Targeting compounds

a technology of biological molecules and compounds, applied in the field of targeting compounds, can solve the problems that conventionally developed pharmaceutical drugs and biological effector molecules are often of limited use in therapy, and achieve the effects of reducing the ability of a targeting agent or biological agent to cross, reducing or inhibiting the ability of the agent to cross the cell membran

Inactive Publication Date: 2013-07-04
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The antibody targeting compound confers various benefits over the components themselves. For example, the antibody portion of the compound may generally extend the half-life of a smaller sized targeting or biological agent in vivo. Also, the biological potency or other biological feature of a particular targeting or biological agent may be modified by the addition of effector function(s) provided by the antibody portion of the compound (e.g., complement mediated effector functions). In addition, the targeting agent or binding agent, through its increased size conferred by linkage to the antibody, may enable the targeting agent to function in new capacities.
[0013]Additionally provided are methods of altering at least one physical or biological characteristic of a targeting agent or biological agent. In one embodiment, the agent is covalently linked to the combining site of an antibody to generate an antibody targeting compound. Methods are also provided for modifying one or more physical or biological properties of the antibody targeting compounds by modifying one or more chemical characteristics of the linker. In some embodiments, the physical or biological properties modified include pharmacokinetics, pharmacodynamics, immunogenicity, binding affinity, susceptibility to degradation, solubility, lipophilicity, hydrophilicity, hydrophobicity, stability, and rigidity.
[0020]Still further provided are methods of inhibiting or reducing the ability of a targeting agent or biological agent to cross a cell membrane. In these methods an antibody targeting compound is formed by covalently linking the combining site of an antibody that does not itself cross the cell membrane to the targeting agent or biological agent, wherein linkage of said antibody to said targeting agent or biological agent reduces or inhibits the ability of the agent to cross the cell membrane.

Problems solved by technology

Conventionally developed pharmaceutical drugs and biological effector molecules are often of limited use in therapy because of high toxicity.

Method used

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Examples

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example 1

Antibody Targeting Compound Comprising an RGD Peptidomimetic Targeting Agent Covalently Linked to the Combining Site of Aldolase Monoclonal Antibody 38C2

[0183]An integrin targeting compound was formed based on the formation of a reversible covalent bond between a diketone linker derivative of an RGD peptidomimetic and the reactive lysine of mouse mAb 38C2. Mouse mAb 38C2 is the prototype for a new class of catalytic antibodies generated by reactive immunization and mechanistically mimic natural aldolase enzymes (Barbas et al., Science 278, 2085-2092, 1997). Through a reactive lysine, these antibodies catalyze aldol and retro-aldol reactions using the enamine mechanism of natural aldolases (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 efficacy in synthetic organic chemistry, aldolase antibodies have been used in the activation of camptothecin, do...

example 2

Antibody Targeting Compound Comprising IL-4 as Targeting Agent Covalently Linked to the Combining Site of Aldolase Monoclonal Antibody 38C2

[0188]Kaposi's sarcoma tumor cells, among other human epithelial tumor cells, express interleukin-4 (IL-4) receptors that can be targeted with a recombinant chimeric protein consisting of IL-4 and a truncated form of bacterial toxin called Pseudomonas exotoxin (Husain et al., 1999, Nat. Med. 5, 817-822). Based on these studies, an IL-4 targeting compound for targeting mAb 38C2 to Kaposi's sarcoma tumor cells is prepared. A linker with a diketone reactive group is conjugated to a lysine side chain of IL-2 using a lysine reactive moiety such as N-hydroxysuccinimide (NHS). Alternatively, a recombinant IL-4 with an added free cysteine is used for conjugation to cysteine reactive moieties such as maleimide. To reduce immunogenicity associated with the linker portion of the targeting compound, the spacer (i.e. linker connecting chain) between the diket...

example 3

Antibody Targeting Compound Comprising VEGF-R2 Binding Peptide as Targeting Agent Covalently Linked to the Combining Site of Aldolase Monoclonal Antibody 38C2

[0189]Vascular endothelial growth factor (VEGF) is a key modulator of tumor angiogenesis. Induced by hypoxia, VEGF expression is upregulated through the induction of VEGF mRNA transcription in the tumor. Following production and release by the tumor, VEGF diffuses to endothelial cells of nearby preexisting blood vessels, which display VEGF receptors (VEGFR). VEGF binds to two tyrosine kinase receptors, VEGFR-1 and VEGFR-2, which are expressed predominantly on endothelial cells. Activation of endothelial cells is associated with the binding of VEGF to VEGFR-2, whereas VEGFR-1 probably functions as a decoy receptor that regulates the local concentration of VEGF (Neufeld et al., 1999, FASEB J. 13, 9-22). Following activation, the endothelial cells proliferate, migrate directionally toward the tumor, and eventually roll up and inte...

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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 noncovalently linking a targeting agent to the combining site of an antibody. By this approach, the covalently modified antibody takes on the binding specificity of the targeting agent. The compound may have biological activity provided by the targeting agent or by a separate biological agent. Various uses of the invention compounds are provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Ser. No. 10 / 420,373, filed Apr. 21, 2003, which claims the benefit of U.S. Pat. No. 8,252,902, filed Oct. 22, 2002, which claims the benefit of U.S. Provisional Application No. 60 / 412,455, filed Sep. 19, 2002, and U.S. Provisional Application No. 60 / 344,614, filed Oct. 22, 2001; the entire disclosures of which are hereby incorporated by reference in their entirety for all purposes.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with United States Government support under Grant Nos. CA27489 and CA86258 by the National Institutes of Health. The United States Government has certain rights in the invention.REFERENCE TO SEQUENCE LISTING[0003]This application includes a Sequence Listing submitted electronically as a text file named 22394US_SequenceListing.txt, created on Feb. 26, 2013, with a size of 3,422 bytes. The sequence listing is incorporated by refe...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00C07K14/54C07K14/71C12N15/115C12N9/00C07K14/47C07K14/575C07K14/16C07K7/06C07K5/09C07D475/04G01N33/53A61K39/395A61K47/48A61P31/00A61P31/04A61P31/12C07K16/40G01N33/15G01N33/566
CPCA61K47/48023C12N2740/16022A61K47/48269A61K47/48346A61K47/48423A61K47/48646A61K47/48684A61K47/48715B82Y5/00C07K16/40A61K49/0058C12N9/0002C07K14/71C07K14/575C07K14/5406C12N15/115C07K14/16C07K7/06C07K5/0817C07D475/04C07K14/47C07K14/005A61K47/48061A61K47/54A61K47/545A61K47/642A61K47/66A61K47/6813A61K47/6871A61K47/6881A61K47/6889A61P31/00A61P31/04A61P31/12A61P35/00A61K39/395
Inventor BARBAS, CARLOS F.RADER, CHRISTOPHSINHA, SUBHASH C.LERNER, RICHARD A.
Owner THE SCRIPPS RES INST
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