Antibody targeting compounds

一种抗体靶向、化合物的技术，应用在靶向生物分子的化合物领域，能够解决限制等问题

Inactive Publication Date: 2005-04-13
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Routinely developed drugs and bioeffector molecules are often limited in therapeutic applications due to high toxicity

Method used

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  • Antibody targeting compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209] Example 1: Antibody Targeting Compounds Containing RGD Peptidomimetic Targeting Formulations Covalently Linked to the Binding Site of Aldolase Monoclonal Antibody 38C2

[0210]Integrin-targeting compounds were formed based on the formation of a reversible covalent bond between a diketone linker derivative of the RGD peptidomimetic and the active lysine of mouse mAb 38C2. The mouse mAb 38C2 is the prototype of a new class of catalytic antibodies generated by reactive immunization and mechanistic mimicry of natural aldolases (Barbas et al., Science 278, 2085-2092, 1997). Using the enamine mechanism of natural aldolases, these antibodies catalyze aldol and retro-aldol reactions via active lysine (Wagner et al., Science 270, 1797-1800, 1995; Barbas et al., Science 278, 2085 -2092, 1997; Zhong et al., Angew. Chem. Int. Ed. 38, 3738-3741, 1999). In addition to their versatility and effectiveness in synthetic organic chemistry, aldolase antibodies have been used as anticancer...

Embodiment 2

[0215] Example 2: Antibody Targeting Compounds Containing IL-4 as a Targeting Agent Covalently Linked to the Binding Site of Aldolase Monoclonal Antibody 38C2

[0216] Among other human endothelial tumor cells, Kaposi's sarcoma tumor cells express the interleukin-4 (IL-4) receptor, which uses a recombinant chimeric protein consisting of IL-4 and endotoxin called Pseudomonas A truncated form of the bacterial toxin can be targeted to a target (Husain et al., 1999, Nat. Med. 5, 817-822). Based on these studies, IL-4 targeting compounds for targeting mAb 38C2 to Kaposi's sarcoma tumor cells were prepared. A linker bearing a diketone reactive group is conjugated to the lysine side chain of IL-2 using a lysine reactive moiety such as N-hydroxysuccinimide (NHS). Alternatively, recombinant IL-4 with added free cysteine ​​is used conjugated to a cysteine ​​active moiety such as maleimide. In order to reduce the immunogenicity associated with the linker portion of the targeting compou...

Embodiment 3

[0217] Example 3: Antibody Targeting Compounds Containing VEGF-R2 Binding Peptides Covalently Linked to the Binding Site of Aldolase Monoclonal Antibody 38C2 as Targeting Agents

[0218] Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis. Induced by hypoxia, upregulation of VEGF expression is induced via VEGF mRNA transcription in tumors. After production and release by tumors, VEGF diffuses to endothelial cells adjacent to pre-existing blood vessels, which display VEGF (VEGFR) receptors. VEGF binds two tyrosine kinase receptors, VEGFR-1 and VEGFR-2, which are mainly expressed on endothelial cells. Activation of endothelial cells is associated with VEGF binding to VEGFR-2, and VEGR-1 may function as a decoy receptor regulating local concentrations of VEGF (Neufeld et al., 1999, FASEB J.13, 9-22). Upon activation, endothelial cells proliferate, migrate directly to the tumor, and finally wind up and connect with each other to form new blood vess...

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Abstract

The present invention provides antibody targeting compounds in which the specificity of the antibody has been reprogrammed by covalently or non-covalently linking a targeting agent to the antibody binding site. By this approach, covalently modified antibodies exhibit binding specificity for the targeted agent. Compounds may have biological activity provided by targeted agents or separate biological agents. Various uses of the compounds of the invention are provided.

Description

Background of the invention [0001] The present invention relates to compounds targeting biomolecules and methods of making and using these compounds. Conventionally developed drugs and bioeffector molecules are often limited in their use in therapy due to high toxicity. Over the years, various approaches have been employed to improve the therapeutic index of such drugs or effectors. One approach is to couple the drug or effector to a ligand-targeting agent such as an antibody. In this case, antibodies are used to alter the distribution of the drug or effector so that most of it can be localized in the body where it is most needed. Improved targeting of small molecular weight drugs or effectors has been achieved by complexing the drug or effector with a large molecular weight compound. For example, European Patent EP 217577 discloses that increased half-life and targeting of a drug can be achieved by complex formation between a hapten modifier and an anti-hapten antibody in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/53A61K39/395A61K47/48A61K49/00A61P31/00A61P31/04A61P31/12C07K16/40G01N33/15G01N33/566
CPCA61K47/54A61K47/545A61K47/642A61K47/66A61K47/6813A61K47/6871A61K47/6881A61K47/6889A61P31/00A61P31/04A61P31/12A61P35/00B82Y5/00C07D475/04C07K14/005C07K16/40C12N9/0002C12N2740/16022A61K39/395A61K49/0058C07K5/0817C07K7/06C07K14/47C07K14/5406C07K14/575C07K14/71C12N15/115
Inventor C·F·巴巴斯C·拉德尔S·C·辛哈R·莱纳
Owner THE SCRIPPS RES INST
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