Bispecific CD3 and CD19 antigen binding constructs

A bispecific, construct technology, applied in the direction of antibodies, anti-receptors/cell surface antigens/cell surface determinants, immunoglobulins, anti-inflammatory agents, etc. Anti-adverse in vivo half-life and other issues

Inactive Publication Date: 2016-04-27
ZYMEWORKS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, blinatumomab has poor in vivo half-life and is difficult to manufacture in terms of production and stability

Method used

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  • Bispecific CD3 and CD19 antigen binding constructs
  • Bispecific CD3 and CD19 antigen binding constructs
  • Bispecific CD3 and CD19 antigen binding constructs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0278] Example 1. Description of bispecific anti-CD19-CD3 antigen binding constructs.

[0279] A number of exemplary bispecific anti-CD3-CD19 antigen binding constructs were designed as described below. figure 1 Exemplary schematics of such constructs are shown in A-C. figure 2 A summary of these variants is shown in . All formats are based on a heterodimeric Fc constructed from known mutations in the CH3 domain (Von Kreudenstein et al., MAbs. 20135(5):646-54):

[0280] The dual scFv heterodimeric Fc molecule contains a heterodimeric Fc with anti-CD19 scFv and anti-CD3 scFv

[0281] • The hybrid heterodimeric Fc molecule comprises a heterodimeric Fc with anti-CD19 scFv and anti-CD3 Fab or a heterodimeric Fc with anti-CD19 Fab and anti-CD3 scFv.

[0282] • A full-size heterodimeric Fc molecule comprising a heterodimeric Fc with anti-CD19 Fab and anti-CD3 Fab; the full-size molecule can be constructed from a common light chain or with an anti-CD19 light chain and an anti-C...

Embodiment 2

[0297] Example 2: Cloning, Expression and Purification of Exemplary Antigen Binding Constructs

[0298] The variants described in Example 1 (antigen binding constructs) and controls were cloned and expressed as follows. Genes encoding antibody heavy and light chains were constructed via gene synthesis using codons optimized for human / mammalian expression. The scFv and Fab sequences were obtained from the known anti-CD19 antibody HD37 (HD37, Kipriyanov et al., 1998, Int. J Cancer: 77, 763-772) and the known anti-CD3 monoclonal antibody OKT3 (ORTHOCLONEOKT3, DrugBank index: DB00075), tirizumab Monoclonal antibody (MGA031, Eli Lilly), blinatumomab (Amgen, US2011 / 0275787) sequences were generated and constructed as described in Example 1.

[0299] The final gene product was subcloned into mammalian expression vector pTT5 (NRC-BRI, Canada) and expressed in CHO cells (Durocher, Y., Perret, S. & Kamen, A. High-level and high-throughput recombinant protein production by transient t...

Embodiment 3

[0305] Example 3: Exemplary bispecific antigen binding as a hybrid heterodimeric Fc or as a full-size antibody Description, Expression and Purification of Synthetic Constructs (Anti-CD3-CD19 or Anti-CD3-CD20)

[0306] V5850, v5851, v5852, v6325, v1813, v1821 and v1823 illustrate bispecific CD3 / CD19 or CD3 / CD20 hybrid antigen binding constructs. These bispecific hybrid variants consist of a Fab on the A or B chain paired with a scFv-Fc on the alternative polypeptide chain. The A chain of the heterodimeric Fc included the following mutations: T350V_L351Y_F405A_Y407V, and the B chain of the heterodimeric Fc included the following mutations: T350V_T366L_K392L_T394W. V1813, v1821 and v1823 illustrate CD3 / CD20 common light chain antigen binding constructs. The common light chain variant is composed of two different Fabs), each Fab) sharing a light chain on a complementary heterodimeric Fc. The composition of the specific variants is indicated in Table 1.

[0307] As for commo...

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Abstract

Bispecific antigen binding constructs are described that bind to CD3 and CD19 or CD20 antigens.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims U.S. Provisional Application Nos. 61 / 845,948, filed July 12, 2013 and U.S. Provisional Application Nos. 61 / 927,877, filed January 15, 2014 and 61 / 978,719, filed April 11, 2014 Benefits of U.S. Provisional Applications. These applications are hereby incorporated by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. The ASCII copy was created in XX, 2014, named XXXXX_CRF_sequencelisting.txt, and the size is XXX,XXX bytes. technical field [0005] The field of the invention is the rational design of multispecific scaffolds, such as antigen binding constructs comprising CD3 binding domains for custom development of biotherapeutics. Background of the invention [0006] In the field of therapeutic proteins, antibodies with their multivalent target ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P21/08
CPCC07K16/2803C07K16/2887C07K16/468A61K2039/505C07K2317/21C07K2317/31C07K2317/526C07K2317/55C07K2317/565C07K2317/622C07K2317/624C07K2317/64C07K2317/76C07K2317/90A61K47/6849C07K16/2809A61P1/04A61P17/00A61P17/06A61P19/02A61P27/02A61P29/00A61P31/00A61P31/12A61P33/00A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06A61P37/08A61P9/00A61P3/10C07K16/30C07K2317/24G01N33/6872G01N2333/70503G01N2333/7051
Inventor G·Y·K·吴S·B·迪克西特T·斯普雷特冯克罗登斯泰恩
Owner ZYMEWORKS INC
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