WO1991000906A1 - Animaux chimeriques et transgeniques pouvant produire des anticorps humains - Google Patents

Animaux chimeriques et transgeniques pouvant produire des anticorps humains Download PDF

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WO1991000906A1
WO1991000906A1 PCT/US1990/003894 US9003894W WO9100906A1 WO 1991000906 A1 WO1991000906 A1 WO 1991000906A1 US 9003894 W US9003894 W US 9003894W WO 9100906 A1 WO9100906 A1 WO 9100906A1
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animal
human
immunoglobulin
fragment
exogenous
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PCT/US1990/003894
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Clive Wood
Randal J. Kaufman
Federick W. Alt
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Genetics Institute, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Humanized animals, e.g. knockin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
    • C07K16/462—Igs containing a variable region (Fv) from one specie and a constant region (Fc) from another
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/01—Animal expressing industrially exogenous proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates generally to immunoglobulin rearrangement in chimeric and transgenic animals, and more specifically to a mouse containing in its germline, and capable of transmitting to its progeny, the ability to generate immunoglobulins characterized by the presence of human heavy chains.
  • Immunoglobulins are the proteins which form antibodies.
  • the basic unit of an immunoglobulin (Ig) molecule is a complex of two identical heavy (H) and two identical light (L) polypeptide chains. Both types of chains contain a region of variable a ino acid seguence at the amino terminal end (V region) in which reside the primary determinants of antigen binding specificity. Each chain also has a region of constant amino acid sequence (C region) comprising the remainder of the chain, in which reside the primary determinants of the effector functions of the antibody, such as complement fixation and antibody-dependent cellular cytotoxicity.
  • variable region of heavy and light chains can be further subdivided into regions of relatively conserved amino acid sequence, framework regions, and regions of highly variable amino acid sequence, hypervariable regions or complementarity determining region ⁇ (CDRs) .
  • CDRs complementarity determining region ⁇
  • variable regions of both the heavy and light chain genes are assembled from component gene segments.
  • the heavy chain variable region gene is assembled from three different elements, variable (V H ) , diversity (D) , and joining (J H ) segments. Families of these segments are encoded in separate clusters along the chromosome. Formation of a functional heavy chain variable region gene involves both joining of a D segment to a J H segment and joining of a V H segment to the pre ⁇ existing DJ K complex to form the complete V H DJ H heavy chain variable region gene.
  • V L variable gene segment
  • J L joining segment
  • kb variable region -several kilobases
  • Human or partially human monoclonal antibodies have been obtained by several methods which have proven less than satisfactory for a variety of reasons.
  • the production of mouse/human hybridomas has been limited because such lines are unstable genetically and progressively lose human chromosomes. Epstein Barr Virus transformed human B lymphocytes tend to produce small quantities of Ig and are unstable.
  • the production of human/human hybridomas has been very limited, due to the lack of a.suitable fusion partner, the lack of sufficient numbers of human B-cells immunized against a desired antigen, poorly defined fusion protocols, and poorly defined culture conditions to support hybrid survival and antibody production.
  • such cells predominantly produce antibodies of only the IgM isotype, which is not appropriate for many clinical uses.
  • hybridomas Another serious limitation with human hybridomas is the difficulty of growing such cell lines in large quantities, jln vitro culture of such hybridomas is very costly and produces limited quantities of Ig compared to the large amounts that can be obtained from harvesting monoclonal antibodies from murine hybridomas.
  • heterologous genes from heterologous species organisms in an animal capable of expressing and regulating the foreign gene construct has been the subject of much recent research.
  • U. S. patent 4,736,866 describes a transgenic animal carrying a recombinant activated oncogene sequence; and J. Van Brunt, Biotechnology. (10):1149 (October 1988).
  • Buccini et al, Nature, 326:409 (1987) and Goodhardt et al, Proc. Natl. Acad. Sci.. USA, 84 . :4229 (1987) refer to the rearrangement of unarranged chicken and rabbit immunoglobulin gene segments in mice.
  • a non-human eukaryotic animal having incorporated into its germline unrearranged DNA fragments bearing exogenous immunoglobulin (Ig) heavy chain gene segments.
  • the animal of the invention is capable of rearranging these segments and producing antibodies characterized by the presence of rearranged exogenous Ig heavy chains . ..
  • the animal of the invention is also capable of producing an antibody also characterized by the presence of light Ig chains endogenous to said animal.
  • the animal of the invention may produce antibody characterized by the presence of exogenous Ig light chains.
  • the exogenous gene segments are of human origin.
  • Another aspect of this invention is an unrearranged DNA fragment for use in producing the animal of the invention.
  • This DNA fragment is composed of at least the following elements: at least one exogenous variable Ig gene segment, at least one exogenous D Ig gene segment, at least one exogenous J Ig gene segment, and at least one ⁇ heavy chain constant Ig region.
