# US 10,765,093 B2 · Humanized transgenic animal > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,765,093 B2 - Document ID: US10765093B2 - Status: Granted - Kind: B2 - Application number: 13/989,781 - Filed: 2011-11-28 - Published: 2013-09-26 - Granted: 2020-09-08 - Earliest claimed: 2010-11-27 - Applicants: James Zhu - Inventors: James Zhu - Web page: https://patentgrep.com/patent/US10765093B2 ## CPC - A01K 67/0278: Knock-in vertebrates, e.g. humanised vertebrates - A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure} - C07K 14/52: Cytokines; Lymphokines; Interferons - C07K 14/535: Granulocyte CSF; Granulocyte-macrophage CSF - C07K 14/71: for growth factors; for growth regulators - C07K 14/715: for cytokines; for lymphokines; for interferons - C12N 15/8509: {for producing genetically modified animals, e.g. transgenic} - A01K 2217/072: maintaining or altering function, i.e. knock in - A01K 2217/15: Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding - A01K 2227/105: Murine - A01K 2267/03: Animal model, e.g. for test or diseases - 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) - 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) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) ## Abstract This present invention relates to transgenic animals useful to study human diseases. Specifically, the invention relates to transgenic animals expressing at least two human proteins (optionally in replacement of the counterpart proteins in the animal) whereas a first human protein interacts with a second human protein. The transgenic animals can then be used for evaluating drugs or building disease models that are related to the expressed human proteins in the animals. The animals and methods disclosed herein reduce the possibility identifying a false-positive compound—the compound that show an effect in a naturally-occurring, non-transgenic animal but may not necessarily work or be therapeutic in human, since the compound may only interrupt the interaction between two animal proteins not necessarily two related human proteins. Also, the animals and methods disclosed herein reduce the possibility of identifying a false-negative compound—a compound that does not work or have any effect in a naturally-occurring, non-transgenic animal but may have therapeutic effect in human, since the compound may only interrupt the interaction between at least two relevant human proteins not necessarily two related animal proteins. ## Claims ### Claim 1 A humanized transgenic animal comprising a first human gene encoding a first human protein and a second human gene encoding a second human protein, wherein the first human protein and the second human protein directly interacts with each other in transducing signals from the exterior of a cell, wherein the direct interaction between the first human protein and the second human protein is without the presence of a third protein, wherein a first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene and a second animal gene substantially homologous to the second human gene in the transgenic animal genome is replaced by the second human gene, and the human genes are wild type human genes, and are operably linked to the transcriptional regulatory sequences of the endogenous animal genes, and wherein the animal is mouse or rat. ### Claim 2 (depends on 1) A method of evaluating whether a molecule modulates human protein interaction in an animal comprising the steps of administering the molecule in a humanized transgenic animal of claim 1 and determining whether the human protein interaction is modulated. ### Claim 3 A humanized transgenic animal comprising a first human gene encoding a first human protein and a second human gene encoding a second human protein, wherein the first human protein and the second human protein directly interacts with each other in transducing signals from the exterior of a cell, wherein the direct interaction between the first human protein and the second human protein is without the presence of a third protein, wherein a first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene and a second animal gene substantially homologous to the second human gene in the transgenic animal genome is replaced by the second human gene, and the human genes are wild type human genes, and are operably linked to transcriptional regulatory sequences of the endogenous animal genes, wherein the first human protein and the second human protein is a pair of proteins selected from the group consisting of (i) VEGF and VEGF receptor; (ii) GM-CSF and GM-CSF receptor; and (iii) mitogen-activated protein (MAP)-kinase-kinase and MAP-kinase, and wherein the animal is mouse or rat. ### Claim 4 (depends on 3) The humanized transgenic animal of claim 3, wherein the first human protein and the second human protein is a pair of proteins selected from the group consisting of (i) VEGF and VEGF receptor; and (ii) GM-CSF and GM-CSF receptor. ### Claim 5 (depends on 3) The humanized transgenic animal of claim 3, wherein the first human protein and the second human protein are VEGF and VEGF receptor, respectively. ### Claim 6 (depends on 3) A method of evaluating whether a molecule modulates human protein interaction in an animal comprising the steps of administering the molecule in a humanized transgenic animal of claim 3 and determining whether the human protein interaction is modulated.