascent ATP in the cytoplasm. In the de novo pathway, GDP-mannose 4,6-dehydrogenase is synthesized via the salvage pathway. GDP-mannose 4,6-dehydratase (GMD) converts GDP-mannose to G GDP-4-keto-6-deoxy-mannose (GKDM) followed by GDP-keto-6-deoxymannose 3,5-epimerase ,4-reductase (FX) mediates the synthesis of GDP-fucose (Im (I-Nishiya, H., et al., supra). Therefore, the lack of GMD enzyme Cell lines with mutations in the FUT8 gene, such as CHO Lec13 cells, or α-1, 6 Reduction of fucosyltransferase activity has been shown to generate afucosylated antibodies. (Pereira, NA, et al., Mabs, 2018, 10(5): For example, approximately 10% fucosylation (Shields, RLet a l., supra) or less can be consistently produced in Lec13 cells ( Shields, RLet et al., supra; Kanda Y., Biotechno l Bioeng.,2006,94(4):680-8), but increased fucosylation This can occur when cells are grown to confluence in static flasks (Perei ra,NA,et al., supra).

[0089] Addition of a bisecting GlcNAc to the oligosaccharide core structure reduces steric hindrance of fucosylation. (Alter, G., et al., supra). β-1,4-mannosyl-glycotanone catalyzes the addition of a bisecting GlcNAc to the glycoprotein Protein 4-β-N-acetylglucosaminyltransferase (β-1,4-mannosyl-glyc Overexpression of polyprotein 4-β-N-acetylglucosaminyltransferase (GnT-III) inhibits F c) significantly reduced fucosylation (Pereira, N.A., et al. l., supra).

[0090] Furthermore, the inactivated Golgi GDP-fucose transporter (GFT) gene The gene (Slc35c1) elicits afucosylated antibodies in CHO-gmt3 cells, for example. It has been shown that fucoproteins are produced by fucoproteins (Pereira, NA, et al., supra). Biochemical inhibitors of silylations, such as 2-fluorofucose and 5-alkynylfucose Any fucose analog can be used to generate afucosylated antibodies. (Pereira, NA, et al., supra). Fucose synthesis in mammalian cells GKDM, an intermediate in the biosynthetic pathway, is synthesized by the bacterial GDP-4-keto-6-deoxymannose receptor. GDP is converted to GDP by bacterial GDP-4-keto-6-deoxy mannose reductase (RMD) -rhamnose, thus bypassing the fucose biosynthetic pathway Afucosylated antibodies have also been produced in cells in which bacterial RMD is heterologously expressed in the cytosol. (Pereira, NA, et al., supra).

[0091] In some embodiments, the antibodies provided herein bind to any of the above enzymes. These antibodies are produced by expressing them in host cells that have a deficiency in some In some embodiments, the host cell expresses a reduced GDP-mannose 4,6-dehydratase ( In some embodiments, the host cell has reduced α-1,6 fucoprotein (GMD) activity. It has silyltransferase activity.

[0092] 5.3 Fc variants with enhanced effector function The antibodies provided herein comprise a nucleotide sequence encoding a lysine at position 248 (K248) (E It has mutations at position 437 (U numbering) and threonine at position 437 (T437) (EU numbering). Lysine at position 248 (K248) (EU numbering) and threonine at position 437 (T437) (EU numbering) are both conserved sequences in the Fc region among different IgG subtypes. These are the residues that were affected (Zhang, D., et al., supra). and K248E (EU numbering) inhibit oligomerization of ribosomal protein upon antigen binding at the cell surface. It has been shown that it promotes and has enhanced effector functions (Zhang, D., et al., supra). The T437R and K248E double mutation (the "RE mutation") was dose-dependent. It was shown that it confers CDC activity to wild-type IgG1 antibodies that did not previously possess CDC activity. (Zhang, D., et al., supra).

[0093] "EU numbering" or "EU index" generally refers to the number of sequences in an immunoglobulin heavy chain constant region. This refers to the residue numbering of the human IgG1 EU antibody. This was calculated by aligning the antibody sequence with the sequence of the Eu antibody (Ede lman,GM,et al.,Proc Natl Acad Sci US A, 1969, 63(1):78-85; Kabat, et al., supra), therefore Thus, each residue that is homologous to a residue in the Eu antibody will have the same residue number as the Eu residue. do.

[0094] Other Fc region mutations, such as S239D / I332E and S239D / I332 Antibodies containing E / A330L (EU numbering) significantly increased FcγR activity through enhanced binding to FcγRs. It has also been shown that IgG4-dependent leukocyte proliferation is enhanced by ADCC (Lazar, GA et al., Proc Natl Acad Sci USA,2006,103(11):40 05-10).

[0095] 5.4 Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) ) Effector function The antibodies or populations of antibodies provided herein have enhanced ADCC activity and enhanced Both have enhanced CDC activity.

[0096] Therapeutic antibodies target natural killer (NK) cells, macrophages, mononuclear phagocytes, and neutrophils. It binds to Fc receptors on the cell surface of effector cells such as leukocytes and eosinophils (Saunde r,KO,Front Immunol.,2019,10:1296), antibody dependent Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) A family of receptors for the Fc region of IgG that mediates important antibody-dependent effector functions are called Fcγ receptors (FcγR) (Cohen-Solal, J .F., Immunol Lett., 2004, 92(3):199-205), Fc FγRI, including the isoforms FcγRIIa, FcγRIIb, and FcγRIIc and Fcγ, including the isoforms FcγRIIIa and FcγRIIIb. RIII (Jefferis, R. and Lund, J., Immunol Lett.,2002,82(1-2):57-65).

[0097] Among various effector functions, ADCC and ADCP have clinically significant antitumor effects. In vitro, FcγRIII receptor (CD16)-mediated A Killing of trastuzumab-coated tumor cells via DCC mechanism As evidenced by the ability of K cells (Cooley, S., et al., Exp He matol.,1999;27(10):1533-41;Carson,WE,e t al.,Eur J Immunol.,2001,31(10):3016-30 25;Kubo,M.,et al.,Anticancer Res.,2003,2 3(6a):4443-9), and in vivo, in tumor invasion after trastuzumab treatment. As evidenced by the increase in NK cell numbers in the Nat Med.,2000,6(4):443-6;Arnould,L.,et a l., Br J Cancer, 2006, 94(2):259-67), e.g., AD CC has been shown to be an important mechanism for the antitumor effects of trastuzumab. Macrophage-mediated ADCP is important for the antitumor effect of trastuzumab. has been shown (Shi, Y., et al., J Immunol., 2015, 19 4(9):4379-86).

[0098] Non-fucosylated or hypofucosylated antibodies have been shown to be superior in CDC or antigen-binding capacity. Their binding ability to FcγRIIIa binding was enhanced without any detectable changes in the FcγRIIIa binding. showed dramatically enhanced ADCC activity (Okazaki, A., et al. ,J Mol Biol.,2004,336(5):1239-49;Kanda,Y .,et al.,Glycobiology,2007,17(1):104-18) N-oligosaccharides in the antibody Fc region are essential for binding to FcγR, which is the Fc domain of the antibody. Involved in vector function (Yamane-Ohnuki, N. and Satoh, M. ,Mabs,2009,1(3):230-6).

[0099] The absence of fucose on the N-oligosaccharides of the antibody Fc region inhibits the proliferation of natural killer (NK) cells and It binds to the FcγRIIIa receptor present on immune effector cells such as macrophages. It has been shown that this dramatically enhances the binding capacity of antibodies, resulting in anti-tumor therapeutic effects ( Pereira, NA, et al., supra). The FcγRIIIa receptor binds to Fc Binds to the Fc region through interactions with the hinge region and CH2 domain (Radaev ,S.,et al.,J Biol Chem.,2001,276:16469-7 7;Sondermann,P.,et al.,Nature,2000,406:2 67-73). Therefore, the absence of fucose eliminates steric hindrance and inhibits Fc-FcγRII. Enhances Ia interactions, leading to enhanced effector function (Pereira, NA .,et al., supra).

[0100] Complement-dependent cytotoxicity (CDC) is another important antibody effector function. In the classical complement activation pathway, the complement C1q heterohexameric headpiece and oligomeric antibodies The binding between the complexes initiates the complement cascade of proteins (Wang, G. et al.,Mol Cell,2016,63:135-45;Diebolder,C .A.et al.,Science,2014,343:1260-3), which is C Opsonization of target cells with C3-derived opsonins (e.g., C3b) and potent inflammation This results in the production of mediators (C3a and C5a), which ultimately induce membrane attack on the target cell membrane. The membrane attack complex (MAC) (C5b-C9) is formed (Rei s,ES,et al.,Nat Rev Immunol.,2018,18:5 -18) CDC also reported the use of the anti-CD20 mAb rituximab and the anti-CD38 mAb daratumab. It has also been shown that tafamidis has a clinically significant antitumor effect (de Weer s,M.,et al.,J Immunol.,2011,186:1840-8;L okhorst,HM,et al.,N Engl J Med.,2015,3 73:1207-19;Taylor,RPand Lindorfer,MA ,Semin Immunol.,2016,28:309-16).

[0101] Fc region that promotes antibody oligomerization, such as RE mutations and E345R (EU numbering) Mutations in α- and β-actin have been demonstrated to significantly enhance the CDC activity of antibodies (Dieb older, CA et al., supra; Zhang, D., et al., supra).

[0102] In some embodiments, the ADCC activity of the antibody is greater than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is 10% higher than that of a normal fucosylated antibody. In some embodiments, the ADCC activity of the antibody is 20% higher than that of an antibody having 30% higher than antibodies with normal fucosylation. In some embodiments, the AD of the antibody The CC activity is 40% higher than that of an antibody with normal fucosylation. The ADCC activity of this antibody is 50% higher than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is 60% greater than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is higher than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is 70% higher than that of normal fucosins. In some embodiments, the ADCC activity of the antibody is 80% higher than that of an antibody having a methylation group. 90% higher than antibodies with normal fucosylation. In some embodiments, the antibody The ADCC activity is more than twice that of antibodies with normal fucosylation. The ADCC activity of this antibody is more than three times that of an antibody with normal fucosylation. In this embodiment, the ADCC activity of the antibody is more than four times greater than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is greater than that of an antibody with normal fucosylation. In some embodiments, the ADCC activity of the antibody is greater than 5-fold higher than that of normal fucosylated antibodies. In some embodiments, the ADCC activity of the antibody is more than six times that of an antibody having In some embodiments, the ADCC of the antibody is more than 7-fold higher than that of an antibody having fucosylation of The activity is more than 8-fold greater than that of an antibody with normal fucosylation. The ADCC activity of antibodies with normal fucosylation is more than nine times higher. In this embodiment, the ADCC activity of the antibody is more than 10-fold higher than that of an antibody with normal fucosylation.

[0103] In some embodiments, the antibodies also have higher CDC activity. In this embodiment, the CDC activity of the antibody is 10% higher than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 20% greater than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 3 times greater than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 0.0% higher than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 40% higher than that of the antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 50% higher than that of the antibody with the RE mutation. In some embodiments, the CDC activity of the antibody is 60% higher than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is 70% higher than that of an antibody without the mutation. In some embodiments, the CDC activity of the antibody is 80% higher than that of an antibody without the RE mutation. In some embodiments, the C of the antibody is 90% higher than that of an antibody without the RE mutation. The DC activity is more than twice that of the antibody without the RE mutation. The CDC activity of the antibody is more than three times that of the antibody without the RE mutation. The CDC activity of the antibody is more than four times that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is more than five times that of an antibody without the RE mutation. In some experiments, the CDC activity of this antibody is more than six times that of the antibody without the RE mutation. In this form, the CDC activity of the antibody is more than 7 times that of the antibody without the RE mutation. In embodiments, the CDC activity of the antibody is more than 8-fold greater than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is more than 9-fold greater than that of an antibody without the RE mutation. In some embodiments, the CDC activity of the antibody is more than 10-fold greater than that of an antibody without the RE mutation. do.

[0104] 5.5 Anti-HLA-G antibodies and related molecules In one aspect, provided herein are anti-HLA-G antibodies.

[0105] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 172 and a VL comprising the sequence MHGB732, which contains a VH comprising the amino acid sequence of SEQ ID NO: 174. In one embodiment, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 173 and a VL comprising the amino acid sequence of SEQ ID NO: 175. and VH containing the amino acid sequence MHGB738.

[0106] In some embodiments, provided herein are antibodies that bind to HLA-G, The antibody comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of SEQ ID NO: 174. VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequence of and (ii) a VH comprising VL CDR1, VL CDR3, and VL CDR3, respectively, of SEQ ID NO: 172. VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of and a VL comprising a VL CDR3. Provided herein are antibodies that bind to (i) the antibody of SEQ ID NO: 175. VH CDR1, VH CDR2, and VH CDR3 amino acid sequences, respectively. a VH comprising CDR1, VH CDR2, and VH CDR3; and (ii) SEQ ID NO: 1. 73, the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having sequences In some embodiments, provided herein are antibodies that bind to HLA-G, The antibody comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of SEQ ID NO: 174. and VH CDR1, VH CDR2, and VH CDR3 amino acid sequences. and (ii) a VH comprising VL CDR1, VL CDR3, respectively, of SEQ ID NO: 173. VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of and a VL comprising a VL CDR3. Provided herein are antibodies that bind to (i) the antibody of SEQ ID NO: 175. VH CDR1, VH CDR2, and VH CDR3 amino acid sequences, respectively. VH comprising VH CDR1, VH CDR2, and VH CDR3; and (ii) SEQ ID NO: 172 amino acids of VL CDR1, VL CDR2, and VL CDR3, respectively and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the sequences include.

[0107] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL The CDR1, VL CDR2, and VL CDR3 sequences are numbered according to the Kabat numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VH CDR4, VH CDR5, VH CDR6, VH CDR7, VH CDR8, VH CDR9, VH CDR10, VH CDR11, VH CDR22, VH CDR33, VH CDR12, VH CDR13, VH CDR14, VH CDR15, VH CDR26, VH CDR37 The VL CDR1, VL CDR2, and VL CDR3 sequences are shown according to the Chothia numbering scheme. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VH CDR4, VH CDR5, VH CDR6, VH CDR7, VH CDR8, VH CDR9, VH CDR10, VH CDR11, VH CDR12, VH CDR13, VH CDR14, VH CDR15, VH CDR16, VH CDR17, VH CDR18, VH CDR1 R3, VL CDR1, VL CDR2, and VL CDR3 sequences are numbered using IMGT numbering. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VH CDR4, VH CDR5, VH CDR6, VH CDR7, VH CDR8, VH CDR9, VH CDR10, VH CDR11, VH CDR12, VH CDR13, VH CDR14, VH CDR15, VH CDR16, VH CDR17, VH CDR18, VH CDR19 VL CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are numbered according to AbM numbering. Follow the system.

[0108] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CDR1 having the amino acid sequence of SNSAAWN (SEQ ID NO: 184), RT VH C having the amino acid sequence YYRSKWYNDYAVSVKS (SEQ ID NO: 185) DR2, and V having the amino acid sequence of DRRYGIVGLPFAY (SEQ ID NO: 186) (ii) a VH comprising the H CDR3, and (iii) KSSQSVLHSSNNKNYLT (SEQ ID NO: 187), VL CDR1 having the amino acid sequence of WASTRES (SEQ ID NO: 188) VL CDR2 having the amino acid sequence HQYYSTPPT (SEQ ID NO: 189) and a VL comprising a VL CDR3 having the amino acid sequence

[0109] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CDR1 having the amino acid sequence of GDSVSSNSA (SEQ ID NO: 190); VH CDR2 and DRR having the amino acid sequence of YYRSKWY (SEQ ID NO: 191) comprising a VH CDR3 having the amino acid sequence of YGIVGLPFA (SEQ ID NO: 192), VH, and (ii) an amino acid sequence of SQSVLHSSNNKNY (SEQ ID NO: 193). VL CDR1 having the amino acid sequence of WAS (SEQ ID NO: 194), and a VL CDR3 having the amino acid sequence of YYSTPP (SEQ ID NO: 195). L.

[0110] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) VH CDR1 having the amino acid sequence of GDSVSSNSAA (SEQ ID NO: 196) TYYRSKWYN (SEQ ID NO: 197), and VH CD having the amino acid sequence AGDRRYGIVGLPFAY (SEQ ID NO: 198) (ii) a VH comprising R3; and (iii) amino acid sequence of QSVLHSSNNKNY (SEQ ID NO: 199). VL CDR1 having the sequence: WAS (SEQ ID NO: 200) CDR2, and a VL C having the amino acid sequence HQYYSTPPT (SEQ ID NO: 201) VL, including DR3.

[0111] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CD having the amino acid sequence of GDSVSSNSAAWN (SEQ ID NO: 202) R1, a VH CDR having the amino acid sequence of RTYYRSKWYND (SEQ ID NO: 203) 2, and a VH having the amino acid sequence of DRRYGIVGLPFAY (SEQ ID NO: 204). (ii) VH comprising CDR3; and (iii) KSSQSVLHSSNNKNYLT (SEQ ID NO: 20 5), VL CDR1 having the amino acid sequence of WASTRES (SEQ ID NO: 206) VL CDR2 having the amino acid sequence of HQYYSTPPT (SEQ ID NO: 207) and a VL comprising a VL CDR3 having the sequence

[0112] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CDR1 having the amino acid sequence of SNRAAWN (SEQ ID NO: 208), RT VH C having the amino acid sequence YYRSKWYNDYAVSVKS (SEQ ID NO: 209) DR2, and a VH CD having the amino acid sequence of VRPGIPFDY (SEQ ID NO: 210). R3; and (ii) KSSQSVLFSSNNKNYLA (SEQ ID NO: 211). VL CDR1, having the amino acid sequence of WASTRES (SEQ ID NO: 212) VL CDR2 having the sequence QQYHSTPWT (SEQ ID NO: 213) and a VL comprising a VL CDR3 having a sequence

[0113] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CDR1 having the amino acid sequence of GDSVSSNRA (SEQ ID NO: 214); VH CDR2 having the amino acid sequence of YYRSKWY (SEQ ID NO: 215), and VRP A VH comprising a VH CDR3 having the amino acid sequence of GIPFD (SEQ ID NO: 216); (ii) a VL having the amino acid sequence of SQSVLFSSNNKNY (SEQ ID NO: 217) CDR1, a VL CDR2 having the amino acid sequence of WAS (SEQ ID NO: 218), and YH a VL comprising a VL CDR3 having the amino acid sequence of STPW (SEQ ID NO: 219); include.

[0114] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) VH CDR1 having the amino acid sequence of GDSVSSNRAA (SEQ ID NO: 220) TYYRSKWYN (SEQ ID NO: 221), and A VH CDR3 having the amino acid sequence of ARVRPGIPFDY (SEQ ID NO: 222) (ii) a VH having the amino acid sequence QSVLFSSNNKNY (SEQ ID NO: 223). VL CDR1 having the amino acid sequence of WAS (SEQ ID NO: 224) and a VL CDR3 having the amino acid sequence QQYHSTPWT (SEQ ID NO: 225). Includes, VL and includes.

[0115] In another aspect, provided herein is an antibody that binds to HLA-G, the antibody comprising: (i) a VH CD having the amino acid sequence of GDSVSSNRAAWN (SEQ ID NO: 226) R1, a VH CDR having the amino acid sequence of RTYYRSKWYND (SEQ ID NO: 227) 2, and a VH CDR3 having the amino acid sequence of VRPGIPFDY (SEQ ID NO: 228). and (ii) a VH comprising: VL CDR1, WASTRES (SEQ ID NO: 230) and the amino acid sequence of QQYHSTPWT (SEQ ID NO: 231). and a VL comprising a VL CDR3 having

[0116] In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 174. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 172. In some embodiments, the antibody has at least one amino acid sequence identical to that of SEQ ID NO: 174. In some embodiments, the antibody comprises a VH comprising an amino acid sequence having 95% identity. The antibody is an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 172. The VL comprises the amino acid sequence.

