BISPECIFIC ANTIBODY

Abstract

The present invention addresses the problem of providing a novel drug to prevent, suppress the progression of symptoms, suppress recurrence, or treat an autoimmune disease. As a result of diligent studies, the inventors of the present invention focused, among other things, on a bispecific antibody to PD-1 / CD19 as a substance capable of solving the problem, and confirmed that the bispecific antibody can serve as a novel drug to prevent, suppress the progression of symptoms, suppress recurrence, or treat autoimmune diseases. It was also confirmed that the bispecific antibody has a feature that allows it to interact with PD-1 and PD-L1, which is a ligand of PD-1.

Description

BISECIFIC ANTIBODY Field of Invention The present invention relates to a bispecific antibody capable of specifically binding to PD-1 and CD19, respectively (hereinafter may be abbreviated as PD-1 / CD19 bispecific antibody) or an antibody fragment thereof (hereinafter may be abbreviated as PD-1 / CD19 bispecific antibody). abbreviated as a PD-1 / CD19 bispecific antibody or the like), and a pharmaceutical composition containing the same as an active ingredient, as well as therapeutic pharmaceutical uses thereof. Background of the Invention PD-1 is an immunosuppressive receptor that belongs to a family of immunoglobulins and is a molecule that has the function of suppressing the immune activation signals of B cells activated by stimulation through an antigen receptor. From the analysis of mice genetically deficient for PD-1 or the like, it is already known that PD-1 signals play an important role in the suppression of autoimmune diseases such as autoimmune dilated cardiomyopathy, lupus-like syndrome, autoimmune encephalomyelitis, lupus systemic erythematosus, graft-versus-host disease, type I diabetes mellitus, and rheumatoid arthritis. Therefore, it is noted that a substance that Lanz Ln / Lznz / E / YiAi Ref. 318459 enhancing PD-1 signals could be a prophylactic or therapeutic agent for autoimmune diseases. CD19 is a membrane protein that is expressed on B cells and stimulates molecular transfer into the B cell together with the B cell receptor complex. So far, there are several reports on PD-1 bispecific antibodies to treat autoimmune diseases (patent literature 1 to 3), but one of the targets is CD3, which is a member of the T-cell receptor complex. In addition, there is the report on a bispecific antibody targeting PD-1 and CD19 to treat the tumor (patent literature 4), but there is no report on a PD-1 / CD19 bispecific antibody to prevent, suppress the progression of symptoms. or recurrence, or treat the autoimmune disease at all. appointment list patent literature Patent Literature 1: International Publication Number WO2003 / 011911 Patent Literature 2: International Publication Number WO2004 / 072286 Patent Literature 3: International Publication Number WO2013 / 022091 Patent Literature 4: Chinese Patent Publication Lanz Ln / Lznz / E / YiAi number 106939050. Summary of the Invention Technical problem The purpose of the present invention is to provide a new pharmaceutical agent for preventing, suppressing symptom progression or recurrence, or treating autoimmune diseases and the like. Solution to the problem The present inventors diligently studied and focused on the PD-1 / CD19 bispecific antibody of the present invention as a substance capable of solving the above-mentioned problem, and have completed the present invention. Furthermore, the inventors of the present invention confirmed that the PD-1 / CD19 bispecific antibody has the feature of allowing interaction between PD-1 and PDL1 as its ligand. In addition, the inventors of the present invention found a PD-1 / CD19 bispecific antibody that can be easily separated from its by-products in the purification process by one or more amino acid substitutions or additions to the heavy chain of the second branch that is it specifically binds to CD19, constituting the same bispecific antibody as PD-1 / CD19. That is, the present invention relates to the I cast Ln / Lznz / E / YiAi next. [1] A bispecific antibody or an antibody fragment thereof, having the first arm that specifically binds PD-1 and the second arm that specifically binds CD19, and that both specifically bind PD-1 and CD19, respectively, where the first branch that specifically binds PD-1 has any of a VH selected from (A) a heavy chain variable region (hereinafter, heavy chain variable region may be abbreviated as VH) having (a) a heavy chain variable region complementarity determining region 1 (hereinafter, heavy chain variable region complementarity determining region 1 may be abbreviated as VH-CDR1) comprising the established amino acid sequence in SEQ ID NO. 6, (b) a heavy chain variable region complementarity determining region 2 (hereinafter, heavy chain variable region complementarity determining region 2 may be abbreviated as VH-CDR2) comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) a complementarity determining region 3 of the heavy chain variable region (hereinafter Lanz Ln / Lznz / E / YiAi below, the complementarity determining region 3 of the heavy chain variable region can be abbreviated as Lanz Ln / Lznz / E / YiAi VH-CDR3) comprising the amino acid sequence established (B in SEQ ID NO. 8, ) a VH having (a) a VH-CDR1 comprising the amino acid sequence established in SEQ (b) a VH-CDR2 which ID NO. 9, comprises the amino acid sequence set forth in SEQ (c) a VH-CDR3 which ID NO. 10, comprises and the amino acid sequence (C set forth in SEQ) a VH having (a) a VH-CDR1 which ID NO. 11, comprises the amino acid sequence established in SEQ (b) a VH-CDR2 that ID NO. 12, comprises the amino acid sequence established in SEQ (c) a VH-CDR3 that ID NO. 13, comprises and the amino acid sequence (D set forth in SEQ) a VH having (a) a VH-CDR1 which ID NO. 14, comprises the amino acid sequence established in SEQ (b) a VH-CDR2 that ID NO. 15, comprises the amino acid sequence established in SEQ (c) a VH-CDR3 that ID NO. 16, comprises and the sequence of amino acids set forth in SEQ ID NO. 17, and (E) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, where the second branch that specifically binds CD19 has any one of a selected VH LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ of (A) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, Lanz Ln / Lznz / E / YiAi (D) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49, and wherein one to five arbitrary amino acid residues in one or more of the VH-CDRs selected from VH-CDR1, VH-CDR2 and VH-CDR3 in the first branch that specifically binds PD-1 may be substituted with other amino acids, respectively, and / or one to five arbitrary amino acid residues in one or more of VH-CDRs selected from VH-CDR1, VH-CDR2 and VH-CDR3 on the second branch that specifically binds to CD19 can be substituted with other amino acids, LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ respectively. [2] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], wherein the first branch that specifically binds PD-1 has any VH selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, (C) the VH having amino acids set forth in SEQ ID NO. 12, (a) the VH-CDR1 comprising the sequence of (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and where the second branch that specifically joins CD19 has any of a VH selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the sequence of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ amino acids set forth in SEQ ID NO. 37, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) the VH having (a) the VH-CDR1 comprising the sequence of > ω Ν C ? c Ν C amino acids set forth in SEQ ID NO. 47.2 (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. [3] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 is any one selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) the VH that has amino acids the VH-CDR1 comprising established in SEQ (b) the VH-CDR2 that established in SEQ the sequence of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ ID NO. 38 comprises ID NO. 39 the amino acid sequence the VH-CDR3 that established in SEQ (C) the VH that has the VH-CDR1 that comprises ID NO. 40 comprises the amino acid sequence of amino acids established in SEQ (b) the VH-CDR2 that established in SEQ the VH-CDR3 that established in SEQ (D) the VH that has the VH-CDR1 that ID NO. 41 comprises ID NO. 42 comprises ID NO. 43 comprises the the the amino acid sequence of amino acids amino acids sequence established in SEQ (b) the VH-CDR2 that established in SEQ the VH-CDR3 that established in SEQ (E) the VH that has the VH-CDR1 that amino acids established in the SEC amino acids established in the SEC ID NO. 44 comprises ID NO. 45 comprises ID NO. 46 comprises ID NO. 47 ID NO. 48 that of the sequence of (b) the VH-CDR2 comprising the sequence of (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. [4] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 is any one selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. The PD-1 / CD19 bispecific antibody an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 is any one selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and amino acids set forth in SEQ ID NO. 40, (c) the VH-CDR3 comprising the sequence of (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. [6] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to [1] or [2] above, wherein (i) the VH of the first branch that specifically binds PD-Í has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (ii) the VH of the second branch that specifically binds CD19 is any one selected from (A) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35(b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36 the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37 (B) the VH having the VH-CDR1 comprising the amino acid set forth in SEQ ID NO. 38 amino acids amino acids (b) the VH-CDR2 that established in SEQ the VH-CDR3 that established in SEQ comprises ID NO. 39 comprises ID NO. 40 to the sequence of (C) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. [7] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 is any one selected from (A) the VH that has (a) VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the sequence of ID NO. 43 comprises ID NO. 44 comprises ID NO. 45 the the sequence of > ω Ν C Κ' amino acids established in SEQ (D) the VH that has (a) the VH-CDR1 that amino acids established in SEQ (b) the VH-CDR2 that amino acids established in the SEQ (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. [8] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37. [9] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the sequence of LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ amino acids set forth in SEQ ID NO. 40.

[10] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43.

[11] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, Lanz Ln / Lznz / E / YiAi (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46.

[12] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the sequence of LQnZ Ln / Lznz / Ε / ΥΙΛΙ c N C ID NO. 47, ® comprises the sequence of ID NO. 48, v > ω Ñ c K' amino acids established in SEQ (b) the VH-CDR2 that amino acids established in SEQ (c) the VH-CDR3 comprising the amino acid sequence established in SEQ ID NO. 49.

[13] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37.

[14] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40.

[15] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43.

[16] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46.

[17] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49.

[18] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37.

[19] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 has LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ > ω Ν C 29*c Ν C (a) VH-CDR1 comprising the 2 amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40.

[20] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-Í has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43.

[21] The PD-1 / CD19 bispecific antibody or a > N ! c-JN C antibody fragment thereof according to the above item [1] 2 or [2], wherein (i) the VH of the first branch that specifically binds PD-Í has (a) the VH-CDR1 comprising the sequence of amino acids set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46.

[22] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds to PD-Í has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 13 and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49.

[23] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37.

[24] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40.

[25] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the former The Lanz Ln / Lznz / E / YiAi branch that specifically binds to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17 and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43.

[26] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46.

[27] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 49.

[28] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37.

[29] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40.

[30] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43.

[31] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein (i) the VH of the first branch that specifically binds PD -1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46.

[32] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to item Lanz Ln / Lznz / E / YiAi above [1] or [2], wherein (i) the VH of the first branch that specifically binds PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 20, and (ii) the VH of the second branch that specifically binds CD19 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49.

[33] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[32] , wherein the framework region 1 (hereinafter, may be abbreviated as FR1) , framework region 2 (hereinafter, may be abbreviated as FR2) and framework region 3 (hereinafter, may be abbreviated as FR3) in a framework region (hereinafter, framework region may be abbreviated as FR) in the VH of the first branch that specifically binds to PD-1 corresponds to the encoded amino acid sequences Lanz Ln / Lznz / E / YiAi by the IGHV7-4-1 germline V gene or a gene thereof with a somatic mutation(s), respectively.

[34] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item

[33] , wherein the framework region 4 (hereinafter, framework region 4 may be abbreviated as FR4) in the VH of the first branch that specifically binds PD-1 comprises an amino acid sequence (excluding an amino acid sequence included in VH-CDR3) encoded by the J germline JH6c gene or a gene thereof with a mutation or somatic mutations.

[35] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[33] or

[34] , wherein the FR in the VH of the first branch that specifically binds PD -1 is encoded by the IGHV7-4-1 gene of the V germline which may have somatic mutation(s), and comprises FR1 in which in the amino acid sequence set forth in SEQ ID NO. 21, due to the somatic mutation(s), lysine at position 13 was or may be substituted with glutamine, alanine at position 16 was or may be substituted with valine, or lysine at position 19 was or may be substituted with methionine, respectively, or that was or may be substituted with an arbitrary combination of a plurality thereof.

[36] The PD-1 / CD19 bispecific antibody or a Lanz Ln / Lznz / E / YiAi antibody fragment thereof according to any of the above

[33] to

[35] , wherein the FR in the VH of the first branch that specifically binds PD-1 is encoded by the IGHV7-4-1 gene of the V germ line that can have somatic mutation(s), and comprises FR2 where in the amino acid sequence established in SEQ ID NO. 21, the valine at position 37 was or may be substituted with leucine.

[37] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[33] to

[36] , wherein the FR in the VH of the first branch that specifically binds aPD-1 is encoded by the V germline IGHV7-4-1 gene which may have somatic mutation(s), and comprises FR3 wherein in the amino acid sequence set forth in SEQ ID NO. 21, due to the somatic mutation(s), the serine at position 77 was or may be substituted with threonine or the cysteine ​​at position 84 was or may be substituted with serine or asparagine, respectively, or that was or may be substituted with an arbitrary combination of a plurality thereof.

[38] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[33] to

[37] , wherein the FR4 in the VH of the first branch that specifically binds to PD-1 is Lanz Ln / Lznz / E / YiAi encoded by the JH6c germline gene that may have somatic mutation(s) (excluding the region of the gene encoding VH-CDR3), and where in the amino acid sequence ( Trp-Gly-Lys-Gly-Thr-Thr*-Val-Thr-Val-Ser-Ser) (SEQ ID NO. 61) of FR4, the lysine (Lys) was or may be substituted with glutamine or asparagine and / or threonine (Thr) marked with an asterisk was or may be substituted with leucine.

[39] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[38] , wherein FR1, FR2, and FR3 in the FR in the VH of the The second branch that specifically binds to CD19 correspond to the amino acid sequences encoded by the IGHV5-51 germline V gene or the gene thereof with a somatic mutation(s), respectively.

[40] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item

[39] , wherein the FR in VH of the second branch that specifically binds CD19 is encoded by the IGHV5 gene -51 from germ line V which may have somatic mutation(s), and comprises FR1 wherein in the amino acid sequence set forth in SEQ ID NO. 22, due to a somatic mutation or mutations, glutamic acid in position 1 was or may be substituted with glutamine, proline in position 14 was or may be substituted with serine, tyrosine in LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ position 27 was or may be substituted with phenylalanine, or the threonine at position 30 was or may be substituted with isoleucine, respectively, or which was or may be substituted with an arbitrary combination of a plurality from them.

[41] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[39] or

[40] , wherein the FR in the VH of the second branch that specifically binds to CD19 comprises FR2 encoded by the IGHV5-51 germline V gene which may have somatic mutation(s).

[42] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[39] to

[41] , wherein the FR in the VH of the second branch that specifically binds CD19 is encoded by the IGHV5-51 germline V gene which may have somatic mutation(s), and comprises FR3 in which in the amino acid sequence set forth in SEQ ID NO. 22, due to the somatic mutation(s), isoleucine at position 76 was or may be substituted with phenylalanine, serine at position 77 was or may be substituted with threonine or asparagine, threonine at position 78 was or may be substituted with valine, serine at position 84 was or may be substituted with asparagine, methionine at position 93 was or may be substituted with isoleucine or LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ leucine, or the alanine at position 97 was or may be substituted with valine, respectively, or which was or may be substituted with an arbitrary combination of a plurality thereof.

[43] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[42] , wherein the VH of the first branch that specifically binds PD- 1 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, or an amino acid sequence having an identity of at least 80%, 90%, 95%, 98%, or 99% to the same amino acid sequence of VH.

[44] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[43] , wherein the VH of the first branch that specifically binds PD- 1 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5.

[45] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[44] , wherein the VH of the second branch that specifically binds CD19 comprises the amino acid sequence established in any Lanz Ln / Lznz / E / YiAi selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33 and SEQ ID NO. 34, or an amino acid sequence having an identity of at least 80%, 90%, 95%, 98%, or 99% to the same amino acid sequence of VH.

[46] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[45] , wherein the VH of the second branch that specifically binds CD19 comprises the amino acid sequence in which, glutamine at position 114 in the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33 and SEQ ID NO. 34 was or may be substituted with arginine.

[47] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[45] , wherein the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[48] ​​The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[49] A PD-1 / CD19 bispecific antibody or antibody fragment thereof, having the first branch specifically binding to PD-1 and the second branch specifically binding to CD19, wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, or an amino acid sequence having at least 80%, 90%, 95%, 98%, or 99% identity to the same amino acid sequence of VH, and the VH of the second branch that specifically binds a CD19 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, or an amino acid having an identity of at least 80%, 90%, 95%, 98%, or 99% Lanz Ln / Lznz / E / YiAi with the same amino acid sequence of VH.

[50] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in SEQ. ID No. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[51] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in SEQ. ID No. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[52] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the sequence of Lanz Ln / Lznz / E / YiAi amino acids established in SEC. ID No. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[53] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 4, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[54] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1] or [2], wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in SEQ. ID No. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. Lanz Ln / Lznz / E / YiAi 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[55] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or [8], wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 30 or SEQ ID NO. 62.

[56] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or [9], wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 31 or SEQ ID NO. 63.

[57] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[10] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ NO. 32 or SEQ ID NO. 64.

[58] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[11] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 33 or SEQ ID NO. 65.

[59] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[12] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 1, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 34 or SEQ ID NO. 66.

[60] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[13] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 30 or SEQ ID NO. 62.

[61] The PD-1 / CD19 bispecific antibody or a LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ antibody fragment thereof according to the above [1], [2] or

[14] , wherein the VH of the first branch that specifically binds PD-1 comprises the sequence of amino acids set forth in SEQ ID NO. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 31 or SEQ ID NO. 63.

[62] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[15] , wherein the VH of the first branch gue specifically binds to PD- 1 comprises the amino acid sequence set forth in SEQ ID NO. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 32 or SEQ ID NO. 64.

[63] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[16] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 33 or SEQ ID NO. 65.

[64] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to item Lanz Ln / Lznz / E / YiAi above [1], [2] or

[17] , wherein the VH of the first branch that specifically binds PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 2, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 34 or SEQ ID NO. 66.

[65] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[18] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 30 or SEQ ID NO. 62.

[66] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[19] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 31 or SEQ ID NO. 63.

[67] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[20] , wherein the VH of the first branch that is Lanz Ln / Lznz / E / YiAi specifically binds PD-1 comprising the amino acid sequence set forth in SEQ ID NO. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 32 or SEQ ID NO. 64.

[68] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[21] , wherein the VH of the first branch that specifically binds PD- 1 comprises the amino acid sequence set forth in SEQ ID NO. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 33 or SEQ ID NO. 65.

[69] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[22] , wherein the VH of the first branch that specifically binds PD- 1 comprises the amino acid sequence set forth in SEQ ID NO. 3, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 34 or SEQ ID NO. 66.

[70] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[23] , wherein the VH of the first branch that specifically binds PD- 1 includes the sequence of LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ amino acids set forth in SEQ ID NO. 4, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 30 or SEQ ID NO. 62.

[71] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[24] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 4, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 31 or SEQ ID NO. 63.

[72] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[25] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 4, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 32 or SEQ ID NO. 64.

[73] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[26] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 4, and the Lanz Ln / Lznz / E / YiAi VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 33 or SEQ ID NO. 65.

[74] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[27] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 4, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 34 or SEQ ID NO. 66.

[75] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[28] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 30 or SEQ ID NO. 62.

[76] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[29] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 Lanz Ln / Lznz / E / YiAi comprises the amino acid sequence set forth in SEQ ID NO. 31 or SEQ ID NO. 63.

[77] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[30] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 32 or SEQ ID NO. 64.

[78] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item [1], [2] or

[31] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID NO. 33 or SEQ ID NO. 65.

[79] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above [1], [2] or

[32] , wherein the VH of the first branch that specifically binds to PD-1 comprises the amino acid sequence set forth in SEQ ID NO. 5, and the VH of the second branch that specifically binds CD19 comprises the amino acid sequence set forth in SEQ ID Lanz Ln / Lznz / E / YiAi NO. 34 or SEQ ID NO. 66.

[80] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[79] , wherein the first branch that specifically binds PD-1 and / or the second branch specifically binds to CD19 has / comprises a light chain variable region (hereinafter light chain variable region may be abbreviated VL) that has (a) a light chain variable region complementarity determining region 1 the light chain (hereinafter, light chain variable region complementarity determining region 1 may be abbreviated as VL-CDR1) comprising the amino acid sequence set forth in SEQ ID NO. 26, (b) a light chain variable region complementarity determining region 2 (hereinafter, light chain variable region complementarity determining region 2 may be abbreviated as VL-CDR2) comprising the amino acid sequence set forth in SEQ ID NO. 27, and (c) a light chain variable region complementarity determining region 3 (hereinafter light chain variable region complementarity determining region 3 may be abbreviated as VL-CDR3) LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ comprising the amino acid sequence set forth in SEQ ID NO. 28.

[81] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[80] , wherein the first branch that specifically binds PD-1 and / or the second branch specifically binds to CD19 has / comprises the VL comprising the amino acid sequence set forth in SEQ ID NO. 25, respectively.

[82] A bispecific antibody or antibody fragment thereof, having the first branch that specifically binds PD-1 and the second branch that specifically binds CD19, and specifically binds PD-1 and CD19, respectively , where (A) the first branch that specifically binds PD-1 has a VH comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, and a VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and (B) the second branch that specifically binds CD19 has a VH comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and a VL comprising the Lanz Ln / Lznz / E / YiAi amino acid sequence set forth in SEQ ID NO. 25.

