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Antigen binding molecules comprising a TNF family ligand trimer and a tenascin binding moiety

A technology of antigen-binding molecules and trimers, applied in the direction of receptors/cell surface antigens/cell surface determinants, immunoglobulins, animal/human proteins, etc., can solve problems such as adult tissue loss

Active Publication Date: 2018-12-21
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Tenascin-C is transiently expressed in developing embryos but virtually absent in adult tissues

Method used

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  • Antigen binding molecules comprising a TNF family ligand trimer and a tenascin binding moiety
  • Antigen binding molecules comprising a TNF family ligand trimer and a tenascin binding moiety
  • Antigen binding molecules comprising a TNF family ligand trimer and a tenascin binding moiety

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Experimental program
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Embodiment approach

[0733] 1. An antigen-binding molecule containing a TNF family ligand trimer, comprising

[0734] (a) at least one module capable of specifically binding to tenascin-C (TnC), and

[0735] (b) first and second polypeptides linked to each other by a disulfide bond,

[0736] Wherein the antigen binding molecule is characterized in that the first polypeptide comprises two ectodomains or fragments thereof of members of the TNF ligand family connected to each other by a peptide linker and in that the second polypeptide comprises only one of the members of the TNF ligand family Extracellular domains or fragments thereof.

[0737] 2. An antigen-binding molecule containing a TNF family ligand trimer, comprising

[0738] (a) at least one antigen binding moiety capable of specifically binding to tenascin-C (TnC), and

[0739] (b) first and second polypeptides linked to each other by a disulfide bond,

[0740] Wherein the antigen binding molecule is characterized in that the first poly...

Embodiment approach 1 to 6

[0810] 37. The antigen-binding molecule containing TNF families ligand trimer according to any one of embodiments 1 to 6, 11 to 23, 27 to 29 and 31 to 36, wherein the antigen binding molecule comprises

[0811] (i) a first heavy chain comprising a VH domain comprising the amino acid sequence of SEQ ID NO:46 and a first light chain comprising a VL domain comprising the amino acid sequence of SEQ ID NO:45 or

[0812] The first heavy chain comprising the VH domain comprising the amino acid sequence of SEQ ID NO:48 and the first light chain comprising the VL domain comprising the amino acid sequence of SEQ ID NO:47,

[0813] (ii) a second heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 195, and

[0814] (iii) a second light chain comprising the amino acid sequence of SEQ ID NO:196.

[0815] 38. The antigen binding molecule comprising a trimer of TNF family ligands according to any one of embodiments 1 to 37, wherein the antigen bindi...

Embodiment 1

[0854] TnC antigen sequence and antigen production

[0855] All constructs of Table 3 and Table 4 were fused to the C-terminus of GST and expressed in E. coli BL21(DE3). For site-specific biotinylation, an Avi tag was added to the C-terminus of the tenascin sequence and BirA biotin ligase (Avidity, Colorado, USA) was co-expressed on a separate plasmid. The growth medium was 2YT containing 100 μg / ml ampicillin and 20 μg / ml chloramphenicol. Add biotin to a final concentration of 50 μM. Protein expression was induced overnight at 22°C with 1 mM IPTG. Cells were harvested by centrifugation and lysed by sonication in the presence of B-PER reagent (pierce 78260) and 1 mg / ml lysozyme (Sigma L6876). The lysate was centrifuged and the clarified lysate was loaded onto a Glutathione Sepharose column (GE Healthcare; Product No. 17-0756-01). After washing, TnC molecules were cleaved from GST by thrombin (SigmaAldrich; Product No. 10602400001 ) overnight at 4°C. In 50mM Tris buffer pH ...

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Abstract

The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) at least one antigen binding moiety capable of specific binding to Tenascin-C (Tn C) and (b)a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecules are characterized in that the first polypeptide comprises two ectodomains ofa TNF ligand family member or two fragments thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member or a fragment thereof. The invention further relates to methods of producing these molecules and to methods of using the same.

Description

field of invention [0001] The present invention relates to novel antigen-binding molecules containing TNF family ligand trimers, which comprise (a) at least one antigen-binding module capable of specifically binding to tenascin-C (TnC) and (b) First and second polypeptides linked to each other, wherein the antigen binding molecule is characterized in that the first polypeptide comprises two extracellular domains or two fragments thereof of TNF ligand family members linked to each other by a peptide linker, and in that The second polypeptide comprises only an extracellular domain of said TNF ligand family member or a fragment thereof. The invention further relates to methods of making these molecules and methods of using them. Background of the invention [0002] Ligands that interact with molecules of the TNF (tumor necrosis factor) receptor superfamily have critical roles in the organization and function of the immune system. While regulating normal functions such as immu...

Claims

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Application Information

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IPC IPC(8): C07K16/24C07K14/715
CPCC07K14/7151C07K16/241C07K2319/30A61K47/6813A61K47/6845A61P35/00A61K47/65C07K14/525C07K16/18
Inventor M·阿曼P·布鲁恩克C·克劳斯C·费拉拉科勒S·格劳-理查兹C·克雷恩V·列维茨基E·莫斯纳P·尤马纳
Owner F HOFFMANN LA ROCHE & CO AG
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