[0117] In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 175. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 173. In some embodiments, the antibody has at least one amino acid sequence identical to that of SEQ ID NO: 175. In some embodiments, the antibody comprises a VH comprising an amino acid sequence having 95% identity. The antibody is an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 173. The VL comprises the amino acid sequence.

[0118] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. The resulting antibodies are expected to exhibit similar functional properties.

[0119] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0120] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is that of Karlin and Altschul, Proc.Natl.Acad.Sci.USA,1990,87:2264-8 ,modified as in Karlin and Altschul,Proc. Algorithm of Natl.Acad.Sci.USA1993,90:5873-7 Such an algorithm is described in Altschul, et al., J. Mol. .Biol.,1990,215:403 to the NBLAST and XBLAST programs BLAST nucleotide searches are performed using the NBLAST nucleotide program. The parameters of the program are set to, for example, score = 100 and word length = 12, and the program is run. Nucleotide sequences homologous to the nucleic acid molecules described in the document can be obtained. Protein searches are performed using the XBLAST program parameters, e.g., score 50, word count 0, and The sequence length was set to 3, and the amino acid sequence homologous to the protein molecules described herein was To obtain a gapped alignment for comparison purposes, use Altsc hul et al., Nucleic Acids Res.,1997,25:33 Alternatively, Gapped BLAST may be used as described in PS BLAST can also be used to perform iterated searches that detect distant relationships between molecules. (Ibid.) Using the BLAST, Gapped BLAST, and PSI Blast programs When using the program, please refer to the default settings of each program (e.g., XBLAST and NBLAST). Default parameters can be used (e.g., Nativ onal Center for Biotechnology Information n (NCBI, see ncbi.nlm.nih.gov). Used for sequence comparison. Another preferred, non-limiting example of a mathematical algorithm is the Myers and Mill er, 1988, CABIOS 4:11 There are 17 algorithms. The algorithm is ALIGN, part of the GCG sequence alignment software package. The program (version 2.0) was incorporated into the A When using the LIGN program, the PAM120 weight residue table and gap length penalty are required. A threshold of 12 and a gap penalty of 4 can be used.

[0121] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0122] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 174. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with a VH region of SEQ ID NO: 172 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with an HLA. -G binds.

[0123] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 175. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with a VH region of SEQ ID NO: 173 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with an HLA. -G binds.

[0124] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 174. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with a VH region of SEQ ID NO: 173 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with an HLA. -G binds.

[0125] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 175. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with a VH region of SEQ ID NO: 172 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with an HLA. -G binds.

[0126] In some embodiments, the antibody comprises the VH, VL, or CDR sequences of the anti-HLA-G antibodies described above. and further comprising an Fc region having RE mutations but no fucose residues. Provided in the specification.

[0127] In some embodiments, the anti-HLA-G antibodies provided herein comprise an HLA-G antibody having an RE mutation. but no fucose residues.

[0128] Standard techniques known to those skilled in the art can be used, for example, site-directed mutagenesis and amino acid sequence modification. The molecules provided herein are prepared by PCR-mediated mutagenesis, which results in amino acid substitutions. Mutations can be introduced into the nucleotide sequence to be cloned.

[0129] In some embodiments, glutamic acid is present in the Fc region of an antibody provided herein. There is a lysine substitution at position 248 in the ribosomal region (K248E) (EU numbering). In embodiments, an arginine is present at position 437 of the Fc region of an antibody provided herein. substituted with leonine (T437R) (EU numbering). A glutamic acid is substituted for lysine at position 248 in the Fc region of the antibody provided herein. and a substitution at position 437 with threonine (K248E / T437R) (EU numbering hair).

[0130] In some embodiments, the antibodies provided herein comprise a T437R mutation. In some embodiments, the antibodies provided herein comprise a heavy chain containing K248E In some embodiments, the antibodies provided herein comprise a heavy chain comprising a mutation. In some embodiments, the present invention provides a method for treating a pulmonary artery disease (PAG) comprising administering to a subject ... In some embodiments, the antibody comprises a heavy chain comprising a K248E / T437R mutation. The antibodies provided herein comprise a heavy chain comprising a K338A / T437R mutation. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 182. In some embodiments, the heavy chain comprises a T437R mutation. The antibody provided herein comprises the amino acid sequence of SEQ ID NO: 182 but with a K248E mutation. In some embodiments, the antibodies provided herein comprise a heavy chain comprising SEQ ID NO: 1. In some embodiments, the heavy chain comprises the amino acid sequence of 82 but with a K338A mutation. The antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 182, but In some embodiments, the heavy chain comprises a 8E / T437R mutation. The provided antibody comprises the amino acid sequence of SEQ ID NO: 182 but with the K338A / T437R mutation In some embodiments, the antibodies provided herein comprise a heavy chain having the sequence The heavy chain comprises the amino acid sequence of SEQ ID NO: 183 but has T437R. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 183. In some embodiments, the antibody provided herein comprises a heavy chain having a 248E mutation. The antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 183 but with a K338A mutation. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 183. In some embodiments, the heavy chain comprises the amino acid sequence of IL-1, but with K248E / T437R mutations. The antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 183, but contain K33 In some embodiments, the antibody comprises a heavy chain having a 8A / T437R mutation. Contains 182 amino acid sequences, but contains K248E and T437R mutations (RE mutations). In some embodiments, the antibody is MHGB752, which comprises a heavy chain of SEQ ID NO: 183. The heavy chain contains the amino acid sequence but has the K248E mutation and the T437R mutation (RE mutation). In some embodiments, the antibody provided herein is MHGB758. (including the anti-HLA-G antibodies mentioned above) are not fucosylated.

[0131] Fucosylation of the Asn-297 linked N-oligosaccharides was performed using standard techniques known to those skilled in the art. The antibodies provided herein can be generated having heavy chains that do not contain any amino acid residues. For example, cells with a defective GMD enzyme (e.g., CHO Lec13 cells) or mutant FU The T8 gene causes decreased α-1,6 fucosyltransferase activity, 1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase overexpressing the inactivated Golgi GDP-fucose transporter ( GFT) gene Slc35c1 (e.g., CHO-gmt3 cells), bacterial RMD or by heterologously expressing a biochemical inhibitor of fucosylation (e.g., 2-fluorofucose and Mammalian cell lines with the use of fucose analogs such as 5-alkynylfucose have been shown to To produce antibodies that do not have a fucose residue in the Asn-297 linked N-oligosaccharide, As shown (Pereira, N.A., et al., supra; Shields, R. L. et al., supra; Kanda Y., supra).

[0132] In some embodiments, the antibody has a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain that does not contain the amino acid sequence of SEQ ID NO: 180. a light chain containing the sequence and a sequence containing no fucose residue in its Asn-297-linked N-oligosaccharide and a heavy chain comprising the amino acid sequence of 182. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 181 and an Asn- 297-linked N-oligosaccharides containing no fucose residues in the amino acid sequence of SEQ ID NO: 183 In some embodiments, the antibody is MHGB738.CLF, comprising a heavy chain. Amino acid sequence of SEQ ID NO: 182, without a fucose residue in the Asn-297 linked N-oligosaccharide In some embodiments, the antibody comprises a heavy chain comprising the sequence Asn-297 linked N- It comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 183, which does not contain fucose residues in the oligosaccharides. In some embodiments, the antibody comprises K248E, K338A, T437R, K248E / T437R or K338A / T437R mutations, and the Asn-297 linked N-oligonucleotides In some embodiments, the antibody comprises a heavy chain that does not include a fucose residue in the sugar. E, K338A, T437R, K248E / T437R or K338A / T437R mutations and no fucose residue in its Asn-297 linked N-oligosaccharide, SEQ ID NO: 18 In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of K248E, K248E, K248E. 338A, T437R, K248E / T437R or K338A / T437R mutations 183, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. The heavy chain comprises a sequence of amino acids.

[0133] 5.6 Anti-CD37 Antibodies and Related Molecules In some embodiments, provided herein are anti-CD37 antibodies. In embodiments, the antibodies provided herein comprise the VL and VH sequences of Tables 5 and 6 below. VL, VH, or CDR having the amino acid sequence of VL, VH, or CDR contained in the sequence Includes.

[0134] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: VH comprising the amino acid sequence of T26B373, T26B459, or T26B60 8. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:2 and T26B374, T26B460 or T comprising a VH comprising the amino acid sequence of SEQ ID NO: 10 26B611. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO:3. and VH comprising the amino acid sequence of SEQ ID NO: 11. 61 or T26B612. In some embodiments, the antibody is T26B379, comprising a VL comprising the amino acid sequence of SEQ ID NO: 12 and a VH comprising the amino acid sequence of SEQ ID NO: 13; In some embodiments, the antibody is selected from the group consisting of SEQ ID NOs: T26B462 and T26B615. T26, comprising a VL comprising the amino acid sequence of SEQ ID NO:5 and a VH comprising the amino acid sequence of SEQ ID NO:13. In some embodiments, the antibody is B382, T26B463, or T26B613. VL comprising the amino acid sequence of SEQ ID NO: 6 and VH comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antibody is T26B385, T26B464, or T26B610. The antibody has a VL comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 15. Some of the VHs include T26B386, T26B465, or T26B614. In embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:8 and a VL comprising the amino acid sequence of SEQ ID NO:16. The VH comprises the amino acid sequence T26B388, T26B466, or T26B609.

[0135] In some embodiments, the antibody comprises a C1311 comprising a VL comprising the amino acid sequence of SEQ ID NO: 1. VL comprising a CDR having the amino acid sequence of DR and V comprising the amino acid sequence of SEQ ID NO: 9 and VH, which contains a CDR having the amino acid sequence of the CDR contained in H. In embodiments, the antibody comprises an amino acid sequence of the CDRs contained in a VL comprising the amino acid sequence of SEQ ID NO:1. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence of a CDR selected from the group consisting of: The antibody has an amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO: 1. and VL comprising a CDR corresponding to the amino acid sequence of SEQ ID NO: 11. and a VH comprising a CDR having the amino acid sequence a CDR having the amino acid sequence of a CDR contained in a VL having the amino acid sequence of SEQ ID NO: 1; and a VL comprising the amino acid sequence of SEQ ID NO: 12. and a VH comprising CDRs having the sequence SEQ ID NO: VL comprising a CDR having the amino acid sequence of a CDR contained in VL comprising the amino acid sequence of and a CDR amino acid sequence contained in VH comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the antibody comprises an amino acid sequence of SEQ ID NO: 1, and a VH comprising the CDRs. a VL comprising a CDR having the amino acid sequence of a CDR contained in a VL comprising the amino acid sequence; A CDR having the amino acid sequence of a CDR contained in a VH comprising the amino acid sequence of No. 14. In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1. and a VL comprising a CDR having the amino acid sequence of a CDR contained in a VL comprising the VL of SEQ ID NO: 15. VH and a CDR having the amino acid sequence of a CDR contained in VH. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 1. and a VL having a CDR having the amino acid sequence of SEQ ID NO: 16. and a VH comprising a CDR having the amino acid sequence of a CDR contained in the VH. In some embodiments, the antibody comprises a CD4+ receptor comprising a VL comprising the amino acid sequence of SEQ ID NO:2. VL comprising a CDR having the amino acid sequence of R and VH comprising the amino acid sequence of SEQ ID NO: 9 and a VH comprising a CDR having the amino acid sequence of the CDR contained in In one embodiment, the antibody comprises an amino acid sequence of the CDRs contained in a VL comprising the amino acid sequence of SEQ ID NO:2. and a VL comprising a CDR having the sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence of the CDR. The antibody has an amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO: 2. and a VL comprising a CDR of the amino acid sequence of SEQ ID NO: 11. and a VH comprising a CDR having the amino acid sequence A CDR having the amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of CDR contained in VH comprising the amino acid sequence of SEQ ID NO: 12. and a VH comprising CDRs having SEQ ID NO:2. VL comprising a CDR having the amino acid sequence of a CDR contained in a VL comprising the amino acid sequence and a C having the amino acid sequence of the CDR contained in VH comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the antibody comprises a VH comprising an amino acid sequence of SEQ ID NO: 2. VL comprising a CDR having the amino acid sequence of the CDR contained in VL comprising sequence; It contains a CDR having the amino acid sequence of a CDR contained in a VH containing the amino acid sequence of No. 14. , VH, and VH. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO:2. VL and an amino acid sequence of SEQ ID NO: 15, each of which contains a CDR having the amino acid sequence of the CDR contained in VL. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence; In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:2. and a VL having a CDR having the amino acid sequence of SEQ ID NO: 16. and a VH comprising a CDR having the amino acid sequence of the CDR contained in the VH comprising: In some embodiments, the antibody comprises a CDR comprising a VL comprising the amino acid sequence of SEQ ID NO:3. and VH comprising the amino acid sequence of SEQ ID NO: 9. and a VH comprising a CDR having the amino acid sequence of the included CDR. In this embodiment, the antibody has an amino acid sequence of CDR contained in VL comprising the amino acid sequence of SEQ ID NO:3. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence of a DR. The antibody has an amino acid sequence of the CDR contained in the VL comprising the amino acid sequence of SEQ ID NO: 3. VL containing CDR and VH containing the amino acid sequence of SEQ ID NO: 11 and a VH comprising CDRs having the sequence A CDR having the amino acid sequence of a CDR contained in a VL containing the amino acid sequence of sequence number 3. and the amino acid sequence of the CDR contained in VH containing the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises a VH comprising a CDR having the sequence of SEQ ID NO: 3. VL and a CDR having the amino acid sequence of a CDR contained in a VL having the amino acid sequence a CDH having the amino acid sequence of CDR contained in VH comprising the amino acid sequence of SEQ ID NO: 13; In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 3. VL comprising a CDR having the amino acid sequence of the CDR contained in the VL comprising the sequence SEQ ID NO: A CDR having an amino acid sequence of a CDR contained in a VH comprising an amino acid sequence of 14, In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 3. VL and the amino acid sequence of SEQ ID NO: 15. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence of In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:3. and a VL having a CDR having the amino acid sequence of SEQ ID NO: 16. and a VH comprising a CDR having the amino acid sequence of a CDR contained in the VH. In some embodiments, the antibody comprises a CDR comprising a VL comprising the amino acid sequence of SEQ ID NO:4. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 9. and a VH comprising a CDR having the amino acid sequence of a CDR included in the VH. In this embodiment, the antibody comprises a CDR amino acid sequence contained in a VL comprising the amino acid sequence of SEQ ID NO: 4. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence of R. The antibody has a CDR amino acid sequence contained in a VL comprising the amino acid sequence of SEQ ID NO: 4. VL including DR and the amino acid sequence of CDR included in VH having the amino acid sequence of SEQ ID NO: 11 and a VH comprising CDRs having the sequence Contains a CDR having the amino acid sequence of a CDR contained in a VL containing the amino acid sequence of No. 4 and a VL having the amino acid sequence of CDR contained in VH containing the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises an antibody having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, and a VH comprising CDRs selected from the group consisting of SEQ ID NO: 4. VL comprising a CDR having the amino acid sequence of a CDR contained in VL comprising the amino acid sequence; CDR having the amino acid sequence of CDR contained in VH containing the amino acid sequence of SEQ ID NO: 13 In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:4. and a VL comprising a CDR having the amino acid sequence of the CDR contained in the VL comprising SEQ ID NO: 1. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence of 4. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:4. and a VL comprising a CDR having the amino acid sequence of the CDR included in SEQ ID NO: 15. and a VH comprising a CDR having the amino acid sequence of a CDR contained in the VH comprising the amino acid sequence. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:4. a VL having a CDR having the amino acid sequence of SEQ ID NO: 16; and a VH comprising a CDR having the amino acid sequence of a CDR contained in a VH. In some embodiments, the antibody comprises an antibody having an amino acid sequence of SEQ ID NO:5 and an amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO:5. and VL comprising CDRs having the amino acid sequence of SEQ ID NO: 9, and VH comprising the amino acid sequence of SEQ ID NO: 9. and a VH comprising CDRs having the amino acid sequences of the CDRs as set forth in claim 1. The antibody has an amino acid sequence of CDR contained in VL containing the amino acid sequence of SEQ ID NO: 5. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence of is a CD3 having the amino acid sequence of a CDR contained in a VL having the amino acid sequence of SEQ ID NO: 5. VL including R and the amino acid sequence of CDR included in VH including the amino acid sequence of SEQ ID NO: 11 and a VH comprising CDRs having the sequence It contains a CDR having the amino acid sequence of a CDR contained in a VL containing the amino acid sequence of No. 5. VL and the amino acid sequence of the CDR contained in VH containing the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises an amino acid sequence of SEQ ID NO: 5, and a VH comprising CDRs comprising the amino acid sequence of SEQ ID NO: 5. VL comprising a CDR having the amino acid sequence of a CDR contained in VL comprising the amino acid sequence of a CDR; CDR having the amino acid sequence of CDR contained in VH containing the amino acid sequence of sequence number 13 In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:5. and a VL comprising a CDR having the amino acid sequence of the CDR contained in the VL comprising SEQ ID NO: 14. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:5. a VL comprising a CDR having the amino acid sequence of the CDR included therein and an amino acid sequence of SEQ ID NO: 15; and a VH comprising a CDR having the amino acid sequence of the CDR contained in the VH comprising the sequence. In some embodiments, the antibody comprises a C included in a VL comprising the amino acid sequence of SEQ ID NO:5. a VL comprising a CDR having the amino acid sequence of DR and a VL comprising the amino acid sequence of SEQ ID NO: 16; and VH, which contains a CDR having the amino acid sequence of the CDR contained in VH. In this embodiment, the antibody comprises an amino acid sequence of SEQ ID NO:6. and VL comprising CDRs having the amino acid sequence of SEQ ID NO: 9, and VH comprising the amino acid sequence of SEQ ID NO: 9. and a VH comprising a CDR having the amino acid sequence of a CDR selected from the group consisting of: The antibody has an amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO: 6. and VL comprising a CDR corresponding to the amino acid sequence of SEQ ID NO: 10. and a VH comprising a CDR having the amino acid sequence a CDR having the amino acid sequence of a CDR contained in a VL comprising the amino acid sequence of SEQ ID NO: 6; and a VL comprising the amino acid sequence of SEQ ID NO: 11. and a VH comprising CDRs having the sequence SEQ ID NO: VL comprising a CDR having the amino acid sequence of a CDR contained in VL comprising the amino acid sequence of 6. and a CDR amino acid sequence contained in VH comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises an amino acid sequence of SEQ ID NO: 6, and a VH comprising the CDRs. a VL comprising a CDR having the amino acid sequence of a CDR contained in a VL comprising the amino acid sequence; No. It contains a CDR having the amino acid sequence of a CDR contained in a VH containing the amino acid sequence of No. 13. , VH, and VH. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO:6. VL and an amino acid sequence of SEQ ID NO: 14, each of which contains a CDR having the amino acid sequence of the CDR contained in VL. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence; In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:6. and a VL having a CDR having the amino acid sequence of SEQ ID NO: 15. and a VH comprising a CDR having the amino acid sequence of the CDR contained in the VH comprising: In some embodiments, the antibody comprises a CDR comprising a VL comprising the amino acid sequence of SEQ ID NO:6. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 16. and a VH comprising a CDR having the amino acid sequence of the CDR contained in In one embodiment, the antibody comprises an amino acid sequence of the CDRs contained in a VL comprising the amino acid sequence of SEQ ID NO:7. VL comprising CDRs having the sequence of SEQ ID NO: 9 and VH comprising the amino acid sequence of SEQ ID NO: 9. and a VH comprising a CDR having the amino acid sequence of a DR. The antibody has an amino acid sequence of the CDR contained in the VL comprising the amino acid sequence of SEQ ID NO: 7. VL containing CDR and the amino acid sequence of CDR contained in VH having the amino acid sequence of SEQ ID NO: 10. and a VH comprising CDRs having the sequence A CDR having the amino acid sequence of a CDR contained in a VL containing the amino acid sequence of sequence number 7. and the amino acid sequence of the CDR contained in VH containing the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises a VH comprising a CDR having the sequence of SEQ ID NO: 7. VL and a CDR having the amino acid sequence of a CDR contained in a VL having the amino acid sequence and a CD31 having the amino acid sequence of the CDR contained in VH comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 7, and a VH comprising R. VL comprising a CDR having the amino acid sequence of the CDR contained in the VL comprising the sequence SEQ ID NO: A CDR having an amino acid sequence of a CDR contained in a VH comprising an amino acid sequence of 13, In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 7. VL and the amino acid sequence of SEQ ID NO: 14. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence of In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:7. and a VL having a CDR having the amino acid sequence of SEQ ID NO: 15. and a VH comprising a CDR having the amino acid sequence of a CDR contained in the VH. In some embodiments, the antibody comprises a CDR comprising a VL comprising the amino acid sequence of SEQ ID NO:7. VL comprising CDRs having the amino acid sequence of SEQ ID NO: 16, and VH comprising the amino acid sequence of SEQ ID NO: 16. and a VH comprising a CDR having the amino acid sequence of the included CDR. In this embodiment, the antibody has an amino acid sequence of CDR contained in VL comprising the amino acid sequence of SEQ ID NO:8. and a VL comprising a CDR having the amino acid sequence of SEQ ID NO: 9. and a VH comprising a CDR having the amino acid sequence of R. The antibody has a CDR amino acid sequence contained in a VL comprising the amino acid sequence of SEQ ID NO: 8. VL including DR and the amino acid sequence of CDR included in VH having the amino acid sequence of SEQ ID NO: 10 and a VH comprising CDRs having the sequence Contains a CDR having the amino acid sequence of a CDR contained in a VL containing the amino acid sequence of No. 8 and a VL having the amino acid sequence of CDR contained in VH containing the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises an antibody having an amino acid sequence of SEQ ID NO: 8, and a VH comprising CDRs corresponding to SEQ ID NO: 8. VL comprising a CDR having the amino acid sequence of a CDR contained in VL comprising the amino acid sequence; CDR having the amino acid sequence of CDR contained in VH containing the amino acid sequence of SEQ ID NO: 12 In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 8. and a VL comprising a CDR having the amino acid sequence of the CDR contained in the VL comprising SEQ ID NO: 1. VH comprising a CDR having the amino acid sequence of a CDR contained in VH comprising the amino acid sequence of In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 8. and a VL comprising a CDR having the amino acid sequence of the CDR included in SEQ ID NO: 14. and a VH comprising a CDR having the amino acid sequence of a CDR contained in the VH comprising the amino acid sequence. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO:8. a VL having a CDR having the amino acid sequence of SEQ ID NO: 15; and a VH comprising a CDR having the amino acid sequence of a CDR contained in a VH. In some embodiments, the antibody comprises an amino acid sequence of SEQ ID NO:8 comprising a CDR sequence comprising a VL comprising the amino acid sequence of SEQ ID NO:8. and VL comprising CDRs having the amino acid sequence of SEQ ID NO: 16, and VH comprising the amino acid sequence of SEQ ID NO: 17. and a VH comprising a CDR having the amino acid sequence of the CDR contained therein.