[83] A bispecific antibody or an antibody fragment thereof, having the first branch specifically binding to PD-1 and the second branch specifically binding to CD19, and specifically binding to PD-1 and CD19, respectively , wherein the first branch that specifically binds PD-1 cross-competes for (1) binding to PD-1 with the first branch that specifically binds PD-1 having a VH comprising the amino acid sequence set to any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, and a VL comprising the amino acid sequence of SEQ ID NO. 25, or (2) binding to PD-1 with a variable region of a monoclonal antibody that specifically binds to PD-1 comprising the same VH and VL.

[84] A bispecific antibody or an antibody fragment thereof, having the first branch specifically binding to PD-1 and the second branch specifically binding to CD19, and specifically binding to PD-1 and CD19, respectively , wherein binding to PD-1 with the first branch that specifically binds PD-1 is cross-competed by (1) the first branch that specifically binds PD-1 having a VH comprising the sequence of amino acids set to any selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, Lanz Ln / Lznz / E / YiAi SEQ ID NO. 4 and SEQ ID NO. 5, and a VL comprising the amino acid sequence of SEQ ID NO. 25, or (2) a variable region of a monoclonal antibody that specifically binds to PD-1 that has the same VH and VL.

[85] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[83] or

[84] , wherein the second branch that specifically binds CD19 further cross-competes for (1) binding to CD19 with the second branch specifically binding to CD19 having the VH comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and the VL comprising the amino acid sequence set forth in SEQ ID NO. 25, or (2) binding to CD19 with the variable region of the monoclonal antibody that specifically binds to CD19 having the same VH and VL.

[86] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[83] or

[84] , wherein binding to CD19 with the second branch specifically binding to CD19 is further cross-competed by (1) the second branch specifically binds to CD19 having a VH comprising the amino acid sequence set forth in either Lanz Ln / Lznz / E / YiAi selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and the VL comprising the amino acid sequence of SEQ ID NO. 25, or (2) a monoclonal antibody variable region that specifically binds CD19 having the same VH and VL.

[87] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item

[83] or

[84] , wherein the second branch that specifically binds CD19 has any of a VH selected from Lanz Ln / Lznz / E / YiAi (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) the VH having the VH-CDR1 comprising the amino acid set forth in SEQ ID NO. 41 (b) the VH-CDR2 that includes that of Lanz Ln / Lznz / E / YiAi amino acids amino acids established in SEQ the VH-CDR3 that established in SEQ (D) the VH that has the VH-CDR1 that ID NO. 42 comprises ID NO. 43 comprises the the amino acids amino acids established in SEQ (b) the VH-CDR2 that established in SEQ the VH-CDR3 that established in SEQ (E) the VH that has the VH-CDR1 that established in SEQ (b ) the VH-CDR2 that amino acids established in the VH-CDR3 amino acids established in SEQ ID NO. 44 comprises ID NO. 45 comprises ID NO. 46 comprises ID NO. 47 comprises ID NO. 48 comprising the The antibody antibody fragment from the above

[83] or

[84] , where la la la la la SEQ ID NO. 49. sequence sequence sequence sequence sequence sequence sequence bispecific of PD-1 / CD19 or same the VH of of of of of of according to the point of the second branch that specifically binds to CD19 comprises the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, or an amino acid sequence having at least 80%, 90%, 95%, 98%, or 99% identity to the same amino acid sequence of VH.

[89] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above item

[83] or

[84] , wherein the VH of the second branch that specifically binds CD19 comprises the sequence of amino acids established in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66.

[90] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[83] to

[89] , wherein the first branch that specifically binds PD-1 and / or the second branch specifically binds to CD19 has / comprises the VL having (a) the VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, (b) the VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27, and (c) the VL-CDR3 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 28.

[91] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[83] to

[89] , wherein the first branch that specifically binds PD-1 and / or the second branch specifically binds to CD19 has / comprises the VL comprising the amino acid sequence set forth in SEQ ID NO. 25.

[92] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[91] , wherein the PD-1 / CD19 bispecific antibody is an IgG antibody.

[93] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[92] , wherein the IgG antibody of the above

[92] is an IgG1 or IgG4 antibody.

[94] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[92] , wherein the IgG antibody of the above

[92] is an IgGi antibody.

[95] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[92] , wherein the IgG antibody of the above

[92] is an IgG4 antibody.

[96] The PD-1 / CD19 bispecific antibody or a Lanz Ln / Lznz / E / YiAi antibody fragment thereof according to the above

[94] , wherein in two heavy chain constant regions of the IgGi antibody of the above

[94] , the leucine at position 235 according to the system The EU numbering system was replaced by glycine, respectively, and / or glycine at position 236 according to the EU numbering system was replaced by arginine, respectively.

[97] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[94] or

[96] , wherein in a heavy chain constant region having the VH of the first branch that binds specifically to PD-1, both leucine at position 351 and threonine at position 366 according to the EU numbering system were substituted for Usin, and in a constant region of the heavy chain having the VH of the second branch that specifically binds CDI9, leucine at position 351 was replaced with aspartic acid and leucine at position 368 was replaced with glutamic acid.

[98] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[94] or

[96] , wherein in a heavy chain constant region having the VH of the first branch which specifically binds PD-1, the leucine at position 351 according to the EU numbering system was substituted LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ with aspartic acid and leucine at position 368 was substituted with glutamic acid, and in a constant region of the heavy chain that has the VH of the second branch that specifically binds to CD19, both the leucine at position 351 and threonine at position 366 were replaced by lysine.

[99] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[94] and

[96] to

[98] , wherein in two heavy chain constant regions of the antibody of IgGi at any of the above

[94] and

[96] to

[98] , lysine at position 447 was deleted according to the EU numbering system, respectively.

[100] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above

[95] , wherein in two heavy chain constant regions of the IqG4 antibody in the above

[95] , serine at position 228 according to the EU numbering system it was replaced by proline, respectively.

[101] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above

[94] and

[96] to

[99] , wherein the heavy chain having the VH of the second branch that specifically binds to CD19 also has Gly (qlicin), Gly-LysLys-Ala (SEQ ID NO. 67), Gly-Lys-Ala-Lys-Ala (SEQ ID NO. 68), Gly-Arg-Arg -Ala (SEQ ID NO. 69) or Gly-Arg-Ala-Arg-Ala (SEQ ID NO. LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ NO. 70) at its C-terminus.

[102] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[94] ,

[96] ,

[98] ,

[99] and

[101] , wherein the heavy chain having the VH of the first branch that specifically binds PD-1 has the heavy chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 23.

[103] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[94] ,

[96] ,

[98] ,

[99] ,

[101] and

[102] , wherein the heavy chain having the VH of the second branch that specifically binds CD19 has the heavy chain constant region comprising the amino acid sequence set forth in any selected from SEQ ID NO. 24, SEQ ID NO. 71, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 74 and SEQ ID NO. 75.

[104] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[103] , wherein the light chain having the VL of the first branch binds specifically to PD-1 and / or the light chain having the VL of the second branch that specifically binds to CD19 contains a light chain constant region comprising Lanz Ln / Lznz / E / YiAi the amino acid sequence set forth in SEQ ID NO. 29.

[105] A bispecific antibody or antibody fragment thereof, having the first arm specifically bind PD-1 and the second arm specifically bind CD19, and specifically bind PD-1 and CD19, respectively, where (A) a heavy chain having a VH of the first branch that specifically binds PD-1 has a VH comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5, and the heavy chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 23, (B) a light chain having a VL of the first branch that specifically binds PD-1 has a VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and the light chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 29, (C) a heavy chain having a second branch VH that specifically binds CD19 has a VH comprising the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and the heavy chain constant region comprising the sequence Amino acid Lanz Ln / Lznz / E / YiAi set forth in SEQ ID NO. 24, and (D) a light chain having a VL of the second branch that specifically binds CD19 has a VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and the light chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 29.

[106] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[105] , wherein the first branch that specifically binds PD-1 allows the interaction between PD-1 and PD-L1.

[107] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[106] , wherein a complex consisting of heavy chain and light chain of the first branch that specifically binds PD-1 has an isoelectric point between about 7.4 and about 7.7 (preferably, between about 7.5 and about 7.6).

[108] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[107] , wherein a complex consisting of heavy chain and light chain of the second branch specifically binds to CD19 has a dot LQHZ LO / ίΖΠΖ / Β / ΥΙΛΙ isoelectric between about 8.3 and about 8.8 (preferably between about 8.4 and about 8.6).

[109] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[108] , wherein the production of cytokines in the blood or tissue is sufficiently reduced during the administration or within 24 hours after administration.

[110] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[108] , wherein the first branch that specifically binds PD-1 allows the interaction between PD-1 and PD-L1, and where cytokine production is sufficiently reduced.

[111] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to the above point

[109] or

[110] , wherein the cytokine is at least IL-2, IFN-γ or TNF-α.

[112] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[111] , which suppresses B-cell activation by binding to PD-1 and CD19 expressed on the same B cells, respectively.

[113] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the Lanz Ln / Lznz / E / YiAi above points [1] to

[111] , which suppresses T cell activation (preferably memory T cells).

[114] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof as per above

[113] , which suppresses T-cell activation by binding to B-cell expressed CD19 and expressed PD-1 in T cells, respectively.

[115] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[114] , wherein PD-1 is human PD-1 and CD19 is human CD19, respectively.

[116] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[115] , wherein the PD-1 / CD19 bispecific antibody is a monoclonal antibody.

[117] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[116] , wherein the PD-1 / CD19 bispecific antibody is an isolated antibody. [1-1] A pharmaceutical composition containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any one selected from the above items [1] to

[117] , as an active ingredient. [1-2] The pharmaceutical composition according to the previous point [1-1], which also contains at least one carrier LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ pharmaceutically acceptable. [2-1] An agent for preventing, suppressing the progression of symptoms, suppressing the recurrence of, and / or treating an autoimmune disease, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of either of the items selected from items [1] to

[117] as the active ingredient. [2-2] The agent according to the above item [2-1], wherein the autoimmune disease is Behcet's disease, systemic lupus erythematosus, chronic discoid lupus erythematosus, multiple sclerosis (systemic scleroderma and progressive systemic sclerosis), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), aortitis syndrome (Takayasu's arteritis), malignant rheumatoid arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, mixed connective tissue disease, Sjogren's syndrome, Still's disease of the adult, vasculitis, allergic granulomatous vasculitis, hypersensitivity vasculitis, rheumatoid vasculitis, large vessel vasculitis, ANCA-associated vasculitis (eg, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis), Cogan syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica , fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, disease IgG4-related LQnZ Ln / Lznz / Ε / ΥΙΛΙ (eg, primary sclerosing cholangitis and autoimmune insulitis), Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, nonalcoholic steatohepatitis, primary biliary cirrhosis, Goodpasture syndrome , rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, pernicious anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow disease (Graves' disease (hyperthyroidism)), Hashimoto's disease, autoimmune adrenal insufficiency, primary hypothyroidism, Addison's disease ( chronic hypoadrenocorticism), idiopathic Addison's disease, type I diabetes mellitus, slowly progressive type I diabetes mellitus (latent autoimmune diabetes in adults), localized scleroderma, psoriasis, psoriatic arthritis, bullous pemphigoid, pemphigus, pemphigoid, herpes gestationis, bullous dermatosis of Linear IgA, epidermolysis bullosa acquisita, alopecia areata, vitiligo, vitiligo vulgaris, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, sarcoidosis, giant cell arteritis, amyotrophic lateral sclerosis, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, abortion inflammatory bowel disease (for example, ulcerative colitis and Crohn's disease), celiac disease, ankylosing spondylitis, asthma Severe Lanz Ln / Lznz / E / YiAi, chronic urticaria, transplant immunity, familial Mediterranean fever, chronic eosinophilic rhinosinusitis, dilated cardiomyopathy, systemic mastocytosis, or inclusion body myositis. [2-3] An agent for preventing, suppressing symptom progression, suppressing recurrence, and / or treating graft-versus-host disease (GVHD), containing the PD-1 / CD19 bispecific antibody or a fragment of antibody thereof according to any of the above items [1] to

[117] as an active ingredient. [2-4] An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating type I diabetes mellitus, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected from [1] to

[117] above as the active ingredient, and which is administered together with one or more drugs selected from an insulin formulation (for example, insulin human, insulin glargine, insulin lispro, insulin detemir, and insulin aspart, etc.), a sulfonylurea agent (for example, glibenclamide, gliclazide and glimepiride, etc.), a rapid-acting insulin secretion promoter (for example, nateglinide, etc.), a biguanide preparation (for example, metformin, etc.), an insulin resistance-improving agent (for example, pioglitazone, etc.), an α-glucosidase inhibitor (for example, Lanz Ln / Lznz / E / YiAi example, acarbose and voglibose, etc.), a therapeutic agent for diabetic neuropathy (for example, epalrestat, mexiletine and imidapril, etc.), a preparation of GLP-1 analogues (for example , liraglutide, exenatide, and lixisenatide, etc.), and a DPP-4 inhibitor (for example, sitagliptin, vildagliptin, and alogliptin, etc.). [2-5] An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating multiple sclerosis, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected of the above items [1] to

[117] as an active ingredient, and is administered together with one or more drugs selected from a spheroidal agent (for example, cortisone acetate, hydrocortisone, sodium phosphate and hydrocortisone, sodium succinate and Hydrocortisone, Fludrocortisone Acetate, Prednisolone, Prednisolone Acetate, Prednisolone Sodium Succinate, Prednisolone Butyl Acetate, Prednisolone Sodium Phosphate, Halopredone Acetate, Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, Triamsinolone, Acetate triamsinolone, triamsinolone acetonide, dexamethasone, dexamethasone acetate, desamethasone sodium phosphate, dexamethasone palmitate, paramethasone and betamethasone acetate, etc.), interferon β-la, interferon β-lb, glatiramer acetate, mitoxantrone, azathioprine, cyclophosphamide, Lanz Ln / Lznz / E / YiAi cyclosporine, methotrexate, cladribine, adrenocorticotropic hormone (ACTH), corticotropin, mizoribine, tacrolimus, fingolimod, and alemtuzumab. [2-6] An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating systemic lupus erythematosus, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of either selected from the above items [1] to

[117] as an active ingredient, and which is administered together with one or more selected of a spheroidal agent (for example, the spheroidal agents mentioned in the item [2-5] above), an immunosuppressive agent (for example, cyclosporine, tacrolimus and fingolimod, etc.) and belimumab. [2-7] An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating rheumatoid arthritis, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected of the above items [1] to

[117] as an active ingredient, and which is administered together with one or more drugs selected from a spheroidal agent (for example, the spheroidal agents mentioned in the above item

[25] ), an antirheumatic agent (for example, methotrexate, sulfasalazine, bucillamine, leflunomide, mizoribine, and tacrolimus, etc.), an anticytokine agent (for example, infliximab, adalimumab, tocilizumab, etanercept, golimumab, and Lanz Ln / Lznz / E / YiAi certolizumab, etc.) and abatacept. [2-8] An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating an autoimmune disease, containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected of the above items [1] to

[117] as an active ingredient, and is administered together with one or more of the agents listed in the above items [2-4] to

[27] . [2-9] The agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating the diseases according to the above items [2-4] to

[28] , the patient is administered one or more of the medicines listed in the previous points [2-4] to [2-7]. [2-10] The agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating diseases according to the above items [2-4] to [2-8], which is administered after the administration of one or more of the drugs listed in the previous points [2-4] to [2-7]. [2-11] The agent for preventing, suppressing symptom progression, suppressing recurrence, and / or treating diseases according to the above items [2-4] to

[28] , which is administered before administration of one or more of the medications listed in the above points [2-4] Cast Ln / Lznz / E / YiAi to [2-7] . [3-1] An intravenous injection formulation containing the PD-1 / CD19 bispecific antibody or an antibody fragment thereof according to any of the above [1] to

[117] and at least one pharmaceutically acceptable carrier. [3-2] The intravenous injection formulation according to the above item [3-1] for use in the prevention, suppression of symptom progression, suppression of recurrence, and / or treatment of autoimmune diseases. [3-3] The intravenous injection formulation according to the above item [3-1] or [3-2] for use in drip infusion. [4-1] An isolated polynucleotide, or fragment thereof, encoding a heavy chain having a second branch VH that specifically binds CD19 constituting the PD-1 / CD19 bispecific antibody of any one selected from the points older [1] to

[117] . [4-2] An isolated polynucleotide, or fragment thereof, encoding a second branch VH that specifically binds CD19 constituting the PD-1 / CD19 bispecific antibody of any selected from the above [1] to

[117] . [4-3] The isolated polynucleotide or a fragment thereof according to [4-1] or [4-2] above, wherein the VH of Lanz Ln / ίζηζ / Ε / γΐΛ the second branch that specifically binds CD19 is encoded by a polynucleotide comprising the base sequence set forth in any selected SEQ ID NOs. 56 to 60 and SEQ ID NOs. 76 to 80. [4-4] An isolated polynucleotide or fragment thereof, containing a polynucleotide comprising the base sequence set forth in any of SEQ ID NOs. 56 to 60 and SEQ ID NOs. 76 to 80. [5-1] An expression vector having a polynucleotide of any of the above [4-1] to [4-4]. [6-1] An animal cell, into which the expression vector of the above point [5-1] is transfected, or which was transformed by the same vector. [7-1] A method of preventing, suppressing symptom progression, suppressing recurrence, and / or treating an autoimmune disease, comprising administering to a patient an effective amount of the PD-1 / CD19 bispecific antibody or fragment of antibody thereof of any selected from the above items [1] to

[117] . [8-1] A PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected from the above items [1] to

[117] for use in the prevention, suppression of symptom progression, suppression of recurrence of, and / or treatment of LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ autoimmune diseases. [9-1] The use of the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected from the above items [1] to

[117] to manufacture a drug to prevent, suppress the progression of symptoms of, suppressing the recurrence of, and / or for the treatment of autoimmune diseases. [10-1] An isolated anti-CD19 monoclonal antibody, or antibody fragment thereof, that cross-competes for binding to CD19 with an antibody that specifically binds CD19 that has a VH comprising the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and a VL comprising the amino acid sequence set forth in SEQ ID NO. 25. [10-2] An isolated anti-CD19 monoclonal antibody or antibody fragment thereof, where binding to CD19 with the antibody or antibody fragment thereof is cross-competed by an antibody that specifically binds CD19 having a VH comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. Lanz Ln / Lznz / E / YiAi 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and a VL comprising the amino acid sequence set forth in SEQ ID NO. 25. LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ [10-3] An isolated anti-CD19 monoclonal antibody or an antibody fragment thereof, having any VH selected from (A) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (B) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 38, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (C) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, Lanz Ln / Lznz / E / YiAi (D) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (E) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49, and a VL having (a) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, (b) a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27, and (c) a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28. [10-4] An isolated anti-CD19 monoclonal antibody or antibody fragment thereof, having any VH selected from (A) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ (b) a VH-CDR2 having ID NO. 35, comprises the amino acid sequence established in SEQ (c) a VH-CDR3 that ID NO. 36, comprises and the amino acid sequence (B set forth in SEQ) a VH having (a) a VH-CDR1 which ID NO. 37, comprises the amino acid sequence established in SEQ (b) a VH-CDR2 that ID NO. 38, comprises the amino acid sequence established in SEQ (c) a VH-CDR3 that ID NO. 39, comprises and the amino acid sequence (C set forth in SEQ) a VH having (a) a VH-CDR1 which ID NO. 40, comprises the amino acid sequence established in SEQ (b) a VH-CDR2 that ID NO. 41, comprises the amino acid sequence established in SEQ (c) a VH-CDR3 that ID NO. 42, comprises and the amino acid sequence (D set forth in SEQ) a VH having (a) a VH-CDR1 which ID NO. 43, comprises the amino acid sequence established in SEQ (b) a VH-CDR2 that ID NO. 44, includes the sequence of amino acids set forth in SEQ ID NO. 45, and LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ (c) a VH-CDR3 comprising the sequence of Lanz Ln / Lznz / E / YiAi amino acids set forth in SEQ ID NO. 46, and (E) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49, and a VL having (a) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, (b) a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27, and (c) a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28, wherein one to five arbitrary amino acid residues in any one or more of the selected CDRs of VH-CDR1, VHCDR2 and VH-CDR3 in the VH may be substituted with other amino acids. [10-5] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-4], having the VH comprising the established amino acid sequence in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33 and SEQ ID NO. 34, or a VH comprising the amino acid sequence having at least 80%, 90%, 95%, 98% or 99% identity to the same amino acid sequence of VH, and the VL comprising the established amino acid sequence in SEQ ID NO. 25. [10-6] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-4], having the VH comprising the amino acid sequence in wherein glutamine at position 114 in the amino acid sequence set forth in any selected from SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33 and SEQ ID NO. 34 was or may be substituted with arginine, and the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. [10-7] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-4], having the VH comprising the established amino acid sequence in any of the selected elements of SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO. 66, and the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. [10-8] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the Lanz Ln / Lznz / E / YiAi points above [10-1] to [10-7], where CD19 is human CD19. [10-9] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-8], wherein the anti-CD19 antibody is an IgG antibody. [10-10] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to the above [10-9], wherein the IgG antibody described in the above [10-9] is an IgGi antibody or an IgG4 antibody. [10-11] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to the above [10-9], wherein the IgG antibody described in the above [10-9] is an IgGi antibody . [10-12] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to the above [10-9], wherein the IgG antibody described in the above [10-9] is an IgG4 antibody . [10-13] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-11], wherein in the constant region of the heavy chain, (1) leucine at position 351 was substituted with aspartic acid and leucine at position 368 was substituted with glutamic acid or (2) both Lanz Ln / Lznz / E / YiAi the leucine at position 351 as well as the threonine at position 366 in the constant region of the heavy chain were replaced with Usin. [10-14] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-13], which further has Gly (glycine), Gly-Lys -Lys-Ala (SEQ ID NO. 67), Gly-Lys-AlaLys-Ala (SEQ ID NO. 68), Gly-Arg-Arg-Ala (SEQ ID NO. 69) or GlyArg-Ala-Arg-Ala ( SEQ ID NO. 70) at the C-terminus of the heavy chain. [10-15] The isolated anti-CD19 monoclonal antibody or an antibody fragment thereof according to any of the above [10-1] to [10-14], wherein the heavy chains have the chain constant regions heavy weight comprising the amino acid sequence set forth in any selected from SEQ ID NO. 24, SEQ ID NO. 71, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 74 and SEQ ID NO. 75. [11-1] An agent for preventing, suppressing symptom progression, suppressing recurrence, and / or treating autoreactive B cell-mediated disease, containing the PD-1 / CD19 bispecific antibody or an antibody fragment of the same of any one selected from the above items [1] to

