Abgenix, Inc.

Cell Genesys, Inc.

Other

Amgen Fremont Inc.

The University of North Carolina at Chapel Hill

Dana-farber-cancer Institute Inc.

Albert Einstein College of Medicine

Raju S Kucherlapati

Aya Jakobovits

Daniel J Capon

Sue Klapholz

Daniel G Brenner

Oliver Smithies

Beverly H Koller

Larry L Green

Robert B Dubridge

Steven R Williams

Michael J Mendez

Jeffrey W Pollard

Winfried Edelmann

Gary Greenburg

Richard D Kolodner

Susan Klapholz

Mariona Lourdes De Rafael

Burkhard Kneitz

Paula E Cohen

Panos Stevis

Mariona Lourdes Arbones De Rafael

Sue Kalpholz

The present invention relates to transgenic non-human animals that are engineered to contain human immunoglobulin gene loci. In particular, animals in accordance with the invention possess human Ig loci that include plural variable (Vand V&#x3ba;) gene regions. Advantageously, the inclusion of plural variable region genes enhances the specificity and diversity of human antibodies produced by the animal. Further, the inclusion of such regions enhances and reconstitutes B-cell development to the animals, such that the animals possess abundant mature B-cells secreting extremely high affinity antibodies.

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An animal, e.g., transgenic mouse, in which the MSH5 gene is misexpressed. The animal is useful for screening treatments for a number of conditions. Methods for identifying contraceptive agents are also described.

Methods for identifying compounds which modulate the activity of MSH5

An animal, e.g., transgenic mouse, in which the MSH4 gene is misexpressed. The animal is useful for screening treatments for a number of conditions. Methods for identifying contraceptive agents are also described.

Methods for identifying contraceptive compounds

Fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Human antibodies derived from immunized xenomice

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by multiple genetic modifications of embryonic cells in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci. Chimeric and transgenic mammals, particularly mice, are provided, having stably integrated large, xenogeneic DNA segments. The segments are introduced by fusion with yeast spheroplasts comprising yeast artificial chromosomes (YACs) which include the xenogeneic DNA segments and a selective marker such as HPRT, and embryonic stem cells.

Generation of xenogeneic antibodies

Antibodies with fully human variable regions against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Homologous recombination is employed to inactivate genes, particularly genes associated with MHC antigens. Particularly, the &bgr; -microglobulin gene is inactivated for reducing or eliminating the expression of functional Class I MHC antigens. The resulting cells may be used as universal donor cells. In addition, embryonic stem cells may be modified by homologous recombination for use in producing chimeric or transgenic mammalian hosts, which may be used as source of universal donor organs, or as models for drug and transplantation therapies. Methods for homologous recombination in non-transformed mammalian somatic cells are also described.

Homologous recombination for universal donor cells and chimeric mammalian hosts

MSH5 ablated mice and uses therefor

Generation of Xenogenetic antibodies

Homologous recombination is employed to inactivate genes, particularly genes associated with MHC antigens. Particularly, the .beta..sub.2- microglobulin gene is inactivated for reducing or eliminating the expression of functional Class I MHC antigens. The resulting cells may be used as allogeneic donor cells. Methods for homologous recombination in non-transformed mammalian somatic cells are also described.

Homologous recombination for allogeneic donor cells

Growing community of inventors

Darien, CT, United States of America

Raju S Kucherlapati