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Anti-HER3 antibody that binds to her3β-hairpin

An antibody and immunoconjugate technology, applied in the direction of antibodies, antibody medical components, anti-blood group antigen immunoglobulin, etc., can solve problems such as inaccessibility

Inactive Publication Date: 2020-07-10
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] So far it has not been possible to select antibodies that specifically bind the HER3 β-hairpin (and / or the HER4 β-hairpin), since these HER3 (or HER4) β-hairpins all present cryptic epitopes that are in equilibrium at these receptors out of time (see figure 1 )

Method used

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  • Anti-HER3 antibody that binds to her3β-hairpin
  • Anti-HER3 antibody that binds to her3β-hairpin
  • Anti-HER3 antibody that binds to her3β-hairpin

Examples

Experimental program
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Embodiment approach

[0427] 1. An isolated antibody binding to human HER3,

[0428] where the antibody contains

[0429] a) Variable heavy domain VH (VH-A) having the amino acid sequence of SEQ ID NO:33.

[0430] 2. An isolated antibody that binds to human HER3,

[0431] where the antibody contains

[0432] a) a variable heavy chain domain VH (VH-A) having the amino acid sequence of SEQ ID NO: 33; and

[0433] b) a variable light domain VL (VL-D) having the amino acid sequence of SEQ ID NO:41, a variable light domain VL (VL-B) having the amino acid sequence of SEQ ID NO:39, or having the amino acid sequence of SEQ ID NO :42 variable light domain VL (VL-E).

[0434] 3. An isolated antibody that binds to human HER3,

[0435] where the antibody contains

[0436] a) a variable heavy chain domain VH (VH-A) having the amino acid sequence of SEQ ID NO: 33; and

[0437] b) Variable light domain VL (VL-D) having the amino acid sequence of SEQ ID NO:41.

[0438] 4. An isolate...

Embodiment 1

[0515] Antigen and Screening Protein Preparation - Generation of functional β-hairpin HER3 and β-hairpin HER4 constructs for selection of antibodies that bind HER3 β-hairpin and HER4 β-hairpin

[0516] To generate functional β-hairpin HER3 and HER4 constructs, the amino acid sequences of the β-hairpins of HER3 (SEQ ID NO: 1 ) and HER4 (SEQ ID NO: 2) were grafted into the SlyD polypeptide framework comprising the FKBP domain. In such constructs, the grafted β-hairpin is freely accessible, in contrast to the hidden structure in the native unactivated conformation of HER3 or HER4 (in the absence of a ligand such as HRG) (see figure 1 c and 1d, where the β-hairpin of HER3 is hidden).

[0517] All fusion SlyD polypeptides can be purified and refolded using almost the same protocol. Escherichia coli BL21(DE3) cells transformed with specific expression plasmids were grown at 37°C in LB medium containing corresponding antibiotics for selective growth (kanamycin 30 μg / ml, or am...

Embodiment 2

[0528] a) Immunization and selection of HER3 antibody

[0529] To generate antibodies against HER3 and HER4 β-hairpins, Balb / C, NMRI or SJL mice were immunized with different antigens. The following proteins were used as antigens: full-length HER3 ECD, or epitope scaffold proteins TtSlyD-FKBP12-Her3, TtSlyDcys-Her3, TtSlyDcas-Her3, TgSlyDcys-Her3 and TgSlyDser-Her3. The TtSlyD-FKBP12-Her3 variant represents the first epitope scaffold for generating HER3 dimerization domain-specific antibodies. Although the general rationale for using SlyD variants as epitope scaffolds could have been demonstrated earlier using the first generation SlyD-FKBP12 scaffolds, improved scaffold variants with higher stability were developed. These SlyD variants were derived from Thermus thermophilus and Thermus gamma-resistant.

[0530] All mice were immunized three times at time points 0, 6 and 10 weeks after the start of the immunization campaign. At each time point each mouse was immunized ...

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Abstract

The present disclosure relates to specific anti-HER3 antibodies that bind the HER3 β-hairpin, their preparation and use as medicines.

Description

[0001] The present invention relates to anti-HER3 antibodies that bind to the HER3 beta-hairpin, their preparation and use as medicines. [0002] Background of the invention [0003] The HER protein family consists of 4 members: HER1, also known as epidermal growth factor receptor (EGFR) or ErbB-1; HER2, also known as ErbB-2; ErbB-3, also known as HER3; and ErbB-4, Also known as HER4. ErbB family proteins are receptor tyrosine kinases and represent important mediators of cell growth, differentiation and survival. The HER family represents receptor proteins for different ligands like the neuregulin (NRG) family, amphiregulin, EGF and TGF-a. Heregulin (also known as HRG or neuregulin NRG-1) is a ligand for eg HER3 and HER4. [0004] Epidermal growth factor receptor (EGFR ) family, which also includes HER1 (also known as EGFR), HER2, and HER4 (Kraus, M.H. et al., PNAS 86:9193-9197 (1989); Plowman, G.D. et al., PNAS 87: 4905-4909 (1990); Kraus, M.H. et al., PNAS 90:2900-2904 (1...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/32C07K16/34A61K39/395A61P35/00C12N15/13
CPCC07K16/32C07K16/34A61K2039/505A61K2039/6068C07K2317/33C07K2317/24C07K2317/76C07K2317/77C07K2317/73C07K2317/92A61K47/6871A61P35/00A61P35/02C07K16/2863C07K2317/34C07K2317/55
Inventor B·博森迈尔M·耶格F·克罗纳G·尼德费尔纳M·施列姆尔C·皮斯R·别克
Owner F HOFFMANN LA ROCHE & CO AG