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Anti-dll4 antibodies and methods using same.

A technology of antibody and variant, applied in the field of molecular biology

Inactive Publication Date: 2009-07-22
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The precise mechanisms controlling the angiogenic switch are not fully understood, but neovascularization of tumor masses is thought to result from a net balance of numerous angiogenic stimulators and inhibitors (Folkman, Nat. Med. 1(1):27-31 (1995) )

Method used

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  • Anti-dll4 antibodies and methods using same.
  • Anti-dll4 antibodies and methods using same.
  • Anti-dll4 antibodies and methods using same.

Examples

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preparation example Construction

[0432] v. Preparation of antibody-drug conjugates

[0433] In the antibody-drug conjugate (ADC) of the present invention, the antibody (Ab) is coupled to one or more drug moieties (D) via a linker (L), for example, about 1 to about 20 moieties per antibody. drug module. The ADC of general formula I can be prepared through several routes using organic chemical reactions, conditions and reagents known to those skilled in the art, including: (1) the nucleophilic group of the antibody reacts with a divalent linker reagent through a covalent bond to form Ab-L, which subsequently reacts with the drug moiety D; and (2) the nucleophilic group of the drug moiety reacts via a covalent bond with a divalent linker reagent to form D-L, which subsequently reacts with the nucleophilic group of the antibody. Additional methods for preparing ADCs are described herein.

[0434] Ab-(L-D)p I

[0435] A joint may consist of one or more joint components. Exemplary linker building blocks include...

Embodiment 1

[0512] Example 1: Materials and methods

[0513] The following materials and methods were used in the examples.

[0514] HUVEC fibrin gel bead assay. Details of the HUVEC fibrin gel bead assay have been described (Nakatsu, M.N. et al., Microvasc Res 66, 102-12 (2003)). Briefly, Cytodex was coated with 350-400 HUVEC / bead TM 3 beads (Amersham Pharmacia Biotech). Embed approximately 200 HUVEC-coated beads into the fibrin clot in one well of a 12-well tissue culture plate. will be 8 x 10 4 SF cells were plated on top of the clot. Assays were terminated between days 7 and 9 for immunostaining and imaging. In some experiments, HUVEC shoots were visualized by staining with biotin-anti-CD31 (clone WM59, eBioscience) and streptavidin-Cy3. For HUVEC nuclei staining, fibrin gels were fixed overnight in 2% paraformaldehyde (PFA) and stained with 4',6-diamidino-2-phenylindole (DAPI, Sigma). For Ki67 staining, fibrin gels were treated with 10X trypsin-EDTA for 5 min to remove upper...

Embodiment 2

[0542] Example 2: Generation of phage anti-DLL4 antibodies

[0543] A synthetic phage antibody library was constructed on a single framework (humanized anti-ErbB2 antibody, 4D5) by introducing diversity within the complementarity-determining regions (CDRs) of the heavy and light chains (Lee, C.V. et al., J Mol Biol 340, 1073- 93 (2004); Liang, W.C. et al., J Biol Chem 281, 951-61 (2006)). For immobilization in MaxiSorp TM His-tagged human DLL4 (amino acid 1-404) on the immunoplate was implemented against unimmunized ( ) plate panning of the library. After four rounds of enrichment, clones were randomly picked and specific binders were identified using phage ELISA. The resulting hDLL4-binding clones were further screened with His-tagged murine DLL4 protein to identify cross-species clones. For each positive phage clone, the heavy and light chain variable regions were subcloned into a pRK expression vector engineered to express the full-length IgG chain. The heavy and ligh...

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Abstract

The invention provides anti-DLL4 antibodies, and compositions comprising and methods of using these antibodies.

Description

field of invention [0001] The present invention relates generally to the field of molecular biology. More specifically, the present invention concerns anti-DLL4 antibodies and uses thereof. Background of the invention [0002] The development of vascular supply is an essential requirement for many physiological and pathological processes. Actively growing tissues such as embryos and tumors require an adequate blood supply. They meet this need by producing pro-angiogenic factors that promote the formation of new blood vessels through a process called angiogenesis. Tube formation of blood vessels is a complex but ordered biological event involving all or many of the following steps: a) proliferation of ECs from pre-existing endothelial cells (ECs) or differentiation of ECs from progenitor cells; b) migration and joining of ECs to form cord-like structures; c) vascular cords then undergo tubulogenesis to form vessels with a central lumen; d) existing cords or vessels sprout ...

Claims

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Application Information

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IPC IPC(8): C07K16/22C12N15/13C12N5/12A61K39/395A61P35/00
Inventor 严民宏吴雁
Owner GENENTECH INC
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