Kyowa Hakko Kirin Co., Limited

Kirin Pharma Kabushiki Kaisha

Sab, LLC

E. R. Squibb Sons, Inc.

Kirin Beer Kabushiki Kaisha

Kirin Holdings Kabushiki Kaisha

Hematech, LLC

Medarex Inc.

Yoshimi Kuroiwa

Kazuma Tomizuka

Isao Ishida

James M Robl

Hitoshi Yoshida

Barbara A Osborne

Richard A Goldsby

Mitsuo Oshimura

Poothappillai Kasinathan

Kazunori Hanaoka

Hiroaki Matsushita

Stacy E Ferguson

Akiko Sano

Philippe Collas

Minoru Kakeda

Eddie Sullivan

Motonobu Katoh

Akiko Kanai

P Kasinathan

The present invention relates to a human artificial chromosome which is genetically transmissible to the next generation with high efficiency and the method for using the same. More specifically, the present invention relates to: a human artificial chromosome in which an about 3.5 Mb to about 1 Mb region containing an antibody &#x3bb; light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome; a non-human animal carrying the human artificial chromosome and an offspring thereof; a method for producing the non-human animal; a method for producing a human antibody using the nonhuman animal or an offspring thereof; and a human antibody-producing mouse carrying the human artificial chromosome.

Human artificial chromosome containing human antibody lambda light chain gene and non-human animal containing the human artificial chromosome capable of genetic transmission

The invention relates to large-scale production of human antibodies by transgenic animals with high production of fully human IgG up to &#x3e;10 g/L in sera with human IgG1 subclass dominancy. This invention also supports a feasibility of complex chromosome engineering for complicated genetic studies in non-murine mammalian species.

Complex chromosome engineering for production of human antibodies in transgenic animals

A human artificial chromosome vector comprising a gene encoding a human antibody heavy chain, a gene encoding a human antibody light chain, and a gene encoding an IgM heavy chain constant region derived from a nonhuman animal.

Human artificial chromosome vector

Human artificial chromosome containing human antibody &#x3bb; light chain gene and non-human animal containing the human artificial chromosome  capable of genetic transmission

The present invention provides a human artificial chromosome vector comprising a gene encoding the human antibody heavy chain, a gene encoding the human antibody light chain, and a gene encoding IgM heavy chain constant region derived from a nonhuman animal; and being capable of producing a human antibody with a higher efficiency when the vector is introduced into an animal. By immunizing the animal produced using a human artificial chromosome vector of the present invention with a desired antigen, a large quantity of human polyclonal antibodies can be supplied.

The present invention relates to a human artificial chromosome (HAC) vector and a method for producing the same. The present invention further relates to a method for introducing foreign DNA using a human artificial chromosome vector and a method for producing a cell which expresses foreign DNA. Furthermore, the present invention relates to a method for producing a protein.

Human artificial chromosome (HAC) vector

The present invention relates to a method for producing a modified foreign chromosome(s) or a fragment(s) thereof, which comprises the steps of: (a) preparing a microcell comprising a foreign chromosome(s) or a fragment(s) thereof, and transferring said foreign chromosome(s) or a fragment(s) into a cell with high homologous recombination efficiency through its fusion with said microcell; (b) in said cell with high homologous recombination efficiency, inserting a targeting vector by homologous recombination into a desired site of said foreign chromosome(s) or a fragment(s) thereof, and/or a desired site of a chromosome(s) derived from said cell with high homologous recombination efficiency, thereby marking said desired site; and (c) in said cell with high homologous recombination efficiency, causing deletion and/or translocation to occur at the marked site of said foreign chromosome(s) or a fragment(s) thereof.

Method for modifying chromosomes

In general, the invention features genetically modified non-human mammals (e.g., bovines and other ungulates), and methods of making these mammals. In particular, the invention features transgenic ungulates having reduced levels of endogenous IgM heavy chain and/or prion protein.

Method of producing xenogenous antibodies using a bovine

The present invention relates to a method of producing an ungulate having both copies of the IgM heavy chain (mu) rag-1 and/or rag-2 gene eliminated from its genome. Animals which have IgM, rag-1 and/or rag-2 eliminated from their genome are unable to conduct the gene rearrangements that are necessary to generate the antigen receptors of B- or T-lymphocytes, and therefore will not develop native B- or T-cells. Because they are unable to produce B- and T-lymphocytes, these IgM, rag-1, or rag-2 ungulates cannot reject human hematopoietic stem cell preparations, and B- and T-lymphocytes which develop therefrom. Therefore, the present invention also involves injecting into IgM, rag-1, and/or rag-2 deficient ungulates, in utero or shortly after birth, human B- and T-lymphocytes whose immune systems produce human immunoglobulin that can be processed for therapeutic uses in humans.

Production of ungulates, preferably bovines that produce human immunoglobulins

The invention provides cloned transgenic ungulates (e.g., bovines) in which prion protein activity is reduced by one or more genetically engineered mutations. Desirably, these transgenic bovines are also genetically modified to express xenogenous (e.g., human) antibodies. Because of their resistance to prion-related diseases such as bovine spongiform encephalopy (also known as mad cow disease), these bovines are a safer source of human antibodies for pharmaceutical uses and a safer source of agricultural products.

Transgenic bovine having reduced prion protein activity and uses thereof

The invention features novel methods for the production of large quantities of xenogenous antibodies, such as human antibodies. Preferably, this result is effected by inactivation of IgM heavy chain expression and, optionally, by inactivation of Ig light chain expression, and by the further introduction of an artificial chromosome which results in the expression of xenogenous antibodies (e.g., non-bovine antibodies), preferably human antibodies.

Transgenic ungulates capable of human antibody production

The present invention relates to the production of a transgenic bovine which comprises a genetic modification that results in inactivation and loss of expression of its endogenous antibodies, and the expression of xenogenous antibodies, preferably human antibodies. This is effected by inactivation of the IgM heavy chain expression and, optionally, by inactivation of the Ig light chain expression, and by the further introduction of an artificial chromosome which results in the expression of non-bovine antibodies, preferably human antibodies.

Expression of xenogenous (human) immunoglobulins in cloned, transgenic ungulates

The present invention relates to a human artificial chromosome which is genetically transmissible to the next generation with high efficiency and the method for using the same. More specifically, the present invention relates to: a human artificial chromosome in which an about 3.5 Mb to about 1 Mb region containing an antibody &#x3bb; light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome; a non-human animal carrying the human artificial chromosome and an offspring thereof; a method for producing the non-human animal; a method for producing a human antibody using the non-human animal or an offspring thereof; and a human antibody-producing mouse carrying the human artificial chromosome.

Growing community of inventors

Sioux Falls, SD, United States of America

Yoshimi Kuroiwa