  • the ⁇ constant region is of exogenous or endogenous species origin,, and is required to mediate allelic exclusion in the animal, of this invention.
  • the unrearranged DNA fragment also contains an exogenous gamma constant Ig region.
  • the unrearranged DNA fragment of the invention may also contain a switch region of exogenous or endogenous species origin, and exogenous or endogenous species heavy chain enhancers. More preferably the exogenous segments of this unrearranged fragment are of human origin.
  • Still another aspect of the present invention is a method for producing the non-human eukaryotic animal of the present invention comprising introducing into the germline of said animal an unrearranged DNA fragment of this invention.
  • a further aspect of the present invention is a method for producing the non-human eukaryotic animal of the invention comprising transfecting into a stem cell of the animal a heterologous DNA sequence carrying unrearranged gene segments of exogenous, preferably human, Ig heavy chains. This method may permit introduction into the animal of human DNA of greater than 50kb, if desired.
  • Yet another aspect of the invention is a hybridoma cell line and a monoclonal antibody secreted therefrom characterized by the presence of human Ig heavy chains.
  • the monoclonal antibody thus produced may further be characterized by the presence of either human or endogenous animal light chains.
  • An additional aspect of the invention is a method for producing the hybridoma cell line by use of a cell of an animal of the present invention and a method for obtaining a desired monoclonal antibody of the invention.
  • Fig. 1 i-s a graphical illustration of a murine unrearranged DNA fragment according to the present invention.
  • Fig. 2 is a graphical illustration of a more complex human unrearranged DNA fragment according to the present invention.
  • the present invention provides an animal developed by recombinant genetic engineering techniques which is capable of rearranging in a lymphoid specific manner introduced unrearranged exogenous, preferably human, immunoglobulin genes.
  • the animal is thereby capable of producing in vivo resulting B cells which express and use the exogenous Ig polypeptides in a manner identical to the use of its own endogenous Igs produced in the animal's normal B cells.
  • the animal of this invention produces in vivo a diversity of mature B lymphocytes, characterized by the presence of exogenous Ig heavy chains.
  • the animal is capable of using the rearranged products of the unrearranged DNA fragment, e.g., a functionally rearranged exogenous heavy chain, in an immune response.
  • a further characteristic of the animal is an ability to transmit this ability to at least some of its progeny.
  • the animals of this invention are designed by the integration into their germlines of DNA carrying unrearranged or only partially rearranged exogenous Ig gene segments.
  • the unrearranged DNA fragment carrying the gene segments may be microinjected into the fertilized egg of an animal to develop a transgenic animal or transfected into a stem cell which is used to repopulate an embryo to develop a chimeric animal.
  • the human DNA fragments are introduced into a cell of the animal in a manner providing that the introduced DNA is stably maintained in a proportion of those cells and transmitted in the germline of the resulting animal.
  • an unrearranged gene fragment of the invention is constructed to carry at a minimum DNA sequences encoding at least one exogenous variable Ig gene segment, at least one D Ig gene segment, at least one exogenous J Ig gene segment, and at least one ⁇ constant Ig region.
  • the unrearranged gene fragment further contains an exogenous gamma constant Ig region.
  • the ⁇ region may be of exogenous origin or from the animal itself, but is preferably human. This ⁇ region is required to signal appropriate allelic exclusion in the resulting animal.
  • the D gene may be of exogenous origin, e.g., human, or from the animal itself. Additionally a synthetic D gene of about 10 to 20 amino acids in length containing flanking sequences from an animal may be employed in the construct of the invention.
  • the unrearranged gene fragment of this invention optionally contains multiple copies of the unrearranged or partially rearranged human heavy or light chain variable and constant region gene segments.
  • Human gene segments for use in constructing the unrearranged DNA fragment for insertion into a cell of the selected animal of this invention include a D gene which is a short chemically synthesizable fragment.
  • D gene region is described in J. V. Ravetch et al, Cell, 22:583 (1981).
  • Other useful D regions for the unrearranged DNA fragment of the present invention are described in Y. Ichihara et al, Eur. J. Immunol. , 18:649 (1988) . It is expected that other D regions will eventually be isolated and their sequences determined. These D regions may also form useful components of the unrearranged DNA fragment of the present invention in a manner analogous to the use of the above exemplary D gene segments.
  • the D gene need not be of human origin.
  • the flanking regions of the D gene may be of one species' origin, which the coding sequence of the D gene may be from another species.
  • a synthetic D gene may be made by conventional techniques.
  • Presently preferred for use in the construct are any human D or any murine D gene, a variety of which are known in the art, as identified above.
