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Anti-BCMA/anti-4-1BB bispecific antibodies and uses thereof

A bispecific antibody, CDR-H1 technology, applied in the direction of antibodies, antibody medical components, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve problems such as liver toxicity

Pending Publication Date: 2022-07-29
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite anti-tumor efficacy of anti-4-1BB antibodies, anti-4-1BB antibodies have caused severe hepatotoxicity in clinical use

Method used

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  • Anti-BCMA/anti-4-1BB bispecific antibodies and uses thereof
  • Anti-BCMA/anti-4-1BB bispecific antibodies and uses thereof
  • Anti-BCMA/anti-4-1BB bispecific antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1. Preparation of anti-BCMA monoclonal antibodies

[0113] 1-1. Preparation of antigen

[0114] Antigens were prepared as follows for the preparation of anti-BCMA antibodies. Polypeptides comprising amino acid residues 5-54, 1-51, 1-54 and 4-48, respectively, from the N-terminus of the amino acid sequence of human BCMA (GenBank Accession No. NP_001183.2, SEQ ID NO: 1) were used as antigens .

[0115] In particular, preparations containing human BCMA ( Z02731) ("human BCMA(5-54)") antigen of amino acid residues 5-54; containing amino acid residues 1- of human BCMA (made in-house, expressed in CHO cells) fused to the Fc region of human IgG1 51 antigen ("human BCMA-Fc (1-51)"); antigen containing amino acid residues 1-54 of human BCMA fused to the Fc region and a His-tag to its C-terminus (10620-H03H, Yiqiao, Beijing Sino Biological Inc.) ("human BCMA-Fc / His(1-54)"); and an antigen containing amino acid residues 4-48 of human BCMA fused to the Fc region (manuf...

Embodiment 2

[0143] Example 2. Preparation of anti-4-1BB monoclonal antibody

[0144] 2-1. Screening of fully human monoclonal antibodies against 4-1BB (immunotube panning of phage library)

[0145] For panning of the library against target molecules, a total of four rounds of panning were performed using immunotubes coated with 4-1BB.

[0146] Bacterial colonies from the third round of panning output were grown to turbidity in 96 deep-well plates in SB medium containing carbenicillin, at which point 10 11 pfu of VCSM13 helper phage was added to each well. After infection for 1 hour at 37°C with gentle shaking (80 rpm), 70 μg / mL of kanamycin was added and cells were cultured overnight at 30°C with shaking at 200 rpm.

[0147] On the second day, the plates were centrifuged and the phage-containing supernatant was added to 4-1BB antigen-coated ELISA plates blocked with 3% (w / v) BSA in PBST. After 1 hour incubation at room temperature, the plate was washed 3 times with PBST and anti-M13 an...

Embodiment 3

[0165] Example 3. Definition of anti-BCMA / anti-4-1BB bispecific antibodies

[0166] 3-1. Preparation of anti-BCMA / anti-4-1BB bispecific antibody

[0167] As shown in Table 9, various anti-BCMA / anti-4-1BB bispecific antibody candidates were prepared as full-length IgG (anti-BCMA antibody)-scFv (anti-4-1BB antibody). The constant regions of anti-BCMA antibodies contained in bispecific antibodies can still be modified by introducing more than one mutation or change into human IgG1. In the Examples, an NA mutation (N297A) was introduced.

[0168] 【Table 9】

[0169]

[0170]

[0171] The anti-BCMA IgG and anti-4-1BB scFv clones prepared in Example 1 and Example 2, respectively, were exemplarily selected to prepare anti-BCMA / anti-4-1BB bispecific antibodies in IgG-scFv fusion form, one of the antigens The scFv antibody fragment is fused to the C-terminus of an IgG from another antigen. IgG1 with ADCC reduced mutant backbone was used when BCMA was placed in the intact IgG f...

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Abstract

The invention provides an anti-B cell maturation antigen (B-cell maturing antigen; the anti-B cell maturing antigen (B-cell maturing antigen; bCMA) / anti-4-1BB bispecific antibodies or antigen binding fragments thereof, and uses thereof. The bispecific antibodies or antigen-binding fragments thereof may have high binding affinity for both BCMA protein and 4-1BB protein, and may be useful for the prevention or treatment of diseases (e.g., cancer) associated with BCMA, 4-1BB, or both.

Description

technical field [0001] The present disclosure relates to anti-BCMA / anti-4-1BB bispecific antibodies capable of effectively blocking the interaction of BCMA with its ligands and activating 4-1BB signaling; methods of making the same; and uses thereof. Bispecific antibodies can have high binding affinity for both BCMA protein and 4-1BB protein. Background technique [0002] B-cell maturation antigen (BCMA) is a protein of about 20KDa and belongs to the tumor necrosis factor receptor (tumor necrosis factor-receptor; TNFR) superfamily. BCMA is also known to have a B-cell activating factor (BAFF) belonging to the tumor necrosis factor family and a proliferation-inducing ligand (A Proliferation Inducing Ligand; APRIL). Pathologically, BCMA is expressed in the neoplastic plasma cells of patients with multiple myeloma (MM), and survival in patients with multiple myeloma decreases with increased BCMA expression (Moreaux et al, Eur J Haematol 2009 83: 119-129). Multiple myeloma is ...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61P35/00A61K39/00
CPCA61P35/00A61K39/0011C07K16/2878C07K2317/21C07K2317/622C07K2317/565C07K2317/31C07K2317/92C07K2317/524C07K16/468C07K2317/94C07K2317/33C07K2317/75C07K2317/73A61K2039/505A61K2039/545C07K2317/526C07K2317/732
Inventor 朴景珍李良顺林塞彝郑惠真朴庚秀孙镛圭宣星圭孙源晙金恩廷严在铉郑义静朴慜智洪庭铉
Owner エービーエルバイオインク
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