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Compositions and methods for modulating vascular development

An angiogenesis and anti-vascular technology, applied in the field of compositions regulating vascular development

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

AI Technical Summary

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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  • Compositions and methods for modulating vascular development
  • Compositions and methods for modulating vascular development
  • Compositions and methods for modulating vascular development

Examples

Experimental program
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preparation example Construction

[0354] v. Preparation of antibody-drug conjugates

[0355] In an antibody-drug conjugate (ADC), an antibody (Ab) is coupled to one or more drug moieties (D) via a linker (L), for example, about 1 to about 20 drug moieties per antibody . 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.

[0356] Ab-(L-D)p I

[0357] A joint may consist of one or more joint components. Exemplary linker building blocks include 6-maleimidocaproyl ("MC"), male...

Embodiment 1

[0396] Example 1: Materials and methods

[0397] The following materials and methods were used in the examples.

[0398] 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™3 beads (Amersham Pharmacia Biotech) were coated at 350-400 HUVEC / bead. 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 SF, n...

Embodiment 2

[0426] Example 2: Generation of phage anti-DLL4 antibodies

[0427] 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 the His-tagged human DLL4 (amino acids 1-404) immobilized on the Maxisorp immunoplate, the 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 light chain constructs were ...

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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 generally relates to compositions and methods useful for modulating vascular development. The present invention relates in part to the use of delta-like 4 (DLL4) antagonists for the diagnosis and treatment of disorders associated with angiogenesis. 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 ...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K39/395
Inventor 严民宏
Owner GENENTECH INC
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