  • the J gene regions of the human Ig DNA sequences for use in an unrearranged DNA fragment of the present invention are published. See, e.g. Ravetch et al, cited above; and P. A. Hieter et al, J. Biol. Chem.. 257:1516 (1982).
  • the J gene region described by Ravetch, cited above may be obtained requested from the author, based on its publication in the journal, Cell. Additionally, ⁇ and gamma (1 through 4) human gene sequences are published and may be purchased from the Medical Research Council (MRC) in England and employed in the unrearranged DNA fragment. See, e.g., J. W. Ellison et al, Nucl. Acids Res.
  • the constant regions may desirably be constructed by employing -conventional recombinant techniques. See, e.g., T. Maniatis et al, Molecular Cloning (A Laboratory - Manual) , Cold Spring Harbor Laboratory (1982) and J.
  • Human V gene families I through VI are also published and may be constructed by conventional recombinant techniques for insertion into the unrearranged,DNA fragment of the invention. See, e.g. Berman, J. E. et al, EMBO J. , 2: 27 (1988).
  • the DNA sequences of these genes identified above may be synthesized or obtained by conventional recombinant techniques and employed in the unrearranged DNA fragment construct according to the present invention.
  • One of skill in the art can obtain members of these gene families by employing conventional cross- hybridization techniques using a representative member of each family.
  • the unrearranged DNA fragment's human heavy chain gene segments, V, D, and J, will assemble with animal's own light chains during B lymphocyte maturation to generate antibodies characterized by human heavy chains.
  • unrearranged human light chain gene segments may be employed in another unrearranged DNA fragment to enable the resulting animal to produce a diversity of B lymphocytes with both human heavy and light chains.
  • the two unrearranged DNA fragments bearing the human heavy chain genes and the human light chain gene, respectively, may be injected into the same animal.
  • one animal carrying the first unrearranged DNA fragment may be mated with another animal carrying the second unrearranged DNA fragment to produce progeny capable of using both unrearranged DNA fragments.
  • an animal of this invention may be capable of generating antibodies containing human heavy chains and homologous light chains or antibodies characterized by the presence of both human heavy and light chains.
  • the unrearranged DNA fragment of the invention may also contain appropriate transcriptional enhancer and promoter elements.
  • the animal of the present invention will contain human or homologous animal, e.g., murine, constant region "switch" regions proximal to each constant region.
  • the switch regions may also be employed in the design of the unrearranged DNA fragment which is integrated in the animal.
  • the switch region is located immediately upstream of the coding regions of the Ig constant genes in the unrearranged DNA fragment.
  • Such murine switch regions for use in the unrearranged DNA fragment are also published and may be sequenced or obtained by recombinant technology by one of skill in the art. See, e.g. T.
  • Ig heavy chain enhancer sequences useful in the unrearranged DNA fragment of the invention are described in J. Banerji et al, Cell, 3_3_:729 (1983); S. D. Gillies et al, Cell, 3_3:717 (1983); P. Augereau et al, EMBO J.. 5_(8):1791 (1986); and S. Pettersson et al, Nature, 344:165 (1990) and may be obtained by analogous methods.
  • the constructed unrearranged DNA fragment may contain human DNA sequences as well as appropriate sequences from other non-human sources, e.g., the animal itself.
  • other human heavy and light chain gene segments or other non-human sequences such as the switch regions, suitable promoters or enhancers, when their sequences are known, will also be useful to form unrearranged DNA fragments according to the teachings of the present invention and may be used in analogous manner to the exemplary sequences described herein.
  • the gene segments useful in the unrearranged DNA fragments may be obtained by preparing lambda phage genomic and cDNA libraries and identifying specific Ig genes according to known techniques. See, T. Maniatis et al and Sambrook et al, cited above.
  • the unrearranged DNA fragment of this invention may vary considerably in size and is preferably approximately 25 to 50 kb in length for ease of manipulation in cosmids. Larger DNA fragments of human origin may be used for construction of a chimeric animal or transgenic animal and will be propagated in yeast artificial chromosome vectors (YACS) .
  • YACS yeast artificial chromosome vectors
  • animals of the invention may be produced alternatively by isolating a contiguous human DNA fragment carrying naturally unrearranged DNA sequences encoding multiple human Ig heavy chain segments, e.g., V H , D and J H .
  • V H , D and J H multiple human Ig heavy chain segments
  • These naturally unrearranged fragments may be considerably larger in size than the ⁇ ni-jearranged DNA fragment constructs described above and may require propagation in YACS vectors.
  • An example of such a contiguous DNA fragment that could be isolated, in this way is described by Berman, J. E. et al, EMBQ J. , 2:727 (1988). This fragment is of 85-100 kb containing a human V gene segment, multiple human D segments, and the complete human J H - C ⁇ region.
  • the constructed unrearranged DNA fragments may be propagated in conventional plasmids or cosmids known to those of skill in the art.
