Transgenic non-human animals for producing heterologous and chimeric antibodies

Abstract

The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation-in-part of U.S. Ser. No. 08 / 728,463 filed Oct. 10, 1996, which is a continuation-in-part of U.S. Ser. No. 08 / 544,404 filed 10 Oct. 1995, which is a continuation-in-part of U.S. Ser. No. 08 / 352,322 filed 7 Dec. 1994, which is a continuation-in-part of U.S. Ser. No. 08 / 209,741 filed Mar. 9, 1994, which is a continuation-in-part of U.S. Ser. No. 08 / 165,699 filed Dec. 10, 1993, which is a continuation-in-part of U.S. Ser. No. 08 / 161,739 filed Dec. 3, 1993, which is a continuation-in-part of U.S. Ser. No. 08 / 155,301 filed Nov. 18, 1993, which is a continuation-in-part of U.S. Ser. No. 08 / 096,762 filed Jul. 22, 1993, which is a continuation-in-part of U.S. Ser. No. 08 / 053,131 filed Apr. 26, 1993, which is a continuation-in-part of U.S. Ser. No. 07 / 990,860 filed Dec. 16, 1992, which is a continuation-in-part of U.S. Ser. No. 07 / 904,068 filed Jun. 23, 1992, which is a continuation-in-part of U.S. Ser. No. 07 / 85...

AI Technical Summary

Benefits of technology

"The invention provides a way to produce transgenic non-human animals that can produce different types of antibodies, such as IgG, IgA, and IgE. These animals have B cells that can switch between different isotypes, allowing them to make a specific antibody in response to an antigen. The invention also includes methods to induce isotype switching in the animals and to determine if it has occurred. Overall, the invention provides a way to create animals that can produce a wide range of antibodies with different functions."

Problems solved by technology

For example, when immunocompetent human patients are administered therapeutic doses of rodent monoclonal antibodies, the patients produce antibodies against the rodent immunoglobulin sequences; these human anti-mouse antibodies (HAMA) neutralize the therapeutic antibodies and can cause acute toxicity.

However, producing human immunoglobulins that bind specifically with human antigens is problematic.

However, when present methods for generating monoclonal antibodies are applied for the purpose of generating human antibodies that have binding specificities for human antigens, obtaining B-lymphocytes which produce human immunoglobulins a serious obstacle, since humans will typically not make immune responses against self-antigens.

Hence, present methods of generating human monoclonal antibodies that are specifically reactive with human antigens are clearly insufficient.

It is evident that the same limitations on generating monoclonal antibodies to authentic self antigens apply where non-human species are used as the source of B-cells for making the hybridoma.

The results of such experiments, however, have been variable, in some cases, producing incomplete or minimal rearrangement of the transgene.

Transgenic animals that cannot switch isotypes are limited to producing heterologous antibodies of a single isotype, and more specifically are limited to producing an isotype that is essential for B cell maturation, such as IgM and possibly IgD, which may be of limited therapeutic utility.

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