[0136] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. Antibodies derived from these antibodies are expected to exhibit similar functional properties. Exemplary antigen binding proteins include: 5 and Table 6, including those having the VL and VH regions provided herein. This includes:

[0137] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0138] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is the algorithm described by Karlin and Altschul, Proc. c.Natl.Acad.Sci.USA,1990,87:2264-8,mo dified as in Karlin and Altschul,Proc.Na Algorithm of tl.Acad.Sci.USA1993,90:5873-7 Such an algorithm is described in Altschul, et al., J. Mol. Biology. ol., 1990, 215:403, and incorporated into the NBLAST and XBLAST programs. BLAST nucleotide searches are performed using the NBLAST nucleotide program. The parameters are set to, for example, score=100 and word length=12, and the results are shown in the table below. Nucleotide sequences homologous to the nucleic acid molecules listed in the BLAST protein can be obtained. The quality search is performed by setting the parameters of the XBLAST program, e.g., score = 50, word length = Run the program at setting 3 and obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, et al., Nucleic Acids Res., 1997, 25:3389- Utilizing Gapped BLAST as described in 402. Alternatively, PSI B LAST can also be used to perform an iterative search that detects distant relationships between molecules (ibid.). When using the BLAST, Gapped BLAST, and PSI Blast programs The default values ​​for each program (e.g., XBLAST and NBLAST) are Parameters can be used (e.g., National Instruments on the World Wide Web). l Center for Biotechnology Information(N CBI, see ncbi.nlm.nih.gov). Another preferred, non-limiting example of an algorithm is Myers and Miller, 1988, CABIOS 4:11 There are 17 algorithms. The system is based on the ALIGN program, which is part of the GCG sequence alignment software package. It is integrated into the ALIG library (version 2.0) to compare amino acid sequences. When using the N program, use the PAM120 weight residue table and a gap length penalty of 1. 2, a gap penalty of 4 can be used.