  • conventional vectors useful for transgene replication are the cosmid vectors p E15 or pWE16, supplied commercially by Stratagene, La Jolla, California.
  • the larger chromosomal DNA sequences may be propagated in conventional yeast artificial chromosome vectors in yeast as described in D. T. Burke, et al, Science, 236:806 (1987).
  • the animal of the invention is developed by introducing into a cell of the animal this human DNA. This introduction is performed so that the introduced DNA is stably maintained and transmitted in the germline of the animal.
  • Expression of functional Ig genes depends on an accurate rearrangement of DNA in the cells of the animal to bring the several gene segments e.g. variable, diversity, and joining for the heavy chain and variable and joining for the light chain, into juxtaposition.
  • the mechanism of allelic exclusion operates to prevent further rearrangement in a second chromosome once a complete functional unit is achieved in one chromosome.
  • the unrearranged or partially rearranged gene segments in the fragment allow for maximum diversity to be generated in the animal through the use of alternative V H , D and J H genes, and the generation of junctional diversity. Additionally the utilization of unrearranged genes is expected to lead to a more physiological response than programming an animal with completely assembled Ig genes.
  • Transgenic animals can be produced by several standard procedures, the most common being microinjection of the cloned unrearranged DNA fragment into one of the pronuclei of a fertilized egg according to the procedure described in R. Brinster et al, PNAS USA, j32.:4438 (1985). See also, Cqnstantini et al, J. Cell. Phvsiol.. Suppl.:219-226 (1982) ; E. Robertson et al, Nature. 323:445 (1986) ; M. R. Kuehn et al, Nature, .32_6:295 (1987); M. Hooper et al, Nature, 326:292 (1987); and B.
  • the microinjected embryos are developed to term in the uterus of a pseudo pregnant animal. As many as 25% of the resulting progeny can contain the injected unrearranged DNA fragment.
  • This procedure introduces the cloned human Ig genes into every cell of the resulting transgenic animal. Such introduced Ig genes are expressed almost exclusively in the same tissues in which the homologous endogenous genes are expressed.
  • the animals containing the unrearranged DNA fragments generally contain the foreign DNA stably integrated in all cells. This DNA is thereafter propagated in the germline.
  • a naturally unrearranged human DNA fragment as described above, can be introduced into isolated embryonal stem cells of the animal to create chimeric animals.
  • Cells which have integrated the human DNA are grown in culture, and can be used to repopulate animal embryos. Such cells could be selected for those bearing the human DNA by the polymerase chain reaction, with appropriate primers [See, e.g., R. K. Saiki, et al, Science, 239:487 (1988).
  • a drug resistance gene e.g., neo, may be linked to the introduced DNA and the cells selected for growth in the presence of the drug.
  • the resulting chimeric animal contains a population of cells, some of which descend from the altered pluripotent stem cell which carry the human DNA.
  • transgenic animal can then be derived from such a chimeric animal by breeding.
  • Such techniques for obtaining chimeric and transgenic animals are described in K. R. Thomas et al, Cell, 5.1:503 (1987); E. Robertson et al, Nature, 323:445 (1986); M. Hooper et al, Nature, 326:292 (1987) and M. R. Kuehn et al, Nature, 326:295 (1987) .
  • the resulting animal of the invention is thus a chimeric or transgenic non-human eukaryotic animal having incorporated into its germline unrearranged DNA fragments bearing human immunoglobulin gene segments.
  • the animal of the invention is capable of rearranging the human Ig gene segments to form human or partially human antibodies characterized by human heavy chains, which can be used in an immune response to an exogenous antigen.
  • the invention provides a genetically engineered chimeric or transgenic animal capable of producing a Adversity of antibodies characterized by the presence of human heavy chains.
  • a chimeric animal is an animal which derives a specific subset of its cells from a single particular pluripotent stem cell which is introduced into the embryo of a normal animal. That stem cell and its progeny can be distinguished from other cells of the resulting animal, for example, by containing specific DNA sequences which were present in the introduced stem cell and not in the other stem cells that eventually develop to produce the animal.
  • a chimeric animal according to this invention will have a population of cells that contain the heterologous DNA fragment containing unrearranged or partially unrearranged sequences for the heterologous Ig heavy chain genes and a population of cells which do not contain the introduced DNA.
  • the original chimeric animal will have only a certain percentage of its progeny bearing and expressing the foreign DNA.
  • Selective breeding of chimeric animals according to techniques known to one of skill in the art can eventually produce a transgenic animal.
  • a transgenic animal is an animal that carries specifically introduced heterologous DNA, such as an unrearranged DNA fragment of this invention, integrated into its genome so that the introduced sequence is present in every cell of the animal. A transgenic animal is therefore able to transmit the heterologous DNA sequence to some or all of its progeny.