[117] as the active ingredient. [11-2] The agent to prevent, suppress the LQHZ LO / ίΖΠΖ / Β / ΥΙΛΙ symptom progression, suppress recurrence, and / or treat B cell-mediated autoreactive disease according to the above item [11-1], wherein the B cell-mediated autoreactive disease B is systemic lupus erythematosus, Graves' disease, myasthenia gravis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, asthma, cryoglobulinemia, primary sclerosing cholangitis, or malignant anemia. [12-1] An agent for suppressing autoreactive B cells, which contains the PD1 / CD19 bispecific antibody or an antibody fragment thereof of any one selected from the above items [1] to

[117] as an active ingredient. [12-2] The agent for suppressing autoreactive B cells according to the above item [12-1], wherein the suppression of autoreactive B cells is that of immunoglobulin production. [12-3] The agent for suppressing autoreactive B cells according to the above [12-2], wherein the immunoglobulin is IgG or IgM. [13-1] An agent for suppressing the activation of T cells, which contains the bispecific antibody of PD-Í / CD19 or an antibody fragment thereof of any one selected from the above items [1] to

[117] as an ingredient asset. LQH7 LO / ίΖΠΖ / Β / ΥΙΛΙ [13-2] The agent for suppressing T cell activation according to the above item [13-1], wherein the suppression of T cell activation is that of cytokine production. [13-3] The agent for suppressing T cell activation according to the above item [13-1] or [13-2], wherein suppression of T cell activation is that of activation of T cells T from memory. [14-1] A method of suppressing the activation of B cells or autoreactive T cells, comprising administering to a patient an effective amount of the PD-1 / CD19 bispecific antibody or an antibody fragment thereof of any selected from the previous points [1] to

[117] . [15-1] The PD-1 / CD19 bispecific antibody or an antibody fragment thereof from any selected from the above [1] to

[117] for use in suppressing B-cell activation or autoreactive T cells. [16-1] The use of the PD1 / CD19 bispecific antibody or an antibody fragment thereof of any selected from the above items [1] to