[0139] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0140] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO:1. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or the amino acid sequence of SEQ ID NO: 9 At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity to a VH region of the antibody that binds to CD37 In certain embodiments, the antibodies provided herein comprise a polypeptide comprising the polypeptide sequence of SEQ ID NO: 1. At least 80%, at least 85%, at least and CDRs that have 90%, at least 95%, or at least 98% sequence identity with each other. and / or the amino acid sequence of the CDR contained in SEQ ID NO: 9. 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity, and the antibody binds to CD37. In some embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO: 1. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or the amino acid sequence of SEQ ID NO: 10 At least 80%, at least 85%, at least 90%, at least 95%, or a VH region having at least 98% sequence identity, wherein the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise a CD45 fragment contained in SEQ ID NO: 1. At least 80%, at least 85%, at least V comprising CDRs with 90%, at least 95%, or at least 98% sequence identity L region and / or CDR amino acid sequence included in SEQ ID NO: 10 0%, at least 85%, at least 90%, at least 95%, or at least 98% and the antibody binds to CD37. In embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO: 1. At least 80%, at least 85%, at least 90%, at least 95%, or less a VL region having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 11; At least 80%, at least 85%, at least 90%, at least 95%, or comprises a VH region having at least 98% sequence identity, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise the CDRs contained in SEQ ID NO:1. At least 80%, at least 85%, at least 9% of the amino acid sequence VL comprising CDRs with 0%, at least 95%, or at least 98% sequence identity region, and / or the amino acid sequence of the CDR contained in SEQ ID NO: 11, %, at least 85%, at least 90%, at least 95%, or at least 98% The antibody binds to CD37 and contains a VH region containing CDRs with sequence identity. In one embodiment, the antibodies provided herein have a low affinity to the amino acid sequence of SEQ ID NO:1. at least 80%, at least 85%, at least 90%, at least 95%, or less VL region having 98% sequence identity with the amino acid sequence of SEQ ID NO: 12. at least 80%, at least 85%, at least 90%, at least 95%, or The antibody binds to CD37 and comprises a VH region having at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise a CDR sequence similar to that contained in SEQ ID NO:1. At least 80%, at least 85%, at least 90% of the amino acid sequence %, at least 95%, or at least 98% sequence identity between the VL region and the CDRs. and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 12 , at least 85%, at least 90%, at least 95%, or at least 98% The antibody binds to CD37 and comprises a VH region containing CDRs having sequence identity. In some embodiments, the antibodies provided herein have at least one amino acid sequence that is at least partially identical to the amino acid sequence of SEQ ID NO:1. at least 80%, at least 85%, at least 90%, at least 95%, or at least a VL region having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 13; At least 80%, at least 85%, at least 90%, at least 95%, or The antibody comprises a VH region having at least 98% sequence identity with the CD37 antibody, and the antibody binds to CD37. In some embodiments, the antibodies provided herein comprise an antibody comprising an amino acid sequence identical to that of the CDRs contained in SEQ ID NO:1. At least 80%, at least 85%, at least 90% of the amino acid sequence , a VL region comprising CDRs with at least 95%, or at least 98% sequence identity and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 13; At least 85%, at least 90%, at least 95%, or at least 98% of the sequence The antibody binds to CD37 and comprises a VH region that includes identical CDRs. In some embodiments, the antibodies provided herein have a sequence similar to that of SEQ ID NO:1. At least 80%, at least 85%, at least 90%, at least 95%, or at least VL region with 98% sequence identity and / or to the amino acid sequence of SEQ ID NO: 14 At least 80%, at least 85%, at least 90%, at least 95%, or less The antibody binds to CD37 and comprises a VH region that has at least 98% sequence identity with the antibody. In embodiments, the antibodies provided herein comprise an amino acid sequence of the CDRs contained in SEQ ID NO:1. At least 80%, at least 85%, at least 90% of the amino acid sequence, a VL region comprising CDRs having at least 95%, or at least 98% sequence identity; and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 14 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and a VH region comprising CDRs having identical sequences, and wherein the antibody binds to CD37. Therefore, the antibodies provided herein have at least one sequence that is identical to the amino acid sequence of SEQ ID NO: 1. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 VL region with 8% sequence identity and / or at least at least 80%, at least 85%, at least 90%, at least 95%, or less The VH region of the antibody has 98% sequence identity with the CD37 antibody, and the antibody binds to CD37. In embodiments, the antibodies provided herein comprise the amino acid sequence of the CDRs contained in SEQ ID NO:1. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs having at least 95%, or at least 98%, sequence identity; and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 15 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising CDRs having the same functionalities as those of the antibody described above, and the antibody binds to CD37. The antibodies provided herein have at least one sequence that is complementary to the amino acid sequence of SEQ ID NO: 1. 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity to the amino acid sequence of SEQ ID NO: 16. at least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody also contains a VH region with 98% sequence identity to CD37, and the antibody binds to CD37. In one embodiment, the antibodies provided herein comprise the amino acid sequence of the CDRs contained in SEQ ID NO:1. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs that have at least 95%, or at least 98%, sequence identity; and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 16 85%, at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibodies provided herein have a sequence similar to that of SEQ ID NO:2 but differing in at least 8 amino acid sequence from that of SEQ ID NO:2. 0%, at least 85%, at least 90%, at least 95%, or at least 98% and / or a VL region having at least one amino acid sequence identical to the amino acid sequence of SEQ ID NO: 9. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 The antibody comprises a VH region having 8% sequence identity and binds to CD37. The antibodies provided herein comprise the amino acid sequence of the CDRs contained in SEQ ID NO:2. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs with at least 95%, or at least 98%, sequence identity; and / or is at least 80%, at least 8% of the amino acid sequence of the CDR contained in SEQ ID NO: 9 5%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising CDRs corresponding to the CDRs of the present invention, and the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:2, At least 85%, at least 90%, at least 95%, or at least 98% of the sequence VL region with identity and / or at least 8 amino acid sequences to the amino acid sequence of SEQ ID NO: 10 0%, at least 85%, at least 90%, at least 95%, or at least 98% and wherein the antibody binds to CD37. The antibodies provided herein are those that correspond to the amino acid sequences of the CDRs contained in SEQ ID NO:2. at least 80%, at least 85%, at least 90%, at least 9 VL regions containing CDRs with 5%, or at least 98% sequence identity, and / or At least 80%, at least 85% of the amino acid sequence of the CDR included in sequence number 10 %, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising the CDRs, and the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:2, and at least at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region having at least 80 amino acid sequences identical to the amino acid sequence of SEQ ID NO: 11. %, at least 85%, at least 90%, at least 95%, or at least 98% In certain embodiments, the antibody comprises a VH region having sequence identity to the VH region of the antibody, and the antibody binds to CD37. The antibodies provided herein are those that are identical to the amino acid sequence of the CDRs contained in SEQ ID NO:2. At least 80%, at least 85%, at least 90%, at least 95% %, or a VL region containing CDRs with at least 98% sequence identity, and / or a sequence At least 80%, at least 85% of the amino acid sequence of the CDR contained in No. 11 , C having at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising a DR, and the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:2, and at least at least 85%, at least 90%, at least 95%, or at least 98% sequence identity a VL region having at least 80% of the amino acid sequence of SEQ ID NO: 12; , at least 85%, at least 90%, at least 95%, or at least 98% In certain embodiments, the antibody comprises a VH region having sequence identity with CD37. The antibodies provided herein are those which are identical to the amino acid sequence of the CDRs contained in SEQ ID NO:2. At least at least 80%, at least 85%, at least 90%, at least 95% , or a VL region comprising CDRs having at least 98% sequence identity, and / or SEQ ID NO: At least 80%, at least 85%, or at least 100% of the amino acid sequence of the CDRs contained in 12 CDRs with at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:2, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. a VL region having at least 80%, at least 100%, or at least 150% of the amino acid sequence of SEQ ID NO: 13; at least 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region having a similar identity to that of the antibody described herein, and the antibody binds to CD37. The antibodies provided herein have at least one amino acid sequence similar to that of the CDRs contained in SEQ ID NO:2. at least 80%, at least 85%, at least 90%, at least 95%, or is a VL region containing CDRs with at least 98% sequence identity, and / or SEQ ID NO: 1 At least 80%, at least 85%, or at least CDRs having at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:2, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region that is at least 80% identical to the amino acid sequence of SEQ ID NO: 14. at least 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region having the desired binding activity, and the antibody binds to CD37. The antibody provided in the present application has a sequence similar to that of the CDR amino acid sequence contained in SEQ ID NO:2. at least 80%, at least 85%, at least 90%, at least 95%, or a VL region comprising CDRs with at least 98% sequence identity, and / or SEQ ID NO: 14 at least 80%, at least 85%, or at least and CDRs that have 90%, at least 95%, or at least 98% sequence identity with each other. In certain embodiments, the antibody comprises a VH region comprising ... The antibodies provided have a sequence that is at least 80%, at least 8%, identical to the amino acid sequence of SEQ ID NO:2. 5%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region having at least 80% and at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibody provided herein has at least one amino acid sequence identical to that of the CDR contained in SEQ ID NO:2. At least 80%, at least 85%, at least 90%, at least 95%, or at least a VL region comprising CDRs with at least 98% sequence identity, and / or SEQ ID NO: 15; At least 80%, at least 85%, at least or at least 90%, at least 95%, or at least 98% sequence identity with the CDRs. In certain embodiments, the antibody comprises a VH region and binds to CD37. The provided antibody has a sequence that is at least 80%, at least 85%, or both of the amino acid sequences of SEQ ID NO:2. %, at least 90%, at least 95%, or at least 98% sequence identity VL region, and / or at least 80% of the amino acid sequence of SEQ ID NO: 16 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibody comprises a VH region having the following structure: The antibody provided herein has at least one amino acid sequence corresponding to the amino acid sequence of the CDR contained in SEQ ID NO:2. At least 80%, at least 85%, at least 90%, at least 95%, or less a VL region containing CDRs with at least 98% sequence identity, and / or a VL region containing CDRs with at least 98% sequence identity to SEQ ID NO: 16; At least 80%, at least 85%, at least V comprising CDRs with 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises an H region and binds to CD37. The antibody to be tested has a sequence similar to that of SEQ ID NO:3, but is at least 80%, at least 85%, or , V having at least 90%, at least 95%, or at least 98% sequence identity L region, and / or at least 80%, at least 8% of the amino acid sequence of SEQ ID NO: 9 5%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising ... The antibodies provided have at least one amino acid sequence that is identical to the amino acid sequence of the CDR contained in SEQ ID NO:3. at least 80%, at least 85%, at least 90%, at least 95%, or at least a VL region containing CDRs with 98% sequence identity, and / or ... At least 80%, at least 85%, at least 90% of the amino acid sequence of the CDR , a VH region comprising CDRs with at least 95%, or at least 98% sequence identity wherein the antibody binds to CD37. In certain embodiments, the antibody provided herein The antibody may have a sequence that is at least 80%, at least 85%, or at least VL regions having at least 90%, at least 95%, or at least 98% sequence identity , and / or at least 80%, at least 85% of the amino acid sequence of SEQ ID NO: 10 , V having at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises an H region and binds to CD37. The antibody to be tested has at least one amino acid sequence corresponding to the CDR amino acid sequence contained in SEQ ID NO:3. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 VL region containing CDRs with 8% sequence identity, and / or C included in SEQ ID NO: 10 At least 80%, at least 85%, at least 90% of the amino acid sequence of DR; A VH region comprising CDRs having at least 95% or at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise The antibody may be at least 80%, at least 85%, or at least VL regions having 90%, at least 95%, or at least 98% sequence identity with each other; and / or at least 80%, at least 85% to the amino acid sequence of SEQ ID NO: 11; VH with at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibodies provided herein comprise a region, and the antibody binds to CD37. The antibody to be produced has at least one amino acid sequence corresponding to the CDR amino acid sequence contained in SEQ ID NO:3. 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity, and / or a CDR contained in SEQ ID NO: 11 At least 80%, at least 85%, at least 90%, or at least and a VH region comprising CDRs having at least 95%, or at least 98%, sequence identity with the VH region. In certain embodiments, the antibodies provided herein bind to CD37. is at least 80%, at least 85%, or at least VL regions having at least 90%, at least 95%, or at least 98% sequence identity; / or at least 80%, at least 85%, at least VH regions having at least 90%, at least 95%, or at least 98% sequence identity wherein the antibody binds to CD37. In certain embodiments, the antibody provided herein The antibody has at least 80 amino acids to the amino acid sequence of the CDR contained in SEQ ID NO:3. %, at least 85%, at least 90%, at least 95%, or at least 98% VL regions containing CDRs with sequence identity and / or CDRs contained in SEQ ID NO: 12 At least 80%, at least 85%, at least 90%, or at least a VH region comprising CDRs that have 95% or at least 98% sequence identity with each other; The antibody binds to CD37. In certain embodiments, the antibody provided herein binds to: At least 80%, at least 85%, at least 9% of the amino acid sequence of SEQ ID NO: 3 VL regions having 0%, at least 95%, or at least 98% sequence identity, and / or or at least 80%, at least 85%, or at least VH regions having 90%, at least 95%, or at least 98% sequence identity with each other. In certain embodiments, the antibodies provided herein comprise The antibody has at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO:3. , at least 85%, at least 90%, at least 95%, or at least 98% VL regions containing CDRs with sequence identity, and / or sequences of CDRs contained in SEQ ID NO: 13. At least 80%, at least 85%, at least 90%, at least and a VH region comprising CDRs having at least 95% or at least 98% sequence identity thereto, In certain embodiments, the antibodies provided herein bind to CD37. At least 80%, at least 85%, at least 90% of the amino acid sequence of sequence number 3 %, at least 95%, or at least 98% sequence identity, and / or is at least 80%, at least 85%, or at least and VH regions having at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibodies provided herein bind to CD37. is at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 3, At least 85%, at least 90%, at least 95%, or at least 98% of the sequence VL regions containing CDRs with identity, and / or amino acids of the CDRs contained in SEQ ID NO: 14 At least 80%, at least 85%, at least 90%, at least an antibody comprising a VH region containing CDRs having 95% or at least 98% sequence identity thereto; In certain embodiments, the antibodies provided herein comprise a polypeptide having the sequence At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 3 , a VL region having at least 95%, or at least 98% sequence identity, and / or At least 80%, at least 85%, at least a VH region having 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 3 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or the amino acid sequence of the CDRs contained in SEQ ID NO: 15. At least 80%, at least 85%, at least 90%, at least 9% of the sequence and the antibody comprises a VH region containing CDRs having 5% or at least 98% sequence identity. In certain embodiments, the antibodies provided herein bind to CD37. At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 3; VL regions having at least 95%, or at least 98% sequence identity, and / or At least 80%, at least 85%, at least 9% of the amino acid sequence of sequence number 16 0 %, at least 95%, or at least 98% sequence identity to the VH region of the antibody; In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDR contained in column 3 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region comprising a CDR having the amino acid sequence of the CDR contained in SEQ ID NO: 16. At least 80%, at least 85%, at least 90%, at least 95% for columns or a VH region comprising CDRs having at least 98% sequence identity thereto, 37. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 4 At least 80%, at least 85%, at least 90%, at least VL regions with at least 95%, or at least 98% sequence identity, and / or SEQ ID NO: At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 9; and a VH region having at least 95%, or at least 98%, sequence identity with the antibody. In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDRs contained in No. 4, 85%, at least 90%, at least 95%, or at least 98% sequence identity a VL region containing a CDR corresponding to the amino acid sequence of the CDR contained in SEQ ID NO: 9, and / or at least 80%, at least 85%, at least 90%, at least 95%, or The antibody comprises a VH region containing CDRs with at least 98% sequence identity to CD37. In certain embodiments, the antibodies provided herein bind to the amino acid sequence of SEQ ID NO: 4. At least 80%, at least 85%, at least 90%, at least a VL region having 95%, or at least 98% sequence identity, and / or SEQ ID NO: 10 At least 80%, at least 85%, at least 90%, at least and the antibody comprises a VH region having at least 95%, or at least 98%, sequence identity with the CD 37. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 4 At least 80%, at least 85% of the amino acid sequence of the CDR contained in %, at least 90%, at least 95%, or at least 98% sequence identity VL region containing CDR and / or the amino acid sequence of the CDR contained in SEQ ID NO: 10 At least 80%, at least 85%, at least 90%, at least 95%, or the antibody comprises a VH region containing CDRs having at least 98% sequence identity, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise an antibody comprising the amino acid sequence of SEQ ID NO:4. At least 80%, at least 85%, at least 90%, at least 9% of the sequence a VL region having 5%, or at least 98% sequence identity with SEQ ID NO: 11; At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VH region having 95% or at least 98% sequence identity with a CD3 7. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 4. At least 80%, at least 85% of the amino acid sequence of the included CDR , C having at least 90%, at least 95%, or at least 98% sequence identity For the VL region containing DR and / or the amino acid sequence of the CDR contained in SEQ ID NO: 11 At least 80%, at least 85%, at least 90%, at least 95%, or less The antibody binds to CD37 and comprises a VH region containing CDRs with at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO:4. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity, and / or a VL region of SEQ ID NO: 12 At least 80%, at least 85%, at least 90%, at least and the antibody comprises a VH region having at least 95%, or at least 98%, sequence identity with CD37. In certain embodiments, the antibodies provided herein bind to the polypeptide contained in SEQ ID NO:4. At least 80%, at least 85%, or CDs with at least 90%, at least 95%, or at least 98% sequence identity a VL region containing R and / or a CDR amino acid sequence contained in SEQ ID NO: 12 at least 80%, at least 85%, at least 90%, at least 95%, or less The antibody contains a VH region containing CDRs with 98% sequence identity to both the CD37 and CD37 subunits. In certain embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO:4. At least 80%, at least 85%, at least 90%, at least 95% for columns or a VL region having at least 98% sequence identity, and / or an amino acid sequence of SEQ ID NO: 13 At least 80%, at least 85%, at least 90%, at least The antibody comprises a VH region having 95%, or at least 98%, sequence identity to CD37. In certain embodiments, the antibodies provided herein bind to the antibody contained in SEQ ID NO: 4. At least 80%, at least 85%, at least CDRs with at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region comprising at least one amino acid sequence selected from the group consisting of CDRs of SEQ ID NO: 13. at least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody binds to CD37 and contains a VH region containing CDRs with 98% sequence identity to the VH region. In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO:4. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or an amino acid sequence of SEQ ID NO: 14 At least 80%, at least 85%, at least 90%, at least 9% of the sequence 5%, or at least 98% sequence identity between the VH region and the antibody, In certain embodiments, the antibodies provided herein comprise a polypeptide comprising the polypeptide contained in SEQ ID NO:4. At least 80%, at least 85%, at least CDRs having at least 90%, at least 95%, or at least 98% sequence identity. and / or a VL region comprising at least one amino acid sequence corresponding to the amino acid sequence of the CDRs contained in SEQ ID NO: 14. At least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody binds to CD37 and contains a VH region containing CDRs with 98% sequence identity. In certain embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO:4. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or the amino acid sequence of SEQ ID NO: 15 At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity to a VH region of the antibody that binds to CD37 In certain embodiments, the antibodies provided herein comprise a polypeptide comprising the polypeptide sequence of SEQ ID NO:4. At least 80%, at least 85%, at least and CDRs that have 90%, at least 95%, or at least 98% sequence identity with each other. and / or the amino acid sequence of the CDR contained in SEQ ID NO: 15. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 The antibody contains a VH region containing CDRs with 8% sequence identity, and binds to CD37. In certain embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO:4. at least 80%, at least 85%, at least 90%, at least 95%, or VL regions with at least 98% sequence identity and / or the amino acid sequence of SEQ ID NO: 16 At least 80%, at least 85%, at least 90%, at least 95% for columns or a VH region having at least 98% sequence identity thereto, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise a C sequence contained in SEQ ID NO:4. At least 80%, at least 85%, at least or at least 90%, at least 95%, or at least 98% sequence identity with the CDRs. At least one amino acid sequence of the VL region and / or CDR contained in SEQ ID NO: 16 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity, and the antibody binds to CD37. In some embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity and / or the amino acid sequence of SEQ ID NO: 9; At least 80%, at least 85%, at least 90%, at least 95%, or comprises a VH region having at least 98% sequence identity, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise the CDRs contained in SEQ ID NO:5. At least 80%, at least 85%, at least 9% of the amino acid sequence VL comprising CDRs with 0%, at least 95%, or at least 98% sequence identity region, and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 9 , at least 85%, at least 90%, at least 95%, or at least 98% The antibody binds to CD37 and comprises a VH region containing CDRs having sequence identity. In some embodiments, the antibodies provided herein have at least one amino acid sequence similar to that of SEQ ID NO:5. at least 80%, at least 85%, at least 90%, at least 95%, or at least a VL region having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 10; At least 80%, at least 85%, at least 90%, at least 95%, or The antibody comprises a VH region having at least 98% sequence identity with the CD37 antibody, and the antibody binds to CD37. In some embodiments, the antibodies provided herein comprise an antibody comprising the amino acid sequence of the CDRs contained in SEQ ID NO:5. At least 80%, at least 85%, at least 90% of the amino acid sequence , a VL region comprising CDRs with at least 95%, or at least 98% sequence identity and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 10; At least 85%, at least 90%, at least 95%, or at least 98% of the sequence The antibody binds to CD37 and comprises a VH region that includes identical CDRs. In some embodiments, the antibodies provided herein have a sequence similar to that of SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least 95%, or at least VL region with 98% sequence identity and / or to the amino acid sequence of SEQ ID NO: 11 At least 80%, at least 85%, at least 90%, at least 95%, or less The antibody binds to CD37 and comprises a VH region that has at least 98% sequence identity with the antibody. In embodiments, the antibodies provided herein comprise an amino acid sequence of the CDRs contained in SEQ ID NO:5. At least 80%, at least 85%, at least 90% of the amino acid sequence, a VL region comprising CDRs having at least 95%, or at least 98% sequence identity; and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 11 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and a VH region comprising CDRs having identical sequences, and wherein the antibody binds to CD37. in The antibodies provided herein have a sequence similar to that of SEQ ID NO: 5, but which are at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity to the amino acid sequence of SEQ ID NO: 12. at least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody also contains a VH region with 98% sequence identity to CD37, and the antibody binds to CD37. In one embodiment, the antibodies provided herein comprise the amino acid sequence of the CDRs contained in SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs that have at least 95%, or at least 98%, sequence identity; and and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 12 85%, at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibodies provided herein have at least 8 amino acid sequences corresponding to the amino acid sequence of SEQ ID NO:5. 0%, at least 85%, at least 90%, at least 95%, or at least 98% a VL region having at least one sequence identity to the amino acid sequence of SEQ ID NO: 13; At least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody binds to CD37 and comprises a VH region with 98% sequence identity. In some embodiments, the antibodies provided herein comprise a CDR comprising the amino acid sequence of SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs that have 95% or at least 98% sequence identity with each other, and / or or at least 80%, at least at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibody binds to CD37 and comprises a VH region comprising CDRs having: The antibodies provided herein have a sequence similar to that of SEQ ID NO:5 but with a homology of at least 80%. %, at least 85%, at least 90%, at least 95%, or at least 98% VL region having sequence identity and / or at least a portion of the amino acid sequence of SEQ ID NO: 14 at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 The antibody comprises a VH region having 8% sequence identity and binds to CD37. The antibodies provided herein comprise the amino acid sequence of the CDR contained in SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs with at least 95%, or at least 98%, sequence identity; and / or is at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 14, 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising CDRs that bind to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:5. , at least 85%, at least 90%, at least 95%, or at least 98% a VL region having sequence identity to the amino acid sequence of SEQ ID NO: 15, and / or 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity, and the antibody binds to CD37. The antibodies provided herein comprise a CDR amino acid sequence contained in SEQ ID NO:5. At least 80%, at least 85%, at least 90%, at least a VL region comprising CDRs with 95%, or at least 98% sequence identity; and / or At least 80%, at least 8% of the amino acid sequence of the CDR contained in SEQ ID NO: 15 5%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising CDRs corresponding to the CDRs of the present invention, and the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:5, At least 85%, at least 90%, at least 95%, or at least 98% of the sequence VL region with identity and / or at least 8 amino acid sequences to the amino acid sequence of SEQ ID NO: 16 0%, at least 85%, at least 90%, at least 95%, or at least 98% and wherein the antibody binds to CD37. The antibodies provided herein are directed to the amino acid sequences of the CDRs contained in SEQ ID NO:5. at least 80%, at least 85%, at least 90%, at least 9 VL regions containing CDRs with 5%, or at least 98% sequence identity, and / or At least 80%, at least 85% of the amino acid sequence of the CDR contained in column 16 %, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising the CDRs, and the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:6, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity VL region with at least 80% identity to the amino acid sequence of SEQ ID NO: 9 , at least 85%, at least 90%, at least 95%, or at least 98% In certain embodiments, the antibody comprises a VH region having sequence identity with CD37. The antibodies provided herein are those which are identical to the amino acid sequence of the CDRs contained in SEQ ID NO:6. At least at least 80%, at least 85%, at least 90%, at least 95% or a VL region comprising CDRs having at least 98% sequence identity, and / or SEQ ID NO: At least 80%, at least 85%, or at least CDRs with at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:6, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. and / or a VL region having at least 80%, at least at least 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region having a similar identity to that of the antibody described herein, and the antibody binds to CD37. The antibodies provided herein have at least one amino acid sequence similar to that of the CDRs contained in SEQ ID NO:6. at least 80%, at least 85%, at least 90%, at least 95%, or is a VL region containing CDRs with at least 98% sequence identity, and / or SEQ ID NO: 1 At least 80%, at least 85%, at least CDRs having at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibody binds to CD37. The antibodies provided herein have a sequence which is at least 80% identical to the amino acid sequence of SEQ ID NO:6, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region that is at least 80% identical to the amino acid sequence of SEQ ID NO: 11, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region having the desired binding activity, and the antibody binds to CD37. The antibody provided in the present application has a sequence similar to that of the CDR amino acid sequence contained in SEQ ID NO:6. at least 80%, at least 85%, at least 90%, at least 95%, or a VL region comprising CDRs with at least 98% sequence identity, and / or SEQ ID NO: 11 at least 80%, at least 85%, or at least and CDRs that have 90%, at least 95%, or at least 98% sequence identity with each other. In certain embodiments, the antibody comprises a VH region comprising ... The antibodies provided have a sequence that is at least 80%, at least 8%, or 5%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region having at least 80% and at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and wherein the antibody binds to CD37. The antibody provided herein has at least one amino acid sequence similar to that of the CDR contained in SEQ ID NO:6. At least 80%, at least 85%, at least 90%, at least 95%, or at least a VL region containing CDRs with at least 98% sequence identity, and / or SEQ ID NO: 12; At least 80%, at least 85%, at least or at least 90%, at least 95%, or at least 98% sequence identity with the CDRs. In certain embodiments, the antibody comprises a VH region and binds to CD37. The provided antibody has a sequence that is at least 80%, at least 85%, or both of the amino acid sequences of SEQ ID NO:6. %, at least 90%, at least 95%, or at least 98% sequence identity VL region, and / or at least 80% of the amino acid sequence of SEQ ID NO: 13 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibody comprises a VH region having the following structure: The antibody provided herein has at least one CDR amino acid sequence corresponding to the amino acid sequence of the CDR contained in SEQ ID NO:6. At least 80%, at least 85%, at least 90%, at least 95%, or less a VL region containing CDRs with at least 98% sequence identity, and / or a VL region containing CDRs with at least 98% sequence identity to SEQ ID NO: 13; At least 80%, at least 85%, at least V comprising CDRs with 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises an H region and binds to CD37. The antibody to be tested has a sequence similar to that of SEQ ID NO:6, but is at least 80%, at least 85%, or , V having at least 90%, at least 95%, or at least 98% sequence identity L region, and / or at least 80% of the amino acid sequence of SEQ ID NO: 14 85%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region that binds to CD37. The antibody provided has at least one amino acid sequence that corresponds to the amino acid sequence of the CDR contained in SEQ ID NO:6. at least 80%, at least 85%, at least 90%, at least 95%, or less a VL region containing CDRs with 98% sequence identity to the VL region of SEQ ID NO: 14; At least 80%, at least 85%, at least 90%, or at least 100% of the amino acid sequence of the CDR to be VH comprising CDRs with 0%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibodies provided herein comprise a region, and the antibody binds to CD37. The antibody has a sequence which is at least 80%, at least 85%, or VL with at least 90%, at least 95%, or at least 98% sequence identity region, and / or at least 80%, at least 8% of the amino acid sequence of SEQ ID NO: 15 5%, at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises a VH region comprising ... The antibodies provided have at least one amino acid sequence that is at least partially identical to the amino acid sequence of the CDR contained in SEQ ID NO:6. at least 80%, at least 85%, at least 90%, at least 95%, or at least too VL region containing CDRs with 98% sequence identity and / or contained in SEQ ID NO: 15 At least 80%, at least 85%, at least 90% of the amino acid sequence of the CDR , a VH region comprising CDRs with at least 95%, or at least 98% sequence identity wherein the antibody binds to CD37. In certain embodiments, the antibody provided herein The antibody may have a sequence that is at least 80%, at least 85%, or at least VL regions having at least 90%, at least 95%, or at least 98% sequence identity , and / or at least 80%, at least 85% of the amino acid sequence of SEQ ID NO: 16 , V having at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibody comprises an H region and binds to CD37. The antibody to be tested has at least one amino acid sequence corresponding to the CDR amino acid sequence contained in SEQ ID NO:6. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 VL region containing CDRs with 8% sequence identity and / or C contained in SEQ ID NO: 16 At least 80%, at least 85%, at least 90% of the amino acid sequence of DR; A VH region comprising CDRs having at least 95% or at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise The antibody has a sequence that is at least 80%, at least 85%, or at least VL regions having 90%, at least 95%, or at least 98% sequence identity with each other; and / or a sequence which is at least 80%, at least 85%, or at least VH regions having at least 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibodies provided herein comprise a region, wherein the antibody binds to CD37. The antibody has at least 8 amino acids corresponding to the amino acid sequence of the CDR contained in SEQ ID NO:7. 0%, at least 85%, at least 90%, at least 95%, or at least 98% and / or a VL region comprising a CDR having sequence identity of SEQ ID NO: 9. At least 80%, at least 85%, at least 90%, or at least a VH region comprising CDRs that have 95% or at least 98% sequence identity with each other; The antibody binds to CD37. In certain embodiments, the antibody provided herein binds to: At least 80%, at least 85%, at least 9% of the amino acid sequence of SEQ ID NO: 7 VL regions having 0%, at least 95%, or at least 98% sequence identity, and / or or at least 80%, at least 85%, or at least VH regions having 90%, at least 95%, or at least 98% sequence identity with each other. In certain embodiments, the antibodies provided herein comprise The antibody has at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO:7. , at least 85%, at least 90%, at least 95%, or at least 98% VL regions containing CDRs with sequence identity, and / or sequences of CDRs contained in SEQ ID NO: 10. At least 80%, at least 85%, at least 90%, at least and a VH region comprising CDRs having at least 95% or at least 98% sequence identity thereto, In certain embodiments, the antibodies provided herein bind to CD37. At least 80%, at least 85%, at least 90% of the amino acid sequence of sequence number 7 %, at least 95%, or at least 98% sequence identity, and / or is at least 80%, at least 85%, or at least and VH regions having at least 90%, at least 95%, or at least 98% sequence identity. In certain embodiments, the antibodies provided herein bind to CD37. is at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 7, At least 85%, at least 90%, at least 95%, or at least 98% of the sequence VL region containing CDRs with identity, and / or amino acids of the CDRs contained in SEQ ID NO: 11 At least 80%, at least 85%, at least 90%, at least an antibody comprising a VH region containing CDRs having 95% or at least 98% sequence identity thereto; In certain embodiments, the antibodies provided herein comprise a polypeptide having the sequence At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 7 , a VL region having at least 95%, or at least 98% sequence identity, and / or At least 80%, at least 85%, at least a VH region having 90%, at least 95%, or at least 98% sequence identity In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 7 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region containing CDRs having the same amino acid sequence as that of SEQ ID NO: 12. At least 80%, at least 85%, at least 90%, at least 9% of the sequence and the antibody comprises a VH region containing CDRs having 5% or at least 98% sequence identity. In certain embodiments, the antibodies provided herein bind to CD37. At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 7; VL regions having at least 95%, or at least 98% sequence identity, and / or At least 80%, at least 85%, at least 9% of the amino acid sequence of sequence number 13 a VH region having 0%, at least 95%, or at least 98% sequence identity; The antibody binds to CD37. In certain embodiments, the antibody provided herein binds to: At least 80%, at least 10% of the amino acid sequence of the CDR contained in SEQ ID NO: 7 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity VL region containing CDRs having the same function as the VL region of SEQ ID NO: 13, and / or the amino acid sequence of the CDRs contained in SEQ ID NO: 13. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity between the VH region and the CDRs, In certain embodiments, the antibodies provided herein bind to SEQ ID NO: D37. 7 amino acid sequence at least 80%, at least 85%, at least 90%, VL regions with at least 95%, or at least 98% sequence identity, and / or sequences At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 14 %, at least 95%, or at least 98% sequence identity to the VH region of the antibody; In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDR contained in sequence number 7 85%, at least 90%, at least 95%, or at least 98% sequence identity and / or a VL region comprising a CDR having the amino acid sequence of the CDR contained in SEQ ID NO: 14. At least 80%, at least 85%, at least 90%, at least 95% for columns or a VH region comprising CDRs having at least 98% sequence identity thereto, 37. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 7 At least 80%, at least 85%, at least 90%, at least VL regions with at least 95%, or at least 98% sequence identity, and / or SEQ ID NO: At least 80%, at least 85%, at least 90% of the amino acid sequence of No. 15 , a VH region having at least 95%, or at least 98% sequence identity with an antibody In certain embodiments, the antibodies provided herein comprise a polypeptide having the sequence At least 80%, at least 10%, at least 15%, at least 10% of the amino acid sequence of the CDR contained in No. 7 at least 85%, at least 90%, at least 95%, or at least 98% sequence identity. and / or the amino acid sequence of the CDR contained in SEQ ID NO: 15. At least 80%, at least 85%, at least 90%, at least 95%, or a VH region comprising CDRs having at least 98% sequence identity, and the antibody is a CD3 7. In certain embodiments, the antibodies provided herein bind to the polypeptide of SEQ ID NO: 7. At least 80%, at least 85%, at least 90%, or at least VL regions having 95%, or at least 98% sequence identity with SEQ ID NO: At least 80%, at least 85%, at least 90% for the 16 amino acid sequences; and a VH region having at least 95%, or at least 98%, sequence identity with the antibody. In certain embodiments, the antibodies provided herein bind to CD37. At least 80% of the amino acid sequence of the CDRs contained in No. 7, 85%, at least 90%, at least 95%, or at least 98% sequence identity a VL region containing a CDR corresponding to the amino acid sequence of the CDR contained in SEQ ID NO: 16; At least 80%, at least 85%, at least 90%, at least 95%, or comprises a VH region comprising CDRs having at least 98% sequence identity, and the antibody is CD37 In certain embodiments, the antibodies provided herein bind to the antigen of SEQ ID NO: 8. At least 80%, at least 85%, at least 90%, at least a VL region having at least 95%, or at least 98%, sequence identity with SEQ ID NO: 9; At least 80%, at least 85%, at least 90%, at least and the antibody comprises a VH region having at least 95%, or at least 98%, sequence identity with the CD 37. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 8 At least 80%, at least 85% of the amino acid sequence of the CDR contained in %, at least 90%, at least 95%, or at least 98% sequence identity For the VL region containing the CDR and / or the amino acid sequence of the CDR contained in SEQ ID NO: 9 At least 80%, at least 85%, at least 90%, at least 95%, or less The antibody binds to CD37 and comprises a VH region containing CDRs with at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO:8. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with the VL region of SEQ ID NO: 10, and / or At least 80%, at least 85%, at least 90%, at least and the antibody comprises a VH region having at least 95%, or at least 98%, sequence identity with CD37. In certain embodiments, the antibodies provided herein bind to the polypeptides contained in SEQ ID NO: 8. At least 80%, at least 85%, or CDs with at least 90%, at least 95%, or at least 98% sequence identity a VL region containing R and / or a CDR amino acid sequence contained in SEQ ID NO: 10 at least 80%, at least 85%, at least 90%, at least 95%, or less The antibody contains a VH region containing CDRs with 98% sequence identity to both the CD37 and CD37 subunits. do.