  • the original transgenic animal is heterozygous with respect to the foreign DNA, only some of its progeny will inherit the foreign DNA-from it. If the original heterozygous transgenic animal is mated with a normal animal, the progeny will either be heterozygous or non-transgenic. If the transgenic animal is mated with another heterozygous transgenic animal, some of the progeny will be heterozygous, some will not inherit the foreign DNA at all, and some will be homozygous. The homozygous transgenic animal when mated with other homozygous transgenic animals will always produce homozygous transgenic animals carrying the foreign DNA.
  • all animals whether chimeric, or homozygous transgenic or heterozygous.transgenic for the human DNA, will express some level of antibody characterized by the presence of human Ig heavy chains. All such animals capable of producing antibody characterized by the presence of human Ig heavy chains at any level are encompassed by the present invention.
  • any non-human eukaryotic animal may be employed in the present invention, preferably the animals will be conventionally used laboratory animals, such as rodents. More particularly, the animals of the invention are anticipated to be laboratory strains of mice. Any animal carrying the unrearranged DNA fragment of the invention may generate a mixture of its homologous antibodies as well as antibodies characterized by human Ig heavy chains. Natural antigen-independent antibody developmental processes cause the animal to produce mature B lymphocytes to circulate in the transgenic or chimeric animal.
  • the animal's serum or tissue may be examined using commercially available anti-human Ig antisera in an enzyme-linked immunosorbent assay (ELISA) [See, e.g., Voller A. et al, "The Enzyme Linked Immunosorbent Assay", Dynatech Europe, Under House, Guernsey UK (1979) and Bos, E. S. et al, J. Immunoassay, 2.:187 ' (1981) ] .
  • ELISA enzyme-linked immunosorbent assay
  • the tail DNA is prepared and probed in a Southern blot by using a portion of the unrearranged DNA fragment as a probe.
  • the spleen of the animal is removed by conventional splenectomy (spleen cells contain predominantly B lymphocytes) and the tissue examined on a Southern blot for hybridization and rearrangement.
  • An alternative method of detecting appropriate Ig rearrangement is to prepare RNA from central (fetal liver and bone marrow) and peripheral (spleen) lymphoid organs and assay for expression of the rearranged DNA in the fragment via Northern blot analyses with probes specific for human V H and C regions.
  • strains of transgenic or chimeric animals containing different human Ig genes are mated, by standard breeding techniques, and progeny selected that contain multiple different human Ig transgenes. Such progeny are identified by the procedures described above.
  • Hybridoma cell lines secreting monoclonal antibodies directed to a particular antigenic epitope may be developed from the chimeric or transgenic animals of the present invention.
  • the animal is immunized with a selected antigen, for example, a tumor antigen (to generate an anti-tumor antibody), an antibody to an infectious agent, e g., a bacterium or ** •mvirus, e.g., HIV, or other antigenic substance of choice.
  • the mature B lymphocytes in the animals of the invention then generate a specific antibody response to the antigen.
  • Such an antibody response would include heavy chains expressed from the foreign DNA fragments, now rearranged.
  • the unrearranged DNA fragments in the animals have functionally rearranged to produce a human Ig heavy chain and/or Ig light chain, during the pre-B cell stage, the remainder of the differentiation of the B cells is normal.
  • Spleen B cells are isolated from the animals after primary or secondary immunization. Traditional Kohler and Milstein techniques are employed and the splenic B lymphocytes fused with a selected myeloma cell line.
  • hybridoma cell line which when cultured in appropriate culture medium and under suitable conditions known to those of skill in the art secretes a selected monoclonal antibody.
  • the development of a hybridoma cell line according to this invention is not limited to the selection of specific myeloma cell lines or antigens. These hybridoma cell lines are screened by standard techniques for the production of anti-specific antigen antibodies. Hybridomas which use the transgenic heavy chain genes to produce antibody are identifiable by use of a transgene specific probe. Exemplary probes are antisera against the human Ig constant regions.
  • the transgene construct may also incorporate a
  • DHFR or other selectable and/or amplifiable marker.
  • This marker gene may be linked with an independent promoter element, such as DHFR cDNA linked to an SV40 promoter and polyadenylation sequences.
  • DHRF cDNA may be placed immediately downstream of an encephalomyelocarditis virus or polio virus leader 26 sequence without an independent promoter element [See, e.g., J. Pelletier et al, Nature, 334:320 (1988); S. K. Jang et al, J. Virol. , .63..-1651 (1989)].