[117] to manufacture an agent for suppressing B-cell or B-cell activation autoreactive T cells. Advantageous effects of the invention The PD-1 / CD19 bispecific antibody of the LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ The present invention enables the interaction between PD-1 and PD-L1, and is expected to enhance or maintain the effect on prevention, suppression of symptom progression, suppression of recurrence of, and / or therapy for autoimmune diseases. Brief Description of the Figures Figure 1 shows the amino acid sequences of the VL and the constant region of the common light chain. Figure 2 shows the amino acid sequences of the respective CDRs in the VL of the common light chain. Figure 3 shows the amino acid sequences encoded by the genes: IGHV7-4-1 and IGHV5-51 from germline V, respectively. Figure 4 shows a sequence alignment between the VH of the respective clones of the antibodies that specifically bind to PD-1 (hereinafter, can be abbreviated as an anti-PD-1 antibody), the IGHV7-4-1 genes. and JH6c from the germ line. In this figure, the amino acid sequences of the clones represent the same amino acid as that of the corresponding germline IGHV7-4-1 or JH6c gene, and the amino acid abbreviations represent amino acids different from those of the same germline gene. . Figure 5 shows a sequence alignment between the VH of the respective antibody clones that were Lanz Ln / Lznz / E / YiAi specifically bind to CD19 (hereinafter, may be abbreviated as anti-CD19 antibody) and the amino acid sequence encoded by the germline IGHV5-51 gene. Each symbol in this figure represents the same meaning as that in figure 4. Figure 6 shows the amino acid sequences of VH of the respective anti-PD-1 antibody clones. Figure 7 shows the respective CDR amino acid sequences in the VH of the respective anti-PD-1 antibody clones. Figure 8 shows the amino acid sequences of VH of the respective anti-CD19 antibody clones. Figure 9 shows the respective CDR amino acid sequences in the VH of the respective anti-CD19 antibody clones. Figure 10 shows the amino acid sequences of the respective heavy chain constant regions of the PD-1 / CD19 bispecific monoclonal antibody. Figure 11 shows the results of Biacore measurement, demonstrating the PD-1 and CD19 binding activities of the respective PD-1 / CD19 bispecific antibody clones. Figure 12 shows flow cytometry demonstrating the CD19 binding properties of the respective CD19-1(Bi) to CD19-3(Bi) bispecific antibody clones from LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ PD-1 / CD19, respectively. Figure 13 shows flow cytometry demonstrating the CD19 binding properties of the respective PD-1 / CD19 bispecific antibody clones CD19-4(Bi) and CD19-5(Bi), respectively. Figure 14 shows flow cytometry demonstrating the PD-1 binding properties of the respective PD-1 / CD19 CD19-1(Bi) to CD19-3(Bi) bispecific antibody clones, respectively. Figure 15 shows flow cytometry demonstrating the PD-1 binding properties of the respective PD-1 / CD19 bispecific antibody clones CD19-4(Bi) and CD19-5(Bi), respectively. Figure 16 shows flow cytometry demonstrating the PD-1 and CD19 binding properties of the PD-1 / CD19 bispecific antibody clone CD19-6(Bi), respectively. Figure 17 shows flow cytometry demonstrating the PD-1 and CD19 co-binding properties of the respective PD1 / CD19 bispecific antibody clones, respectively. Figure 18 shows flow cytometry demonstrating the influences on the PD-1 / PD-L1 interaction of the respective PD1 / CD19 bispecific antibody clones, respectively. Lanz Ln / Lznz / E / YiAi Figure 19 shows the in vitro effects on IgM production from activated human B cells of the respective PD1 / CD19 bispecific antibody clones, respectively. Note here that in this figure, Ctrl represents the control group. Figure 20 shows the in vivo effects on IgG2 production from activated human B cells of the respective PD-1 / CD19 bispecific antibody clones CD191(Bi) to CD19-4(Bi), respectively. Note here that in this figure, Ctrl represents the control group. Figure 21 shows the in vivo effects on IgG2 production from activated human B cells of the PD-1 / CD19 bispecific antibody clones CD19-5(Bi) and CD196(Bi), respectively. Note here that in this figure, Ctrl represents the control group. Figure 22 shows the effects on cytokine production from human peripheral blood mononuclear cells of the PD-1 / CD19 bispecific antibody clone CD196(Bi). Note here that, in this figure, Medium represents the control group. Detailed description of the invention PD-1 (Cell Death Program 1) is a membrane-type protein composed of the amino acid sequence represented by GenBank accession number NP 005009 in Lanz Ln / Lznz / E / YiAi Humans. In the present disclosure, the term PD1, unless otherwise specifically defined, can be used as meaning inclusive of all its isoforms and additional variants thereof in which an epitope for the first branch that specifically binds to PD -1 of the present invention has been retained. In the present invention, PD-1 is preferably a human PD-1. CD19 is a membrane protein in B cells composed of the amino acid sequence represented by GenBank accession number NB_001171569 or NB_001761 in humans, and a molecular transfer stimulation to B cells together with the cell receptor complex. B. In the present description, the term CD19, unless otherwise specifically defined, can be used as meaning including variants thereof in which a second branch epitope that specifically binds to CD19 has been conserved. the present invention. In the present invention, CD19 is preferably a human CD19. In the present description, the term isolated means becoming a single substantially pure component by being identified, separated and / or purified from impurities containing a plurality or a myriad of components extracted from the host cells. In the present description, the term "monoclonal antibody" means an antibody obtained from a group of Lanz Ln / Lznz / E / YiAi substantially homogeneous antibodies that bind to the same specific antigen. In the present description, the term "bispecific antibody" means an antibody that has the binding specificity for two different antigen molecules or epitopes on one molecule. Furthermore, the term "bispecific monoclonal antibody" means a bispecific antibody obtained from a substantially homogeneous pool of antibodies. The present invention relates to a bispecific antibody capable of specifically binding to PD-1 and CD19, respectively (in the present description, it may be abbreviated as PD-1 / CD19 bispecific antibody). In the present invention, the PD-1 / CD19 bispecific antibody is preferably a PD1 / CD19 bispecific monoclonal antibody, more preferably an isolated PD-1 / CD19 bispecific monoclonal antibody, and further preferably a PD-1 / CD19 bispecific monoclonal antibody. 1 human / human CD19 isolate. Herein, the isolated human PD-1 / human CD19 bispecific monoclonal antibody means an isolated bispecific monoclonal antibody to human PD-1 and human GDI9. Herein, examples of bispecific antibody forms include a diabody, a bispecific sc(Fv)2, a bispecific minibody, a bispecific F(ab')2, a bispecific hybrid antibody, a bispecific diabody covalent Lanz Ln / Lznz / E / YiAi (bispecific DART), a bispecific (FvCysU, a bispecific F(ab'-zipper)2, a bispecific (Fv-zipper)2, a tri-chain bispecific antibody and a bispecific mAb2 and the like . The diabody is a dimer of single-chain peptides in which a VH and VL that recognize different antigens are linked together with a peptide linker (see Proc. Nati. Acad. Sci. USA (1993), Volume 90, No. 14, pages 6444-6448) . Bispecific sc(Fv)2 is a low molecular weight antibody modified so that two VH / VL pairs of two antibodies recognizing different antigens are linked with a peptide linker to form a continuous single-chain form (see J. Biological Chemistry (1994)), 269: pages 199-206). Bispecific F(ab')2 is a low molecular weight antibody to which Fab' fragments of antibodies recognizing two different antigens have been covalently linked through a disulfide bond or the like. The bispecific minibody is a low molecular weight antibody in which the low molecular weight antibody fragments modified in such a way that the CH3 domains of the constant region of the antibodies are linked to scFvs recognizing different antigens, respectively, were covalently linked. of disulfide or the like on the CH3 domains (see Biochemistry (1992), volume 31, number Lanz Ln / Lznz / E / YiAi 6, pages 1579-1584). The bispecific hybrid antibody is an intact antibody in which heavy chain / light chain complexes of the antibody, recognizing two different antigens, are covalently linked to each other through a disulfide bond or the like. In the present invention, the form of the bispecific antibody is preferably a bispecific chimeric antibody. The bispecific hybrid antibody can be produced from a hybridoma produced, for example, by the hybrid hybridoma method (see US4474893). Alternatively, the bispecific hybrid antibody can be produced by causing mammalian animal cells to co-express four types of cDNAs that encode a heavy chain and a light chain of antibodies that recognize and secrete different antigens, respectively. The monoclonal antibodies used in the present invention can be produced by the hybridoma method (see, for example, Kohler and Milstein et al., Nature (1975), Volume 256, pages 495-97, Hongo et al., Hybridoma (1995 ), Volume 14, Number 3, Pages 253-260, Harlow et al., Antibodies: A Laboratory Manual, (Coid Spring Harbor Laboratory Press (1988), Volume 2) and Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas , pages 563-681 (Elsevier, Lanz Ln / Lznz / E / YiAi ΝΥ, 1981)), a recombinant DNA method (see, for example, US4816567), a phage display method (see, for example, Ladner et al., US5223409, US5403484 and US5571698, Dower et al., US5427908 and US5580717 , McCafferty et al., US5969108 and US6172197, and Griffiths et al., US5885793, US6521404, US6544731, US6555313, US6582915 and US6593081). An antibody or monoclonal antibody, when administered to a human, can be produced in the form of a chimeric antibody, humanized antibody, or whole human antibody to reduce or eliminate its antigenicity. The term "chimeric antibody" means an antibody of which the variable region sequence and the constant region sequence are derived from different mammals. Examples thereof include an antibody whose variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody. The chimeric antibody can be produced by linking a gene encoding an antibody variable region isolated from antibody-producing hybridomas isolated by the above-mentioned hybridoma method, recombinant DNA method or phage display method, by well-known techniques, to a gene encoding the antibody constant region derived from humans using well-known methods (see, for example, Cabilly et al., US4816567). LQHZ LO / ίΖΠΖ / Β / ΥΙΛΙ The term "humanized antibody" means an antibody whose complementarity determining region (CDR) sequences derived from a germ line of other mammals such as the mouse were grafted onto human framework region sequences. The humanized antibody can also be produced by joining the genes encoding the CDRs of antibodies isolated from antibody-producing hybridomas isolated according to the above-mentioned method, by well-known techniques, to a gene encoding a framework region of the antibody derived from humans using the methods well known (see, for example, Winter, US5225539 and US5530101; Queen et al., US5585089 and US6180370). The term "human antibody" or "whole human antibody" means an antibody in which both the variable regions composed of the framework regions and the CDR regions and the constant regions are derived from human germ-line immunoglobulin sequences. The human antibody to be used in the present invention can be produced by a method using mice transformed to produce a human antibody, for example, Humab mice (see, for example, Lonberg and Kay et al. US5545806, US5569825, US5625126, US5633425, US5789650, US5877397, US5661016, US5814318, US5874299 and US5770429), KM mice (see, for example, Ishida et al., WO2002 / 43478), Xeno mice (see, for example, US5939598, US6075181, US6114598, US61 50584 and US6162963), either Lanz Ln / Lznz / E / YiAi Te mice (see, eg, Tomizuka et al., Proc Nati. Acad. Sci. USA (2000), pages 722-727). It can also be prepared using SCID mice in which human immune cells have been reconstructed such that the human antibody response occurs upon immunization (see, for example, Wilson et al., US5476996 and US5698767 ). In addition, the human antibody to be used in the present invention can also be produced according to the above-mentioned phage display method. In the present description, the term "PD-1 / CD19 bispecific antibody antibody fragment" is a full-length antibody part and is an antibody having a PD-1 antigen-binding part and an antigen-binding part. to CD19. Examples thereof include F(ab')2 and the like. In this document, the antigen-binding part means a minimal unit of an antibody that can bind an antigen thereof, for example, it is composed of three CDRs in the respective VH and VL regions and framework for organizing the CDRs in a manner that the target antigen can be recognized by the combination of these CDRs. In the present description, the term common light chain means a light chain that can be associated with two or more different heavy chains and can exhibit the binding capacity to each antigen (De Wildt RM, J. Mol. Biol. (1999), vol. 285, pages 895-901, De Kruif et al., J. Mol. LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ 100 Biol. (2009), volume 387, pages 548-58, WO2004 / 009618, WO2009 / 157771 and WO2014 / 051433). Preferable examples of such common light chains include a light chain encoded by the human κ light chain IgVKl-39*01 / IGJKl*01 germline gene (IMGT database nomenclatures) (hereinafter may be abbreviated as light chain). More preferable examples thereof include a light chain having a VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28, and other preferable examples thereof include a light chain having the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. Furthermore, preferable examples of the common light chain constant regions include the light chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 29. The respective amino acid sequences of the VL and the constant region of the common light chain used in the present invention are shown in Figure 1, and the respective amino acid sequences of the CDRs of the variable region are shown in Figure 2. . In the present description, the term "isotype" means the class of antibodies (for example, IgM or IgG) that is encoded by the constant chain region genes. LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 101 heavy. The isotype for the PD-1 / CD19 bispecific antibody of the present invention is preferably IgG, more preferably IgGi or IgG4. Here, IgGi is preferably one whose binding to the Fe receptor is eliminated or decreased. Specifically, the IgGi antibody whose binding to the Fe receptor is eliminated or decreased can be obtained by substituting, deleting or inserting arbitrary amino acids from the constant region of the heavy chain thereof. Examples thereof include an antibody in which leucine at position 235 according to the EU numbering system was substituted with glycine and / or glycine at position 236 was substituted with arginine in two heavy chain constant regions or hinge regions. of them, respectively. Furthermore, to reduce the heterogeneity of the antibody, an antibody in which one amino acid at the C-terminus has been deleted is preferable, for example, Usin at position 447 according to the EU numbering system. In addition, when the bispecific antibody is IgG4, in order to suppress the exchange in an antibody molecule, a variant in which an arbitrary amino acid in a heavy chain constant region thereof was substituted, deleted or inserted is more preferable. For example, the antibody whose serine at position 228 according to the EU numbering system, located in the hinge region, was replaced by proline is preferable. Note here that in the present description, the amino acid positions assigned Lanz Ln / Lznz / E / YiAi 102 to the CDRs and framework regions in the variable regions of the antibody can be specified according to the Kabat numbering system (see Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, Bethesda, Md., (1987) and 1991)). In addition, amino acids in the constant region are indicated according to the EU numbering system according to Kabat amino acid positions (see Sequences of proteins of immunological interest, NIH Publication Number 91-3242). In the Fe regions of the PD-1 / CD19 bispecific antibody of the present invention, arbitrary amino acids can be substituted therein so that two different heavy chains easily associate with each other. Examples of preferred embodiments thereof include a PD-1 / CD19 bispecific antibody of which in the constant region of the heavy chain having the VH of the first branch that specifically binds PD-1, leucine was substituted in position 351 according to the EU numbering system with lysine, and the threonine at position 366 was substituted with Usin and of which in the constant region of the heavy chain having the VH of the second branch that specifically binds to CD19, the leucine at position 351 was replaced by aspartic acid, and the leucine at position 368 was replaced by glutamic acid. In addition, examples thereof also include a PD-1 / CD19 bispecific antibody. LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 103 of which in the constant region of the heavy chain having the VH of the first branch that specifically binds PD-1, leucine at position 351 was substituted under the EU numbering system with aspartic acid, and the leucine at position 368 was replaced by glutamic acid and of which in the constant region of the heavy chain having the VH of the second branch that specifically binds CDI9, leucine at position 351 was replaced by lysine and threonine at position 351. position 366 was replaced by lysine. The first branch that specifically binds to PD-1 In the present description, the first branch that specifically binds to PD-1 (hereinafter, may be abbreviated as the first branch) means a part of the antibody that has at least one VH of the antibody that specifically binds to PD-1 and is capable of specifically binding to PD-1, regardless of whether it is contained in an antibody part or an antibody fragment thereof, or does not exist as a part but as a single substance. For example, the first branch similar to this, is composed of an anti-PD-1 antibody VH and a common light chain VL that can constitute the anti-PD-1 antibody itself, and other examples thereof as well. they include an antibody Fab having the same VH and VL. In this document, the term specifically binds PD-1 is used as a binding feature. LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ 104 direct to PD-1 with a binding activity higher than an affinity of at least 1 x ICE5M, preferably 1 x 10~7M, and more preferably 1 x 10~9M (dissociation constant (Kd value)), and it does not substantially bind to any receptor member belonging to a so-called CD28 family receptor, such as at least CD28, CTLA-4 and ICOS. Furthermore, an antibody in the antibody that specifically binds to PD-1 or in the anti-PD-1 antibody means a full-length antibody, that is, a full-length antibody consisting of two heavy chains and two light chains. disulfide-linked, and preferably a monoclonal antibody thereto. Herein, examples of the first branch that specifically binds to PD-1 include those having the VH having (a) the VH-CDR1 comprising the amino acid sequence represented by HYJi-LH [where J1 represents G (glycine ) or A (alanine), and other letters of the alphabet represent one-letter amino acid abbreviations, respectively], (b) the VH-CDR2 comprising the amino acid sequence represented by W J2NTNTU2NPTX2AQGFTG [where J2 represents L (leucine) or I ( isoleucine), U2 represents E (glutamic acid) or G (glycine), X2 represents F (phenylalanine) or Y (tyrosine), and other letters of the alphabet represent the same LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 105 than above, respectively], and (c) the VH-CDR3 comprising the amino acid sequence represented by GD J3WPTTIWNYYU3X3MZ3V [where J3 represents M (methionine) or L (leucine), U3 represents H (histidine) or Y (tyrosine), X3 represents F (phenylalanine) or Y (tyrosine), Z3 represents D (aspartic acid) or E (glutamic acid), and other letters of the alphabet represent the same as above, respectively]. In addition, examples of other embodiments of the first branch that specifically bind PD-1 include those having any of the VHs selected from (Ib) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 6, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 7, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 8, (2b) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 9, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 10, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 11, (3b) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 12, the VH-CDR2 comprising the established amino acid sequence LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 106 in SEQ ID NO. 13, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 14, (4b) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 15, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 16, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 17, and (5b) the VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 18, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 19, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. twenty. Furthermore, examples of the first PD-1-specific binding branch of the present invention include those of which one to five arbitrary amino acid residues are substituted with other amino acids (preferably, conservative amino acids therefor) in the respective VH-CDR of any of the VHs selected from (Ib) to (5b) above, and having substantially the same PD-1 binding activity as that of the original first branch without any substitutions with the same amino acids. Examples thereof include those of which an amino acid residue in the VH-CDR1 is substituted with other amino acids (preferably amino acids conservative thereto), and LQH7 Ln / LZnZ / E / Yli One to five amino acid residues in VH-CDR2 or VH-CDR3 are substituted with other amino acids (preferably amino acids conservative thereto), respectively. Furthermore, as shown in Figure 4 , in the respective CDRs of the anti-PD-1 antibody clones corresponding to the first branches that specifically bind to PD1, respectively, different amino acids can be included between the clones or any combination. of a plurality of them that can be interchangeable between the clones. Here, substitution with a conservative amino acid means interchangeability with a residue having a similar side chain. For example, a group of amino acids having an aliphatic side chain includes glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having an aliphatic hydroxyl side chain includes serine and threonine; A group of amino acids having an amide-containing side chain includes asparagine and glutamine; a group of amino acids having an aromatic side chain includes phenylalanine, tyrosine, and tryptophan; a group of amino acids that have a basic side chain includes lysine, arginine, and histidine; and a group of amino acids having a sulfur-containing side chain includes cysteine ​​and methionine. Examples of preferred conservative amino acid substitutions include those between valine, leucine and isoleucine, those between phenylalanine and LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 108 tyrosine, those between lysine and arginine, those between alanine and valine, as well as those between asparagine and glutamine. Furthermore, as used herein, the sentence having substantially the same PD-1 binding activity as that of the original first branch without any substitutions with the aforementioned amino acids means that the PD-1 binding activity of the first branch substituted with the same amino acids is 95% or more, preferably 98% or more, and more preferably 99% or more of the original first branch without any substitution with the same amino acids. Furthermore, examples of the first PD-1 specifically binding branch of the present invention include those having a VH containing the respective VH-CDRs having the above-mentioned specific amino acid sequences, and whose amino acid sequence of the framework region is encoded by a specific germline gene or a gene thereof with a somatic mutation(s). For example, the VH represented by any selected from (Ib) to (5b) above may be encoded by the recombinant VDJ gene or the gene thereof with a somatic mutation(s) in which the germline V gene is IGHV7-4-1 and the germline J gene is JH6c. In this document, the amino acid sequence encoded by the gene LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 109 Germline V IGHV7-4-1 corresponds to that set forth in SEQ ID NO. 21 (figure 3). The framework region in the VH of the first branch that specifically binds PD-1 of the present invention may be encoded by the recombinant germline VDJ gene with somatic mutation(s). For example, since FR1, FR2, and FR3 in the VH represented by any selected from (Ib) to (5b) above, of which a germline V gene is IGHV7-4-1, are different from the ammonia acid sequence encoded by the IGHV7-4-1 gene at the amino acid position shown in Figure 4, have undergone somatic mutations at the same respective positions. For example, as for FR1, in the amino acid sequence set forth in SEQ ID NO. 21, Lysine at position 13 may be substituted with glutamine, alanine at position 16 may be substituted with valine, or lysine at position 19 may be substituted with methionine, respectively, or may be substituted in an arbitrary combination of a plurality of them. As for FR2, valine at position 37 in the amino acid sequence set forth in SEQ ID NO. 21 may be substituted with leucine. As for FR3, in the amino acid sequence established in SEQ ID NO. 21, the serine at position 77 may be substituted with threonine, or the cysteine ​​at position 84 may be substituted with serine or LQH7 Ln / LZnZ / E / Yli 110 asparagine, respectively, or which may be substituted in an arbitrary combination of a plurality thereof. Furthermore, as for the VH FR4 represented by any one selected from (Ib) to (5b) mentioned above, in the amino acid sequence (Trp-Gly-Lys-Gly-Thr-Thr*-Val-ThrVal-Ser- Ser) (SEQ ID NO. 41) of FR4 derived from germline J gene JH6c, lysine (Lys) may be substituted with glutamine or asparagine, and / or threonine (Thr) marked with an asterisk may be substituted with leucine. Respective FR1, FR2, FR3 and FR4 having the combination of any amino acid substitutions mentioned above do not have a substantial effect on the functions of the first branch that specifically binds PD-1, and can be used as framework regions. In addition, examples of the first PD-1 specifically binding branch of the present invention also include those having the respective CDRs having the amino acid sequence specified as above and wherein the amino acid sequences of FR in the VH are encoded by the specific germline gene or the gene thereof with a somatic mutation(s). Examples of such first branches include those having the VH comprising the amino acid sequence in any selected one of SEQ ID NOs. 1 to 5. Furthermore, examples of such early LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 111 branches that specifically bind to PD-1 also include those that have a VH comprising an amino acid sequence that is at least 80% identical, preferably at least 90% identical, more preferably at least 95% identical. identity, still more preferably at least 98% identity, and still more preferably at least 99% identity to the amino acid sequence set forth in any selected of SEQ ID NOs. 1 to 5, and wherein the VH amino acid sequence difference from the original first branch does not have a substantial effect on PD-1 binding activity (hereinafter, may be abbreviated as homologous first branch). In this document, the term % identity used in comparison with the identity of the amino acid sequences is defined as the percentage of the amino acid sequence identical to the reference amino acid sequence (herein, when necessary to maximize identity). sequence, the reference amino acid sequence in which the gap has been inserted) when two sequences are aligned. Furthermore, as used herein, the phrase how different from the VH amino acid sequence of the original first branch does not have a substantial effect on PD-1 binding activity means that the PD-1 binding activity of the first homologous branching is 95% or more, preferably Lanz Ln / Lznz / E / YiAi 112 98% or more, and more preferably 99% or more of that of the original first branch. In yet another embodiment, the first branch that specifically binds to PD-1 of the present invention also includes those that have a variable region (herein, the variable region contains a VH and a VL constituting it) of the anti- -PD-1 that cross competes for (1) binding to PD-1 with the first branch having the VH represented by any selected from (Ib) to (5b) above or the VH comprising the sequence of amino acids set to any selected from SEQ ID NOs. 1 to 5 and the VL of the common light chain of the present disclosure (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25), or (2) binding to PD-1 with the variable region of the monoclonal antibody that specifically binds to PD-1 that has the same VH and VL, and also includes those that have the variable region of the anti-PD-1 antibody with which PD-1 binding cross-competes for (3) the first branch having the VH represented by any one selected from (Ib) to (5b) or the VH comprising the amino acid sequence set forth in any selected one of SEQ ID NOs. 1 to 5 and the VL of the same common light chain, or (4) the variable region of the monoclonal antibody that specifically binds PD-1 that has the LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 113 same VH and VL. As used herein, the sentence cross competition for PD-1 binding means inhibiting the binding of the first branch to PD-1, regardless of the degree thereof, by binding to the epitope that is the same or partially overlaps with that of the first exemplified branch herein, or that the binding to PD-1 of the antibody that binds to the epitope that is the same or partially overlaps with that of the first exemplified branch, is inhibited by the same first exemplified branch, regardless of its degree. Whether or not it cross competes can be assessed by a competitive binding assay. For example, it can be determined by Biacore analysis, ELISA assay, flow cytometry, enzyme-linked immunosorbent assay (ELISA), fluorescence energy transfer (FRET) method, and microvolume fluorometric assay technology (FMAT (registered trademark)). . Examples of the first branch that cross competes for binding to PD-1 for the first branch having the VH represented by the above-mentioned (5b) and the VL of the common light chain, include the first branch having the VH represented by any one selected from (Ib) to (4b) above and the VL of the common light chain (preferably, the VL having the VL-CDR1 comprising the amino acid sequence Lanz Ln / Lznz / E / YiAi 114 set forth in SEQ ID NO. 26, the VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28), and also the first branch that the VH has that comprises the amino acid sequence established in any one selected from SEQ ID NOs. 1 to 4 and the VL of the common light chain (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25). In addition, examples of the first branch cross-compete for binding to PD-1 with the first branch having the VH represented by any selected from (Ib) to (4b) above or the VH comprising the sequences of amino acids described in any selected from SEQ ID NOs. 1 to 4 and the common light chain VL includes the first branch having the VH represented by (5b) mentioned above and the common light chain VL (preferably, the VL having the VL-CDR1 comprising the sequence of amino acids established in SEQ ID NO.26, the VL-CDR2 comprising the amino acid sequence established in SEQ ID NO.27 and VLCDR3 comprising the amino acid sequence established in SEQ ID NO.28), and furthermore the first branch that the VH has that comprises the amino acid sequence established in SEQ ID NO. 5 and the VL of the common light chain LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 115 (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25). Herein, preferable examples of the first branch that specifically binds to PD-1 of the present invention include the first branch having the VH represented by any one selected from (Ib) to (5b) mentioned above. Furthermore, as mentioned above, preferable examples of the first branch also include those having the VH of which one to five arbitrary amino acid residues are substituted with other amino acids (preferably amino acids conservative thereto) in the respective CDRs. and the same substitutions do not substantially affect PD-1 binding activity. In addition, as mentioned above, they also include those who have VH where the amino acid sequences of the framework regions are encoded by the V germline IGHV7-4-1 gene or the J germline JH6c gene or genes of the same with a somatic mutation or mutations. Then, more preferable examples of the first branch include those having the VH comprising the amino acid sequence set forth in any of the SEQ ID NOs. 1 to 5. In addition, the first branch that specifically binds to PD-1 of the present invention is preferably the one that has the VL of the light chain. 116 common light chain of the present disclosure, and such common light chain is preferably the IGVK1-39 / JK1 common light chain. A more preferable example thereof is a light chain having the VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 2-6, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28, and a further preferable example thereof is the VL-containing light chain comprising the amino acid sequence set forth in SEQ ID NO. 25. Furthermore, preferable examples of the light chain constant regions include the light chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 29. In addition, the first branch that specifically binds PD-1 is preferably one that allows for interaction between PD-1 and PD-L1, interaction between PD-1 and PD-L2, or both interactions thereof. In this document, the sentence allow interaction between PD-1 and PD-L1, interaction between PD-1 and PD-L2, or both interactions thereof means that even when the PD-1 / CD19 bispecific antibody of the present invention in a 20-fold excess over the PD-L1 or PD-L2 concentration of the soluble form, the interaction between PD-L1 and PD-1, the interaction between PD-L2 and PD-1, or both interactions of the themselves LQH7 Ln / LZnZ / E / Yli 117 is maintained at 50% or more, preferably 70% or more, and more preferably 80% or more, as compared to those in which there is no PD-1 / CD19 bispecific antibody of the present invention. Furthermore, the definition of allowing the interaction between PD-1 and PD-L1, the interaction between PD-1 and PD-L2, or both interactions thereof may have the same meaning as that of not substantially inhibiting the interaction between PD -1 and PD-L1, the interaction between PD-1 and PD-L2, or both interactions thereof. The correspondence relationships between the respective clones of the anti-PD-1 monoclonal antibody obtained for constructing the PD-1 / CD19 bispecific antibody of the present invention and the VH amino acid sequences thereof and the sequence identification numbers thereof are shown in Fig. 6. The correspondence relationships between the CDR amino acid sequences in the VH of the respective anti-PD-1 monoclonal antibody clones and the SEQ ID number thereof are shown in Fig. figure 7. The second branch that specifically binds to CD19 In the present description, the second branch that specifically binds to CD19 (hereinafter, it can be abbreviated as the second branch) means an antibody part that has at least one VH of an antibody that specifically binds to CD19 and is capable of binding Lanz Ln / Lznz / E / YiAi 118 specifically to CD19, regardless of whether it is contained in a part of the antibody or an antibody fragment thereof, or does not exist as a part but as a single substance. For example, such a second branch is composed of a VH of the anti-CD19 antibody and the VL of the common light chain that may constitute the same anti-CD19 antibody, and other examples thereof include a Fab part of the antibody that includes the same VHs. and VL. In this document, the sentence that specifically binds CD19 is used as a direct binding feature to CD19 with a binding activity higher than at least 1 x 10~5M, preferably 1 x 10~7M, and more preferably more than 1 x 10~9M affinity (dissociation constant (Kd value)) and does not bind substantially to any other protein. Furthermore, the antibody in the antibody that specifically binds to CD19 or in the anti-CD19 antibody means a full-length antibody consisting of two heavy chains and two disulfide-linked light chains, and preferably a monoclonal antibody thereof. Herein, examples of the second branch that specifically binds to CD19 include those having the VH having (a) the VH-CDR1 comprising the amino acid sequence represented by SYWIJ4 [wherein J4 represents G (glycine) or A (alanine), and other letters of the alphabet represent one-letter amino acid abbreviations, LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 119 respectively], (b) the VH-CDR2 comprising the amino acid sequence represented by IIU4PGDSDTRYSPSFQG [where U4 represents W (tryptophan) or Y (tyrosine), or other letters of the alphabet represent the same as above, respectively], and ( c) the VH-CDR3 comprising the amino acid sequence represented by X4TIVZ4J5U5X5Z5AJ6DU6 [wherein X4 represents K (lysine), Q (glutamine), H (histidine) or R (arginine), Z4 represents G (glycine) or A (alanine) , J5represents T (threonine) or V (valine), U5represents V (valine), I (isoleucine) or T (threonine), X5represents M (methionine), Y (tyrosine), G (glycine) or H (histidine), Z5represents T (threonine), N (asparagine), L (leucine) or W (tryptophan), Js represents F (phenylalanine) or S (serine), and U6 represents I (isoleucine), F (phenylalanine) or Y (tyrosine) and other letters of the alphabet represent the same as the previous ones, respectively]. Furthermore, examples of other embodiments of the second branch that specifically bind CD19 include those having any VH selected from (Id) a VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 35, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 36, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 37, (2d) a VH having the VH-CDR1 comprising the LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 120 amino acid sequence set forth in SEQ ID NO. 38, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 39, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 40, (3d) a VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 41, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 42, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 43, (4d) a VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 44, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 45, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 46, and (5d) a VH having the VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 47, the VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 48, and the VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 49. In addition, examples of the second CD19-specific binding branch of the present invention also include those in which one to five arbitrary amino acid residues are substituted with other amino acids (preferably, amino acids conservative thereto) in the VH- respective