[0141] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO:8. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or an amino acid sequence of SEQ ID NO: 11 At least 80%, at least 85%, at least 90%, at least 9% of the sequence 5%, or at least 98% sequence identity between the VH region and the antibody, In certain embodiments, the antibodies provided herein comprise a polypeptide comprising the polypeptide of SEQ ID NO: 8. At least 80%, at least 85%, at least CDRs having at least 90%, at least 95%, or at least 98% sequence identity. and / or a VL region comprising at least one amino acid sequence corresponding to the amino acid sequence of the CDR contained in SEQ ID NO: 11. At least 80%, at least 85%, at least 90%, at least 95%, or at least The antibody binds to CD37 and contains a VH region containing CDRs with 98% sequence identity. In certain embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO:8. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or the amino acid sequence of SEQ ID NO: 12 At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity to a VH region of the antibody that binds to CD37 In certain embodiments, the antibodies provided herein comprise a polypeptide comprising the polypeptide sequence of SEQ ID NO: 8. At least 80%, at least 85%, at least and CDRs that have 90%, at least 95%, or at least 98% sequence identity with each other. and / or the amino acid sequence of the CDR contained in SEQ ID NO: 12. at least 80%, at least 85%, at least 90%, at least 95%, or at least 9 The antibody contains a VH region containing CDRs with 8% sequence identity, and binds to CD37. In certain embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO:8. at least 80%, at least 85%, at least 90%, at least 95%, or VL regions with at least 98% sequence identity and / or the amino acid sequence of SEQ ID NO: 13 At least 80%, at least 85%, at least 90%, at least 95% for columns or a VH region having at least 98% sequence identity thereto, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise a C sequence contained in SEQ ID NO:8. At least 80%, at least 85%, at least or at least 90%, at least 95%, or at least 98% sequence identity with the CDRs. VL region and / or CDR amino acid sequence contained in SEQ ID NO: 13 80%, at least 85%, at least 90%, at least 95%, or at least 98% % sequence identity, and the antibody binds to CD37. In some embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO: 8. At least 80%, at least 85%, at least 90%, at least 95%, or a VL region having at least 98% sequence identity, and / or the amino acid sequence of SEQ ID NO: 14 At least 80%, at least 85%, at least 90%, at least 95%, or a VH region having at least 98% sequence identity, wherein the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise a CD45 fragment contained in SEQ ID NO: 8. At least 80%, at least 85%, at least V comprising CDRs with 90%, at least 95%, or at least 98% sequence identity L region and / or CDR amino acid sequence contained in SEQ ID NO: 14 0%, at least 85%, at least 90%, at least 95%, or at least 98% and the antibody binds to CD37. In embodiments, the antibodies provided herein are directed to the amino acid sequence of SEQ ID NO:8. At least 80%, at least 85%, at least 90%, at least 95%, or less a VL region having at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 15; At least 80%, at least 85%, at least 90%, at least 95%, or comprises a VH region having at least 98% sequence identity, and the antibody binds to CD37. In certain embodiments, the antibodies provided herein comprise the CDRs contained in SEQ ID NO:8. At least 80%, at least 85%, at least 9% of the amino acid sequence VL comprising CDRs with 0%, at least 95%, or at least 98% sequence identity region, and / or the amino acid sequence of the CDR contained in SEQ ID NO: 15 %, at least 85%, at least 90%, at least 95%, or at least 98% The antibody binds to CD37 and contains a VH region containing CDRs with sequence identity. In some embodiments, the antibodies provided herein have a low affinity to the amino acid sequence of SEQ ID NO:8. at least 80%, at least 85%, at least 90%, at least 95%, or less VL region with 98% sequence identity to the amino acid sequence of SEQ ID NO: 16, and / or at least 80%, at least 85%, at least 90%, at least 95%, or The antibody binds to CD37 and comprises a VH region having at least 98% sequence identity. In certain embodiments, the antibodies provided herein comprise the CDRs contained in SEQ ID NO:8. At least 80%, at least 85%, at least 90% of the amino acid sequence %, at least 95%, or at least 98% sequence identity between the VL region and the CDRs. and / or at least 80% of the amino acid sequence of the CDR contained in SEQ ID NO: 16 , at least 85%, at least 90%, at least 95%, or at least 98% The antibody binds to CD37 and comprises a VH region containing CDRs with homology.

[0142] In some embodiments, a polypeptide comprising the VH, VL, or CDR sequences of the anti-CD37 antibodies described above is provided. and an antibody further comprising an Fc region having an RE mutation but no fucose residues. In some embodiments, the antibody has the amino acid sequence of SEQ ID NO: 37. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid sequence of SEQ ID NO: 39. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 54. In the example, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 55. and a heavy chain comprising SEQ ID NO: a light chain comprising the amino acid sequence of SEQ ID NO: 40 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 56; In some embodiments, the antibody has the amino acid sequence of SEQ ID NO: 41. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 42 and a light chain comprising the amino acid sequence of SEQ ID NO: and a heavy chain comprising the amino acid sequence of SEQ ID NO:58. In the example, the antibody has a light chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 59. and a heavy chain comprising SEQ ID NO: a light chain comprising the amino acid sequence of SEQ ID NO: 44 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 60; In some embodiments, the antibody has the amino acid sequence of SEQ ID NO: 45. In some embodiments, the anti- The antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 but with the K248E / T437R mutations. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 47, but K248. In some embodiments, the antibody comprises a heavy chain having a E / T437R mutation. 8 amino acid sequence but with the K248E / T437R mutation. In embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 49 but with the K248E / T437R mutation. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 50. In some embodiments, the anti- The antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 51 but with the K248E / T437R mutations. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 52, but K248. In some embodiments, the antibody comprises a heavy chain having a E / T437R mutation. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:59. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 60. include.

[0143] In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 61 but with K248E / In some embodiments, the antibody comprises a heavy chain having a T437R mutation. The heavy chain contains the amino acid sequence but with the K248E / T437R mutations. In one embodiment, the antibody comprises the amino acid sequence of SEQ ID NO: 63 but contains K248E / T437R mutations. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain having a K248E / T437R mutation. , comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 65 but with the K248E / T437R mutations In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 66 but with K248E / In some embodiments, the antibody comprises a heavy chain having a T437R mutation. The heavy chain contains the amino acid sequence but with the K248E / T437R mutations. In one embodiment, the antibody comprises the amino acid sequence of SEQ ID NO: 68 but contains K248E / T437R mutations. The heavy chain comprises:

[0144] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 37 and an A The amino acid sequence of SEQ ID NO: 45, which does not contain a fucose residue in the sn-297-linked N-oligosaccharide, In some embodiments, the antibody is T26B373.CLF, and the antibody comprises a heavy chain comprising: A light chain comprising the amino acid sequence of SEQ ID NO: 38 and its Asn-297 linked N-oligosaccharides containing fucosylated and a heavy chain comprising the amino acid sequence of SEQ ID NO: 46, excluding the base residues. In some embodiments, the antibody is a light chain reaction (CLF) comprising the amino acid sequence of SEQ ID NO: 39. and the Asn-297 linked N-oligosaccharide of SEQ ID NO: 47 does not contain a fucose residue. and a heavy chain comprising the amino acid sequence T26B375.CLF. The antibody has a light chain comprising the amino acid sequence of SEQ ID NO: 40 and an N-amino acid sequence linked to Asn-297 of the light chain. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 48, which does not contain a fucose residue in the oligosaccharide. In some embodiments, the antibody has the amino acid sequence of SEQ ID NO: 41. a light chain containing the sequence and a sequence containing no fucose residue in its Asn-297-linked N-oligosaccharide and a heavy chain comprising the amino acid sequence of number 49. In one embodiment, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 42 and a light chain comprising Asn-29 thereof. a heavy chain comprising the amino acid sequence of SEQ ID NO: 50, which does not contain a fucose residue in the 7-linked N-oligosaccharide; In some embodiments, the antibody is T26B385.CLF, comprising SEQ ID NO: 4 The light chain contains the amino acid sequence of 3 and its Asn-297 linked N-oligosaccharide contains a fucose residue. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 51, but not comprising the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 44 and a The amino acid sequence of SEQ ID NO: 52 does not contain a fucose residue in the Asn-297 linked N-oligosaccharide and a heavy chain comprising: a light chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain having a nucleotide sequence linked to Asn-297 of the N-oligosaccharide; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 53, excluding cos residues. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 38. light chain and its Asn-297 linked N-oligosaccharide does not contain a fucose residue and a heavy chain comprising the amino acid sequence T26B460.CLF. In the antibody, the antibody has a light chain comprising the amino acid sequence of SEQ ID NO: 39 and its Asn-297 linked N- and a heavy chain comprising the amino acid sequence of SEQ ID NO: 55, which does not contain fucose residues in the oligosaccharide. In some embodiments, the antibody is 26B461.CLF. The light chain contains a fucose sequence and its Asn-297 linked N-oligosaccharide does not contain a fucose residue. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising Asn-2 A heavy chain comprising the amino acid sequence of SEQ ID NO: 57, which does not contain a fucose residue in the 97-linked N-oligosaccharide. In some embodiments, the antibody is T26B463.CLF, comprising SEQ ID NO: The light chain contains 42 amino acids and a fucose residue in its Asn-297 linked N-oligosaccharide. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 58, In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43 and a The amino acid sequence of SEQ ID NO: 59 does not contain a fucose residue in the Asn-297 linked N-oligosaccharide. and a heavy chain comprising the sequence T26B465.CLF. comprises a light chain comprising the amino acid sequence of SEQ ID NO: 44 and its Asn-297 linked N-oligosaccharides. and a heavy chain comprising the amino acid sequence of SEQ ID NO: 60, which does not contain a fucose residue. 6. CLF. In some embodiments, the antibody is an Asn-297 linked N-oligonucleotide. The heavy chain contains no fucose residues in the sugar chain and has the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody comprises a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 46, which does not include the amino acid sequence of SEQ ID NO: 46. , the amino acid sequence of SEQ ID NO: 47, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the Asn-297 linked N-terminal amino acid sequence. - a heavy chain comprising the amino acid sequence of SEQ ID NO: 48, which does not contain fucose residues in the oligosaccharides. In some embodiments, the antibody contains a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 49, but not including the amino acid sequence of SEQ ID NO: 49. is an amino acid sequence of SEQ ID NO: 50 that does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the Asn-297 linkage. It includes a heavy chain comprising the amino acid sequence of SEQ ID NO: 51, which does not contain fucose residues in the N-oligosaccharide. In some embodiments, the antibody has a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52, which does not include SEQ ID NO: 53. The antibody is an antibody of SEQ ID NO: 53 that does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of Asn-297. The heavy chain contains the amino acid sequence of SEQ ID NO: 54, which does not contain fucose residues in the N-oligosaccharides. In some embodiments, the antibody contains a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 55, without the group. The antibody has the structure of SEQ ID NO: 56, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of Asn-297 A heavy chain comprising the amino acid sequence of SEQ ID NO: 57, which does not contain a fucose residue in the linking N-oligosaccharide. In some embodiments, the antibody has fucose at its Asn-297 linked N-oligosaccharide. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 58, but no residues are present. , the antibody has SEQ ID NO: 59, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of: A heavy chain comprising the amino acid sequence of SEQ ID NO: 60, which does not contain a fucose residue in the 7-linked N-oligosaccharide In some embodiments, the antibody comprises fucose at its Asn-297 linked N-oligosaccharide. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 61, without any of the α- and β-amino acid residues. The antibody has SEQ ID NO: 6, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of Asn-2. A heavy chain comprising the amino acid sequence of SEQ ID NO: 63, which does not contain a fucose residue in the 97-linked N-oligosaccharide. In some embodiments, the antibody comprises fucosylated N-oligosaccharides linked to its Asn-297. Some embodiments include a heavy chain comprising the amino acid sequence of SEQ ID NO: 64, without any base residue. In the example, the antibody has SEQ ID NO: 1, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising a sequence of Asn- 297. A heavy chain comprising the amino acid sequence of SEQ ID NO: 66, which does not contain a fucose residue in the linked N-oligosaccharide. In some embodiments, the antibody comprises a phosphodiesterase (Pd)-linked N-oligosaccharide. The heavy chain comprises the amino acid sequence of SEQ ID NO: 67, excluding the codon residue. In this embodiment, the antibody has SEQ ID NO: 1, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of K248E. , T437R or K248E / T437R mutations, and its Asn-297 linked N-oligonucleotide The heavy chain contains no fucose residues in the sugar chain and has the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody contains a K248E, a T437R, or a K248E / T437R mutation. and no fucose residue in its Asn-297 linked N-oligosaccharide, In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence K248E, T43 7R or K248E / T437R mutations, and its Asn-297 linked N-oligosaccharide The heavy chain comprises the amino acid sequence of SEQ ID NO: 47, without the codon residue. In some embodiments, the antibody comprises a K248E, a T437R, or a K248E / T437R mutation, Amino acid sequence of SEQ ID NO: 48, which does not contain a fucose residue in the Asn-297 linked N-oligosaccharide In some embodiments, the antibody comprises a heavy chain comprising the sequence K248E, T437R or It contains the K248E / T437R mutation and its Asn-297 linked N-oligosaccharide contains a fucose residue. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 49, without the group. The antibody contains a K248E, T437R or K248E / T437R mutation and its Asn -297 linked N-oligosaccharide does not contain a fucose residue, and the amino acid sequence of SEQ ID NO: 50 In some embodiments, the antibody comprises a heavy chain comprising K248E, T437R, or K248 E / T437R mutation and contains a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 51, which does not include the amino acid sequence of SEQ ID NO: 51. , K248E, T437R or K248E / T437R mutations, and A heavy chain comprising the amino acid sequence of SEQ ID NO: 52, which does not contain a fucose residue in the linking N-oligosaccharide. In some embodiments, the antibody comprises fucose at its Asn-297 linked N-oligosaccharide. Some embodiments include a heavy chain comprising the amino acid sequence of SEQ ID NO: 53, without any cis residue. In the example, the antibody has SEQ ID NO: 1, which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of Asn. -297-linked N-oligosaccharide does not contain a fucose residue, and the amino acid sequence of SEQ ID NO: 55 In some embodiments, the antibody comprises a heavy chain comprising the Asn-297 linked N-oligosaccharide and a heavy chain comprising the amino acid sequence of SEQ ID NO: 56, which does not contain a fucose residue. In embodiments, the antibody does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 57. amino acid sequence of SEQ ID NO: 58, without a fucose residue in the Asn-297 linked N-oligosaccharide In some embodiments, the antibody comprises a heavy chain comprising the sequence Asn-297 linked N- The heavy chain contains the amino acid sequence of SEQ ID NO: 59, and does not contain fucose residues in the oligosaccharides. In some embodiments, the antibody contains a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 60, but not comprising the amino acid sequence of SEQ ID NO: 60. The antibody contains a K248E, T437R or K248E / T437R mutation and its Asn-2 97 linked N-oligosaccharides containing no fucose residues and a heavy chain comprising the amino acid sequence of SEQ ID NO: 61 In some embodiments, the antibody comprises a K248E, T437R or K248E / T437R chain. Contains the T437R mutation and does not contain a fucose residue in its Asn-297-linked N-oligosaccharide In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 62. 248E, T437R or K248E / T437R mutations, and the Asn-297 linkage A heavy chain comprising the amino acid sequence of SEQ ID NO: 63, which does not contain fucose residues in the N-oligosaccharides In some embodiments, the antibody is K248E, T437R, or K248E / T437 R mutation and does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of K248E. , T437R or K248E / T437R mutations, and its Asn-297 linked N-oligonucleotide The heavy chain contains the amino acid sequence of SEQ ID NO: 65, and does not contain a fucose residue in the sugar. In some embodiments, the antibody contains a K248E, a T437R, or a K248E / T437R mutation. Contains and the Asn-297 linked N-oligosaccharide of SEQ ID NO: 66 does not contain a fucose residue. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence K248E, T437 R or K248E / T437R mutations, and its Asn-297 linked N-oligosaccharide is fucosylated Some embodiments include a heavy chain comprising the amino acid sequence of SEQ ID NO: 67, without any base residues. In one embodiment, the antibody comprises a K248E, a T437R, or a K248E / T437R mutation, The amino acid sequence of SEQ ID NO: 68, which does not contain a fucose residue in the Asn-297 linked N-oligosaccharide The heavy chain comprises a sequence.

[0145] 5.7 Anti-GPRC5D Antibodies and Related Molecules In other embodiments, anti-GPRC5D antibodies are provided herein. In embodiments, the antibodies provided herein are comprised in the VL and VH sequences of Table 13. It comprises a VL, VH, or CDR having the amino acid sequence of a VL, VH, or CDR.

[0146] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 33 and a VL comprising the amino acid sequence of SEQ ID NO: 34. GC5B747 or GC5B752, which contains a VH comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the antibody comprises a CD14 domain comprising a VL comprising the amino acid sequence of SEQ ID NO: 33. VL comprising a CDR having the amino acid sequence of R and V comprising the amino acid sequence of SEQ ID NO: 34 and VH, which contains a CDR having the amino acid sequence of the CDR contained in H.

