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 os 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 file d 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 / 8...

AI Technical Summary

Benefits of technology

[0036] The invention also provides vectors, methods, and compositions useful for suppressing the expression of one or more species of immunoglobulin chain(s), without disrupting an endogenous immunoglobulin locus. Such methods are useful for suppressing expression of one or more endogenous immunoglobulin chains while permitting the expression of one or more transgene-encoded immunoglobulin chains. Unlike genetic disruption of an endogenous immunoglobulin chain locus, suppression of immunoglobulin chain expression does not require the time-consuming breeding that is needed to establish transgenic animals homozygous for a disrupted endogenous Ig locus. An additional advantage of suppression as compared to engognous Ig gene disruption is that, in certain embodiments, chain suppression is reversible within an individual animal. For example, Ig chain suppression may be accomplished with: (1) transgenes encoding and expressing antisense RNA that specifically hybridizes to an endogenous Ig chain gene sequence, (2) antisense oligonucleotides that specifically hybridize to an endogenous Ig chain gene sequence, and (3) immunoglobulins that bind specifically to an endogenous Ig chain polypeptide.

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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