# US 10,370,641 B2 · Enhanced expression of human or humanized immunoglobulin in non-human transgenic animals

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- Number: US 10,370,641 B2
- Document ID: US10370641B2
- Status: Granted
- Kind: B2
- Application number: 15/272,051
- Filed: 2016-09-21
- Published: 2017-08-03
- Granted: 2019-08-06
- Earliest claimed: 2006-09-01
- Assignees: Therapeutic Human Polyclonals, Inc.
- Applicants: Therapeutic Human Polyclonals, Inc.
- Inventors: Roland Buelow
- Web page: https://patentgrep.com/patent/US10370641B2

## CPC

- A01K 67/0278: Knock-in vertebrates, e.g. humanised vertebrates
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07K 14/70503: {Immunoglobulin superfamily}
- C09K 5/045: {containing only fluorine as halogen}
- C12N 5/0635: {B lymphocytes}
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A01K 67/0276: Knock-out vertebrates
- A01K 2207/15: Humanized animals
- A01K 2217/052: inducing gain of function
- A01K 2217/054: inducing loss of function
- A01K 2217/072: maintaining or altering function, i.e. knock in
- A01K 2227/107: Rabbit
- A01K 2267/01: Animal expressing industrially exogenous proteins
- C07H 21/04: with deoxyribosyl as saccharide radical
- C09K 2205/126: Unsaturated fluorinated hydrocarbons
- C12N 15/79: Vectors or expression systems specially adapted for eukaryotic hosts
- C12N 15/85: for animal cells
- C12N 2510/02: Cells for production
- C12N 2510/04: Immortalised cells
- C12N 2517/02: Cells from transgenic animals
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C09K: MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Igα and/or Igβ sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Igα and/or Igβ sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Igα and/or Igβ results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies.

## Claims

### Claim 1

An isolated B-cell from a transgenic rabbit whose genome comprises: (a) a transgene construct encoding a full-length, human Igα , subunit of SEQ ID NO: 1, under the control of a B-cell specific promoter/enhancer of CD79a; (b) a transgene construct encoding a full-length, human Igβ subunit of SEQ ID NO: 7, under the control of a B-cell specific promoter/enhancer of CD79b; and (c) a transgene construct encoding an unrearranged human immunoglobulin heavy chain locus, wherein the resultant transgene products, as a result of the simultaneous expression of the transgene constructs (a)-(c), combine to form a human B-cell receptor complex, such that human CD79a, human CD79b and human IgM are simultaneously present on the surface of said B-cell.

### Claim 2 (depends on 1)

The isolated B-cell of claim 1, wherein said transgenic rabbit is further characterized by impaired expression of endogenous Igα and/or Igβ.

### Claim 3 (depends on 2)

The isolated B-cell of claim 2, wherein expression of endogenous Igα and/or Igβ is knocked down in said transgenic rabbit.

### Claim 4 (depends on 3)

The isolated B-cell of claim 3, which is immortalized.

### Claim 5 (depends on 2)

The isolated B-cell of claim 2, which is immortalized.

### Claim 6 (depends on 1)

The isolated B-cell of claim 1, which is immortalized.