[0147] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. Antibodies derived from these antibodies are expected to exhibit similar functional properties. Exemplary antigen binding proteins include: 13, including those having the VL and VH regions provided herein. It can be enjoyed.

[0148] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0149] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is that of Karlin and Altschul, Proc.Natl.Acad.Sci.USA,1990,87:2264-8 ,modified as in Karlin and Altschul,Proc. Natl.Acad.Sci.USA,1993,90:5873-7 Such algorithms are described in Altschul, et al., J.Mo NBLAST and XBLAST programs in I. Biol., 1990, 215:403 BLAST nucleotide searches are integrated into the NBLAST nucleotide program. The program parameters are set to, for example, score = 100 and word length = 12, and the results are Nucleotide sequences homologous to the nucleic acid molecules described herein can be obtained. For protein searches, set the parameters of the XBLAST program to, for example, a score of 50, The code length was set to 3, and amino acid sequences homologous to the protein molecules described herein were identified. To obtain a gapped alignment for comparison purposes, use Alts chul et al., Nucleic Acids Res.,1997,25:3 Alternatively, Gapped BLAST may be utilized as described in P SI BLAST can also be used to perform iterative searches that detect distant relationships between molecules. (Ibid.) Using the BLAST, Gapped BLAST, and PSI Blast programs When using the program, please refer to the default settings of each program (e.g., XBLAST and NBLAST). Default parameters can be used (for example, ional Center for Biotechnology Informati on (NCBI, see ncbi.nlm.nih.gov). Another preferred, non-limiting example of a mathematical algorithm is the algorithm proposed by Myers and Mil ler, 1988, CABIOS 4:11 There are 17 algorithms. The algorithm is ALIG, part of the GCG sequence alignment software package. It is incorporated into the N program (version 2.0) for comparing amino acid sequences. When using the ALIGN program, the PAM120 weight residue table, gap length penalty, A gap penalty of 12 and a gap penalty of 4 can be used.

[0150] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0151] In certain embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO: 33. At least 80%, at least 85%, at least 90%, at least 95% for columns or a VL region having at least 98% sequence identity, and / or an amino acid sequence of SEQ ID NO: 34 At least 80%, at least 85%, at least 90%, at least and a VH region having 95%, or at least 98%, sequence identity with GPRC5. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 33. At least 80%, at least 85% of the amino acid sequence of the CDR contained in %, at least 90%, at least 95%, or at least 98% sequence identity VL region containing CDR and / or the amino acid sequence of the CDR contained in SEQ ID NO: 34 At least 80%, at least 85%, at least 90%, at least 95%, or the antibody comprises a VH region containing CDRs having at least 98% sequence identity with GPRC5D Combine with.

[0152] In some embodiments, glutamic acid is present in the Fc region of an antibody provided herein. There is a lysine substitution at position 248 in the ribosomal region (K248E) (EU numbering). In embodiments, an arginine is present at position 437 of the Fc region of an antibody provided herein. substituted with leonine (T437R) (EU numbering). A glutamic acid is attached to a lysine at position 248 of the Fc region of an antibody provided herein, and a 4 A substitution at position 37 with threonine (K248E / T437R) (EU numbering).

[0153] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 101 and a light chain comprising the amino acid sequence of the sequence and a heavy chain comprising the amino acid sequence of SEQ ID NO: 102. In one embodiment, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 101 and a second light chain comprising the amino acid sequence of SEQ ID NO: 103. and a heavy chain comprising the amino acid sequence GC5B752. 102, containing the mutations K248E, T437R or K248E / T437R In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 103. The heavy chain comprises a nucleotide sequence.

[0154] In some embodiments, the antibodies provided herein contain fucose in the Fc region. In some embodiments, the antibody does not comprise a light chain comprising the amino acid sequence of SEQ ID NO: 101. and the Asn-297-linked N-oligosaccharide of SEQ ID NO: 102, which does not contain a fucose residue. and a heavy chain comprising the amino acid sequence GC5B747.CLF. The antibody has a light chain comprising the amino acid sequence of SEQ ID NO: 101 and its Asn-297 linked N- and a heavy chain comprising the amino acid sequence of SEQ ID NO: 103, which does not contain fucose residues in the oligosaccharides. In some embodiments, the antibody is GC5B752.CLF. A heavy chain comprising the amino acid sequence of SEQ ID NO: 102, which does not contain a fucose residue in the linking N-oligosaccharide. In some embodiments, the antibody comprises fucosylated N-oligosaccharides linked to its Asn-297. The heavy chain comprises the amino acid sequence of SEQ ID NO: 103, without any base residues.

[0155] In some embodiments, the antibodies provided herein comprise a K248E in the Fc region. In some embodiments, the antibody comprises a T437R mutation and is free of fucosylation. comprises a light chain comprising the amino acid sequence of SEQ ID NO: 101 and its Asn-297 linked N-oligosaccharides and a heavy chain comprising the amino acid sequence of SEQ ID NO: 103, which does not contain a fucose residue. In some embodiments, the antibody is 752.CLF. It contains the K248E / T437R mutation and its Asn-297 linked N-oligosaccharide contains a fucose residue. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 102, without the amino acid group. The antibody has SEQ ID NO: 1 which does not contain a fucose residue in its Asn-297 linked N-oligosaccharide. The heavy chain comprises an amino acid sequence of 03.

[0156] 5.8 Anti-KLK2 antibodies and related molecules In one aspect, provided herein is an anti-KLK2 antibody.

[0157] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 108 and a VL comprising the sequence and VH comprising the amino acid sequence of No. 107. In one embodiment, provided herein is an antibody that binds to KLK2, the antibody comprising: (i) a sequence VH CDR1, VH CDR2, and VH CDR3 amino acids in column number 107, respectively. VH and VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequence (ii) VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 108, respectively. VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequence of CDR3 In some embodiments, the VL comprises a VH CDR1, a VH CDR2, The VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences were obtained from Kab In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VH CDR4, VH CDR5, VH CDR6, VH CDR7, VH CDR8, VH CDR9, VH CDR10, VH CDR11, VH CDR12, VH CDR13, VH CDR14, VH CDR15, VH CDR16, VH CDR17, VH CDR18, VH CDR1 2. VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are In some embodiments, the VH CDR1, VH VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences The columns follow an exemplary numbering system. In some embodiments, the VH CDR1, V H CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 The sequences follow the Contact numbering system. In some embodiments, the VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL The CDR3 sequences follow the IMGT numbering system. DR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL The CDR3 sequences follow the AbM numbering system.

[0158] In another aspect, provided herein is an antibody that binds to KLK2, the antibody comprising: i) a VH CDR1 having the amino acid sequence of GGSISSYYWS (SEQ ID NO: 109); VH C having the amino acid sequence YIYYSGSTNYNPSLKS (SEQ ID NO: 110) DR2, and the amino acid sequence of TTIFGVVTPNFYYGMDV (SEQ ID NO: 111) and (ii) a VH comprising a VH CDR3 having RASQGISSYLA (SEQ ID NO: 11 2), a VL CDR1 having the amino acid sequence of AASTLQS (SEQ ID NO: 113); VL CDR2 having the amino acid sequence of QQLNSYPLT (SEQ ID NO: 114) and a VL comprising a VL CDR3 having the sequence Provided herein are antibodies that: (i) identify the sequence of GGSISSYY (SEQ ID NO: 115), VH CDR1 having the amino acid sequence of IYYSGST (SEQ ID NO: 116) VH CDR2 having the amino acid sequence AGTTIFGVVTPNFYYGMDV( (ii) a VH comprising a VH CDR3 having the amino acid sequence of SEQ ID NO: 117; and (iii) a QG VL CDR1 having the amino acid sequence of ISSY (SEQ ID NO: 118), AAS (SEQ ID NO: 119), 119), and VL CDR2 having the amino acid sequence of QQLNSYPLT (SEQ ID NO: 1 20), and a VL comprising a VL CDR3 having the amino acid sequence of Provided herein are antibodies that bind to KLK2, the antibodies being (i) SYYWS( VH CDR1 having the amino acid sequence of SEQ ID NO: 121), YIYYSGSTNYNPS VH CDR2 having the amino acid sequence of LKS (SEQ ID NO: 122), and TTIFGVV VH CDR3 having the amino acid sequence of TPNFYYGMDV (SEQ ID NO: 123) , VH, and (ii) an amino acid sequence of RASQGISSYLA (SEQ ID NO: 124). VL CDR1, VL CDR having the amino acid sequence of AASTLQS (SEQ ID NO: 125) R2, and a VL CDR having the amino acid sequence of QQLNSYPLT (SEQ ID NO: 126) In another aspect, an antibody that binds to KLK2 is described herein as comprising a VL comprising: The antibody is provided, wherein the antibody has (i) the amino acid sequence of GGSISSY (SEQ ID NO: 127). VH CDR1 having the amino acid sequence of YSG (SEQ ID NO: 128); and a VH having the amino acid sequence TIFGVVTPNFYYGMD (SEQ ID NO: 129). (ii) the amino acid sequence of SQGISSY (SEQ ID NO: 130), VL CDR1 having the amino acid sequence of AAS (SEQ ID NO: 131) 2, and a VL CDR3 having the amino acid sequence of LNSYPL (SEQ ID NO: 132). In another aspect, provided herein is an antibody that binds to KLK2. The antibody comprises: (i) a VH having the amino acid sequence GGSISSY (SEQ ID NO: 127); CDR1, a VH CDR2 having the amino acid sequence of YYSGS (SEQ ID NO: 168), and VH CD having the amino acid sequence of TIFGVVTPNFYYGMD (SEQ ID NO: 129) (ii) a VH comprising R3; and (iii) an amino acid sequence of RASQGISSY (SEQ ID NO: 169). VL CDR1 having the amino acid sequence of AASTLQS (SEQ ID NO: 170) CDR2, and VL having the amino acid sequence of QQLNSYPLT (SEQ ID NO: 171) In another embodiment, an antibody that binds to KLK2 is described herein. The antibody is provided in the present invention, wherein the antibody comprises: (i) an amino acid sequence of SSYYWS (SEQ ID NO: 133). The amino acid sequence of VH CDR1, WIGYIYYSGSTN (SEQ ID NO: 134) VH CDR2 having: AGTTIFGVVTPNFYYGMD (SEQ ID NO: 135) and (ii) a VH comprising a VH CDR3 having the amino acid sequence: VL CDR1 having the amino acid sequence of FLIYAASTLQ (SEQ ID NO: 136) 137), and VL CDR2 having the amino acid sequence of QQLNSYPL (SEQ ID NO: 13 8), and a VL comprising a VL CDR3 having the amino acid sequence of Provided herein is an antibody that binds to LK2, the antibody comprising: (i) GGSISSY VH CDR1, YIYYSGSTN, having the amino acid sequence of YWS (SEQ ID NO: 139) VH CDR2 having the amino acid sequence of (SEQ ID NO: 140), and TTIFGVVTPN VH comprising a VH CDR3 having the amino acid sequence of FYYGMDV (SEQ ID NO: 141). and (ii) a VL having the amino acid sequence of RASQGISSYLA (SEQ ID NO: 142). CDR1, VL CDR2 having the amino acid sequence of AASTLQS (SEQ ID NO: 143), and a VL CDR3 having the amino acid sequence of QQLNSYPLT (SEQ ID NO: 144). In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 107. In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 108. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 107. VH, which comprises an amino acid sequence having at least 95% identity to In this embodiment, the antibody has at least 95% identity to the amino acid sequence of SEQ ID NO: 108. The VL comprises an amino acid sequence having the same identity.

[0159] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. The resulting antibodies are expected to exhibit similar functional properties.

[0160] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0161] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is that of Karlin and Altschul, Proc.Natl.Acad.Sci.USA,1990,87:2264-8 ,modified as in Karlin and Altschul,Proc. Algorithm of Natl.Acad.Sci.USA1993,90:5873-7 Such an algorithm is described in Altschul, et al., J. Mol. .Biol.,1990,215:403 to the NBLAST and XBLAST programs BLAST nucleotide searches are performed using the NBLAST nucleotide program. The parameters of the program are set to, for example, score = 100 and word length = 12, and the program is run. Nucleotide sequences homologous to the nucleic acid molecules described in the document can be obtained. Protein searches are performed using the XBLAST program parameters, e.g., score 50, word count 0, and The sequence length was set to 3, and the amino acid sequence homologous to the protein molecules described herein was To obtain a gapped alignment for comparison purposes, use Altsc hul et al., Nucleic Acids Res.,1997,25:33 Alternatively, Gapped BLAST may be used as described in PS BLAST can also be used to perform iterated searches that detect distant relationships between molecules ( (Ibid.) BLAST, Gapped BLAST, and PSI Blast programs are used. When doing so, please use the default settings of each program (e.g., XBLAST and NBLAST). default parameters can be used (for example, onal Center for Biotechnology Information n (NCBI, see ncbi.nlm.nih.gov). Used for sequence comparison. Another preferred, non-limiting example of a mathematical algorithm is the Myers and Mill er, 1988, CABIOS 4:11 There are 17 algorithms. The algorithm is ALIGN, part of the GCG sequence alignment software package. The program (version 2.0) was incorporated into the A When using the LIGN program, the PAM120 weight residue table and gap length penalty are required. A threshold of 12 and a gap penalty of 4 can be used.

[0162] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0163] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 107. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with a VH region of SEQ ID NO: 108 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with a KLK. Combine with 2.

[0164] In some embodiments, a polypeptide comprising the VH, VL, or CDR sequences of the anti-KLK2 antibodies described above is provided. and an antibody further comprising an Fc region having an RE mutation but no fucose residues. In some embodiments, the anti-KLK antibody provided herein is Two antibodies contain Fc regions with RE mutations but no fucose residues.

[0165] Standard techniques known to those skilled in the art can be used, for example, site-directed mutagenesis and amino acid sequence modification. The molecules provided herein are prepared by PCR-mediated mutagenesis, which results in amino acid substitutions. Mutations can be introduced into the nucleotide sequence to be cloned.

[0166] In some embodiments, glutamic acid is present in the Fc region of an antibody provided herein. There is a lysine substitution at position 248 in the ribosomal region (K248E) (EU numbering). In embodiments, an arginine is present at position 437 of the Fc region of an antibody provided herein. substituted with leonine (T437R) (EU numbering). A glutamic acid is attached to a lysine at position 248 of the Fc region of an antibody provided herein, and a 4 A substitution at position 37 with threonine (K248E / T437R) (EU numbering).

[0167] In some embodiments, the antibodies provided herein comprise a T437R mutation. In some embodiments, the antibodies provided herein comprise a heavy chain containing K248E In some embodiments, the antibodies provided herein comprise a heavy chain comprising a mutation. In some embodiments, the present invention provides a method for treating a pulmonary artery disease (PAG) comprising administering to a subject ... In some embodiments, the antibody comprises a heavy chain comprising a K248E / T437R mutation. The antibodies provided herein comprise a heavy chain comprising a K338A / T437R mutation. In some embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO: 155. In some embodiments, the heavy chain comprises a T437R but has a T437R. The provided antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 155 but having K248E. In some embodiments, the antibodies provided herein comprise the antibody of SEQ ID NO: 155. In some embodiments, the heavy chain comprises the amino acid sequence of the present invention but has K338A. The antibody provided in claim 1 comprises the amino acid sequence of SEQ ID NO: 155, but K248E / T43 In some embodiments, the antibodies provided herein comprise a heavy chain having a 7R mutation. The antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 155 but with the K338A / T437R mutations. In some embodiments, the antibody provided herein comprises SEQ ID NO: 155. KL2 containing the amino acid sequence of but with K248E and T437R mutations (RE mutations) It's B870.

[0168] In some embodiments, the antibodies provided herein (including the anti-KLK2 antibodies described above) The Asn- The present invention provides a method for the preparation of a medicament ... For example, antibodies can be generated from mice that are deficient in the GMD enzyme (e.g., CHO Lec13 cells), a mutant FUT8 gene causes α-1,6 fucosyltransferase β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosidase activity decreased Overexpressing glucosaminyltransferase (GnT-III), inactivated glutamate GDP-fucose transporter (GFT) gene Slc35c1 (e.g., CHO -gmt3 cells), heterologously expressing bacterial RMD, or biochemical inhibitors of fucosylation (e.g., For example, the use of fucose analogs such as 2-fluorofucose and 5-alkynylfucose The mammalian cell line involved has a fucose residue in the Asn-297 linked N-oligosaccharide on the heavy chain. It has been shown that the immune system produces antibodies that are not specific to the immune system (Pereira, NA, et al. , supra; Shields, RLet al., supra; Kanda Y., supra).

[0169] In some embodiments, the antibody has a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain that does not contain the amino acid sequence of SEQ ID NO: 146. a light chain containing the sequence and a sequence containing no fucose residue in its Asn-297-linked N-oligosaccharide and a heavy chain comprising the amino acid sequence of 155. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 146 and an Asn- 297-linked N-oligosaccharides containing no fucose residues in the amino acid sequence of SEQ ID NO: 153 In some embodiments, the antibody is KL2B870.CLF, comprising a heavy chain. The amino acid sequence of SEQ ID NO: 155 does not contain a fucose residue in the Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the sequences K248E, K338A, T4 37R, K248E / T437R or K338A / T437R mutations, 297 linked N-oligosaccharides containing no fucose residues and containing the amino acid sequence of SEQ ID NO: 155 The heavy chain comprises

[0170] 5.9 Anti-PSMA Antibodies and Related Molecules In one embodiment, an anti-PSMA antibody is provided herein.

[0171] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 232 and a VL comprising the sequence and PSMB896, which contains a VH comprising the amino acid sequence of SEQ ID NO: 233. In one embodiment, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 232 and a VL comprising the amino acid sequence of SEQ ID NO: 234. and VH containing the amino acid sequence PSMB898.

[0172] In some embodiments, provided herein are antibodies that bind to PSMA, The antibody comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of SEQ ID NO: 233. VH CDR1, VH CDR2, and VH CDR3 with VH CDR3 amino acid sequence and (ii) a VH comprising VL CDR1, VL CDR2, VL CDR3, VL CDR4, VL CDR5, VL CDR6, VL CDR7, VL CDR8, VL CDR9, VL CDR10, VL CDR11, VL CDR12, VL CDR13, VL CDR14, VL CDR15, VL CDR16, VL CDR17, VL CDR18, VL VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3. and a VL comprising a VL CDR3. Provided herein are antibodies comprising: (i) a nucleotide sequence of SEQ ID NO: 234, respectively; VH CDs having VH CDR1, VH CDR2, and VH CDR3 amino acid sequences (ii) a VH comprising R1, VH CDR2, and VH CDR3; and (iii) a VH of SEQ ID NO: 232 , which have the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. and a VL comprising VL CDR1, VL CDR2, and VL CDR3. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR4, VL CDR5, VL CDR6, VL CDR7, VL CDR8, VL CDR9, VL CDR10, VL CDR11, VL CDR12, VL CDR13, VL CDR14, VL CDR15, VL CDR16, VL CDR17, VL CDR18, VL CDR19 ...9, VL CDR11, VL CDR12, VL CDR13, VL CDR14, VL CDR15, VL CDR16, V R1, VL CDR2, and VL CDR3 sequences follow the Kabat numbering system In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL The CDR1, VL CDR2, and VL CDR3 sequences are numbered according to the Chothia numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3 The VL CDR1, VL CDR2, and VL CDR3 sequences are numbered according to the IMGT numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR 3, VL CDR1, VL CDR2, and VL CDR3 sequences are numbered according to the AbM numbering system. Follow the system.