CDRs of any of the VHs LQH7 ίΩ / ίΖΩΖ / Ε / ΥΙ 121 selected from (Id) to (5d) above, and having substantially the same CD19 binding activity as that of the original second branch without any substitutions with the same amino acids. Examples thereof include those of which one amino acid residue in VH-CDR1 is substituted with other amino acids (preferably, a conservative amino acid thereto), and one to five amino acid residues in VH-CDR2 or VH- CDR3 are substituted with other amino acids (preferably amino acids conservative thereto), respectively. Furthermore, as shown in Figure 5, in the respective CDRs of the anti-CD19 antibody clones corresponding to the first branches that specifically bind to CD19, respectively, the different amino acids between the clones or any combination of a plurality of the They can be exchanged between clones. In this document, the sentence having substantially the same CD19 binding activity as that of the original second branch without any substitutions with the same amino acids mentioned above, means that the CD19 binding activity of the second branch substituted with the same amino acids is 95% or more, preferably 98% or more, and more preferably 99% or more of the original second branch without any substitution with the same amino acids. Note in this document that the examples of substitution with Conservative 122 amino acids in the respective VH-CDRs of the second branch include those of the amino acid substitutions in the first branch mentioned above. In addition, the second branch that specifically binds to CD19 in the present invention also includes those which have a VH containing the respective CDRs comprising the above-mentioned specific amino acid sequence, and whose FR amino acid sequences are encoded by a gene of the specific germ line or a gene thereof with somatic mutation(s). For example, any of the VHs selected from (Id) to (5d) above may be encoded by a recombinant VDJ gene or a gene thereof with a somatic mutation(s) in which the germline V gene is IGHV5-51. Here, the amino acid sequence encoded by the IGHV5-51 germline V gene corresponds to the amino acid sequence set forth in SEQ ID NO. 22 (figure 3). The framework regions in the VH of the second branch that specifically bind to CD19 of the present invention may be encoded by the recombinant germline VDJ gene with a somatic mutation(s). For example, given that FR1 and FR3 in the VH represented by any selected from (Id) to (5d) above LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 123 above, of which the germline V gene is IGHV5-51, are different from an amino acid sequence encoded by the IGHV5-51 gene at the amino acid positions shown in Figure 5, have undergone somatic mutations in the same respective positions. For example, as for FR1, in the amino acid sequence set forth in SEQ ID NO. 22, glutamic acid at position 1 can be substituted with glutamine, proline at position 14 can be substituted with serine, tyrosine at position 27 can be substituted with phenylalanine, or threonine at position 30 can be substituted with isoleucine, respectively, or which may be substituted in an arbitrary combination of a plurality thereof. As for FR3, in the amino acid sequence established in SEQ ID NO. 22, isoleucine at position 76 can be substituted with phenylalanine, or serine at position 77 can be substituted with threonine or asparagine, threonine at position 78 can be substituted with valine, serine at position 84 can be substituted with asparagine, methionine at position 93 may be substituted with isoleucine or leucine, or alanine at position 97 may be substituted with valine, respectively, or which may be substituted in an arbitrary combination of a plurality thereof. The respective FR1 and FR3 having a combination of any of the above amino acid substitutions do not have a substantial effect on LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ 124 functions of the second branch that specifically binds to CD19, and can be used as framework regions. In addition, examples of the second CD19-specific binding branch of the present invention also include those having the VH containing the respective CDRs comprising the above-mentioned specific amino acid sequence, and of which the amino acid sequence of FR it is encoded by a specific germline gene or a gene thereof with a somatic mutation(s). Examples of such second branches include those having the VH comprising the amino acid sequence set forth in any selected one of SEQ ID NOs. 30 to 34. In addition, examples of such second branches that specifically bind to CD19 also include those that have a VH comprising an amino acid sequence that is at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 98%, and still more preferably at least 99% identity to the amino acid sequence set forth in any selected SEQ ID NOs. 30-34, and wherein the VH amino acid sequence difference from the original second branch has no substantial effect on CD19 binding activity (hereinafter, may be abbreviated as second homologous branch). In this LQH7 Ln / LZnZ / E / Yli 125 document, the phrase difference from the VH amino acid sequence of the original second branch has no substantial effect on CD19 binding activity means that the binding activity of the second branch homologous to CD19 is 95% or more , preferably 98% or more, and more preferably 99% or more of that of the original second branch. In yet another embodiment, examples of the CD19-specifically binding second branch of the present invention also include those having a variable region (herein, the variable region contains the constituting VH and VL) of the anti- -CD19 cross-competes for (1) binding to CD19 with the second branch having the VH represented by any selected from (Id) to (5d) above, or the VH comprising the amino acid sequence set forth in any Selected from SECs. ID Nos. 30 to 34 and the VL of the common light chain of the present disclosure (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25), or (2) binding to CD19 with the region monoclonal antibody variable that specifically binds to CD19 having the same VH and VL, and also includes those that have an anti-CD19 antibody variable region with which CD19 binding is cross-competed by (3) the second branch that has LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 126 VH represented by any selected from (Id) to (5d) above, or the VH comprising the amino acid sequence set forth in any selected from SEQ ID NOs. 30 to 34 and the same VL of the common light chain, or (4) the variable region of the monoclonal antibody that specifically binds CD19 having the same VH and VL. As used herein, cross-competition for binding to CD19 means inhibiting the binding of the second branch to CD19, regardless of the degree thereof, by binding to an epitope that is the same or partially overlaps with the second branch exemplified in the present disclosure, or that the binding to CD19 of the antibody that binds to the epitope that is the same or partially overlaps with that of the exemplified second branch is inhibited by the same exemplified second branch, regardless of the degree thereof. Herein, whether or not it cross-competes can be similarly evaluated according to the same method as described in the descriptions with respect to the first branch specifically binding to PD-1. Herein, preferable examples of the second branch specifically binding to CD19 of the present invention include the second branch having the VH represented by any one selected from (Id) to (5d) mentioned above. Furthermore, as mentioned above, preferable examples of the second LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 127 branch also include those having the VH of which one to five arbitrary amino acid residues are substituted with other amino acids (preferably amino acids conservative thereto) in the respective CDRs and the same substitutions do not substantially affect binding activity to GDI 9. In addition, as mentioned above, examples of the second branch include those having the VH where the amino acid sequences of the framework regions are encoded by the IGHV5-51 germline V gene or a germline V gene. itself with a somatic mutation or mutations. Then, more preferable examples of the second branch include those having the VH comprising the amino acid sequence set forth in any of the SEQ ID NOs. 30 to 34. Furthermore, examples of other preferable embodiments of the CD19-specifically binding second branch of the present invention include the second branch having the VH comprising any of the amino acid sequences selected from SEQ ID NO. 30 to 34 where the glutamine at position 114 was or may be substituted with arginine, more preferably, the second branch having the VH comprising any of the selected amino acid sequence of SEQ ID NO. 30 to 34 in which glutamine in position 114 was replaced by arginine, which corresponds to the second branch that the VH has that LQH7 Ln / LZnZ / E / Yli 128 comprises any of the amino acid sequences selected from SEQ ID NO. 62 to 66, respectively. These amino acid substitutions can increase the isoelectric point (pi value) of a complex consisting of the heavy chain and the light chain having the second branch (hereinafter, the second branch-heavy chain / light chain complex) and , therefore, facilitates the separation of the bispecific antibody from, in particular, the homodimers consisting of the second branch-heavy chain / light chain complexes, in the PD1 / CD19 bispecific antibody purification process of the present invention . The isoelectric point for the second branch-heavy chain / light chain is preferably between about 8.3 and about 8.9, and more preferably, between about 8.4 and about 8.8. And, the isoelectric point for a complex consisting of the heavy chain and the light chain having the first branch (hereinafter, the first branch-heavy chain / light chain complex) is preferably between about 7.4 and about 7.7, and more preferably, between about 7.5 and about 7.6. The second branch that specifically binds to CD19 of the present invention is preferably that which has the common light chain of the present disclosure, and such common light chain is preferably the common light chain LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 129 IGVK1-39 / JK1. A more preferable example thereof is the light chain having a VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ ID NO. 28, and a further preferable example thereof is the light chain having the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. Furthermore, preferable examples of the light chain constant region include the light chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 29. Hereinafter, the correspondence relationships between the respective anti-CD19 antibody clones for constructing the PD-1 / CD19 bispecific antibody of the present invention and the VH amino acid sequence thereof, and the SEQ ID numbers of the The same are shown in Fig. 8. The correspondence relationships between the respective CDR amino acid sequences in the VH of the respective anti-CD19 antibody clones and the SEQ ID number thereof are shown in Fig. 9. On the other hand, examples of preferable embodiments of the PD-1 / CD19 bispecific antibodies of the present invention include those whose first branch that specifically binds to PD-1 has LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 130 (A) the VH in which one to five arbitrary amino acid residues may be substituted with other amino acids (preferably amino acids conservative thereto) in any or more of the CDRs selected from VHCDR1, VH-CDR2 and VH-CDR3 of the VH represented by any one selected from (Ib) to (5b) mentioned above, and (B) the VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ. ID No. 28, and the second branch that specifically binds CD19 has (C) the VH in which one to five arbitrary amino acid residues may be substituted with other amino acids (preferably amino acids conservative thereto) in any or more than CDRs selected from VHCDR1, VH-CDR2 and VH-CDR3 of the VH represented by any selected from the above-mentioned (Id) to (5d), and (D) the VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ. ID No. 28. The most preferable examples of the antibodies LQHZ ίΩ / ίΖΩΖ / Ε / ΥΙ 131 PD-1 / CD19 bispecifics of the present invention include those of which the first branch that specifically binds to PD-1 has (A) the VH represented by any selected from (Ib) to (5b) above, and (B) the VL having the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ. ID No. 28, and the second branch that specifically binds to CD19 has (C) the VH represented by any selected from the above-mentioned (Id) to (5d), and (D) the VL that has the CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 26, CDR2 comprising the amino acid sequence set forth in SEQ ID NO. 27 and CDR3 comprising the amino acid sequence set forth in SEQ. ID No. 28. Furthermore, examples of other preferred embodiments of the PD-1 / CD19 bispecific antibodies of the present invention include those whose first branch that specifically binds to PD-1 has (A) the VH comprising the amino acid sequence set forth in either selected from SEQ ID NOs. 1 to Lanz Ln / Lznz / E / YiAi 132 5, or a VH comprising an amino acid sequence having at least 80% identity with the same amino acid sequence of VH, and (B) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and the second branch that specifically binds CDI9 has (C) the VH comprising the amino acid sequence set forth in any of SEQ ID NOs. 30 to 34 and 62 to 66, or a VH comprising an amino acid sequence having at least 80% identity to the same amino acid sequence of VH, and (D) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. Other more preferable examples thereof include the PD-1 / CD19 bispecific antibody of which the first branch that specifically binds to PD-1 has (A) the VH comprising the amino acid sequence set forth in any of SEQ ID NOs. 1 to 5, and (B) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and the second branch that specifically binds CD19 has (C) the VH comprising the amino acid sequence set forth in any of SEQ ID NOs. 30 to 34 and 62 to LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 133 6, and (D) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. Furthermore, other more preferable examples thereof include the PD-1 / CD19 bispecific antibody of which the first branch that specifically binds to PD-1 has (A) the VH comprising the amino acid sequence set forth in any of SEQ IDs Us. 1 to 5, and (B) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25, and where the second branch that specifically binds CD19 has (C) the VH comprising the amino acid sequence set forth in any of SEQ ID NOs. 62 to 66, and (D) the VL comprising the amino acid sequence set forth in SEQ ID NO. 25. An isotype of the PD-1 / CD19 bispecific antibody of the present invention is preferably an IgG antibody, more preferably an IgGi antibody or an IgG4 antibody, and most preferably an IgGi antibody. When the antibody is an IgGi antibody, the IgGi antibody in which leucine at position 235 according to the EU numbering system was substituted with glycine and / or glycine at position 236 was substituted with arginine in two regions heavy chain constants or hinge regions of the Lanz Ln / Lznz / E / YiA 134 same, is preferable. In addition, the bispecific antibody from which the C-terminal amino acids of the heavy chains have been removed is preferable, for example, Usin at position 447 according to the EU numbering system. In addition, when the PD-1 / CD19 bispecific antibody is an IgGo antibody, an antibody of which the serine at position 228 according to the EU numbering system, located in the hinge region, has been replaced by proline is preferable. In addition, when the PD1 / CD19 bispecific antibody is an IgGi antibody, examples of preferable embodiments thereof include those of which in the constant region of the heavy chain having the VH of the first branch that specifically binds PD -1, leucine at position 351 according to the EU numbering system was substituted with Usin and threonine at position 366 was substituted with Usin, and in the constant region of the heavy chain having the VH of the second branch that binds specifically to CD19, leucine at position 351 was replaced with aspartic acid, and leucine at position 368 was replaced with glutamic acid. In addition, an IgGi antibody of which in the constant region of the heavy chain having the VH of the first branch that specifically binds to PD-1, the leucine at position 351 according to the EU numbering system is replaced by aspartic acid and leucine at position 368 was replaced LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 135 with glutamic acid, and in the constant region of the heavy chain having the VH of the second branch that specifically binds CD19, leucine at position 351 was substituted with lysine and threonine at position 366 substituted was also preferable with lysine. Examples of preferable embodiments of the PD-1 / CD19 bispecific IgGi antibody in which all of the above-mentioned amino acid substitutions in the constant region of the heavy chain are taken include those in which the heavy chain having the VH of the first branch specifically binds to PD-1 has the heavy chain constant region comprising the amino acid sequence set forth in SEQ ID NO. 23, and the heavy chain having the VH of the second branch that specifically binds CD19 has the heavy chain constant region comprising the amino acid sequence set forth in any one selected from SEQ ID NO. 24 and SEQ ID NO. 71 to 75. These amino acid sequences are exemplified in Figure 10. Herein, the heavy chain having the VH of the second branch that specifically binds to CD19 may further have Gly (glycine), Gly-Lys-Lys-Ala (SEQ ID NO. 67), Gly-Lys-Ala- Lys-Ala (SEQ ID NO. 68), Gly-Arg-Arg-Ala (SEQ ID NO. 69) or Gly-Arg-Ala-Arg-Ala (SEQ ID NO. 70), via LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ the amide binding to its C-terminal amino acid at its C-terminus 136 terminal. The addition of the amino acid or peptide can increase the isoelectric point (pi value) of the second branch-heavy chain / light chain complex and thus facilitates the separation of the PD-1 / CD19 bispecific antibody of the present invention. of, in particular, a homodimer consisting of the second branch-heavy chain / light chain complexes, as in the case of the amino acid substitution in the second branch VH, mentioned above. Note here that the isoelectric point with respect to the second branch-heavy chain / light chain complex of which the amino acid or peptide was added to its C-terminus is preferably between about 8.3 and about 8.9, and more preferably, between about 8.4 and around 8.8. Examples of the most preferred embodiments of the PD-1 / CD19 bispecific antibody of the present invention include the clones CD19-1(Bi), CD19-2(Bi), CD19-3(Bi), CD194(Bi) and CD19. -5(Bi) generated in the manner described in Example 12 of the present description, as well as the clone CD19-6(Bi) generated in the manner described in Example 13. Examples of preferable features of the PD-1 / CD19 bispecific antibody of the present invention include allowing interaction between PD-1 and PD-L1, interaction between PD-1 and PD-L2, or both interactions thereof. In this document, the sentence that allows the LQH7 Ln / LZnZ / E / Yli 137 interaction between PD-1 and PD-L1, interaction between PD-1 and PD-L2, or both interactions thereof means the same as described in the descriptions regarding the first branch that specifically binds PD-1 . Further, examples of preferable features of the PD-1 / CD19 bispecific antibody of the present invention include sufficiently reducing cytokine production. In this document, the sentence "sufficiently reduce cytokine production" means that, for example, during intravenous administration or 24 hours after this administration, by drip infusion of the PD-1 / CD19 bispecific antibody of the present invention, by For example, the concentration of cytokines including IL-2, IFN-y and / or TNF-α in the blood or tissue do not increase, or even if they do increase, it is to such a degree that it can be suppressed by the administration of spheroids. Further, examples of preferable features of the PD-1 / CD19 bispecific antibody of the present invention include suppressive effect against activation of T cells (eg, memory T cells). The suppressive effect can be evaluated as the suppressive effect against the production of cytokines (eg IL2). Manufacturing and purification method of the PD-1 / CD19 bispecific antibody Lanz Ln / Lznz / E / Yi 138 The PD-1 / CD19 bispecific antibody and its antibody fragment of the present invention can also be made by the method described in WO2014 / 051433, WO2013 / 157953 or WO2013 / 157954. Specifically, the PD1 / CD19 bispecific antibody and the antibody fragment thereof of the present invention can be manufactured by transferring an expression vector in which (1) a polynucleotide encoding the heavy chain having the VH of the first branch that specifically binds to PD-1, (2) a polynucleotide encoding the heavy chain having the VH of the second branch that specifically binds CD19, and (3) a polynucleotide encoding the common light chain has been inserted, respectively , in mammalian animal cells to transform them, and then causing them to express and secrete both the heavy chain and the common light chain. Herein, any host cell can be used to express the PD-1 / CD19 bispecific antibody of the present invention as long as they can be gene-transferred by expression vectors to express them. Preferable examples of host cells include insect cells such as SF-9 and SF-21, more preferably, mammalian cells such as mouse cells, including CHO cells, BHK cells, SP2 / 0 cells, and NS-0 myeloma cells, primate cells such as LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 139 COS and Vero cells and MDCK cells, BRL 3A cells, hybridoma, tumor cells, immortalized primary cells, W138, HepG2, HeLa, HEK293, HT1080 and embryonic retinal cells such as PER.C6 and the like. Note here that, in the selection of the expression system, expression vectors for mammalian cells and the host cells thereof can be used such that the antibodies are appropriately glycosylated. Human cell lines, preferably PER.06, are advantageously used to obtain antibodies corresponding to glycosylated standards for humans. Protein production in transformed host cells by gene transfer from expression vectors can be carried out with reference to, for example, Current Protocols in Protein Science (1995), Coligan JE, Dunn BM, Ploegh HL, Speicher DW, Wingfield PT, ISBN 0-471-11184-8, Bendig, 1988. In addition, general guidelines, procedures, and practical methods for maximizing host cell culture productivity can be carried out with reference to Mammalian Cell Biotechnology: a Practical Approach (M. Butler, ed., IRL Press, 1991). The expression of antibodies in host cells is described, for example, in publications such as EP0120694, EP0314161, EP0481790, EP0523949, US4816567, WO2000 / 63403 and the like. In this document, culture conditions for LQH7 ίΩ / ίΖΩΖ / Ε / ΥΙ 140 host cells can be optimized by well-known methods, and the amount of protein production therein can be optimized. Culturing can be performed by batch culture, feed culture, continuous culture, or hollow fiber culture in a petri dish, roller bottle, or reaction chamber. To produce the recombinant protein by cell culture on a large scale and continuously, it is preferable to allow the cells to proliferate in suspension. Furthermore, it is preferable to culture cells in a condition without serum of animal or human origin or serum components of animal or human origin. Antibodies expressed in and recovered from host cells or culture thereof by well-known methods can be purified using well-known methods. Examples of purification methods include immunoprecipitation method, centrifugation method, filtration, size exclusion chromatography, affinity chromatography, cation and / or anion exchange chromatography, hydrophobic interaction chromatography and the like. Furthermore, protein A or protein G affinity chromatography may preferably be used (see, for example, US4801687 and US5151504 ). Anti-CD19 monoclonal antibody The present invention includes an antibody LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 141 monoclonal antibody that specifically binds to CD19 (hereinafter, may be abbreviated as anti-CD19 monoclonal antibody) and an antibody fragment thereof to construct the PD-1 / CD19 bispecific antibody of the present invention. One embodiment of the anti-CD19 monoclonal antibody of the present invention is a monoclonal antibody capable of specifically binding to CD19 by association of a VH thereof with the VL of the common light chain of the present invention. In this document, the phrase "bind specifically to CD19" is used as a feature of direct binding to CD19 with higher binding activity (dissociation constant (Kd value)) than at least 1 x 10 -5M, preferably 1 x 10 ~7M, and more preferably an affinity of 1 x 1CU9M, and does not bind substantially to any other protein. As used herein, the antibody in the monoclonal antibody that specifically binds to CD19, means a full-length antibody consisting of two heavy chains and two disulfide-linked light chains. In addition, a fragment of the monoclonal antibody that specifically binds to CD19 is part of the full-length antibody, which includes at least an antigen-binding part, and examples thereof include Fab, Fab', Fv, scFv, F(ab ')2 and the like. Examples of the anti-CD19 monoclonal antibodies of the present invention include those having LQnZ Ln / ίΖΠΖ / Β / ΥΙΛΙ 142 any of the VHs selected from the above-mentioned (Id) to (5d) constituting the second branch VH that specifically binds CD19 or the VH comprising the amino acid sequence set forth in any selected one of SEQ ID NOs. 30 to 34 and the VL as the common light chain of the present disclosure (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25). Furthermore, examples of anti-CD19 monoclonal antibodies of the present invention also include those in which one to five arbitrary amino acid residues are substituted with other amino acids (preferably amino acids conservative thereto) in the respective CDRs of any of the VHs selected from (Id) to (5d) above, and having substantially the same CD19 binding activity as that of the anti-CD19 monoclonal antibody having the original VH without any substitutions with the same amino acids. Examples thereof include those in which one amino acid residue in CDR1 is substituted with other amino acids (preferably amino acids conservative thereto) and one to five amino acid residues in CDR2 or CDR3 are substituted with other amino acids ( preferably, conservative amino acids thereof), respectively. Furthermore, as shown in Figure 5, in the respective CDRs of the antibody clones LQH7 Ln / LZnZ / E / Yli 143 monoclonal anti-CD19, different amino acids between clones or any combination of a plurality thereof can be interchanged between clones. In this document, the sentence having substantially the same CD19 binding activity as that of the anti-CD19 monoclonal antibody having the parental VH without any substitutions with the same amino acids means that the CD19 binding activity of the anti-CD19 monoclonal antibody substituted with the same amino acids is 95% or more, preferably 98% or more, and more preferably 99% or more than that of the anti-CD19 monoclonal antibody having the original VH without any substitution with the same amino acids. Furthermore, examples of the anti-CD19 monoclonal antibodies of the present invention include those containing the respective CDRs comprising the above-mentioned specific amino acid sequence, and wherein the amino acid sequences of the framework regions are encoded by a gene of the specific germ line or a gene thereof with a somatic mutation(s). Examples thereof include a specific VH encoded by the specific germline gene or a gene thereof with a somatic mutation(s), described in the disclosure with respect to the aforementioned CD19-specifically binding second branch. In addition, in the anti-CD19 monoclonal antibodies of Lanz Ln / Lznz / E / YiAi 144 the present invention, the examples of those which contain the respective CDRs in any of the VHs selected from the above-mentioned items (Id) to (5d), and in which the FR amino acid sequences thereof are encoded by a Specific germline gene or a gene thereof with a somatic mutation(s) include those having the VH comprising the amino acid sequence set forth in any selected one of SEQ ID NOs. 30 to 34. Furthermore, examples of such anti-CD19 monoclonal antibodies include those having an amino acid sequence of V H which is at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 98%, still more preferably at least 99% identity to the amino acid sequence set forth in any selected SEQ ID NOs. 30 to 34, and having CD19-binding activity that is substantially the same as that of the anti-CD19 monoclonal antibody having the original VH. In this document, the sentence that has CD19 binding activity that is substantially the same as that of the anti-CD19 monoclonal antibody having the original VH means that it has 95% or more, preferably 98% or more, and more preferably 99%. % or more of the CD19 binding activity relative to that of the anti-CD19 monoclonal antibody having the original VH. Also, other examples of antibodies LQH7 Ln / LZnZ / E / Yli Anti-CD19 monoclonals of the present invention also include (1) an anti-CD19 monoclonal antibody that cross-competes for binding to CD19 with an anti-CD19 monoclonal antibody having any of the VHs selected from the dots (Id) to (5d) mentioned above or the VH comprising the amino acid sequence set forth in any selected one of SEQ ID NOs. 30 to 34, and the VL of the common light chain of the present disclosure (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25), and (2) an anti-CD19 monoclonal antibody with which binding to CD19 cross-competes with an anti-CD19 monoclonal antibody having any of the VHs selected from (Id) to (5d) above or the VH comprising the amino acid sequence set forth in any of SEQ IDs Us. 30 to 34 and the same VL of the common light chain. Furthermore, other examples of the anti-CD19 monoclonal antibodies of the present invention also include those having the VH comprising the amino acid sequence in which glutamine at position 114 in the amino acid sequence set forth in any selected one of SEQ IDs NO. 30 to 34 was or may be substituted with arginine, and the VL of the common light chain of the present disclosure (preferably, the VL comprising the amino acid sequence set forth in SEQ ID NO. 25), LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 146 and are more preferably those having the VH comprising the amino acid sequence in which glutamine at position 114 in the amino acid sequence set forth in any of SEQ ID NO. 30 to 34 was substituted with arginine and the VL of the same common light chain, corresponding to anti-CD19 monoclonal antibodies having the VH comprising any of the amino acid sequences selected from SEQ ID NO. 62 to 66 and the same VL of the common light chain, respectively. Polynucleotide encoding the PD1 / CD19 bispecific antibody A polynucleotide encoding the PD-1 / CD19 bispecific antibody comprises: (1) a polynucleotide encoding the heavy chain having the first branch VH that specifically binds PD-1, (2) a polynucleotide encoding the heavy chain having the VH of the second branch that specifically binds to CD19, and (3) polynucleotides encoding common light chains. Here, the polynucleotide encoding the heavy chain having the VH of the first branch that specifically binds PD-1 comprises a polynucleotide encoding the VH of the first branch that specifically binds PD-1 and a polynucleotide encoding the VH of the first branch that specifically binds PD-1. heavy chain constant region having the same VH. Similarly, a polynucleotide encoding the heavy chain that has VH LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 147 of the second branch that specifically binds CD19 comprises a polynucleotide encoding the VH of the second branch that specifically binds CD19 and a polynucleotide encoding the constant region of the heavy chain having the same VH. The polynucleotide encoding the PD-1 / CD19 bispecific antibody may be any polynucleotide as long as it encodes the parts constituting the PD-1 / CD19 bispecific antibody, respectively, and may be any of genomic DNA, cDNA, synthetic DNA , RNA and a DNA-RNA hybrid. As codons coding for an amino acid, one to six types are already known. For example, Phe corresponds to TTT or TTC, Leu corresponds to TTA, TTG, CTT, CTC, CTA or CTG, lie corresponds to ATT, ATC or ATA, Met corresponds to ATG, Val corresponds to GTT, GTC, GTA or GTG, Ser corresponds to TCT, TCC, TCA or TCG, Pro corresponds to CCT, CCC, CCA or CCG, Thr corresponds to ACT, ACC, ACA or ACG, Ala corresponds to GCT, GCC, GCA or GCG, Tyr corresponds to TAT or TAC , His corresponds to CAT or CAC, Gln corresponds to CAA or CAG, Asn corresponds to AAT or AAC, Lys corresponds to AAA or AAG, Asp corresponds to GAT or GAC, Glu corresponds to GAA or GAG, Cys corresponds to TGT or TGC, Trp corresponds to TGG, Arg corresponds to CGT, CGC, CGA, or CGG, Ser corresponds to AGT or AGC, Arg corresponds to AGA or AGG, and Gly corresponds to GGT, GGC, GGA, or GGG, respectively. Therefore, the examples of the LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 148 polynucleotides encoding the PD-1 / CD19 bispecific antibody include a polynucleotide consisting of which each codon corresponding to each amino acid was arbitrarily combined. Preferable examples of the first branch VH-encoding polynucleotide that specifically binds PD-1 include the polynucleotide comprising the base sequence set forth in any selected one of SEQ ID NOs. 50 to 54 encoding the VHs of clones PD1-1 to PD1-5, respectively. Preferable examples of the second branch VH-encoding polynucleotide that specifically binds CD19 include a polynucleotide comprising the base sequence set forth in any selected one of SEQ ID NOs. 56 to 60 and SEQ ID NOs. 76 to 80 encoding the VHs of clones CD19-5, CD19-1, CD19-4, CD19-2 and CD19-3, respectively. Further, examples of the polynucleotide encoding the common light chain variable region include the polypeptide comprising the base sequence set forth in SEQ ID NO. 55. pharmaceutical use The PD-1 / CD19 bispecific antibody and the like of the present invention is useful for preventing, suppressing symptom progression, suppressing recurrence, and / or treating autoimmune diseases or graft-versus-host diseases (GVHD). LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 149 Examples of autoimmune diseases that can be prevented, of which the progression of symptoms can be suppressed, and / or that can be treated with the PD-1 / CD19 bispecific antibody or the like of the present invention include Behcet's disease, Systemic lupus erythematosus, chronic discoid lupus erythematosus, multiple sclerosis (systemic scleroderma and proqresive systemic sclerosis), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), aortitis syndrome (Takayasu's arteritis), malignant rheumatoid arthritis, arthritis rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, mixed connective tissue disease, Sjogren's syndrome, adult Still's disease, vasculitis, allergic granulomatous vasculitis, hypersensitivity vasculitis, rheumatoid vasculitis, large vessel vasculitis, ANCA-associated vasculitis (eg, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica, fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related disease (for example, primary sclerosing cholangitis and autoimmune insulitis, etc. .), Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, nonalcoholic steatohepatitis, primary biliary cirrhosis, Goodpasture syndrome, glomerulonephritis of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 150 rapidly progressing, megaloblastic anemia, autoimmune hemolytic anemia, pernicious anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow's disease (Graves' disease (hyperthyroidism)), Hashimoto's disease, autoimmune adrenal insufficiency, primary hypothyroidism, Addison's disease (chronic hypoadrenocorticism ), idiopathic Addison's disease, type I diabetes mellitus, slowly progressive type I diabetes mellitus (latent autoimmune diabetes in adults), localized scleroderma, psoriasis, psoriatic arthritis, bullous pemphigoid, pemphigus, pemphigoid, herpes gestationis, linear IgA bullous dermatosis , epidermolysis bullosa acquisita, alopecia areata, vitiligo, vitiligo vulgaris, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, sarcoidosis, giant cell arteritis, amyotrophic lateral sclerosis, Harada's disease, autoimmune optic neuropathy, idiopathic azoospermia, habitual abortion, inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), celiac disease, ankylosing spondylitis, severe asthma, chronic urticaria, transplant immunity, familial Mediterranean fever, chronic eosinophilic rhinosinusitis, dilated cardiomyopathy, systemic mastocytosis, inclusion body myositis and the like. LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ In the present invention, the term treat 151 means to cure or improve a certain disease or symptom thereof. The term prevent means that the occurrence of a certain disease or symptom thereof is prevented or delayed for a certain period of time. The term "suppressing the progression of symptoms" means that the progress or aggravation of symptoms is suppressed to arrest the progress of the diseases. The meaning of preventing also includes suppressing recurrence. The term suppress recurrence means that the recurrence of a certain disease or syndrome thereof is prevented or the possibility of recurrence is reduced. Furthermore, another embodiment of the PD-1 / CD19 bispecific antibody and the like of the present invention is useful for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating diseases mediated by autoreactive B cells. Examples of B-cell mediated autoreactive diseases include systemic lupus erythematosus, Graves' disease, myasthenia gravis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, asthma, cryoglobulinemia, primary biliary sclerosis, pernicious anemia, and the like. In the same pharmaceutical use, the PD-1 / CD19 bispecific antibody or the like of the present invention acts through suppressive effects against autoreactive B cells. Here, examples of suppressive effects against autoreactive B cells include the effects Lanz Ln / Lznz / E / YiAi 152 suppressors against immunoglobulin production such as IgG and IgM. In addition, the PD-1 / CD19 bispecific antibody or the like of the present invention has suppressive effects against activation of memory T cells. Here, examples of suppressive effects against memory T cell activation include suppressive effects against cytokine production. The PD-1 / CD19 bispecific antibody or the like of the present invention is usually administered systemically or locally by parenteral administration. Specific examples of such administration methods include administration by injection, intranasal administration, transpulmonary administration, percutaneous administration, and the like. Examples of administration by injection include intravenous injection, intramuscular injection, intraperitoneal injection and the like. For intravenous injection, intravenous drip infusion is preferable. The dose thereof varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment period and the like. The single dose thereof for an adult patient is usually within a range of 0.1 pg / kg to 300 mg / kg, particularly preferably, within a range of 0.1 mg / kg to 10 mg / kg, from one to several times a day by parenteral administration, or within an interval of 30 LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 153 minutes to 24 hours per day by intravenous maintenance