Monoclonal Antibodies for Orphan GPCRs in the CNS

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$697,020.00
Award Year:
2012
Program:
SBIR
Phase:
Phase I
Contract:
1R43MH097383-01
Award Id:
n/a
Agency Tracking Number:
R43MH097383
Solicitation Year:
2012
Solicitation Topic Code:
NIMH
Solicitation Number:
PA10-081
Small Business Information
201 Elliott Avenue West, SEATTLE, WA, -
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
33364923
Principal Investigator:
PATGRAY
(206) 650-6765
pgray@omeros.com
Business Contact:
GREGORYDEMOPULOS
(206) 676-5000
gdemopulos@omeros.com
Research Institute:
Stub




Abstract
DESCRIPTION (provided by applicant): Monoclonal Antibodies for Orphan GPCRs in the CNS GPCRs comprise a large family of structurally related membrane proteins with critical functions in neurobiology. As such, they are key therapeutic targets. However, many members of the vast GPCR family remain orphans. A broad range of neurological indications, including schizophrenia, pain, Parkinson's and Alzheimer's diseases, and autism have been linked to orphan GPCRs, making them attractive targets for therapy. The paucity of reagents specific for the orphan GPCRs, however, has stymied drug development. Monoclonal antibodies (MAbs) are known as excellent research tools and have proven to be highly effective therapeutics. However, GPCRs are notoriously difficult antigens against which to raise antibodies, for reasons that include poor immunogenicity, high conservation between species, and a low membrane profile. XORI Corporation has established an innovative platform for rapid identification and optimization of MAbs exvivo that has the potential to circumvent the challenges presented by GPCRs. The platform has been validated by discovery and optimization of high affinity mAbs (KDlt 5 nM) against five cell surface proteins, including one GPCR. We propose to generate MAbsagainst orphan GPCRs that are highly expressed in neurological tissues. Specifically, we will (1) isolate MAbs specific for amino terminal domains of ten orphan GPCRs expressed in the brain, (2) isolate MAbs for ten full length recombinant orphan GPCRs bycell surface selection, and (3) determine functionality of the orphan GPCR monoclonal antibodies by biochemical and cellular characterization. These antibodies will provide invaluable new research tools and will position XORI for Phase II funding to evaluate diagnostic and therapeutic potential in vivo. Phase I deliverable: ten monoclonal antibodies specific for orphan GPCRs and three monoclonal antibodies with orphan GPCR-specific agonistic or antagonistic activity. These MAbs will open doorways to understanding function of the orphan receptors and will have the potential for diagnostic and therapeutic utility. Relevance: G protein-coupled receptors (GPCRs) comprise an important class of drug targets in neurological disease, but a large percentage of themremain poorly understood. We propose to generate monoclonal antibodies against a number of the orphan GPCRs using a novel ex vivo antibody discovery technology that circumvents the main challenges to antibody generation specific to GPCRs. These antibodies will provide important research reagents and may have diagnostic and therapeutic utility. PUBLIC HEALTH RELEVANCE: G protein-coupled receptors (GPCRs) comprise an important class of drug targets in neurological disease, but a large percentageof them remain poorly understood. We propose to generate monoclonal antibodies against a number of the orphan GPCRs using a novel ex vivo antibody discovery technology that circumvents the main challenges to antibody generation specific to GPCRs. These antibodies will provide important research reagents and may have diagnostic and therapeutic utility.

* information listed above is at the time of submission.

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