[0173] In another aspect, provided herein is an antibody that binds to PSMA, the antibody comprising: i) VH CDR1 having the amino acid sequence of SYAMS (SEQ ID NO: 244), AISGG VH CDR2 having the amino acid sequence of IGSTYYADSVKG (SEQ ID NO: 245), and a VH CDR having the amino acid sequence of DGVGATPYYFDY (SEQ ID NO: 246). 3, and (ii) an amino acid sequence of SGSSSNIGINYVST (SEQ ID NO: 247). VL CDR1 having the amino acid sequence DNNKRPS (SEQ ID NO: 248) The amino acid sequence of VL CDR2 and GTWDSSLSAVV (SEQ ID NO: 249) In another embodiment, the antibody binds to PSMA. provided herein are antibodies that: (i) bind to an amino acid sequence of SYAMS (SEQ ID NO: 250); VH CDR1, AISGGSGSTYYADSVKG (SEQ ID NO: 25) 1), and a VH CDR2 having the amino acid sequence of DGVGATPYYFDY (SEQ ID NO: 252), and (ii) a VH comprising a VH CDR3 having the amino acid sequence VL CDR1, DNNKR having the amino acid sequence of IGINYVS (SEQ ID NO: 253) VL CDR2 having the amino acid sequence of PS (SEQ ID NO: 254), and GTWDSSLS and a VL comprising a VL CDR3 having the amino acid sequence of AVV (SEQ ID NO: 255). In another aspect, provided herein is an antibody that binds to PSMA, the antibody comprising: (i) VH CDR1 having the amino acid sequence of GFTFSSYAMS (SEQ ID NO: 256) , a VH CDR2 having the amino acid sequence of AISGGIGSTY (SEQ ID NO: 257), and and VH CDR3 having the amino acid sequence of DGVGATPYYFDY (SEQ ID NO: 258). and (ii) a VH comprising the amino acid sequence of SGSSSNIGINYVS (SEQ ID NO: 259). VL CDR1 having the amino acid sequence DNNKRPS (SEQ ID NO: 260) VL CDR2, and the amino acid sequence of GTWDSSLSAVV (SEQ ID NO: 261) In another embodiment, an antibody that binds to PSMA comprises a VL comprising a VL CDR3 ... As provided herein, the antibody comprises: (i) GFTFSSYAMS (SEQ ID NO: 262) VH CDR1 having the amino acid sequence of AISGGSGSTY (SEQ ID NO: 263) VH CDR2 having the amino acid sequence DGVGATPYYFDY (SEQ ID NO: 264) and (ii) a VH comprising a VH CDR3 having the amino acid sequence VL CDR1 having the amino acid sequence of YVS (SEQ ID NO: 265), DNNKRPS (sequence VL CDR2 having the amino acid sequence of GTWDSSLSAVV ( and a VL comprising a VL CDR3 having the amino acid sequence of SEQ ID NO: 267. In aspects, provided herein is an antibody that binds to PSMA, the antibody comprising: (i) G VH CDR1 having the amino acid sequence of FTFSSY (SEQ ID NO: 268), SGGIGS (SEQ ID NO: 269), and a VH CDR2 having the amino acid sequence of GVGATPYYFD (ii) a VH comprising a VH CDR3 having the amino acid sequence of (SEQ ID NO: 270); and VL CDR1 having the amino acid sequence of SSNIGINY (SEQ ID NO: 271), DNN( VL CDR2 having the amino acid sequence of SEQ ID NO: 272), and WDSSLSAV (sequence and a VL comprising a VL CDR3 having the amino acid sequence of: Provided herein are antibodies that bind to PSMA, the antibodies comprising: (i) a GFT VH CDR1 having the amino acid sequence of FSSY (SEQ ID NO: 274), VH CDR2 having the amino acid sequence of SGGSGS (SEQ ID NO: 275), VH CDR2 having the amino acid sequence of GVGATPYYFD (sequence number 275), (ii) a VH comprising a VH CDR3 having the amino acid sequence of (i) SSS; VL CDR1 having the amino acid sequence of SNIGINY (SEQ ID NO: 277), DNN (sequence VL CDR2 having the amino acid sequence of WDSSLSAV (SEQ ID NO: 278), and a VL comprising a VL CDR3 having the amino acid sequence of SEQ ID NO:279. Provided herein are antibodies that bind to PSMA, the antibodies comprising: (i) SYAM; VH CDR1 having the amino acid sequence of S (SEQ ID NO: 280), AISGGIGSTYY VH CDR2 having the amino acid sequence of ADSVKG (SEQ ID NO: 281), and DGVG V comprising a VH CDR3 having the amino acid sequence of ATPYYFDY (SEQ ID NO: 282). H, and (ii) an amino acid sequence of SGSSSNIGINYVS (SEQ ID NO: 283). VL CDR1, VL CD having the amino acid sequence of DNNKRPS (SEQ ID NO: 284) R2, and VL C having the amino acid sequence of GTWDSSLSAVV (SEQ ID NO: 285) In another embodiment, an antibody that binds to PSMA is described herein. The antibody is provided as follows: (i) an antibody having the amino acid sequence of SYAMS (SEQ ID NO: 286); VH CDR1, amino acid sequence of AISGGSGSTYYADSVKG (SEQ ID NO: 287) VH CDR2 having the sequence DGVGATPYYFDY (SEQ ID NO: 288), and (ii) a VH comprising a VH CDR3 having the sequence: VL CDR1 having the amino acid sequence of (SEQ ID NO: 289), DNNKRPS (SEQ ID NO: 290), 290), and VL CDR2 having the amino acid sequence of GTWDSSLSAVV (SEQ ID NO: and a VL comprising a VL CDR3 having the amino acid sequence of SEQ ID NO:291.

[0174] In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 232. In some embodiments, the antibody has at least one amino acid sequence identical to that of SEQ ID NO: 233. In some embodiments, the antibody comprises a VH comprising an amino acid sequence having 95% identity. The antibody is an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:232. The VL comprises the amino acid sequence.

[0175] In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 234. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 232. In some embodiments, the antibody has at least one amino acid sequence that is identical to that of SEQ ID NO: 234. In some embodiments, the antibody comprises a VH comprising an amino acid sequence having 95% identity. The antibody is an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:232. The VL comprises the amino acid sequence.

[0176] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. The resulting antibodies are expected to exhibit similar functional properties.

[0177] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0178] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is that of Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 1990, 87:2264-8 , modified as in Karlin and Altschul,Proc. Algorithm of Natl.Acad.Sci.USA1993,90:5873-7 Such an algorithm is described in Altschul, et al., J. Mol. .Biol.,1990,215:403 to the NBLAST and XBLAST programs BLAST nucleotide searches are performed using the NBLAST nucleotide program. The parameters of the program are set to, for example, score = 100 and word length = 12, and the program is run. Nucleotide sequences homologous to the nucleic acid molecules described in the document can be obtained. Protein searches are performed using the XBLAST program parameters, e.g., score 50, word count 0, and The sequence length was set to 3, and the amino acid sequence homologous to the protein molecules described herein was To obtain a gapped alignment for comparison purposes, use Altsc hul et al., Nucleic Acids Res.,1997,25:33 Alternatively, Gapped BLAST may be used as described in PS BLAST can also be used to perform iterated searches that detect distant relationships between molecules ( (Ibid.) BLAST, Gapped BLAST, and PSI Blast programs are used. When doing so, please use the default settings of each program (e.g., XBLAST and NBLAST). default parameters can be used (for example, onal Center for Biotechnology Information n (NCBI, see ncbi.nlm.nih.gov). Used for sequence comparison. Another preferred, non-limiting example of a mathematical algorithm is the Myers and Mill er, 1988, CABIOS 4:11 There are 17 algorithms. The algorithm is ALIGN, part of the GCG sequence alignment software package. The program (version 2.0) was incorporated into the A When using the LIGN program, the PAM120 weight residue table and gap length penalty are required. A threshold of 12 and a gap penalty of 4 can be used.

[0179] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0180] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 233. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity to a VH region of SEQ ID NO: 232 At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95%, or at least 98%, sequence identity with the PSM. In certain embodiments, the antibodies provided herein bind to SEQ ID NO: 23. At least 80%, at least 85%, at least 90%, at least VH regions with at least 95%, or at least 98% sequence identity, and / or sequences At least 80%, at least 85%, at least 9% of the amino acid sequence of No. 232 a VL region having 0%, at least 95%, or at least 98% sequence identity; The antibody binds to PSMA.

[0181] In some embodiments, a polypeptide comprising the VH, VL, or CDR sequences of the anti-PSMA antibodies described above is provided. and further comprising an Fc region having an RE mutation but no fucose residues. In some embodiments, the anti-PS antibodies provided herein are The MA antibody contains an Fc region with RE mutations but no fucose residues.

[0182] Standard techniques known to those skilled in the art can be used, for example, site-directed mutagenesis and amino acid sequence modification. The molecules provided herein are prepared by PCR-mediated mutagenesis, which results in amino acid substitutions. Mutations can be introduced into the nucleotide sequence to be cloned.

[0183] In some embodiments, glutamic acid is present in the Fc region of an antibody provided herein. There is a lysine substitution at position 248 in the ribosomal region (K248E) (EU numbering). In embodiments, an arginine is present at position 437 of the Fc region of an antibody provided herein. substituted with leonine (T437R) (EU numbering). A glutamic acid is attached to a lysine at position 248 of the Fc region of an antibody provided herein, and a 4 A substitution at position 37 with threonine (K248E / T437R) (EU numbering).

[0184] In some embodiments, the antibodies provided herein comprise a T437R mutation. In some embodiments, the antibodies provided herein comprise a heavy chain containing K248E In some embodiments, the antibodies provided herein comprise a heavy chain comprising a mutation. In some embodiments, the present invention provides a method for treating a pulmonary artery disease (PAG) comprising administering to a subject ... In some embodiments, the antibody comprises a heavy chain comprising a K248E / T437R mutation. The antibodies provided herein comprise a heavy chain comprising a K338A / T437R mutation. In some embodiments, the antibodies provided herein have the amino acid sequence of SEQ ID NO:242. In some embodiments, the heavy chain comprises a T437R mutation. The antibody provided herein comprises the amino acid sequence of SEQ ID NO: 242 but with a K248E mutation. In some embodiments, the antibodies provided herein comprise a heavy chain comprising SEQ ID NO:2. In some embodiments, the heavy chain comprises the amino acid sequence of 42 but with a K338A mutation. The antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 242, but In some embodiments, the heavy chain comprises a 8E / T437R mutation. The provided antibody comprises the amino acid sequence of SEQ ID NO: 242 but with the K338A / T437R mutation In some embodiments, the antibodies provided herein comprise a heavy chain having the sequence The heavy chain comprises the amino acid sequence of SEQ ID NO: 243 but has T437R. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 243. In some embodiments, the antibody provided herein comprises a heavy chain having a 248E mutation. The antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 243 but with a K338A mutation. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 243. In some embodiments, the heavy chain comprises the amino acid sequence of IL-1, but with K248E / T437R mutations. The antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 243, but contain K33 In some embodiments, the antibody comprises a heavy chain having a 8A / T437R mutation. Contains 242 amino acid sequences but contains K248E and T437R mutations (RE mutations) In some embodiments, the antibody is PSMB896. PSMB898 contains the 5'-kappa-nucleotide sequence but has K248E and T437R mutations (RE mutations). do.

[0185] In some embodiments, the antibodies provided herein (including the anti-PSMA antibodies described above) The Asn- The present invention provides a method for the preparation of a medicament ... For example, antibodies can be generated from mice that are deficient in the GMD enzyme (e.g., CHO Lec13 cells), a mutant FUT8 gene causes α-1,6 fucosyltransferase β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosidase activity decreased Overexpressing glucosaminyltransferase (GnT-III), inactivated glutamate GDP-fucose transporter (GFT) gene Slc35c1 (e.g., CHO -gmt3 cells), heterologously expressing bacterial RMD, or biochemical inhibitors of fucosylation (e.g., For example, the use of fucose analogs such as 2-fluorofucose and 5-alkynylfucose The mammalian cell line involved has a fucose residue in the Asn-297 linked N-oligosaccharide on the heavy chain. It has been shown that the immune system produces antibodies that are not specific to the immune system (Pereira, NA, et al. , supra; Shields, RLet al., supra; Kanda Y., supra).

[0186] In some embodiments, the antibody has a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain that does not contain the amino acid sequence of SEQ ID NO: 241. a light chain containing the sequence and a sequence containing no fucose residue in its Asn-297-linked N-oligosaccharide and a heavy chain comprising the amino acid sequence of 242. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 241 and an Asn- 297-linked N-oligosaccharides containing no fucose residues, comprising the amino acid sequence of SEQ ID NO: 243 In some embodiments, the antibody is PSMB898.CLF, comprising a heavy chain. The amino acid sequence of SEQ ID NO: 242 does not contain a fucose residue in the Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain comprising the Asn-297 linked N-amino acid sequence. The heavy chain comprises the amino acid sequence of SEQ ID NO: 243, which does not contain a fucose residue in the oligosaccharide. In some embodiments, the antibody comprises K248E, K338A, T437R, K248E / T4 37R or K338A / T437R mutations, and its Asn-297 linked N-oligosaccharide The heavy chain comprises the amino acid sequence of SEQ ID NO: 242, which does not contain any fucose residues. In embodiments, the antibody is K248E, K338A, T437R, K248E / T437R or K338A / T437R mutations, and the Asn-297 linked N-oligosaccharide is fucose The heavy chain comprises the amino acid sequence of SEQ ID NO: 243, without any amino acid residues.

[0187] 5.10 Anti-BCMA Antibodies and Related Molecules In one aspect, provided herein is an anti-BCMA antibody.

[0188] In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 299 and a VL comprising the sequence and VH comprising the amino acid sequence of 298. In one aspect, provided herein is an antibody that binds to BCMA, the antibody comprising: (i) a sequence VH CDR1, VH CDR2, and VH CDR3 amino acids in column number 298, respectively. VH and VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequence (ii) the VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 299, respectively. VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequence of CDR3 In some embodiments, the VL comprises a VH CDR1, a VH CDR2, The VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences were obtained from Kab In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VH CDR4, VH CDR5, VH CDR6, VH CDR7, VH CDR8, VH CDR9, VH CDR10, VH CDR11, VH CDR12, VH CDR13, VH CDR14, VH CDR15, VH CDR16, VH CDR17, VH CDR18, VH CDR1 2. VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are In some embodiments, the VH CDR1, VH VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences The columns follow an exemplary numbering system. In some embodiments, the VH CDR1, V H CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 The sequences follow the Contact numbering system. In some embodiments, the VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL The CDR3 sequences follow the IMGT numbering system. DR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL The CDR3 sequences follow the AbM numbering system.

[0189] In another aspect, provided herein is an antibody that binds to BCMA, the antibody comprising: i) a VH CDR1 having the amino acid sequence of GFTFSSYA (SEQ ID NO: 292), IS VH CDR2 having the amino acid sequence of GSGGST (SEQ ID NO: 293), and AKDE A VH CDR3 having the amino acid sequence of GYSSGHYYGMDV (SEQ ID NO: 294) and (ii) a VL having the amino acid sequence of QSISSSF (SEQ ID NO: 295). CDR1, a VL CDR2 having the amino acid sequence of GAS (SEQ ID NO: 296), and Q comprising a VL CDR3 having the amino acid sequence of HYGSSPMYT (SEQ ID NO: 297), VL.

[0190] In some embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 298. In some embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 299. In some embodiments, the antibody has at least one amino acid sequence that is identical to that of SEQ ID NO: 298. In some embodiments, the antibody comprises a VH comprising an amino acid sequence having 95% identity. The antibody is an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:299. The VL comprises the amino acid sequence.

[0191] In yet another aspect, provided herein is an antibody that competes with one of the above antibodies. Such antibodies may also target the same epitope as, or overlap with, one of the above-mentioned antibodies. It can bind to the same epitope as the antibody described above. The resulting antibodies are expected to exhibit similar functional properties.

[0192] In certain embodiments, the antibodies described herein are selected from the exemplary antibodies described in Section 7, below. antibodies, including those with amino acid sequences that have a specific percent identity compared to the antibodies described above. .

[0193] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be performed using a number of methods. This can be achieved using a mathematical algorithm, which is used to compare two sequences. A preferred, non-limiting example of a genetic algorithm is the algorithm described by Karlin and Altschul, Proc. c.Natl.Acad.Sci.USA,1990,87:2264-8,mo dified as in Karlin and Altschul,Proc.Na Algorithm of tl.Acad.Sci.USA1993,90:5873-7 Such an algorithm is described in Altschul, et al., J. Mol. Biology. ol., 1990, 215:403, and incorporated into the NBLAST and XBLAST programs. BLAST nucleotide searches are performed using the NBLAST nucleotide program. The parameters are set to, for example, score=100 and word length=12, and the results are shown in the table below. Nucleotide sequences homologous to the nucleic acid molecules listed in the BLAST protein can be obtained. The quality search is performed by setting the parameters of the XBLAST program, e.g., score = 50, word length = Run the program at setting 3 and obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, et al., Nucleic Acids Res., 1997, 25:3389- Utilizing Gapped BLAST as described in 402. Alternatively, PSI B LAST can also be used to perform an iterative search that detects distant relationships between molecules (ibid.). When using the BLAST, Gapped BLAST, and PSI Blast programs The default values ​​for each program (e.g., XBLAST and NBLAST) are Parameters can be used (e.g., National Instruments on the World Wide Web). l Center for Biotechnology Information(N CBI, see ncbi.nlm.nih.gov). Another preferred, non-limiting example of an algorithm is Myers and Miller, 1988, CABIOS 4:11 There are 17 algorithms. The system is based on the ALIGN program, which is part of the GCG sequence alignment software package. It is integrated into the ALIG library (version 2.0) to compare amino acid sequences. When using the N program, use the PAM120 weight residue table and a gap length penalty of 1. 2, a gap penalty of 4 can be used.

[0194] The percent identity between two sequences may be determined as described above, with or without allowing gaps. In calculating percent identity, the identity can be determined using techniques similar to those of Typically, only exact matches are counted.

[0195] In certain embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 298. At least 80%, at least 85%, at least 90%, at least 95% %, or at least 98% sequence identity with SEQ ID NO: 299, and / or At least 80%, at least 85%, at least 90%, or at least and the antibody comprises a VL region having 95% or at least 98% sequence identity with the BCM. Binds to A.

[0196] In some embodiments, a polypeptide comprising the VH, VL, or CDR sequences of the anti-BCMA antibodies described above is provided. and further comprising an Fc region having an RE mutation but no fucose residues. This is provided in the specification.

[0197] In some embodiments, the anti-BCMA antibodies provided herein comprise an RE mutation. It contains an Fc region having a nucleotide sequence containing ATP but no fucose residues.

[0198] Standard techniques known to those skilled in the art can be used, for example, site-directed mutagenesis and amino acid sequence modification. The molecules provided herein are prepared by PCR-mediated mutagenesis, which results in amino acid substitutions. Mutations can be introduced into the nucleotide sequence to be cloned.

[0199] In some embodiments, glutamic acid is present in the Fc region of an antibody provided herein. There is a lysine substitution at position 248 in the ribosomal region (K248E) (EU numbering). In embodiments, an arginine is present at position 437 of the Fc region of an antibody provided herein. substituted with leonine (T437R) (EU numbering). A glutamic acid is attached to a lysine at position 248 of the Fc region of an antibody provided herein, and a 4 A substitution at position 37 with threonine (K248E / T437R) (EU numbering).