administration. It goes without saying that, as mentioned above, since the dosage varies depending on various conditions, it may be less than the above-mentioned dosage, or it may need to be higher than the above. Formulation When the PD-1 / CD19 bispecific antibody or the like of the present invention is formulated to be used as an injection or infusion solution for drip infusion, the injection or infusion solution may be in any form of a solution, suspension, or aqueous emulsion, or it can be formulated as a solid agent together with a pharmaceutically acceptable carrier so that it dissolves, suspends or emulsifies by adding a solvent at the time of use. Examples of solvents that can be used in the injection or infusion solution for drip infusion include distilled water for injection, a physiological saline solution, a glucose solution and an isotonic solution and the like (for example, solutions in which sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, propylene glycol or the like) . Herein, examples of pharmaceutically acceptable carriers include a stabilizer, a solubilizing suspending agent, an emulsifier, a Lanz Ln / Lznz / E / YiAi 154 soothing agent, a buffering agent, a preservative, an antiseptic agent, a pH adjuster, an antioxidant and the like. As a stabilizer, for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, can be used. dibutylhydroxytoluene or the like. As a solubilizer, for example, an alcohol (for example, ethanol, etc.), a polyol (for example, propylene glycol and polyethylene glycol, etc.), a nonionic surfactant (for example, Polysorbate 20 (Trademark ), Polysorbate 80 (registered trademark) and HCO-50, etc.) or the like. As a suspending agent, for example, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate or the like can be used. As an emulsifier, for example, gum arabic, sodium alginate, tragacanth or the like can be used. As a calming agent, for example, benzyl alcohol, chlorobutanol, sorbitol or the like can be used. As a buffering agent, for example, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 155 glutamic acid buffer, an epsilon aminocaproic acid buffer or the like. As a preservative, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, borax or the like can be used. As an antiseptic agent, for example, benzalkonium chloride, parahydroxybenzoic acid, chlorobutanol or the like can be used. As a pH adjuster, for example, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid or the like can be used. As an antioxidant, for example, (1) aqueous antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite, (2) oil-soluble antioxidants such as ascorbyl palmitate, hydroxyanisole can be used. butylated, butylated hydroxytoluene, lecithin, propyl gallate, and α-tocopherol, and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, and phosphoric acid. The injection or infusion solution for drip infusion can be produced by performing sterilization in the final process, or sterilization by aseptic handling, for example, sterilization by filtration with a filter or LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ 156 similar and later filling it in an aseptic container. The solution for injection or infusion for drip infusion can be used by dissolving the lyophilized or vacuum-dried aseptic powder (which may include a pharmaceutically acceptable carrier powder) in an appropriate solvent at the time of use. Combined use or combined formulation In addition, the PD-1 / CD19 bispecific antibody and the like of the present invention can be used in combination with other agents that are used to prevent, suppress symptom progression, suppress recurrence, and / or treat autoimmune diseases. In the present invention, examples of dosage forms in use in combination with other agents (combined use) may include a combined formulation form that contains both ingredients in one formulation and a form that is administered in separate formulations. Such combined uses may complement the effects on prevention, suppression of symptom progression, suppression of recurrence, and / or treatment of other agents, or may maintain or reduce the dose or frequency of administration of other agents. When the PD-1 / CD19 bispecific antibody or the like of the present invention and other agents are administered separately, they may be administered simultaneously for a certain period of time, and then only the PD-1 / CD19 bispecific antibody or the like or others. LQH7 Ln / LZnZ / E / Yli 157 agents, can be managed. Alternatively, the PD-1 / CD19 bispecific antibody or the like of the present invention may be administered initially, and after completion of the administration thereof, other agents may be administered. Other agents may be initially administered, and after completion of the administration thereof, the PD1 / CD19 bispecific antibody or the like of the present invention may be administered. The respective administration methods may be the same or different from each other. A kit containing a formulation containing the PD1 / CD19 bispecific antibody or the like of the present invention and a formulation containing other agents may also be provided. Herein, doses of other agents may be appropriately selected based on the dose in clinical use. In addition, other agents can be administered in combination of two or more kinds of arbitrary agents in an appropriate ratio. Furthermore, examples of other agents include not only those already known, but also those to be discovered in the future. For example, when the PD-1 / CD19 bispecific antibody or the like of the present invention is applied to prevent, suppress progression of symptoms or recurrence and / or treat type I diabetes mellitus, it may be used in combination with one or more than the selected agents of an insulin preparation (for example, LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 158 insulin human, insulin glargine, insulin lispro, insulin detemir, and insulin aspart, etc.), a sulfonylurea agent (for example, glibenclamide, gliclazide, and glimepiride, etc.), a rapid-acting insulin secretion promoter (for example, nateglinide, etc.), a biguanide preparation (eg, metformin, etc.), an insulin resistance-improving agent (eg, pioglitazone, etc.), an α-glucosidase inhibitor (eg, example, acarbose and voglibose, etc.), a therapeutic agent for diabetic neuropathy (for example, epalrestat, mexiletine and imidapril, etc.), the preparation of GLP-1 analogues (for example, liraglutide, exenatide and lixisenatide, etc. .) and a DPP-4 inhibitor (for example, sitagliptin, vildagliptin and alogliptin, etc.) and the like. Further, for example, when the PD-1 / CD19 bispecific antibody or the like of the present invention is applied to prevent, suppress progression of symptoms or recurrence and / or treat multiple sclerosis, it may be used in combination with any or more than agents selected from a spheroidal agent (for example, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, butyl acetate, and prednisolone, prednisolone sodium acetate, Lanz Ln / Lznz / E / YiAi 159 methylpredrocortisone, methylprednisolone acetate, methylprednisolone sodium succinate, triamsinolone, triamsinolone acetate, triamsinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone betamethasone acetate, etc.), interferon β -la, interferon β-la, glatiramer acetate, mitoxantrone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, cladribine, adrenocorticotropic hormone (ACTH), corticotropin, mizoribine, tacrolimus, fingolimod, alemtuzumab and the like. In addition, for example, when the PD-1 / CD19 bispecific antibody or the like of the present invention is applied to prevent, suppress progression of symptoms or recurrence and / or treat systemic lupus erythematosus, it may be used in combination with any or more of agents selected from a spheroidal agent (eg, the spheroidal agents mentioned above), an immunosuppressive agent (eg, cyclosporine, tacrolimus, and fingolimod, etc.), and belimumab. For example, when the PD-1 / CD19 bispecific antibody or the like of the present invention is applied to prevent, suppress symptom progression or recurrence and / or treat rheumatoid arthritis, it may be used in combination with any one or more of agents selected from a spheroidal agent (for example, the spheroidal agents LQH7 ίΩ / ίΖΩΖ / Ε / ΥΙ 160 mentioned above), an antirheumatic agent (for example, methotrexate, sulfasalazine, bucillamine, leflunomide, mizoribine and tacrolimus, etc.), an anticytokine agent (for example, infliximab, adalimumab, tocilizumab, etanercept, golimumab and certolizumab, etc.) , abatacept and the like. When applied to prevent, suppress symptom progression or recurrence of and / or treat other autoimmune diseases, the PD1 / CD19 bispecific antibody or the like of the present invention may be used in combination with one or more of the other agents mentioned above. . The present invention will now be described in more detail by the following examples, but the scope of the present invention is not limited thereto. A person skilled in the art can make various changes and modifications based on the description of the present invention, and such changes and modifications are also included in the present invention. examples Example 1: Immunization of MeMo (Trademark) Mice Using a Recombinant Human PD-1-Fe Fusion Protein As a method for obtaining the first PD-1 specifically binding branch of the present invention, a method for immunizing MeMo mice (brand LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 161 registered) (see WO2009 / 157771) with a recombinant human PD-1 protein. MeMo (registered trademark) mice are those genetically modified such that a gene fragment containing a non-recombinant human V heavy chain gene region, a D gene region, and a J gene region, as well as the The recombinant human κ light chain IgVK1-39*01 / IGJkI*01 germline gene has been linked to a mouse constant region gene. By directly immunizing them with a target protein for the antibody, antibodies composed of common heavy chains and light chains, with diversity, can be produced. With a recombinant human PD-1-Fc fusion protein (R&D Systems, serial number 1086-PD) emulsified using a Gerbu MM adjuvant (Gerbu Biotechnik, serial number #3001), MeMo (trademark) mice were immunized. from 12 to 16 weeks of age at an interval of 14 days. On days 0, 14 and 28 after immunization, recombinant human PD-1-Fc fusion protein was administered subcutaneously, and subsequently, recombinant human PD-1-Fc fusion protein dissolved in PBS was administered subcutaneously. On days 21, 35, 56, 77, and 98 post-immunization, serum antibody concentration was assessed by flow cytometry using HEK293 strained T-cell lines with LQnZ Ln / Lznz / Ε / ΥΙΛΙ 162 Human PD-1. When HEK293T cell lines forcefully expressed with human PD-1 were stained in 1000-fold diluted serum, mouse lymphatic tissues whose MFI value increased more than three-fold compared with that of HEK293T cell lines not expressing PD-1. 1 human as a control, were used to construct a phage display library. Mice meeting the criteria for library construction were further immunized with recombinant PD-1-Fc fusion protein for three days from the antibody titer assessment date, and from which spleens and cells were harvested. inguinal lymph nodes. Spleens and radial lymph nodes were also collected from mice in which the serum antibody concentration against human PD-1 and cynomolgus monkey PD-1 was 1 / 100 or more, and the antibody concentration was not increased by immunization. additional. RNA was extracted from these lymphoid tissues and cDNA synthesis was then carried out. Example 2: Construction of a phage display library to obtain an anti-PD-1 antibody (protein immunization) Using the DNA prepared in Example 1 and primers specific for the immunoglobulin heavy chain variable region family, the PCR reaction was carried out. LQH7 Ln / LZnZ / E / Yli 163 The obtained PCR products were digested with the restriction enzymes Sfil and Xhol, and inserted into the phagemid vector [having the gene (germline human κ light chain IgVKl39*01 / IGJkI*01 gene) encoding the common light chain] digested with the same restriction enzymes to construct the library. Example 3: Detection of anti-PD-1 antibodies Using plates coated with human PD-1-Fc fusion protein, human PD-1-His tag fusion protein, cynomolgus monkey PD-1-His tag fusion protein, or PD fusion protein mouse -l-His tag, phage selection based on PD1 binding property was performed. When using human PD-1-Fc fusion protein, during incubation with a phage, human IgG (SIGMA, serial number 14506) was added to it to absorb Fe-reactive clones. Binding phage were enriched for capable of binding to human PD-1, cynomolgus monkey PD-1 and mouse PD-1. Using selections on the cynomolgus PD-1 forced expression HEK293 T cell lines, phage capable of binding cynomolgus PD-1 were enriched for. Escherichia coli strain TG1 clones transformed with the phages obtained by selection were obtained to produce a master plate. Furthermore, based on the PD-1 binding property in a plate on which the PD-1 fusion protein was adsorbed Lanz Ln / Lznz / E / YiAi 164 Fe human, phage selection of periplasmic space extracts of the clones obtained by the aforementioned selection was carried out. Note here that as a selection criterion, clones with signals three times greater than the signal (OD450 value) in a negative control well (PBS) were defined as positive clones. Example 4: DNA sequencing candidate clones for anti-PD-1 antibodies DNA sequencing was carried out for the heavy chain variable region genes of the positive clones obtained by selection in Example 3. The analyzed DNA sequences were classified into supergroups (a group having the same length as the heavy chain CDR3, in which an amino acid sequence of the same CDR3 is 70% or more homologous to each other) and groups (a group in which the amino acid sequences of the heavy chain CDR3 are the same). Hundreds of clones were obtained, which were classified into supergroups and groups. Example 5: Selection based on the evaluation of the binding property to cells expressing PD-1 From the respective sorted supergroups, anti-PD-1 monoclonal antibody clones meeting the following conditions were selected and isolated: (1) have somatic mutations in the CDRs with high LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 165 frequency, (2) having a very commonly used VH germline gene, and (3) having a high signal in selection based on the binding property to human PD-1-Fc fusion protein. Using the Fab fragments contained in these periplasmic spatial extracts, the binding properties to the human PD-1 forced expression CHO-S cell line and the monkey PD-1 forced expression CHO-S cell line were evaluated. cynomolgus by detection with anti-mouse IgG polyclonal antibodies. Among the 117 clones tested (105 cluster types), in 22 clones, including anti-PD1 monoclonal antibody clones PD1-1, PD1-2, PD1-3, and PD1-4, binding to the CHO-S cell line expressing human PD-1. Example 6: Preparation of amino acid substituted products of the anti-PD-1 monoclonal antibody Clones PD1-1 and PD1-4 contain deamidation portions (Asn-Gly) in the framework 4 region of their heavy chain variable region, respectively. To obtain a PD-1 branch with reduced risk of deamidation, a variant was produced in which the deamidation moieties have been converted. Asparagine (Asn) at position 119 according to the EU numbering system for clone PD14 was altered to glutamine by a mutation method LQH7 Ln / LZnZ / E / Yli 166 specific at the well-known site, to prepare and isolate the clone PD1-5. The binding property to human PD-1 forced expression CHO-S cells of this clone was the same as that of clone PD1-4. Example 7: Immunization to MeMo (registered trademark) using the plasmid vector expressing CD19 As a method for obtaining the second branch specifically binding to CD19 of the present invention, a method of immunizing MeMo (registered trademark) mice (see WO2009 / 157771) with plasmid vectors expressing human CD19 and plasmid vectors expressing human CD19 was selected. express cynomolgus monkey CD19. MeMo (registered trademark) mice are those genetically modified such that a gene fragment containing a non-recombinant human V heavy chain gene region, a D gene region and a J gene region, and a Germline recombinant human κ light chain IgVxl-39*01 / IGJkI*01 has been linked to a mouse constant region gene. By directly immunizing them with plasmid vectors expressing a target protein for the antibody, antibodies composed of common heavy chains and light chains, with diversity, can be produced. With human CD19-expressing plasmid vectors and / or cynomolgus monkey CD19-expressing plasmid vectors, LQH7 ίΩ / ίΖΩ7 / Ε / ΥΙ 167 MeMo (trademark) mice of 12 to 16 weeks of age respectively or alternatively were immunized. On days 0, 3, 6, 14, 17, 28, 31, 42, 49, 63 and / or 70 after immunization, the expression plasmid vectors were administered. The concentration of antibodies in the serum was assessed by flow cytometry using human CD19-expressing cell lines. When human CD19-expressing cell lines were stained in the 100-fold diluted serum, mouse lymphatic tissues whose MFI value increased more than three times higher than that of cell lines not expressing human CD19 were used as a control to construct a sample. phage display library. Mice meeting the criteria for constructing the library construct were further immunized, and from which spleens and inguinal lymph nodes were harvested. RNA was extracted from these lymphoid tissues and cDNA synthesis was then carried out by reverse transcription reaction using IgG constant region-specific primers. Example 8: Construction of a phage display library to obtain an anti-CD19 antibody Using the DNA prepared in Example 7 and primers specific for the immunoglobulin heavy chain variable region family, the PCR reaction was carried out. The PCR products obtained were digested with enzymes of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 168 restriction and inserted into a digested phagemid vector [having the gene (human κ light chain IgVxl-39*01 / IGJkI*01 germline gene) encoding the common light chain] digested with the same enzymes as constraint to build the library. Example 9: Selection of anti-CD19 antibodies Using human CD19-Fc fusion protein (R&D systems, serial number 9269-CD), cynomolgus monkey CD19Fc fusion protein (NovoPro Bioscience, serial number 504385), Raji's human B-cell lines or the Cynomolgus monkey CD19 forced expression HEK293T cell lines, phage selection based on CD19 binding property was performed. Escherichia coli strain TG1 clones transformed with the phages obtained by selection were obtained to produce a master plate. Note here that as a criterion for selection, clones with signals more than three times greater than the signal (OD450 or MFI value) obtained by a negative control were defined as positive clones. Example 10: DNA sequencing for anti-CD19 antibody candidate clones DNA sequencing for the heavy chain variable region gene of the positive clones obtained by the selection in Example 9 was carried out. The analyzed DNA sequences were classified into supergroups. LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 169 (a group of which the length of the CDR3 heavy chain is the same and the amino acid sequence of the heavy chain variable region is 70% or more mutually homologous) and groups (a group of which the amino acid sequences of the variable region of the heavy chain and the CDR3 of the heavy chain are mutually the same, respectively). In the first selection, hundreds of clones were obtained, which were classified into super groups, groups and 4 types of germ lines. In the second selection, hundreds of clones were obtained, which were classified into super groups, groups and 8 types of germ lines. There are 19 types of supergroups different from those of the first selection. Example 11: Selection based on the evaluation of the binding property to CD19 From the respective sorted supergroups, anti-CD19 monoclonal antibody clones meeting the following conditions were selected and isolated: (1) having somatic CDR mutations with high frequency, (2) having a very frequently used germline VH gene, and (3) having a high signal in selection based on the CD19-binding property. Using the Fab fragments contained in these periplasmic space extracts, the property of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 170 binding to CD19. It was confirmed that among the clones tested, several clones including CD19-1, CD19-2, CD19-3, CD19-4 and CD19-5 anti-CD19 monoclonal antibody clones can bind to the human CD19-expressing cell line. Example 12: Preparation of the PD1 / CD19 bispecific antibody Expression vectors expressing the respective first branch heavy chains that specifically bind to PD-1 were prepared by joining the DNAs encoding the respective heavy chain variable regions of the monoclonal antibody clones PD1-1 to PD1-5 from anti-PD-1 selected in examples 5 and 6, to the DNAs encoding the constant region of the IgGi heavy chain, respectively. On the other hand, expression vectors expressing the respective second branch heavy chains that specifically bind to CD19 were prepared by ligating the DNAs encoding the respective heavy chain variable regions of the CD19-1 to CD19- monoclonal antibody clones. 5 anti-CD19 selected in example 11, to the DNAs encoding the constant region of the IgGi heavy chain, respectively. In this document, since the gue genes express the constant region of the heavy chain, as for the first branch that specifically binds PD-1, a gene expressing the Fe region having a LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 171 L351D / L368E variation (DE variation), and as for the second branch that specifically binds to CD19, a qen expressing the Fe region having L351K / T366K variation (KK variation) was used. These expression vectors were constructed to further contain a gene encoding the IGVK1-39 / JK1 common light chain so that they will be co-expressed. In addition, to eliminate the effector activity of Fe, genes expressing these heavy chain constant regions were modified to express as those in which the leucine at position 235 was replaced with glycine and the additional glycine at position 236 was replaced with arginine in the constant region of the heavy chain and, in addition, to avoid post-translational processing, those modified for expression such as those in which lysine was removed at position 447 at the C-terminus of the region were used. heavy chain constant. Both expression vectors were genetically transferred into Free Style 293F cells to produce antibodies in culture supernatants. Culture supernatants were collected and then treated by protein A affinity chromatography, to purify clones CD19-1(Bi), CD19-2(Bi), CD193(Bi), CD19-4(Bi) and CD19. -5(Bi) as the PD-1 / CD19 bispecific antibody of the present invention, respectively. Note here that, having the second branches specifically binding to CD19 derived from Lanz Ln / Lznz / E / YiAi 172 anti-CD19 monoclonal antibody clones CD19-1, CD19-2, CD19-3, CD19-4 and CD19-5, used in their preparation, these PD-1 / CD19 bispecific monoclonal antibody clones correspond to the clones of antiPD-1 monoclonal antibodies, respectively. All of these PD-1 / CD19 bispecific antibody clones have the first branch that specifically binds to PD-1, derived from clone PD1-5. Example 13: Preparations of the anti-CD19 monoclonal antibody variants and PD1 / CD19 bispecific antibodies thereof The possibility exists that the PD-1 / CD19 bispecific antibody clones prepared in Example 12 may not be sufficiently separated or purified from the first branch-heavy chain / light chain complexes, from the second branch-heavy chain complex. / light chain and / or the respective homodimers consisting of them, as by-products. Therefore, in order to improve the separation of the bispecific antibody from those by-products in purification by cation exchange chromatography, amino acid variants of the anti-CD19 monoclonal antibodies were prepared in which the isoelectric point was increased. A variant of which glutamine at position 114 in SEQ ID NO. 30 representing the VH amino acid sequence of clone CD19-5 was substituted with arginine LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 173 by a known method of site-directed mutagenesis. In the present invention, the variant was named CD19-6. The isoelectric points of the antibodies were calculated using Genetyx (Genetics Inc.), a software for gene and amino acid sequence analysis. Furthermore, the respective variants having the forms in which glycine and the peptides represented by SEQ ID NOs. 67 to 70 were added to the C-terminus of the heavy chain having the VH of CD19-6 (hereinafter, collectively referred to as GDI 9-6 / C-terminal peptide adduct), respectively, were prepared by a genetic modification technique. known. In the present invention, the variant having the form in which the peptide represented by SEQ ID NO. 67 was added to the C-terminus of CD19-6 and was designated CD19-7. According to the same method as in example 12, the respective expression vectors described in the same example into which the respective DNAs encoding the variants of these anti-CD19 monoclonal antibodies and a DNA encoding the clone PD1-5 were inserted, respectively, were transferred by a gene into Free Style 293F cells to produce antibodies in the culture supernatant. The culture supernatants were collected and treated by protein A affinity chromatography to purify the bispecific antibodies of the present invention, derived LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ 174 of the respective variants prepared in this example, respectively. Among these bispecific antibodies, the CD19-6-derived bispecific antibody clone was named GDI 9-6(Bi), and the CD19-7-derived bispecific antibody clone was named GDI9-7(Bi). Example 14: Purification and separation of the PD-1 / CD19 bispecific antibody and its by-products Success and failure in the purification and separation of by-products that might be generated during the productions of the PD-1 / CD19 bispecific antibodies prepared in Examples 12 and 13, respectively, were verified. Culture supernatants containing the same bispecific antibodies collected in Examples 12 and 13, respectively, were processed separately by protein A affinity chromatography and size exclusion chromatography to purify the same bispecific antibodies, and the anti- -PD-1 and anti-CD19 antibody corresponding to the by-products, respectively. Solvents containing these respective purified antibodies were replaced in ultrafiltration buffer to have a pH of 6.0. The respective antibodies purified after buffer replacement were applied to a column of LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ cation exchange TSKgel SP-STAT Column (Tosoh, model 175 number 0021964) equilibrated with buffer solution A (pH 7.0). The respective purified antibodies bound to the column were eluted by a salt gradient using buffer B (pH 7.0) containing 1 mol / 1 sodium chloride. The mobile phase flow rate was 0.5 mL / min, and elution was performed with a linear gradient from buffer A to buffer B. A ratio of 0% buffer B was set from 0 to 10 minutes after the start of the application of the respective purified antibodies, and then linearly increased from 0 to 100% from 10 to 40 minutes, and set to 100% from 40 to 50 minutes. The retention times (minutes) in the cation exchange chromatography of the clones CD19-2 (Isoelectric Bump: 8.32), CD19-6 (Ip: 8.49) and CD19-7 (Ip: 8.75) were 15,167, 15,749 and 17,521, respectively, and those of clones CD19-6 and CD19-7 were elongated, respectively. On the other hand, the clones PD1-3 (Ip: 7.67) and PD1-5 (Ip: 7.52) did not bind to the cation exchange column and were eluted from it. On the other hand, the clones of the bispecific antibodies CD19-2(Bi) and CD19-2(Bi) of PD-1 / CD19 did not bind to the cation exchange column, and were eluted from it, but the times of retention (minutes) of clones CD19-6(Bi) and CD19-7(Bi) were 13,715 and 14,955, LQH7 Ln / LZnZ / E / Yli 176 respectively. As described above, by increasing the isoelectric point by an amino acid substitution in the second branch or the addition of a specific peptide at the C-terminus of the heavy chain thereof, the separation of the bispecific antibody of the present invention as a Targeting of anti-PD-1 antibody and anti-CD19 antibody as by-products in purification by cation exchange chromatography was improved, which made it possible to provide the bispecific antibody of the present invention in which the contamination of their by-products was extremely reduced. . Example 15: Evaluation of the binding property of the PD-1 / CD19 bispecific antibody By the Biacore assay using human IgGl-Fc fused extracellular recombinant protein of human PD-1 (R&D systems, serial number 1086-PD), the binding affinities to the recombinant protein of PD-1 of the first branch of the PD-1 / CD19 bispecific monoclonal antibodies obtained in Examples 12 and 13, respectively. Note here that for immobilization of the recombinant proteins, the CM5 sensor chip of the S Series sensor chips (GE Health Care, serial number 29-1049-88) was used. Similarly, using the Biacore assay that LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 177 uses the extracellular recombinant protein CD19 fused with human IgGl-Fc (R&D systems, serial number 9269-CD), the CD19 binding affinities of the second branch of the same antibodies were evaluated, respectively. Figure 11 shows the binding affinities (Kd value) to PD1 of the first branch and the CD19 binding affinities of the second branch with respect to the respective clones. It was confirmed that the PD-1 and CD19 binding affinities of CD19-6(Bi) were improved, respectively, compared to those of CD19-5(Bi) without the amino acid substitution in Example 13. Example 16: Verification of the binding property of the PD-1 / CD19 bispecific antibody The PD1 / CD19 bispecific antibodies obtained in Examples 12 and 13 were verified to specifically bind to human PD-1, cynomolgus monkey PD-1, human CD19, and cynomolgus CD19, respectively. Clones CD19-1(Bi) through CD19-6(Bi) were added to human PD-1 stress-forming CHO-S cell lines, cynomolgus monkey PD-1 stress-forming CHO-S cell lines, CHO-S cell lines, human CD19-forced CHO-K1 cell lines, cynomolgus CD19-forced CHO-K1 cell lines, and CHO-K1 cell lines, respectively, and incubated on ice for 20 minutes. After washing these cells, they Lanz Ln / Lznz / E / YiAi 178 added 100 μΐ of PE-labeled goat anti-human IgGFc F(ab')2 fragment antibody (ThermoFisher, serial number H10104) and incubated on ice for 20 minutes. After washing these cells, the PD-1 binding property of the first branch and the CD19 binding property of the second branch of these antibodies were evaluated by flow cytometry, respectively. Figures 12 to 16 show the results thereof in this test. All clones bind to human PD-1, cynomolgus monkey PD-1, human CD19, and cynomolgus CD19. Note here that no non-specific binding was detected in this binding system. The PD-1 / CD19 bispecific monoclonal antibodies obtained in Example 12 were verified to specifically bind to PD-1 and CD19 simultaneously, respectively. Initially, clones CD19-1(Bi) to CD195(Bi) were added to human CD19 forced expression CHO-K1 cell lines and CHO-K1 cell lines, respectively, and incubated on ice for 20 minutes. After washing these cells, 100 μΐ of the recombinant protein of the extracellular region of human PD-1 fused with 6 x His tag (R&D systems, serial number 8986-PD) was added and incubated on ice for 20 minutes. After washing these cells, 100 μΐ of Alexa Fluor 488-labeled mouse anti-His tag antibody (MBL, LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 179 serial number D291-A48) and incubated on ice for 20 minutes. After washing these cells, the amounts of PD-1 extracellular region recombinant protein binding were assessed by flow cytometry. Figure 17 shows the results thereof in this test. All clones bound to PD-1 and CD19 simultaneously. Note here that no non-specific binding was detected in this binding system. Example 17: Evaluation of the binding property of the first branch of the PD-1 / CD19 bispecific antibody To evaluate the effects on the PD1 / PD-L1 interaction of the first arms of the PD-1 / CD19 bispecific antibodies obtained in Example 12, a competitive binding assay was performed with respect to the binding to PD-1 of the same bispecific antibody clones and soluble PD-L1 recombinant proteins. Initially, the clones CD19l(Bi) to CD19-5(Bi), nivolumab and the human anti-PD-1 antibody J105 (Immunology Letters, 2002, volume 83, issue 3, pages 215-220) were added to the lines. human BD-1 forced expression CHO-S cells on ice, respectively. In addition, soluble PD-L1 recombinant proteins (R&D systems, serial number 156-B7) labeled with biotin were added on ice using the biotin labeling kit (Dojin, serial number LK03). After washing these cells, APC-labeled streptavidin (BioLegend, serial number 405207) was added on ice. After LQH7 Ln / LZnZ / E / Yli After washing these cells, the amounts of binding of soluble PD-L1 recombinant proteins were assessed by flow cytometry. Figure 18 shows the results thereof in this test. Clones CD19-1(Bi) to CD19-5(Bi) allowed the binding of soluble PD-L1 recombinant protein to PD-1. On the other hand, Nivolumab and J105 completely inhibited the binding of soluble PD-L1 recombinant protein to PD-1 under the same conditions. It was shown by the same evaluation that bispecific antibodies having anti-PD-1 monoclonal antibody clones PD1-1 to PD1-4 obtained in Example 5 as the first branch, respectively, also allowed protein binding. recombinant soluble PD-L1 to PD-1. Example 18: In Vitro Suppressive Effects of PD-1 / CD19 Bispecific Antibody Against Activated B Cells Suppressive effects against human IgM production were evaluated using B cells isolated from healthy human peripheral blood mononuclear cells (LONZA, model number CC-2702) by B-Cell Isolation Kit II, human (Miltenyi Biotec, model number serial number 130-091151). Human B cells were seeded in cell culture plates and the anti-human anti-CD79B antibody (LifeSpan Biosciences, serial number LS-C134648), the LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 181 recombinant human CD40L protein (Enzo Life Sciences, serial number ALX-522-110) and recombinant human IL-21 protein (R&D systems, serial number 8879-IL) to perform the activation treatment. The clones CD19-1(Bi) to CD19-5(Bi) or the control antibody were added thereto, and the IgM contained in the culture supernatant after the activation treatment was quantified by ELISA (ThermoFisher, serial no. BMS 2098). Figure 19 shows the results thereof. All clones CD19-1(Bi) to CD195(Bi) suppressed IgM production. Note here that an amount of IgM production (pg / ml) in the figure is represented as the mean value ± the standard error (N = 4). Example 19: In Vivo Suppressive Effects of PD-1 / CD19 Bispecific Antibody Against Activated B Cells Suppressive effects against human IgG2 production were evaluated using NOD.Cg-PrkdcscidI12 rgtmlWjl / SzJ mice (hereinafter abbreviated as NSG mice) transplanted with peripheral blood mononuclear cells derived from healthy individuals (LONZA, number serial number CC-2702) . 1 x 107 peripheral blood mononuclear cells derived from healthy individuals were transplanted per NSG mouse. On days 3, 7, 10, 14 and 17 after transplantation, 3 mg / kg / day of clones CD19-1(Bi) to CD19-4(Bi) or control antibody were administered intraperitoneally once a day, respectively. Blood was collected from the vein of the Lanz Ln / Lznz / E / YiAi 182 glue on day 21 after transplantation to prepare the serum. On the other hand, clones CD19-5(Bi) and CD19-6(Bi) were administered intraperitoneally on days 3, 7 and 10 after transplantation at the same dose, respectively. At this time, a control antibody was also administered intraperitoneally in parallel. Tail vein blood was collected on day 14 after transplantation to prepare serum. The human IgG2 contained in the serum was quantified by ELISA (ThermoFisher, serial number BMS 2093). Figures 20 and 21 show their results. All clones CD19-1(Bi) to CD19-4(Bi) suppressed IgG2 production. Note here that a production amount of IgG2(pg / ml) in the figures is represented as the mean value ± the standard error (N = 4-8). Example 20: Evaluation of the cross-competitive property for binding to PD-1 of the bispecific antibody of PD-1 / CD19 A cross-competition assay was performed to evaluate the cross-competitive properties for PD-1 binding of bispecific antibodies having the respective clones PD1-1 to PD1-5 as the first branch, which are the PD-1 antibodies used for produce PD-1 / CD19 bispecific antibodies. Initially, the bispecific antibody having the clone PD1-5 as the first branch was added to the CHO-S line cells expressing human PD-1 on ice. Besides, LQH7 ίΩ / ίΖΩΖ / Ε / ΥΙ 183 biotinylated bispecific monoclonal antibodies having clones PD1-1 to PD1-5 as the first branch, respectively, were added thereto, respectively, and then incubated on ice. After washing these cells, PE-labeled streptavidin (BD Pharmingen, serial number 554061) was added and incubated on ice. After washing these cells, the amounts of binding of these biotinylated antibodies were measured using flow cytometry. It was shown that the bispecific antibody that has the clone PD1-5 as the first branch can inhibit the binding to PD-1 of the same antibodies that have the clones PD1-1 to PD1-4 as the first branch, respectively, and therefore can cross-compete with these for binding to PD-1. Example 21: Evaluation of the in vitro effects of the PD-1 / CD19 bispecific antibody against the release of cytokines from human peripheral blood mononuclear cells In order to analyze the cytokine-releasing activity of the PD-1 / CD19 bispecific antibody, the experiment was carried out in which the bispecific antibody of the present invention or the mouse anti-human CD3 antibody OKT3 (BioLegend, serial number 317304) are added to human peripheral blood mononuclear cells (hereinafter referred to as human PBMCs), respectively. Clone CD19-6(Bi) and OKT3 were added to PBMCs. LQH7 Ln / ίΖΠΖ / Β / ΥΙΛΙ 184 human (LONZA, serial number CC-2702), which were then cultured. IL-2 contained in culture supernatants was quantified by flow cytometry using the Cytometric Bead Array (BD Biosciences, serial number 551809). Figure 25 shows the results thereof. Note here that a production amount of IL-2 (pg / ml) in the figure is represented by the mean value ± standard error (N = 3). OKT3 markedly induced IL-2 production, but no IL-2 production was detected relative to CD19-6(Bi). Example 22: Evaluation of the physicochemical stability of the PD-1 / CD19 bispecific antibody It was confirmed that the PD1 / CD19 bispecific antibody of the present invention performs well in any of the physicochemical stability evaluations, including structural stability in differential scanning calorimetry (DSC) measurement, colloidal stability in diffusion coefficient change (DLS) and chemical stability (for example, change in protein concentration, change in molecular structure, presence or absence of association / aggregation, presence or absence of charge variant generation, structure change, CD19 binding activity) under stress conditions (eg, at pH 3 to 4y5°C or at pH 7.5°C and five freeze-thaw cycles). LQH7 ίΩ / ί7Ω7 / Ε / ΥΙ 185 Industry Applicability The PD-1 / CD19 bispecific antibody or an antibody fragment thereof of the present invention is useful for preventing, suppressing symptom progression, suppressing recurrence, and / or treating autoimmune diseases or graft-versus-host diseases (GVHD). . It is noted that as of this date, the best method known to the applicant for putting said invention into practice is the one that is clear from the present description of the invention.