  • This latter structure may be placed immediately downstream of the coding sequence of the secreted exon terminus for the heavy chain constant region, upstream of necessary polyA addition sequences. This ensures the presence and expression of the DHFR message that is expected in,resulting hybridomas expressing the Ig transgene. If the structure is attached in this manner to the gamma constant region in a construct similar to that of Example 2 with ⁇ and gamma constant regions, selection for expresion of DHFR by conventional means would allow selection of cells that have class switched from transgene ⁇ to gamma expression. In either strategy, the presence of the marker gene would allow selection for the maintenance of the chromosome bearing the transgene and may amplify transgene sequences.
  • Monoclonal antibodies characterized by the presence of human Ig heavy chains have great potential therapeutic use in the treatment of a variety of human disorders amenable to antibody treatment.
  • the presence of the human heavy chains in these antibodies are likely to be considerably less provocative of an anaphylactic response in a human patient than antibodies characterized by the presence of non-human heavy chains.
  • Monoclonal antibodies have immense potential for use as prophylactic, diagnostic, and therapeutic agents in the treatment of various types of human ailments. Potential or actual applications of these reagents include the provision of passive immunity against various microorganisms and viruses when injected into human patients.
  • these antibodies may be employed in the neutralization of viruses, parasites, and bacteria, for example, bacterial toxins or snake venoms.
  • the antibodies may also be used to neutralize pharmaceutical drugs with low toxicity thresholds, such as digoxin, or in treating drug overdoses. Additionally such antibodies may neutralize B lineage cells producing autoimmune antibodies or T lineage cells producing cell- mediated self-destructive responses. Among other conditions which can be neutralized by use of these antibodies are allergic responses. Significantly, the neutralization of tumor cells is another important area of therapy for the antibodies of this invention. These antibodies may also be employed in mediating normal antibody functions.
  • An unrearranged DNA fragment construct according to this invention is called pV ⁇ [See Fig. 1A] . It contains the murine germline V 186 . 2 segment [Bothwell, A.L.M. et al, Cell. 2_4:625 (1981)], which is known to be used in the antibody response to 4-hydroxy-3-nitrophenyl (NP) .
  • a panel of hybridomas are generated from the transgenic mice containing this construct, immunized with the NP-hapten conjugated to keyhole limpet hemocyanin.
  • This V segment is upstream of a D Q52 -J H 2 rearrangement / with unrearranged J H 3 and J H 4 segments and the heavy chain enhancer downstream.
  • This D Q52 -J H 2 rearrangement is generated by recombination of these sequences after transfection into the Abelson murine leukemia virus-transformed pre-B cell line, 38B9 [Blackwell, T.K. and Alt, F. W. , Cell. 37:105 (1984)].
  • the nucleotide sequence of this DJ H join, called 112-2 has been determined [Blackwell, T. K. et al, Nature, 324:585 (1986].
  • the "spacer" between the 3' end of the V 186 has been determined [Blackwell, T. K. et al, Nature, 324:585 (1986].
  • the D JH 2 segment is comprised of approximately 3.5 kb of sequence derived from the V 186 .
  • Downstream of the heavy chain enhancer is the coding sequences for the murine ⁇ constant region, derived from a genomic clone, called p ⁇ 5 [Alt, F. . et al, Cell. 22:381 (1981)].
  • This clone contains an approximately 10.5 kb Eco RI fragment bearing the ⁇ coding region. The entire Eco RI fragment is incorporated into pV ⁇ .
  • This construct is designed with the intention of excising the V 186 . 2 -DJ H - ⁇ region on a single Not I fragment of approximately 22 kb, that can be purified for microinjection.
  • a DNA fragment construct contains no vector DNA that could potentially interfere with the rearrangement or expression of the immunoglobulin gene.
  • the cos id construct, pV ⁇ is prepared as follows: i) The 10.5 kb genomic ⁇ fragment is cloned into a derivative of pSP65, called pSP65N, having a unique Not I site. Another plasmid for this use is the Bluescript plasmid [Stratagene, La Jolla, CA] .
  • Plasmid pSP65N is prepared from pSP65 [Promega Biotec, Madison, WI] by destroying the unique Hindlll site, and replacing it with a unique Not I site using synthetic oligodeoxy ribonucleotides.
  • the genomic ⁇ fragment is an Eco RI fragment, and therefore, can be cloned into Eco RI- digested pSP65N.
  • appropriate restriction enzymes that cleave within the ⁇ sequence such as Bgl II and Xho I, a clone can be selected that has the 3' end of the fragment. This plasmid is called pSP65N ⁇ .
  • V 186.2 and D Jf) 2 segments are on Eco RI fragments of approximately 7 kb and 4 kb, respectively.
  • the Eco RI fragment bearing V 186.2 is cloned into the Eco RI site of pSP65N, and a clone selected that has the Not I site of the plasmid at the 5' end of the V 186 . 2 coding region.