[0200] In some embodiments, the antibodies provided herein comprise a T437R mutation. In some embodiments, the antibodies provided herein comprise a heavy chain containing K248E In some embodiments, the antibodies provided herein comprise a heavy chain comprising a mutation. In some embodiments, the present invention provides a method for treating a pulmonary artery disease (PAG) comprising administering to a subject ... In some embodiments, the antibody comprises a heavy chain comprising a K248E / T437R mutation. The antibodies provided herein comprise a heavy chain comprising a K338A / T437R mutation. In some embodiments, the antibodies provided herein comprise the amino acid sequence of SEQ ID NO: 300. In some embodiments, the heavy chain comprises a T437R but has a T437R. The provided antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 300 but having K248E. In some embodiments, the antibodies provided herein comprise the antibody of SEQ ID NO: 300. In some embodiments, the heavy chain comprises the amino acid sequence of the present invention but has K338A. The antibody provided in claim 1 comprises the amino acid sequence of SEQ ID NO: 300, but K248E / T43 In some embodiments, the antibodies provided herein comprise a heavy chain having a 7R mutation. The antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 300 but with the K338A / T437R mutations. Includes.

[0201] In some embodiments, the antibodies provided herein (including the anti-BCMA antibodies described above) The Asn- The present invention provides a method for the preparation of a medicament ... For example, antibodies can be generated from mice that are deficient in the GMD enzyme (e.g., CHO Lec13 cells), a mutant FUT8 gene causes α-1,6 fucosyltransferase β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosidase activity decreased Overexpressing glucosaminyltransferase (GnT-III), inactivated glutamate GDP-fucose transporter (GFT) gene Slc35c1 (e.g., CHO -gmt3 cells), heterologously expressing bacterial RMD, or biochemical inhibitors of fucosylation (e.g., For example, the use of fucose analogs such as 2-fluorofucose and 5-alkynylfucose The mammalian cell line involved has a fucose residue in the Asn-297 linked N-oligosaccharide on the heavy chain. It has been shown that the immune system produces antibodies that are not specific to the immune system (Pereira, NA, et al. , supra; Shields, RLet al., supra; Kanda Y., supra).

[0202] In some embodiments, the antibody has a fucose residue in its Asn-297 linked N-oligosaccharide. In some embodiments, the antibody comprises a heavy chain that does not contain the Asn-297 linked N-terminus group. - a heavy chain comprising the amino acid sequence of SEQ ID NO: 300, wherein the oligosaccharide does not contain a fucose residue In some embodiments, the antibody comprises K248E, K338A, T437R, K248E / T437R or K338A / T437R mutations, and their Asn-297 linked N-oligonucleotides The heavy chain comprises the amino acid sequence of SEQ ID NO: 300, which does not contain a fucose residue in the glycoprotein.

[0203] 5.11 Other Exemplary Antibodies In some embodiments, the antibodies provided herein are intended to be specific antibodies that are not specifically identified. a VL, VH, or CDR having an amino acid sequence of a VL, VH, or CDR included in The antibody comprises an Fc region with RE mutations but without fucosylation. Exemplary known antibodies include, but are not limited to, ReoPro (abciximab ), Humira (adalimumab), Hyrimoz (adalimumab-adaz), Cy ltezo (adalimumab-adbm), Abrilada (adalimumab-afzb) , Amjevita (adalimumab-atto), Hadlima (adalimumab-bw wd), Campath, Lemtrada (alemtuzumab), Praluent (alemtuzumab) Rirocumab), Tecentriq (atezolizumab), Bavencio (avelumab) ), Simulect (basiliximab), Benlysta (belimumab), Benl ysta (belimumab), Fasenra (benralizumab), Avastin (bevacizumab) bevacizumab), Mvasi (bevacizumab-awwb), Zirabev (bevacizumab-b) vzr), Zinplava (bezlotoxumab), Blincyto (blinatumomab) ), Siliq (brodalumab), Beovu (brolucizumab-dbll), Crys vita (burosumab-twza), Ilaris (canakinumab), Cablivi ( Caplacizumab-yhdp), Libtayo (cemiplimab-rwlc), Erbit ux (cetuximab), Adakveo (crizanlizumab-tmca), Zenapa x (daclizumab), Zinbryta (daclizumab), Darzalex (daratum Mab), Prolia, Xgeva (denosumab), Unituxin (dinutuximab) ), Dupixent (dupilumab), Imfinzi (durvalumab), Soli ris (eculizumab), Empliciti (elotuzumab), Gamifant (e mapalumab-lzsg), ​​Hemlibra (emicizumab-kxwh), Vyepti (eptinezumab-jjmr), Aimovig (erenumab-aooe), Repat ha (evolocumab), Ajovy (freemansumab-vfrm), Emgalit y (galcanezumab-gnlm), Simponi (golimumab), Simponi A ria (golimumab), Tremfya (guselkumab), Trogarzo (Ivaliz) Mab-uiyk), Praxbind (idarucizumab), Remicade (influenza) infliximab), Renflexis (infliximab-abda), Avsola (infliximab-abda) Fliximab-axxq), Inflectra (infliximab-dyyb), Ix ifi (infliximab-qbtx), Yervoy (ipilimumab), Sarcli sa (isatuximab-irfc), Taltz (ixekizumab), Takhzyro (lanadelumab-flyo), Nucala (mepolizumab), Nucala (mepolizumab) Mab), Poteligeo (mogamulizumab-kpkc), Tysabri (natalizumab- Mab), Portrazza (necitumumab), Opdivo (nivolumab), Anth im (obiltoxaximab), Gazyva (obinutuzumab), Ocrevus (obinutuzumab) Clerizumab), Arzerra (ofatumumab), Lartruvo (olaratumab) ), Xolair (omalizumab), Synagis (palivizumab), Vectibi x (panitumumab), Keytruda (pembrolizumab), Perjeta (Pertz) ramucirumab), Cyramza (ramucirumab), Lucentis (ranibizumab), Ul tomiris (ravulizumab-cwvz), raxibacumab (raxibacumab), Ci nqair (reslizumab), Skyrizi (risankizumab-rzaa), Ritu xan (rituximab), Truxima (rituximab-abbs), Ruxienc e(rituximab-pvvr), Evenity(romosozumab-aqqg), Kevz ara (sarilumab), Cosentyx (secukinumab), Sylvant (silvants) citabine), Tepezza (teprotumumab-trbw), Ilumya (tildrakiz Mab-asmn), Actemra (tocilizumab), Actemra (tocilizumab) , Herceptin (trastuzumab), Kanjinti (trastuzumab-ann s), Ogivri (trastuzumab-dkst), Ontruzant (trastuzumab bu-dttb), Herzuma (trastuzumab-pkrb), Trazimera ( trastuzumab-qyyp), Stelara (ustekinumab), Stelara (U These include sutekinumab, and Entyvio (vedolizumab). Methods for reducing fucosylation are described in other sections provided herein. and are well known in the art.

[0204] 5.12 Polynucleotides In certain embodiments, the present disclosure provides polynucleotides encoding the antibodies described herein. The term "polynucleotide encoding a polypeptide" includes Polynucleotides containing only the coding sequence of a gene, as well as additional coding and / or non-coding sequences. The polynucleotides of the present disclosure include polynucleotides in the form of RNA. or DNA. DNA includes cDNA, genomic DNA, and synthetic DNA. It can be double-stranded or single-stranded, and if single-stranded, can be the coding strand or the non-coding strand ( The nucleotide sequence may be the antisense strand.

[0205] In certain embodiments, the polynucleotide is used to direct, for example, the expression of a polypeptide from a host cell. Polynucleotides that aid in expression and secretion (e.g., polypeptides for controlling polypeptide transport) The coding sequence for the polypeptide fused in the same reading frame as the leader sequence (which functions as a secretory sequence) The polypeptide contains a sequence. The polypeptide is then transfected into a host cell to form a "mature" form of the polypeptide. It may have a leader sequence that is cleaved accordingly.

[0206] In certain embodiments, the polynucleotide is fused in the same reading frame as the marker or tag sequence. For example, in some embodiments, the coding sequence for a polypeptide in a bacterial host In this case, the marker sequence may be used in a vector that allows for efficient purification of a polypeptide fused to the marker. In some embodiments, the marker is a hexahistidine tag provided by the marker. The affinity tag may be used in conjunction with other affinity tags.

[0207] In certain embodiments, the polynucleotides provided herein are those listed in Table 17 below. In certain embodiments, the polynucleotides described herein are selected from the polynucleotides listed in The polynucleotides provided are those listed in Tables 20 and 22 below. In certain embodiments, the polynucleotides provided herein are selected from , selected from the polynucleotides listed in Table 26 below.

[0208] In certain embodiments, the polynucleotides provided herein are those listed in Tables 9 to 10 below. In certain embodiments, the polynucleotides described herein are selected from those listed in Table 12. The polynucleotides provided herein are those listed in Tables 15 and 16 below. In certain embodiments, the polynucleotides provided herein are selected from the group consisting of nucleotides. The polynucleotides are selected from those listed in Table 2 below.

[0209] [Table 2]

[0210] In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 69. and / or the heavy chain nucleotide sequence of SEQ ID NO: 77. The nucleotides may be a light chain nucleotide sequence of SEQ ID NO: 70 and / or a heavy chain nucleotide sequence of SEQ ID NO: 78. In some embodiments, the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 71. The light chain nucleotide sequence and / or the heavy chain nucleotide sequence of SEQ ID NO: 79. In this embodiment, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 72 and / or The heavy chain nucleotide sequence of SEQ ID NO: 80. The nucleotide sequence is a light chain nucleotide sequence of SEQ ID NO: 73 and / or a heavy chain nucleotide sequence of SEQ ID NO: 81. In some embodiments, the polynucleotide comprises the light chain nucleotide of SEQ ID NO: 74. The heavy chain nucleotide sequence of SEQ ID NO: 82 is also included in some embodiments. In the present invention, the polynucleotide has the light chain nucleotide sequence of SEQ ID NO: 75 and / or SEQ ID NO: 8 In some embodiments, the polynucleotide comprises a heavy chain nucleotide sequence of the sequence comprising the light chain nucleotide sequence of SEQ ID NO:76 and / or the heavy chain nucleotide sequence of SEQ ID NO:84 In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 69. and / or the heavy chain nucleotide sequence of SEQ ID NO: 85. The nucleotides may be a light chain nucleotide sequence of SEQ ID NO: 70 and / or a heavy chain nucleotide sequence of SEQ ID NO: 86. In some embodiments, the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 71. The light chain nucleotide sequence and / or the heavy chain nucleotide sequence of SEQ ID NO: 87. In this embodiment, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 72 and / or In some embodiments, the polynucleotide comprises the heavy chain nucleotide sequence of SEQ ID NO: 88. The nucleotide sequence of the light chain is SEQ ID NO: 73 and / or the heavy chain is SEQ ID NO: 89. In some embodiments, the polynucleotide comprises the light chain nucleotide of SEQ ID NO: 74. The heavy chain nucleotide sequence of SEQ ID NO: 90 is also included in some embodiments. In the present specification, the polynucleotide is a light chain nucleotide sequence of SEQ ID NO: 75 and / or SEQ ID NO: 9 In some embodiments, the polynucleotide comprises a heavy chain nucleotide sequence of the sequence 76 and / or the heavy chain nucleotide sequence of SEQ ID NO: 92 In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 69. and / or the heavy chain nucleotide sequence of SEQ ID NO: 93. The nucleotides may be selected from the light chain nucleotide sequence of SEQ ID NO: 76 and / or the heavy chain nucleotide sequence of SEQ ID NO: 94. In some embodiments, the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 74. The light chain nucleotide sequence and / or the heavy chain nucleotide sequence of SEQ ID NO: 95. In this embodiment, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 70 and / or In some embodiments, the polynucleotide comprises the heavy chain nucleotide sequence of SEQ ID NO: 96. The nucleotide sequence of the light chain is SEQ ID NO: 71 and / or the heavy chain is SEQ ID NO: 97. In some embodiments, the polynucleotide comprises the light chain nucleotide of SEQ ID NO: 73. The heavy chain nucleotide sequence of SEQ ID NO: 98 is also included in some embodiments. In the present specification, the polynucleotide is a light chain nucleotide sequence of SEQ ID NO: 75 and / or SEQ ID NO: 9 In some embodiments, the polynucleotide comprises the heavy chain nucleotide sequence of SEQ ID NO: 9. 72 and / or the heavy chain nucleotide sequence of SEQ ID NO: 100. nothing.

[0211] In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 104. and / or the heavy chain nucleotide sequence of SEQ ID NO: 105. The polynucleotide may comprise the light chain nucleotide sequence of SEQ ID NO: 104 and / or SEQ ID NO: 106 The heavy chain nucleotide sequence of

[0212] In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 161. and / or the heavy chain nucleotide sequence of SEQ ID NO: 160. The polynucleotide may comprise the light chain nucleotide sequence of SEQ ID NO: 161 and / or SEQ ID NO: 162 In some embodiments, the polynucleotide comprises a heavy chain nucleotide sequence of SEQ ID NO: 161 and / or the heavy chain nucleotide sequence of SEQ ID NO: 163. nothing.

[0213] In some embodiments, the polynucleotide comprises the light chain nucleotide sequence of SEQ ID NO: 180. and / or the heavy chain nucleotide sequence of SEQ ID NO: 182. The polynucleotide may comprise the light chain nucleotide sequence of SEQ ID NO: 181 and / or SEQ ID NO: 183 The heavy chain nucleotide sequence of

[0214] The disclosure further relates to variants of the polynucleotides described herein, e.g., For example, it encodes fragments, analogs, and / or derivatives. The disclosure also provides polynucleotides encoding polypeptides, including the antibodies described herein, and at least at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, and in some embodiments at least about 96%, 97%, 98% or Polynucleotides are provided, including polynucleotides with nucleotide sequences that are 99% identical. Provide.

[0215] As used herein, "identical to a reference nucleotide sequence at least, e.g., 95%" The phrase "polynucleotides having the same nucleotide sequence" refers to polynucleotides A sequence may contain up to 5 point mutations per 100 nucleotides of the reference nucleotide sequence. means that the nucleotide sequence of a polynucleotide is identical to the reference sequence, except for the In other words, it is intended to be at least 95% identical to the reference nucleotide sequence. To obtain a polynucleotide having a nucleotide sequence, the nucleotides of the reference sequence are Up to 5% of these may be deleted or substituted with alternative nucleotides, or all nucleotides of the reference sequence may be A maximum of 5% of the nucleotides in the reference sequence may be inserted. These mutations may occur at the 5' or 3' terminal positions of the reference nucleotide sequence, or at any of the terminal positions. It can occur anywhere between nucleotides of the reference sequence, either individually between nucleotides of the reference sequence or within...

Claims

1. A population of antibodies, (i) 8 of the oligosaccharides covalently attached to said population of said antibodies via its N297 residue less than 0% contain a core fucose residue; (ii) the population of antibodies, the Fc region of which comprises a K338A mutation and a T437R mutation; or an antibody comprising a K248E mutation and a T437R mutation (RE mutation), The numbering of amino acid residues is according to the EU numbering system, Optionally, a population of antibodies, wherein each antibody in said population of antibodies comprises said RE mutation.

2. 70 of the oligosaccharide covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

3. 60 of the oligosaccharide covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

4. 50 of the oligosaccharide covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

5. 40 of the oligosaccharide covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

6. 30 of the oligosaccharide covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

7. 20 of the oligosaccharides covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

8. 10 of the oligosaccharides covalently attached to the population of the antibody via its N297 residue 2. The antibody population of claim 1, wherein less than % of the antibodies comprise a core fucose residue.

9. a population of antibodies comprising an antibody, wherein the antibody is covalently bound to said antibody via its N297 residue. wherein the oligosaccharide does not contain a core fucose residue, and the antibody has a K338A mutation and a T437R mutation, or K248E mutation and T437R mutation (RE mutation), A population of antibodies in which the numbering of amino acid residues follows the EU numbering system.

10. The antibody is capable of expressing the antibody in a host cell that lacks the addition of fucose to the oligosaccharide attached to the antibody. by expressing a polynucleotide encoding the antibody or fragment thereof in A population of antibodies according to any one of claims 1 to 9, produced by

11. The host cell has reduced GDP-mannose 4,6-dehydratase (GMD) activity. or has reduced α-1,6 fucosyltransferase activity. A population of antibodies.

12. The population of antibodies has enhanced antibody-dependent cellular cytotoxicity (ADCC) and enhanced complement. The antibody of any one of claims 1 to 11, having both IgG1 and IgG2-dependent cytotoxicity (CDC). A group of bodies.

13. The population of antibodies according to any one of claims 1 to 12, wherein the antibodies are IgG1.

14. The collection of antibodies according to any one of claims 1 to 13, wherein the antibodies bind to HLA-G. Group.

15. The population of antibodies according to any one of claims 1 to 13, wherein the antibodies bind to CD37. 。

16. The antibody of any one of claims 1 to 13, wherein the antibody binds to GPRC5D. Group.

17. The population of antibodies according to any one of claims 1 to 13, wherein the antibodies bind to KLK2. 。

18. The population of antibodies according to any one of claims 1 to 13, wherein the antibodies bind to PSMA. 。

19. The population of antibodies according to any one of claims 1 to 13, wherein the antibodies bind to BCMA. 。

20. Any of claims 1 to 13, wherein the antibody is a monospecific antibody or a multispecific antibody. A population of antibodies according to claim 1.

21. the Fc region comprises a K338A mutation and a T437R mutation, and the amino acid residue numbering is 21. A population of antibodies according to any one of claims 1 to 20, according to the EU numbering system.

22. The Fc region comprises a K248E mutation and a T437R mutation (RE mutation), and The anti-cancer agent according to any one of claims 1 to 20, wherein the group numbering is according to the EU numbering system. A group of bodies.

23. A population of antibodies, (i) 8 of the oligosaccharides covalently attached to said population of said antibodies via its N297 residue less than 0% contain a core fucose residue; (ii) the population of antibodies is modified in its Fc region to increase the CDC activity of the antibodies; A population of antibodies comprising antibodies with one or more mutations in the region.

24. A first means for increasing the ADCC activity of the antibody, and a second means for increasing the CDC activity of the antibody. and a second means for adding the antibody to the population of antibodies.

25. A population of antibodies according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising:

26. A method for producing a population of antibodies, comprising: attaching an oligonucleotide to the antibody via the N297 residue. The antibody or fragment thereof is coated in a host cell lacking the addition of fucose residues to sugars. and expressing a polynucleotide encoding the Fc region of said antibody. K338A and T437R mutations, or K248E and T437R mutations (RE mutations) The method includes an antibody comprising the antibody (heterologous).

27. The host cell has reduced α-1,6 fucosyltransferase activity. Item 27. The method according to item 26.

28. the host cell has reduced GDP-mannose 4,6-dehydratase activity; 27. The method of claim 26.

29. The gene encoding α-1,6 fucosyltransferase is either mutated or normal. or is knocked out in the host cell.

27. The method of claim 26.

30. The gene encoding GDP-mannose 4,6-dehydratase is mutated, It is expressed at a lower level than normal or is knocked out in the host cell.

27. The method of claim 26 .

31. 1. A method for producing a population of antibodies, comprising: (i) a K338A mutation and a T437R mutation in the Fc region of the population of antibodies; introducing a 48E mutation and a T437R mutation (RE mutation); (ii) the amount of core fucose in the oligosaccharide bound to the antibody via the N297 residue and producing said population of said antibodies having a reduced affinity for said antibodies.

32. A method of treating a disease or disorder in a subject, comprising administering to a subject a compound according to any one of claims 1 to 24. administering to said subject the population of antibodies described.

33. 33. The method of claim 32, wherein the disease or disorder is a solid tumor cancer.

34. The disease or disorder is renal adenocarcinoma, pancreatic adenocarcinoma or lung adenocarcinoma, non-small cell lung cancer, and 33. The method of claim 32, wherein the cancer is selected from the group consisting of ovarian cancer.

35. A method for the treatment of a cancer in a host, comprising administering a population of antibodies according to any one of claims 1 to 24. A method for regulating immunity.

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