Claims

Having described the invention as above, the contents of the following claims are claimed as property:

1. A bispecific antibody or an antibody fragment thereof, characterized in that it has the first branch specifically binding to PD-1 and the second branch specifically binding to CD19, and that they bind specifically to PD-1 and CD19, respectively, wherein the first branch specifically binding to PD-1 comprises any VH selected from (A) a VH having LQH7 ίΩ / ί7Ω7 / E / YI (a) a VH-CDR1 comprising the amino acid sequence set forth in (b) a VH-CDR2 the SEC that ID NO. 18, comprising the amino acid sequence set forth in (c) a VH-CDR3 the SEC that ID NO. 19, comprising and the amino acid sequence set forth in (B) a VH that (a) a VH-CDR1 the SEC that ID NO. 20, comprises the amino acid sequence established in (b) a VH-CDR2 the SEC that ID NO.6, comprises the amino acid sequence established in (c) a VH-CDR3 the SEC that ID NO. 7, comprises and the amino acid sequence established in SEC ID NO. 8, 187 LQH7 ίΩ / ί7Ω7 / E / YI (C) a VH having (a) a VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 9, (b) a VH-CDR2 that amino acids established in SEC comprises ID NO. 10, the and sequence of (c) a VH-CDR3 that amino acids established in SEC comprises ID NO. 11, the sequence of (D) a VH having (a) a VH-CDR1 that amino acids established in SEC comprises ID NO. 12, the sequence of (b) a VH-CDR2 that amino acids established in SEC comprises ID NO. 13, the and sequence of (c) a VH-CDR3 that amino acids established in SEC comprises ID NO. 14, the sequence of (E) a VH having (a) a VH-CDR1 that amino acids established in SEC comprises ID NO. 15, the sequence of (b) a VH-CDR2 that amino acids established in SEC comprises ID NO.16, the and sequence of (c) a VH-CDR3 that amino acids established in SEC ID NO. 17, the and sequence of the second branch that binds specifically to CD19 comprises any of the VHs selected from (A) a VH having (a) a VH-CDR1 comprising the sequence of 188 amino acids established in SEC ID NO. 35, (b) a VH-CDR2 comprising the amino acids established in SEC ID NO. 36, and (c) a VH-CDR3 comprising the amino acids established in SEC ID NO. 37, (B) a VH having (a) a VH-CDR1 comprising the amino acids established in SEC ID NO. 38, (b) a VH-CDR2 comprising the amino acids established in SEC ID NO. 39, and (c) a VH-CDR3 comprising the amino acids established in SEC ID NO. 40, (C) a VH having (a) a VH-CDR1 comprising the amino acids set forth in SEC ID NO. 41, (b) a VH-CDR2 comprising the amino acids set forth in SEC ID NO.42, and (c) a VH-CDR3 comprising the amino acids set forth in SEC ID NO. 43, (D) a VH having (a) a VH-CDR1 comprising the amino acids set forth in SEC ID NO. 44, (b) a VH-CDR2 comprising the amino acids set forth in SEC ID NO. 45, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 46, and (E) a VH having (a) a VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 47, (b) a VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 48, and (c) a VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO.49, and wherein one to five arbitrary amino acid residues may be substituted with amino acid preservatives in one or more of the selected CDRs of VH-CDR1, VH-CDR2, and VH-CDR3 in the VH of the first branch specifically binding to PD-1, respectively; and / or one to five arbitrary amino acid residues may be substituted with amino acid preservatives in one or more of the selected CDRs of VH-CDR1, VH-CDR2, and VH-CDR3 in the VH of the second branch specifically binding to CD19, and wherein the first branch specifically binding to PD-1 and the second branch specifically binding to CD19 have the VL having (a) the VL-CDR1 comprising the amino acid sequence established in SEC ID NO. 26, (b) the VL-CDR2 comprising the amino acid sequence established in SEC ID NO. 27, and (c) the VL-CDR3 comprising the LQH7 ίΩ / ί7Ω7 / E / YI 190 amino acid sequence established in SEC ID NO.28, respectively.