  • the Eco RI site proximal to the Not I site is destroyed, by carrying out a partial Eco RI digestion, purifying the single cut DNA from a low melt agarose gel, digesting with T4 DNA polymerase in the presence of all of the four different deoxynucleoside triphosphates, and religating.
  • pSP65NV is digested with Eco RI, and the Eco RI fragment bearing the DJ H 2 segment is ligated into this site.
  • a resultant clone is selected that has the V and DJ H 2 segments in the correct orientation.
  • Such a clone has a Xho I site immediately upstream of the DJ H 2, and 2.4 kb from the 3' Eco RI site.
  • the internal Eco RI site of this clone is destroyed, by a similar procedure to that used in (ii) above.
  • pSP65NVDJ has a Not I-Eco RI fragment of approximately 11 kb.
  • pV ⁇ is constructed by ligating the 11 kb Not I-Eco RI fragment of pSP65NVDJ with the 10.5 kb Eco RI-Not I ⁇ fragment generated by complete Not I - partial Eco RI digest of pSP65N ⁇ , in the presence of a Not I - digested cosmid vector.
  • a derivative of the cosmid vector p E15 [Stratagene, La Jolla] is used in the construction of this unrearranged DNA fragment construct in which the SV40 promoter-neo gene cassette has been replaced by a mutant dihydrofolate reductase (DHFR) gene.
  • DHFR dihydrofolate reductase
  • This gene is useful as a dominant selectable marker.
  • This gene is incorporated into the DNA construct flanking the Ig gene segments, and is used for co-amplifying and increasing the expression of the rearranged DNA in resultant hybridomas from the transgenic animal.
  • An example of the use of a mutant DHFR gene to amplify the expression of linked DNA sequences is provided by H. Dora et al, J. Immunol., 139:4232 (1987).
  • This ligation is carried out under standard conditions for cosmid ligations.
  • the ligation products are incubated with jLn vitro bacteriophage lambda packaging extracts, and then used to infect __)___ coli HB101.
  • the resultant colonies are screened by restriction enzyme digestion analysis, and in situ hybridization to the different fragments that make up the desired construct.
  • Another unrearranged DNA fragment construct according to this invention comprises an unrearranged human V H gene segment, the human J H locus with a single upstream, unrearranged D segment, the murine ⁇ gene including its upstream ⁇ switch region, the murine gamma 2b switch region, and the human gamma 1 coding region.
  • the murine ⁇ may be changed for the human ⁇ region, since both regions have been found to signal allelic exclusion in transgenic mouse models.
  • Human switch regions may also be substituted for switch regions of murine origin, i) The human 1-9II V H gene segment of the V H 4 family described in Berman, J. E. et al, EMBO J.
  • J H fragment also includes one unrearranged D segment [J. V. Ravetch et al, Cell, 22:583 (1981)].
  • a clone, called pSP65NHVJ, is selected in which the J H locus is in the correct orientation to the V H segment, placing the D segment between the V H and J H segments.
  • pSP65NHVJ The murine germline ⁇ gene found on plasmid p ⁇ [Grosschedl et al, Cell, .38.:647 (1984)], is excised therefrom on an approximately 10.5 kb Eco Rl-Xho I fragment. This fragment is cloned into the Bluescript plasmid digested with Eco RI and Xho I. The resulting clone is then digested with Xho I, which cleaves in the vector polylinker.
  • the cleaved DNA is treated with T4 DNA polymerase in the presence of all four deoxynucleoside triphosphates, and then ligated with synthetic DNA linkers containing an Sfi I site.
  • the DNA is then digested with Sfi I and religated.
  • the resulting plasmid, p ⁇ Sfi I contains an approximately 10.5 kb genomic fragment, with a unique Eco RI site at the 5' end, and a unique Sfi I site at the 3' end.
  • the murine gamma 2b switch region is excised from the genomic clone SL1 in a bacteriophage lambda vector, on an Eco RI-Hindlll fragment of approximately 4.4 kb [See, e.g., Stanton and Marcu, Nucl. Acids Res. , JL0 . :5993 (1982)].
  • This DNA is cloned into the Eco RI and flindlll sites of the Bluescript plasmid.
  • the 5* vector Not I site is then destroyed, and replaced with the same synthetic Sfi I linkers, as described in (ii) .
  • the 3' vector Sal I site is destroyed, and synthetic Not I linkers are used to create a new Not I site.
  • the resulting clone is called pBS gamma 2b.
  • the human gamma l gene is excised from the clone HG3 on a Hindlll fragment [Ellison, J. . et al, Nucleic Acids Res.. 10:4071 (1982)]. This Hindlll fragment is cloned into the Hindlll site of pBS gamma 2b.
  • a recombinant clone, called pBS gamma 1 is selected that has the gamma 1 gene in the correct orientation, with respect to the gamma 2b switch region.
  • the same or similar gamma 1 fragments may be obtained from other genomic human gamma 1 clones, if desired.
