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Immune-Derived Moieties Reactive Against Bioactive Lipids, and Methods of Making and Using Same

a technology of immunodeficiency lipoprotein and reactive lipid, which is applied in the field of monoclonal antibodies, can solve the problems of lpa being difficult to target antibody production, s1p within these systems can have detrimental effects, and lipids have traditionally been considered poor targets for antibody-based therapeutic and diagnostic/prognostic approaches, etc., to achieve the effect of minimizing the likelihood of bioactive lipids

Inactive Publication Date: 2008-06-12
SABBADINI ROGER A +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0065]In certain preferred embodiments, such a derivatized bioactive lipid may be used to identify an antibody reactive against an epitope of the particular bioactive lipid present in the immunogen used to generate the antibodies being detected. To perform this role a particular derivatized bioactive lipid or derivatized bioactive lipid conjugate may be attached to a solid support, preferably the solid phase of an assay device, such as an ELISA plate, a Biacore chip, etc. Attachment to a solid support minimizes the likelihood that the bioactive lipid will be washed away during antibody binding and detection.

Problems solved by technology

As such, lipids have traditionally been considered to be poor targets for antibody-based therapeutic and diagnostic / prognostic approaches.
LPA has proven to be difficult targets for antibody production, although there has been a report in the scientific literature of the production of polyclonal murine antibodies against LPA (Chen et al.
Alterations of endogenous levels of S1P within these systems can have detrimental effects, eliciting several pathophysiologic conditions, including cancer, heart failure, and infectious and autoimmune diseases.
What is particularly unique about the anti-S1P approach is that while sphingolipid-based anti-cancer strategies that target key enzymes of the sphingolipid metabolic pathway, such as SPHK, have been proposed, the lipid mediator S1P itself was not previously emphasized, largely because of difficulties in directly mitigating this lipid target, in particular because of the difficulty first in raising antibodies against a lipid target such as S1P, and second, in detecting antibodies in fact produced against the S1P target.
As already noted, similar difficulties exist with respect to treatments and diagnostic approaches directed at other lipid targets.
As will be appreciated, it is not always possible to distinguish between “preventing” and “suppressing” a disease or disorder because the ultimate inductive event or events may be unknown or latent.

Method used

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  • Immune-Derived Moieties Reactive Against Bioactive Lipids, and Methods of Making and Using Same
  • Immune-Derived Moieties Reactive Against Bioactive Lipids, and Methods of Making and Using Same
  • Immune-Derived Moieties Reactive Against Bioactive Lipids, and Methods of Making and Using Same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthetic Scheme for Making a Representative Thiolated Analog of S1P

[0173]The synthetic approach described in this example results in the preparation of an antigen by serial addition of structural elements using primarily conventional organic chemistry. A scheme for the approach described in this example is provided in FIG. 1, and the compound numbers in the synthetic description below refer to the numbered structures in FIG. 1.

[0174]This synthetic approach began with the commercially available 15-hydroxyl pentadecyne, 1, and activation by methyl sulphonyl chloride of the 15-hydroxy group to facilitate hydroxyl substitution to produce the sulphonate, 2. Substitution of the sulphonate with t-butyl thiol yielded the protected thioether, 3, which was condensed with Garner's aldehyde to produce 4. Gentle reduction of the alkyne moiety to an alkene (5), followed by acid catalyzed opening of the oxazolidene ring yielded S-protected and N-protected thiol substituted sphingosine, 6. During ...

example 2

Synthetic Schemes for Making Thiolated Fatty Acids

[0194]The synthetic approach described in this example details the preparation of a thiolated fatty acid to be incorporated into a more complex lipid structure that could be further complexed to a protein or other carrier and administered to an animal to elicit an immune response. The approach uses using conventional organic chemistry. A scheme showing the approach taken in this example is provided in FIG. 2, and the compound numbers in the synthetic description below refer to the numbered structures in FIG. 2.

[0195]Two syntheses are described. The first synthesis, for a C-12 thiolated fatty acid, starts with the commercially available 12-dodecanoic acid, compound 14. The bromine is then displaced with t-butyl thiol to yield the protected C-12 thiolated fatty acid, compound 15. The second synthesis, for a C-18 thiolated fatty acid, starts with the commercially available 9-bromo-nonanol (compound 16). The hydroxyl group in compound 16...

example 3

Synthetic Scheme for Making a Thiolated Analog of LPA

[0203]The synthetic approach described in this example results in the preparation of thiolated LPA. The LPA analog can then be further complexed to a carrier, for example, a protein carrier, which can then be administered to an animal to elicit an immugenic response to LPA. This approach uses both organic chemistry and enzymatic reactions, the synthetic scheme for which is provided in FIG. 3. The compound numbers in the synthetic description below refer to the numbered structures in FIG. 3.

[0204]The starting materials were compound 15 in Example 2 and enantiomerically pure glycerophoshocholine (compound 22). These two chemicals combined to yield the di-acetylated product, compound 23, using DCC to facilitate the esterification. In one synthetic process variant, the resulting di-acylated glycerophosphocholine was treated first with phospholipase-A2 to remove the fatty acid at the sn-2 position of the glycerol backbone to produce co...

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Abstract

Compositions and methods for producing monoclonal antibodies and their derivatives reactive against bioactive lipid targets are described. These compositions include derivatized lipids, each of which comprises a bioactive lipid that having a polar head group and at least one hydrocarbon chain (e.g., a lysolipid such as lysophosphatidic acid or sphingosine-1-phosphate) in which a carbon atom has been derivatized with a pendant reactive group; immunogens made by linking a derivatized lipid to a carrier moiety (e.g., a carrier protein, polyethylene glycol, colloidal gold, alginate, or a silicone bead); monoclonal antibodies and derivatives produced by immunizing an animal with such an immunogen; and therapeutic and diagnostic compositions containing such antibodies and antibody derivatives. Methods for making such derivatized lipids, immunogens, and monoclonal antibodies and derivatives, methods for detecting such antibodies once generated, and therapeutic and diagnostic methods for using such antibodies and derivatives, are also described.

Description

RELATED APPLICATIONS[0001]This patent application claims priority to U.S. provisional patent application Ser. No. 60 / 810,185, filed 31 May 2006 (attorney docket number LPT-3100-PV), U.S. provisional patent application Ser. No. 60 / 835,569, filed 4 Aug. 2006 (attorney docket number LPT-3100-PV2), and U.S. provisional patent application Ser. No. 60 / 923,644, filed 16 Apr. 2007 (attorney docket number LPT-3100-PV3). These applications are hereby incorporated by reference in their entirety for any and all purposes.GOVERNMENT FUNDING[0002]This invention was funded at least in part by funds supplied by the U.S. government pursuant to grant application NCI 2R44CA110298-2. As a result, the U.S. government may have certain rights in the inventions described herein.TECHNICAL FIELD[0003]The present invention relates to monoclonal antibodies, and methods for generating antibodies against immunogens that comprise a bioactive lipid molecule that plays a role in human and / or animal disease as a sign...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/18
CPCA61K47/48053A61K47/48215A61K47/48284A61K47/4833A61K2039/505G01N33/92C07K16/30C07K2317/24C07K2317/56C07K2317/73C07K2317/74C07K16/18A61K47/60A61K47/544A61K47/643A61K47/646A61P35/00A61P35/02A61P35/04A61P43/00
Inventor SABBADINI, ROGER A.GARLAND, WILLIAM A.HANSEN, GENEVIEVE
Owner SABBADINI ROGER A
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