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Antibodies against erbb3 and uses thereof

A technology of antibodies and monoclonal antibodies, applied in the fields of antibodies, antibody medical components, anti-tumor drugs, etc., can solve the problem that ErbB3 has not been paid attention to

Active Publication Date: 2010-03-17
14NER ONCOLOGY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although the role of ErbB3 in cancer has been studied (see, for example, Horst et al. (2005) 115, 519-527; Xue et al. (2006) Cancer Res. 66, 1418-1426), ErbB3 Still underappreciated as a target for clinical intervention

Method used

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  • Antibodies against erbb3 and uses thereof
  • Antibodies against erbb3 and uses thereof
  • Antibodies against erbb3 and uses thereof

Examples

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preparation example Construction

[0355]Sterile injection solutions are prepared by incorporating the active compound in the required amount and, as required, one or a combination of ingredients listed above in an appropriate solvent, followed by sterile microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization), which yield a powder of the active ingredient plus any desired additional ingredients from a previously sterile-filtered solution thereof. .

[0356] Dosage regimens are adjusted to provide the optimum response (eg, a therapeutic response) desired. For example, a single bolus may be administered, several divided doses may be administered at different times or the administer...

Embodiment 1

[0399] Example 1: Preparation of Antibodies Using Phage Display

[0400] To obtain human anti-ErbB3 antibodies referred to herein as Ab#6, Ab#3, Ab#14, Ab#17 and Ab#19, human Fab phage libraries comprising unique combinations of immunoglobulin sequences from human donors (Hoet et al., supra, the entire contents of which are incorporated herein by reference) performed an initial screen for ErbB3 binders.

[0401] Using purified ErbB3 and a Chinese hamster ovary cell line expressing cell surface ErbB3, 73 unique Fab sequences were identified from the library. These 73 clones were then reformatted into phage-free Fabs only. Using high-throughput methods, these Fabs were expressed on a small scale and tested for binding using ELISA and Flexchip methods, which are a high-throughput surface plasmon resonance (SPR) technique. The 73 Fabs without phage were spotted on the chip surface and the binding kinetics and epitope blocking to ErbB3-his fusion target protein or ErbB3-Fc prot...

Embodiment 2

[0403] Example 2: Optimization of Anti-ErbB3 Fab

[0404] Following the identification of Fabs that block the binding of the ErbB3 ligand (neuretonin) to ErbB3, the following codon optimization was performed on the VH and VL sequences of the Fabs.

[0405] Specifically, expression constructs expressed as IgGl or IgG2 isotypes were used to rearrange the VH and VL regions. This construct includes a Selexis backbone with expression cassettes for replacement of the appropriate heavy and light chain sequences. Selexis vectors contain the CMV promoter and matching poly-A signal.

[0406] The VH and VL nucleic acid sequences of codon-optimized Ab#6 are shown in SEQ ID NO: 25 and 26, respectively, and these sequences of Ab#3 are shown in SEQ ID NO: 27 and 28, respectively, as shown in FIG. 22 .

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Abstract

The present invention provides a novel class of monoclonal antibodies which bind ErbB3 receptor and inhibits various ErbB3 functions. For example, the antibodies described herein are capable of binding to ErbB3 and inhibiting EGF-like ligand mediated phosphorylation of the receptor.

Description

Background technique [0001] The ErbB / HER subfamily of polypeptide growth factor receptors includes epidermal growth factor (EGF) receptors (EGFR, ErbB1 / HER1), neu oncogene products (ErbB2 / HER2), and the recently identified ErbB3 / HER3 and ErbB4 / HER4 receptors Proteins (see, eg, Hynes et al. (1994) Biochim. Biophys. Acta. Rev. Cancer 1198, 165-184). Each of these receptors is presumed to consist of an extracellular ligand-binding domain, a transmembrane domain, a cytoplasmic protein tyrosine kinase (PTK) domain, and a C-terminal phosphorylation domain (see, e.g., Kim et al., (1998) Biochem. J. 334, 189-195). [0002] In vitro experiments have shown that the protein tyrosine kinase activity of ErbB3 proteins is significantly reduced compared to other ErbB / HER family members, and this reduction is partly due to non-conservative amino acid substitutions in the predicted catalytic domain of ErbB3 (see, For example Guy et al. (1994) Proc. Natl. Acad Sci. USA. 91, 8132-8136; Sierke ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00A61K33/243
CPCC07K16/2863C07K2317/55A61K39/39558C07K16/32A61K31/337A61K39/3955C07K2317/21C07K2316/96A61K33/24A61K2039/505A61K31/517C07K2317/92C07K2317/73C07K2317/76A61P1/00A61P11/00A61P13/08A61P13/12A61P15/00A61P17/00A61P35/00A61P43/00A61K33/243A61K2300/00C07K16/28A61K39/395A61K9/0019C07K2317/34C07K2317/565
Inventor B·舍贝尔U·尼尔森M·费尔德豪斯
Owner 14NER ONCOLOGY INC
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