2. The bispecific antibody or an antibody fragment thereof according to claim 1, characterized in that the first branch that binds specifically to PD-1 comprises any of the VHs selected from (A) the VH having VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 20, (B) the VH having (a) VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 6, (b) VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 7, and (c) VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 8, (C) the VH having (a) the VH-CDR1 comprising amino acid sequence established in SEC ID NO. 10 amino acids established in SEC ID NO.9, (b) the VH-CDR2 comprising the sequence of 191 (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 11, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 12, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 13, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 14, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 17, and the second branch that specifically binds to CD19 comprises any of the VHs selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set out in SEC ID NO.35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 37, LQH7 ίΩ / ί7Ω7 / E / YI 192 LQH7 ίΩ / ί7Ω7 / E / YI (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC (b) the VH-CDR2 that ID NO. 38, comprises the 5 amino acid sequence set forth in SEC (c) the VH-CDR3 that ID NO. 39, comprises and the amino acid sequence set forth in SEC (C) the VH having (a) the VH-CDR1 that ID NO. 40, comprises the 10 amino acid sequence established in SEC (b) the VH-CDR2 that ID NO. 41, comprises the amino acid sequence established in SEC (c) the VH-CDR3 that ID NO. 42, comprises and the 15 amino acid sequence established in SEC (D) the VH that has (a) the VH-CDR1 that ID NO. 43, comprises the amino acid sequence established in SEC (b) the VH-CDR2 that ID NO.44, comprising the 20 amino acid sequence established in SEC (c) the VH-CDR3 that ID NO. 45, comprises and the amino acid sequence established in SEC (E) the VH having (a) the VH-CDR1 that ID NO. 46, comprises and the 25 amino acid sequence established in SEC (b) the VH-CDR2 that ID NO. 47, comprises the 193 amino acid sequence established in SEC ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 49, and wherein the first branch specifically binding to PD-1 and the second branch specifically binding to CD19 have the VL having (a) the VL-CDR1 comprising the amino acid sequence established in SEC ID NO. 26, (b) the VL-CDR2 comprising the amino acid sequence established in SEC ID NO. 27, and (c) the VL-CDR3 comprising the amino acid sequence set out in SEC ID NO. 28, respectively.

3. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that (i) the VH of the first branch that binds specifically to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 18, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 19, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 20, and (ii) the VH of the second branch that binds specifically to CD19 is any one selected from Lanz Ln / Lznz / E / YiAi 194 (A) the VH having LQHZ ίΩ / ίZΩZ / E / YI (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 35, (b) the VH-CDR2 comprising the 5 amino acid sequence set out in SEC ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence set out in SEC ID NO.37, (B) the VH having (a) the VH-CDR1 comprising the 10 amino acid sequence set forth in SEC ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 40, 15 (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in (b) the VH-CDR2 in SEC ID NO. 41, comprising the 20 amino acid sequence set forth in (c) the VH-CDR3 in SEC ID NO. 42, comprising and the amino acid sequence set forth in SEC ID NO. 42, comprising (D) the VH having (a) the VH-CDR1 in SEC ID NO. 43, comprising the 25 amino acid sequence set forth in (b) the VH-CDR2 in SEC ID NO. 44, comprises the 195 amino acid sequence established in SEC ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO.

49.

4. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that (i) the VH of the first branch that binds specifically to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 6, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 7, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 8, and (ii) the VH of the second branch that binds specifically to CD19 is any one selected from (A) the VH having (a) the VH-CDR1 comprising the LQH7 1Ω / 17Ω7 / E / YI 196 amino acid sequence set forth in SEC ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.37, LQH7 ίΩ / ί7Ω7 / E / YI (B) the VH having (a) the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 39, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 40, (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 41, (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 45, and (c) the VH-CDR3 comprising the 197 amino acid sequence established in SEC ID NO.46, and (E) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO.

49.

5. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that (i) the VH of the first branch that binds specifically to PD-1 has (a) VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 9, (b) VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 10, and (c) VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 11, and (ii) the VH of the second branch that binds specifically to CD19 is any one selected from (A) the VH having (a) VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 35, (b) VH-CDR2 comprising the LQH7 Ln / LZnZ / E / Yli 198 amino acid sequence set forth in SEC ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.37, (B) the VH having 5 (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 38, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 39, and (c) the VH-CDR3 comprising the 10 amino acid sequence set forth in SEC ID NO. 40, LQH7 ίΩ / ίZOΩ7 / E / YI (C) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 41, (b) the VH-CDR2 comprising the 15 amino acid sequence set forth in SEC ID NO. 42, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 43, (D) the VH having (a) the VH-CDR1 comprising the 20 amino acid sequence set forth in SEC ID NO. 44, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 45, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO.46, and (E) the VH having 199 (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 47, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO.

49.

6. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that (i) the VH of the first branch that binds specifically to PD-1 has (a) VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 12, (b) VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 13, and (c) VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 14, and (ii) the VH of the second branch that binds specifically to CD19 is any one selected from (A) the VH having (a) VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 35, (b) VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 36, and (c) the VH-CDR3 comprising the LQH7 Ln / LZnZ / E / Yli 200 amino acid sequence established in SEC ID NO.37, (B) the VH having LQH7 Ln / ίZΖΠZΖ / Β / YΙΛΙ (a) the VH-CDR1 comprising the amino acid sequence established in SEC (b) the VH-CDR2 that ID NO. 38, comprises the amino acid sequence established in SEC (c) the VH-CDR3 that ID NO. 39, comprises and the amino acid sequence established in SEC (C) the VH having (a) the VH-CDR1 that ID NO. 40, comprises the amino acid sequence established in SEC (b) the VH-CDR2 that ID NO. 41, comprises the amino acid sequence established in SEC (c) the VH-CDR3 that ID NO. 42, comprises and the amino acid sequence established in SEC (D) the VH having (a) the VH-CDR1 that ID NO. 43, comprises the amino acid sequence established in SEC (b) the VH-CDR2 that ID NO. 44, comprises the amino acid sequence established in SEC (c) the VH-CDR3 that ID NO. 45, comprises and the amino acid sequence established in SEC (E) the VH that has (a) the VH-CDR1 that ID NO.46, comprising and the amino acid sequence established in SEC ID NO. 47, 201 (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 48, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.

49.

7. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that (i) the VH of the first branch that binds specifically to PD-1 has (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 15, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 16, and (c) the VH-CDR3 comprising the amino acid sequence set forth in SEC ID NO. 17, and (ii) the VH of the second branch that binds specifically to CD19 is any one selected from (A) the VH having (a) the VH-CDR1 comprising the amino acid sequence set forth in SEC ID NO. 35, (b) the VH-CDR2 comprising the amino acid sequence set forth in SEC ID NO. 36, and (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.37, (B) the VH having 202 the VH-CDR1 comprising the amino acid sequence LQH7 ίΩ / ί7Ω7 / E / YI established in SEC ID NO. 38 (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 39 the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 40 (C) the VH having the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 41 (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 42 the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 43 (D) the VH having the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 44 (b) the VH-CDR2 comprising the amino acid sequence established in SEC ID NO. 45 the VH-CDR3 comprising the amino acid sequence established in SEC ID NO. 46 (E) the VH having the VH-CDR1 comprising the amino acid sequence established in SEC ID NO. 47 the SEC ID NO.48 (b) the VH-CDR2 comprising the sequence of 203 (c) the VH-CDR3 comprising the amino acid sequence established in SEC ID NO.

49.

8. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 7, characterized in that in the VH of the first branch that binds specifically to PD-1, FR1, FR2 and FR3 correspond to the amino acid sequences encoded by the IGHV7-4-1 gene of germline V which may have somatic mutation(s), respectively, and FR4 comprises the amino acid sequence encoded by the JH6c gene of germline J which may have somatic mutation(s) (excluding an amino acid sequence included in VH-CDR3).

9. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 8, characterized in that FR1, FR2 and FR3 in the VH of the second branch that bind specifically to CD19 correspond to the amino acid sequences encoded by the germline IGHV5-51 gene V which may have somatic mutation(s), respectively.

10. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 9, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set out in any LQH7 ίΩ / ί7Ω7 / E / YI 204 selected from SEC ID NO. 5, SEC ID NO. 1, SEC ID NO. 2, SEC ID NO. 3 and SEC ID NO. 4, or an amino acid sequence having at least 80% identity with the same amino acid sequence of VH.

11. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 10, characterized in that the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set out in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO. 66, or an amino acid sequence having at least 80% identity with the same amino acid sequence of VH.

12. The bispecific antibody or an antibody fragment thereof according to claim 1 or 2, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set forth in any selected from SEC ID NO. 5, SEC ID NO. 1, SEC ID NO. 2, SEC ID NO. 3, and SEC ID NO. 4, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and LQH7 Ln / LZnZ / E / Yli 205 SEC ID NO.

66.

13. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 3, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set forth in SEC ID NO. 5, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO.

66.

14. The bispecific antibody or an antibody fragment thereof according to claim 1, 2 or 4, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set forth in SEC ID NO. 1, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO.

66.

15. The bispecific antibody or an antibody fragment thereof according to claims 1, 2 or 5, characterized in that the VH of the first branch LQH7 ίΩ / ί7Ω7 / E / YI 206 that binds specifically to PD-1 comprises the amino acid sequence set forth in SEC ID NO. 2, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO.

66.

16. The bispecific antibody or an antibody fragment thereof according to claim 1, 2 or 6, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set forth in SEC ID NO. 3, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO.

66.

17. The bispecific antibody or an antibody fragment thereof according to claims 1, 2 or 7, characterized in that the VH of the first branch that binds specifically to PD-1 comprises the amino acid sequence set forth in SEC ID NO. 4, and the VH of the second branch that binds specifically to CD19 comprises the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. LQH7 ίΩ / ί7Ω7 / E / YI 207 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO.

66.

18. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 17, characterized in that the VLs of the first branch that binds specifically to PD-1 and the second branch that binds specifically to CD19 comprise the amino acid sequence set forth in SEC ID NO. 25, respectively.

19. A bispecific antibody or an antibody fragment thereof, having the first branch specifically binding to PD-1 and the second branch specifically binding to CD19, and which bind specifically to PD-1 and CD19, respectively, characterized in that (A) the first branch specifically binding to PD-1 has a VH comprising the amino acid sequence set forth in any selected from SEC ID NO. 5, SEC ID NO. 1, SEC ID NO. 2, SEC ID NO. 3 and SEC ID NO. 4, and a VL comprising the amino acid sequence set forth in SEC ID NO. 25, and (B) the second branch specifically binding to CD19 has a VH comprising the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65 and SEQ ID NO.66, and a VL comprising the LQH7 ίΩ / ί7Ω7 / E / YI 208 amino acid sequence established in SEC ID NO.

25.

20. A bispecific antibody or an antibody fragment thereof, characterized in that the first branch specifically binds to PD-1 and the second branch specifically binds to CD19, and which bind specifically to PD-1 and CD19, respectively, wherein the first branch specifically binding to PD-1 cross-competes for (1) PD-1 binding with the first branch specifically binding to PD-1 having a VH comprising the amino acid sequence set out in any selected from SEC ID NO. 5, SEC ID NO. 1, SEC ID NO. 2, SEC ID NO. 3 and SEC ID NO. 4, and a VL comprising the amino acid sequence of SEC ID NO. 25, or (2) PD-1 binding with a variable region of a PD-1-binding monoclonal antibody having the same VH and VL.

21. A bispecific antibody or an antibody fragment thereof, characterized in that the first branch specifically binds to PD-1 and the second branch specifically binds to CD19, and which bind specifically to PD-1 and CD19, respectively, wherein the binding to PD-1 by the first branch specifically binding to PD-1 is cross-competed by (1) the first branch specifically binding to PD-1 having a VH comprising the amino acid sequence set out in any selected from SEC ID NO. 5, SEC LQH7 ίΩ / ί7Ω7 / E / YI 209 ID NO. 1, SEC ID NO. 2, SEC ID NO. 3 and SEC ID NO. 4, and a VL comprising the amino acid sequence of SEC ID NO. 25, or (2) a variable region of a PD-1-binding monoclonal antibody having the same VH and VL.

22. The bispecific antibody or an antibody fragment thereof according to claim 20 or 21, characterized in that the second branch specifically binding to CD19 cross-competes for (1) CD19 binding with the second branch specifically binding to CD19 having the VH comprising the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO. 66, and the VL comprising the amino acid sequence set forth in SEC ID NO. 25, or (2) CD19 binding with a variable region of a monoclonal antibody specifically binding to CD19 having the same VH and VL.

23. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 22, characterized in that the first branch that binds specifically to PD-1 allows interaction between PD-1 and PD-L1.

24. The bispecific antibody or an antibody fragment thereof in accordance with any of LQH7 ίΩ / ί7Ω7 / E / YI 210 claims 1 to 23, characterized in that it is an IqG antibody.

25. The bispecific antibody or an antibody fragment thereof according to claim 24, characterized in that the IgG antibody is an IgG1 antibody or an IgG4 antibody.

26. The bispecific antibody or an antibody fragment thereof according to claim 24, characterized in that the IgG antibody is an IgGi antibody.

27. The bispecific antibody or an antibody fragment thereof according to claim 26, characterized in that the binding to the Fe receptor is eliminated or reduced.

28. The bispecific antibody or an antibody fragment thereof according to claim 27, characterized in that in two heavy chain constant regions of the bispecific antibody, each leucine at position 235 according to the EU numbering system was replaced by glycine, and / or each glycine at position 236 was replaced by arginine.

29. The bispecific antibody or an antibody fragment thereof according to any of claims 26 to 28, characterized in that in a heavy chain constant region having the VH of the first LQH7 ίΩ / ί7Ω7 / E / YI 211 branch that binds specifically to PD-1, the leucine at position 351 according to the EU numbering system was substituted with lysine and the threonine at position 366 was substituted with lysine, and in a heavy chain constant region having the VH of the second branch that binds specifically to CD19, the leucine at position 351 was substituted with aspartic acid and the leucine at position 368 was substituted with glutamic acid.

30. The bispecific antibody or an antibody fragment thereof according to any of claims 26 to 28, characterized in that in a heavy chain constant region having the first branch VH specifically binding to PD-1, the leucine at position 351 according to the EU numbering system was substituted with aspartic acid, and the leucine at position 368 was substituted with glutamic acid, and in a heavy chain constant region having the second branch VH specifically binding to CD19, the leucine at position 351 was substituted with lysine, and the threonine at position 366 was substituted with lysine.

31. The bispecific antibody or an antibody fragment thereof according to any of claims 26 to 30, characterized in that in two heavy chain constant regions of the bispecific antibody, each lysine at position 447 according to the EU numbering system 212 was removed.

32. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 27, characterized in that the heavy chain having the VH of the first branch that binds specifically to PD-1 has a heavy chain constant region comprising the amino acid sequence set out in SEC ID NO.

23.

33. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 28, 30 and 32, characterized in that the heavy chain having the VH of the second branch that binds specifically to CD19 has a heavy chain constant region comprising the amino acid sequence set out in any selected from SEC ID NO. 24, SEC ID NO. 71, SEC ID NO. 72, SEC ID NO. 73, SEC ID NO. 74 and SEC ID NO.

75.

34. The bispecific antibody or an antibody fragment thereof according to any of claims 1 to 33, characterized in that the light chain having the VL of the first branch binds specifically to PD-1 and / or the light chain having the VL of the second branch binds specifically to CD19, have / comprising a light chain constant region comprising the amino acid sequence set out in SEC ID LQH7 ίΩ / ί7Ω7 / E / YI 213 NO.

29.

35. A bispecific antibody or an antibody fragment thereof, characterized in that it has a first branch specifically binding to PD-1 and a second branch specifically binding to CD19, and which bind specifically to PD-1 and CD19, respectively, wherein (A) a heavy chain having a VH of the first branch specifically binding to PD-1 has a VH comprising the amino acid sequence set forth in any selected from SEC ID NO. 5, SEC ID NO. 1, SEC ID NO. 2, SEC ID NO. 3 and SEC ID NO. 4, and the heavy chain constant region comprising the amino acid sequence set forth in SEC ID NO. 23, (B) a light chain having a VL of the first branch specifically binding to BD-1 has a VL comprising the amino acid sequence set forth in SEC ID NO. 25, and the light chain constant region comprising the amino acid sequence set forth in SEC ID NO.29, (C) a heavy chain having a second branch VH specifically binding to CD19 has a VH comprising the amino acid sequence set forth in any selected from SEC ID NO. 62, SEC ID NO. 30, SEC ID NO. 31, SEC ID NO. 32, SEC ID NO. 33, SEC ID NO. 34, SEC ID NO. 63, SEC ID NO. 64, SEC ID NO. 65 and SEC ID NO. 66, and LQH7 ίΩ / ί7Ω7 / E / YI 214 the heavy chain constant region comprising the amino acid sequence set forth in SEC ID NO. 24, and (D) a light chain having a second branch VL specifically binding to CD19 has a VL comprising the amino acid sequence set forth in SEC ID NO. 25, and the light chain constant region comprising the amino acid sequence set forth in SEC ID NO.

29.

36. A pharmaceutical composition, characterized in that it comprises the bispecific antibody or an antibody fragment thereof selected in accordance with any of claims 1 to 35, and a pharmaceutically acceptable carrier.

37. An agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating autoimmune diseases, characterized in that it comprises the bispecific antibody or an antibody fragment thereof selected in accordance with any of claims 1 to 35 as an active ingredient.

38. The agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating autoimmune diseases according to claim 37, characterized in that the autoimmune disease is Behcet's disease, systemic lupus erythematosus, chronic discoid lupus erythematosus, multiple sclerosis, scleroderma, polymyositis, dermatomyositis, polyarteritis nodosa, aortitis syndrome, malignant rheumatoid arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, mixed connective tissue disease, Sjogren's syndrome, adult-onset Still's disease, vasculitis, allergic granulomatous vasculitis, hypersensitivity vasculitis, rheumatoid vasculitis, large vessel vasculitis, ANCA-associated vasculitis, Cogan syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica, fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related disease,Guillain-Barré syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, Goodpasture syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, pernicious anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Graves' disease, Hashimoto's disease, autoimmune adrenal insufficiency, primary hypothyroidism, Addison's disease, idiopathic Addison's disease, type I diabetes mellitus, slowly progressive type I diabetes mellitus, localized scleroderma, psoriasis, psoriatic arthritis, bullous pemphigoid, pemphigus, pemphigoid, herpes gestationis, linear IgA bullous dermatosis, acquired epidermolysis bullosa, alopecia areata, vitiligo, vitiligo vulgaris, neuromyelitis LQH7 ίΩ / ί7Ω7 / E / YI 216 optic, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, sarcoidosis, giant cell arteritis,Amyotrophic lateral sclerosis, Harada's disease, autoimmune optic neuropathy, idiopathic azoospermia, recurrent miscarriage, inflammatory bowel disease, celiac disease, ankylosing spondylitis, severe asthma, chronic urticaria, transplant immunity, familial Mediterranean fever, chronic eosinophilic rhinosinusitis, dilated cardiomyopathy, systemic mastocytosis, or inclusion body myositis.

39. The agent for preventing, suppressing the progression of symptoms, suppressing recurrence, and / or treating autoimmune diseases according to claim 37 or 38, characterized in that it is administered together with one or more drugs selected from an insulin formulation, a sulfonylurea agent, a rapid-acting insulin secretion promoter, a biguanide preparation, an insulin resistance-enhancing agent, an α-glucosidase inhibitor, a diabetic neuropathy therapeutic agent, a GLP-1 analogue preparation, a DPP-4 inhibitor, a spheroid agent, interferon β10, interferon β11, glatiramer acetate, mitoxantrone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, cladribine, adrenocorticotropic hormone (ACTH), corticotropin, mizoribine, tacrolimus, fingolimod, LQH7 Ln / LZnZ / E / Yli 217 alemtuzumab, an immunosuppressant, belimumab, an anti-rheumatic drug, an anticytokine drug, and abatacept.

40. An agent for preventing, suppressing symptom progression, suppressing recurrence, and / or treating graft-versus-host disease (GVHD), characterized in that it comprises the bispecific antibody or an antibody fragment thereof selected in accordance with any one of claims 1 to 35, as an active ingredient.