Transgenic non-human animals capable of producing heterologous a

Details Transgenic non-human animals capable of producing heterologous a Transgenic non-human animals capable of producing heterologous a

1994-09-19

1999-03-02

Ziska, Suzanne E.

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

4351723, 536 2353, 536 231, 536 235, 800DIG1, 800DIG4, C12N 1500, C07H 2102, C07H 2104

Patent

active

058773975

ABSTRACT:
The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppressed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterologous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.

REFERENCES:
patent: 4204244 (1980-05-01), Fell et al.
patent: 5175384 (1992-12-01), Krimpenfort
patent: 5416260 (1995-05-01), Koller
Muler et al Nature 295: 428, 1982.
Srujzerian et al PNAS 86: 6709, 1989.
Buttin, Exogenous Ig gene rearrangement in transgenic mice: a new strategy for human monoclonal antibody production? TIG--vol. 3, No. 8 (Aug. 1987).
Green et al., Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs, Nature Genetics 7:13-21 (1994).
Hofker et al., Complete physical map of the human immunoglobulin heavy chain constant region gene complex, Proc. Natl. Acad. Sci. USA 86:5567-5571 (1989).
Humphries et al., A new human immunoglobulin V.sub.H family preferentially rearranged in immature B-cell tumours, Nature 331:446-449 (1988).
Jaenisch, Transgenic Animals, Science 240:1468-1474 (1988).
Jakobovits et al., Analysis of homozygous mutant chimeric mice: Deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production, Proc. Natl. Acad. Sci. USA 90:2551-2555 (1993).
Lonberg et al., Antigen-specific human antibodies from mice comprising four distinct genetic modifications, Nature 368:856-859 (1994).
Miller et al., Structural alterations in J regions of mouse immunoglobulin .lambda. genes are associated with differential gene expression, Nature 295:428-430 (1982).
Morrison, Success in specification, Nature 368:812-813 (1994).
Pettersson et al., A second B cell-specific enhancer 3' of the immunoglobulin heavy-chain locus, Nature 344:165-168 (1990).
Scangos and Bieberich, Gene transfer into mice, Advances in Genetics 24: 285-322 (1987).
Stites et al., Basic & Clinical Immunology, p. 50 (1984).
Tanaka et al., An antisense oligonucleotide complementary to a sequence in I.gamma.2b Increase .gamma.2b germline transcrips, stimulates B cell DNA synthesis, and inhibits immunoglobulin secretion, The Journal of Experimental Medicine 175:597-607 (1992).
Taki et al., Targeted insertion of a variable region gene into the immunoglobulin heavy chain locus, Science 262:1268-1271 (1993).
Taylor et al., Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM, International Immunology 6:579-591 (1994).
Vlasov et al., Arrest of immunoglobulin G mRNA translation in vitro with an alkylating antisense oligonucleotide derivative, Chemical Abstracts, p. 28, 112:229433X (1990).
Weiss, Mice making human-like antibodies, The Washington Post, Apr. 28, 1994.
Alt et al., Immunoglobulin genes in transgenic mice, TIG--Aug. 1985.
Berman et. al., Content and organization of the human Ig V.sub.H locus: definition of three new V.sub.H families and linkage to the Ig C.sub.H locus, The EMBO J. 7:727-738 (1988).
Berton et. al., Synthesis of germ-line .gamma.1 immunoglobulin heavy-chain transcripts in resting B cells: Induction by interleukin 4 and inhibition by interferon .gamma., Proc. Natl. Acad. Sci. (U.S.A) 86:2829-2833 (1989).
Bollag et al., Homologous recombination in mammalian cells, Annu. Rev. Genet. 23:199-225 (1989).
Bruggemann et al., Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus, Eur. J. Immunol. 21:1323-1326 (1991).
Bruggemann et al., A repertoire of monoclonal antibodies with human heavy chains from transgenic mice, Proc. Natl. Acad. Sci. USA 86:6709-6713 (1989).
Bucchini et al., Rearrangement of a chicken immunoglobulin gene occurs in the lymphoid lineage of transgenic mice, Nature 326:409-411 (1987).
Capecchi, The new mouse genetics: Altering the genome by gene targeting, TIG 5:70-76 (1989).
Capecchi, Altering the genome by homologous recombination, Science 244:1288-1292 (1989).
Coffman et. al., T cell activity that enhances polyclonal IgE production and its inhibition by interferon-.gamma., J. Immunol. 136:949-954 (1986).
Coffman et al., A mouse T cell product that preferentially enhances IgA production, J. Immunol. 139:3685-3690 (1987).
Doetschman et al., Targetted correction of a mutant HPRT gene in mouse embryonic stem cells, Nature 330:576-578 (1987).
Durdik et al., Isotype switching by a microinjected .mu. immunoglobulin heavy chain gene in transgenic mice, Proc. Natl. Acad. Sci. USA 86:2346-2350 (1989).
Esser and Radbruch, Rapid induction of transcription of unrearranged S.gamma.1 switch regions in activated murine B cells by interleukin 4, The EMBO J. 8:483-488 (1989).
Ferrier et al., Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate, The EMBO J. 9:117-125 (1990).
Forni, extensive splenic B cell activation in IgM-transgenic mice, Eur. J. Immunol. 20:983-989 (1990).
Gerstein et al., Isotype switching of an immunoglobulin heavy chain transgene occurs by dna recombination between different chromosomes, Cell 63:537-548 (1990).
Goodhardt et al., Rearrangement and expression of rabbit immunoglobulin .kappa. light chain gene in transgenic mice, Proc. Natl. Acad. Sci. (U.S.A.) 84:4229-4233 (1987).
Gordon, Transgenic mice in immunology, The Mount Sinai Journal of Medicine 53:223-231 (1986).
Hagman et al., Inhibition of immunoglobulin gene rearrangement by the expression of a .lambda.2 transgene, J. Exp. Med. 169:1911-1929 (1989).
Ichihard et al., Organization of human immunoglobulin heavy chain diversity gene loci, The EMBO J. 7:4141-4150 (1988).
Iglesias et al., Expression of immunoglobulin delta chain causes allelic exclusion in transgenic mice, Nature 330:482-484 (1987).
James and Bell, Human monoclonal antibody production current status and future prospects, J. of Immunol. Methods 100:5-40 (1987).
Jasin and Berg, Homologous integration in mammalian cells without target gene selection, Genes & Development 2:1353-1363 (1988).
Kenny et al., Alternation of the B cell surface phenotype, immune response to phosphocholine and the B cell repertoire in M167 .alpha. plus .kappa. transgenic mice, J. of Immunol. 142:4466-4474 (1989).
Jung et al., Shutdown of class switching recombination by deletion of a switch region control element, Science 259:984-987 (1993).
Kitamura et al., A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin .mu. chain gene, Nature 350:423-426 (1991).
Koller and Smithies, Inactivating the .beta..sub.2 -microglobulin locus in mouse embryonic stem cells by homologous recombination, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989).
Lin et al., Recombination in mouse L cells between DNA introduced into cells and homologous chromosomal sequences, Proc. Natl. Acad. Sci. USA 82:1391-1395 (1985).
Linton et al., Primary antibody-forming cells secondary B cells are generated from separate precursor cell subpopulations, Cell 59:1049-1059 (19

Affiliated with

Also associated with

Rating

Transgenic non-human animals capable of producing heterologous a does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Transgenic non-human animals capable of producing heterologous a, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transgenic non-human animals capable of producing heterologous a will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-424655