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NOVEL HIV NEUTRALIZING HUMAN MABS FROM TRANSGENIC MICE

Award Number: R01AI050452
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 02/01/2002
PERIOD OF PERFORMANCE END DATE: 01/31/2007

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NOVEL HIV NEUTRALIZING HUMAN MABS FROM TRANSGENIC MICE - DESCRIPTION: This project will use the transgenic "XenoMouse" system, developed by Abgenix, to isolate novel human monoclonal antibodies against HIV-1 which possess potential clinical utility. These mice contain -2 megabases of the human Ig heavy and kappa light chain loci that functionally recapitulate the human humoral immune system. In preliminary studies, we have immunized Xenomice with a number of HIV envelope antigens, including recombinant fusion proteins expressing several of the variable loop domains of the viral surface protein, and a recombinant gpl20 derived from the primary virus isolate, SF162. This latter antigen was uccessful in eliciting Mabs that recognized native viral envelope proteins, including antibodies with potent neutralizing activities for the SF162 strain. Multiple types of epitopes were recognized, including some that had not been previously described. Domains recognized by neutralizing Mabs included the CD4-binding domain and other conserved conformational epitopes in gpl20, as well as sites in the V3 and V1/V2 hypervariable regions. The most potently neutralizing antibodies were directed against type-specific V1/V2 epitopes. In further proposed studies, the epitopes recognized by current neutralizing antibodies will be fully characterized, and the complete range of their neutralizing activities determined. Additional immunizations will be performed with related gpl20 immunogens derived from additional strains, including non-clade B strains. In order to elicit antibodies to native epitopes important for neutralization that may not survive gpl20 purification, immunizations will also be performed with native envelope complexes expressed on virion particles and on mouse B cells expressing the complete e n v gene. Immunizations will also be performed with viral particles expressing the HIV receptors, CD4, CCR5 and CXCR4, on their surfaces, as well as with mixtures of particles expressing both Env and HIV receptors, in order to generate human antibodies against 'activated gpl20' epitopes, or against the receptors themselves. To facilitate the identification of antibodies with functional activities, hybridomas will be screened directly by a sensitive neutralization assay, in addition to traditional binding assays. Epitopes recognized by Mabs with neutralizing activities will be fully mapped, and the full range of antiviral activities of interesting Mabs will be characterized. It is anticipated that these studies should help define the diversity of neutralization epitopes present both on the surface of HIV-1 and its cellular receptors. Ultimately, these studies may lead to the generation of a cocktail of novel human Mabs with antiviral activities against multiple clinical strains, that could serve as an effective immunotherapeutic reagent to control and prevent HIV infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $379,859 )
2006	2006	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	1/27/2006	NON-COMPETING CONTINUATION	$379,859
														Subtotal = $379,859

Issue Date FY: 2005 ( Subtotal = $389,000 )
2005	2005	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Microbiology and Infectious Diseases Research	000	4	2/28/2005	NON-COMPETING CONTINUATION	$389,000
														Subtotal = $389,000

Issue Date FY: 2004 ( Subtotal = $389,000 )
2004	2004	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Microbiology and Infectious Diseases Research	000	3	1/5/2004	NON-COMPETING CONTINUATION	$389,000
														Subtotal = $389,000

Issue Date FY: 2003 ( Subtotal = $389,000 )
2003	2003	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Microbiology and Infectious Diseases Research	000	2		NON-COMPETING CONTINUATION	$389,000
														Subtotal = $389,000

Issue Date FY: 2002 ( Subtotal = $389,000 )
2002	2002	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Microbiology and Infectious Diseases Research	000	1	1/24/2002	NEW	$389,000
														Subtotal = $389,000

Grand Total All Awards = $1,935,859

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NOVEL HIV NEUTRALIZING HUMAN MABS FROM TRANSGENIC MICE

Award Number: R01AI050452

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 02/01/2002

PERIOD OF PERFORMANCE END DATE: 01/31/2007

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