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Bispecific binding proteins binding an immunomodulatory protein and a tumor antigen

A protein-binding, bispecific technology, applied in immunoglobulin, anti-animal/human immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc. Issues such as lack of targeting cancer cells

Inactive Publication Date: 2019-03-15
ABBVIE BIOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although various approaches allow physicians a wide choice of available treatments to treat cancer, existing therapeutics suffer from a number of disadvantages, such as lack of selectivity in targeting cancer cells over normal healthy cells and cancer resistance to treatment

Method used

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  • Bispecific binding proteins binding an immunomodulatory protein and a tumor antigen
  • Bispecific binding proteins binding an immunomodulatory protein and a tumor antigen
  • Bispecific binding proteins binding an immunomodulatory protein and a tumor antigen

Examples

Experimental program
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Effect test

example 1

[0359] Example 1 - Generation and Characterization of Anti-CD40 Antibodies

[0360] 8.1.1. Generation of mouse anti-human CD40 hybridoma

[0361] Monoclonal antibodies were produced by intraperitoneal immunization of Balb / C mice or SJL mice with mouse 3T12 cells overexpressing human CD40. Spleens were harvested and the spleen cells were fused with the multiple myeloma cell line NS0. Hybridomas were selected using aminopterin. Selected hybridomas expressing anti-CD40 antibodies with agonistic activity were screened and subcloned to isolate individual clones.

[0362] 8.1.2. CD40 analysis

[0363] To screen for antibodies with agonistic activity, a panel of functional assays was developed, including NF-κB pathway stimulation, monocyte activation, DC activation, and human CD40 ligand (SEQ ID NO: 272) (CD40L) competition. In these analyses, anti-human CD40G28-5 (mouse IgG1) (Biolegend) was included as a positive control along with an isotype-matched mouse antibody (muIgG 1 ) ...

example 2

[0413] Example 2 - Generation and Characterization of Anti-Mesothelin Antibodies

[0414] 8.2.1. Generation of fully human anti-human mesothelin antibodies

[0415] Generation of fully human anti-mesothelin antibody via in vitro RNA display technology (Hseh, C-M., Kutskova, Y.A. and Memmott, J.E., U.S. Patent Application No. US 2010 / 0105569) followed by affinity maturation for anti-mesothelin antibody HuAb17 .

[0416] Sequence alignment showed that the mesothelin antibody HuAb17 shared the highest identity with human germlines VH1-46 / JH4 and IGLV3-1 / Jk2. To improve the affinity of HuAbl7 for mesothelin, hypermutated CDR residues were identified from other human antibody sequences in the IgBLAST database that also shared high identity with germline VH1-46 and IGLV3-1. These hypermutated CDR positions were then subjected to restricted mutagenesis of the corresponding HuAbl7 CDR residues by PCR using primers with low degeneracy to generate three antibody libraries in scFv form...

example 4

[0459] Example 4 - Design and in vitro evaluation of bispecific binding proteins that bind CD40 and mesothelin

[0460] 8.4.1. Principle and molecular design

[0461] Tumors targeting anti-CD40 binding proteins should ideally activate CD40 upon binding to tumor antigens on the tumor cell membrane. Tumor antigen binding can provide cross-linking for activation of CD40 multimerization and initiation of downstream signaling. In the absence of tumor antigen, the binding protein should exhibit minimal CD40 agonistic activity. Upon binding to cell surface tumor antigens, the binding protein will increase CD40 agonist activity. To this end, different bispecific binding protein formats were tested.

[0462] One form is the dual variable domain immunoglobulin (DVD-Ig) ( Figure 2A ), which contain two tandem variable (V) domains connected by a linker, followed by the constant region of a conventional antibody. To construct a CD40 / tumor antigen DVD-Ig, place the V-domain against th...

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PUM

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Abstract

The present disclosure provides bispecific proteins that bind to two antigens, as well as their compositions, uses, and methods of making.

Description

[0001] 1. Cross-references to related applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 342,393, filed May 27, 2016, and 62 / 414,897, filed October 31, 2016, under 35 U.S.C. § 119(e), both The entire contents of both applications are incorporated herein by reference. [0003] 2. Sequence Listing [0004] This application contains a Sequence Listing filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Created on May 17, 2017, this ASCII copy is named 381493-284WO_SL.txt and is 674,449 bytes in size. 3. Technical field [0005] In particular, the present application relates to novel bispecific binding proteins, compositions comprising these novel proteins, nucleic acids encoding these proteins, and methods of making and using them. 4. Background technology [0006] Cancer therapy encompasses a wide range of treatments, including surgery, radiation and chemotherapy. Although various appro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30
CPCC07K16/2803C07K16/2827C07K16/2863C07K16/2878C07K16/30C07K16/3069C07K2317/24C07K2317/31C07K2317/33C07K2317/56C07K2317/622C07K2317/64C07K2317/73C07K2317/75C07K2317/92A61K38/00A61P35/00A61P37/00C07K16/42A61K2039/505A61K2039/54C07K16/468
Inventor 赤松谦子P.卡尔普C.M.福赛思P.Y.黄D.鲍威尔斯A.F.瓦尔叶世鸣
Owner ABBVIE BIOTHERAPEUTICS
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