  • the following fragments are then prepared: (1) a Not I-partial Eco RI V H -D-J H fragment of pSP65NHVJ (2 kb) ; (2) an Eco Rl-Sfi I ⁇ fragment of p ⁇ Sfi I (10.5 kb) ; and (3) a Sfi I-Not I Sgamma 2b-human gamma 1 fragment of pBS gamma 1.
  • These fragments are then ligated with a Not I digested cosmid vector, under standard cosmid ligation conditions, as in Example 1.
  • Clones are identified that contain a V-D-J H - ⁇ -S gamma2b-gamma 1 unrearranged DNA fragment construct. Such a construct is excised from the clone by Not I digestion, and purified for microinjection.
  • Example 3 Production of a Transgenic Mouse
  • the unrearranged DNA fragment constructs described in Examples 1 and 2 are employed to produce transgenic mice, as follows:
  • mice were obtained essentially as described by B. Hogan et al, "Manipulating the Mouse Embryo, A Laboratory Manual", Cold Spring Harbor
  • mice are transgenic, according to the invention.
  • Sail-EcoRI double digestion of the unrearranged DNA fragment construct should generate an llkb fragment containing V186-2 and DJ H 2. Rearrangement of these two gene segments and deletion of the spacer DNA is predicted to generate a Sall-EcoRI fragment of approximately 4kb.
  • tail DNA of 1763 is found to have an unrearranged band of llkb, and the endogenous _T H band of approximately 6.2kb.
  • a 4kb band is found, indicating rearrangement of the DNA fragment in the spleen but not the tail tissue of the animal.
  • the remaining spleen DNA preparation of mouse 1763 is digested with Sail and EcoRI, and the DNA in the 3.5-4.5kb size range is eluted from a preparative agarose gel.
  • This DNA is cloned into the bacteriophage lambda vector, lambda ZAP [Stratagene] .
  • the resulting plaques are screened with a J H probe and picked.
  • the inserts are converted to plas ids using the lambda ZAP excision method. These plasmids are rescreened with the same probe, and positive colonies isolated.
  • the nucleotide sequence of each insert is then determined using synthetic oligonucleotides to prime chain synthesis. Two oligonucleotides are employed, one hybridizing to the 3' end of J H 2, and the other hybridizing to the 5' end of V 186.2 .
  • the nucleotide sequence of four of the DNA fragment rearrangements from spleen DNA are determined from the ATG initiation codon of V 186 . 2 to the 3 ' end of the DJ R 2 segment. From the sequence of the V H -to-DJ H joins of the first four rearranged V region sequences, the DNA fragments are observed to be rearranged with junctional variation occurring. These rearranged V H -DJ dock joins appear indistinguishable from those expected for endogenous gene segments. In two of the four sequences, there is a loss of one or more base pairs from the 3' end of V 186 . 2 . In all four sequences, there is a loss of two or more base- pairs from the 5' sequence of the DJ H segment.
  • N-regions are inserted between the recombined V and DJ H segments of one or three base- pairs.
  • this sample of junction sequences is small, there appears to be a preference for G-C base- pairs in the N-regions.
  • This observation is consistent with the known nucleotide preference of terminal deoxynucleotidyl transferase, which has been implicated in adding the extra bases of the N-region to such junctions. [See, e.g., F. W. Alt et al, Proc. Natl. Acad. Sci. USA, 29:4118 (1982) and Kurosawa et al, J. Exp. Med.. 155:201 (1982)].
  • sequences of the rearranged DNA fragment V regions are identical, outside the region of the V H -to DJ H join, and identical to the known sequences of V 186 _ 2 and J H 2.
  • no somatic mutation occurs in the sequenced rearranged DNA constructs, a result that would be expected from the analysis of rearrangements in total spleen DNA.
  • Numerous modifications and variations in practice of this invention are expected to occur to those skilled in the art. For example, as more human immunoglobulin gene sequences are identified, one of skill in the art can easily apply the teaching of the this invention to construct appropriate transgenes for the preparation of a transgenic animal capable of expressing an antibody characterized by the presence of that particular immunoglobulin. Such modifications therefore are believed to fall within the scope of this invention.

Abstract

Cette invention prévoit un animal eucaryotique non humain et chimérique ou transgénique possédant des fragments d'ADN sans réarrangement incorporés à sa ligne de germes, lesdits fragments portant des segments exogènes de gènes d'immunoglobuline. Cet animal peut réarranger ces segments et produire des anticorps caractérisés par la présence de chaînes lourdes Ig d'espèces exogènes réarrangées.
PCT/US1990/003894 1989-07-12 1990-07-11 Animaux chimeriques et transgeniques pouvant produire des anticorps humains WO1991000906A1 (fr)

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