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US-20260123609-A1 - GENETICALLY MODIFIED NON-HUMAN ANIMAL WITH HUMAN OR CHIMERIC CD98HC

US20260123609A1US 20260123609 A1US20260123609 A1US 20260123609A1US-20260123609-A1

Abstract

Provided are genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD98HC, and methods of use thereof.

Inventors

  • Ruili Lv
  • Zhiyuan Shen
  • Chong Li

Assignees

  • BIOCYTOGEN JIANGSU CO., LTD.
  • BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO., LTD.

Dates

Publication Date
20260507
Application Date
20221216
Priority Date
20211217

Claims (20)

  1. 1 . A genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric cluster of differentiation 98 heavy chain (CD98HC).
  2. 2 . The animal of claim 1 , wherein the sequence encoding the human or chimeric CD98HC is operably linked to an endogenous regulatory element at the endogenous CD98HC gene locus in the at least one chromosome.
  3. 3 . The animal of claim 1 or 2 , wherein the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to human CD98HC (NP_002385.3 (SEQ ID NO: 2)).
  4. 4 . The animal of claim 1 or 2 , wherein the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 11.
  5. 5 . The animal of claim 1 or 2 , wherein the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to amino acids 215-630 of SEQ ID NO: 2.
  6. 6 . The animal of any one of claims 1-5 , wherein the animal is a mammal, e.g., a monkey, a rodent, a mouse, or a rat.
  7. 7 . The animal of any one of claims 1-6 , wherein the animal is a mouse.
  8. 8 . The animal of any one of claims 1-7 , wherein the animal does not express endogenous CD98HC or expresses a decreased level of endogenous CD98HC as compared to CD98HC expression level in a wild-type animal.
  9. 9 . The animal of any one of claims 1-8 , wherein the animal has one or more cells expressing human or chimeric CD98HC.
  10. 10 . The animal of any one of claims 1-9 , wherein the animal has one or more cells expressing human or chimeric CD98HC, and the expressed human or chimeric CD98HC can interact with a human integrin, activating downstream signaling pathways.
  11. 11 . The animal of any one of claims 1-9 , wherein the animal has one or more cells expressing human or chimeric CD98HC, and the expressed human or chimeric CD98HC can interact with an endogenous integrin, activating downstream signaling pathways.
  12. 12 . A genetically-modified, non-human animal, wherein the genome of the animal comprises a replacement of a sequence encoding a region of endogenous CD98HC with a sequence encoding a corresponding region of human CD98HC at an endogenous CD98HC gene locus.
  13. 13 . The animal of claim 12 , wherein the sequence encoding the corresponding region of human CD98HC is operably linked to an endogenous regulatory element at the endogenous CD98HC locus, and one or more cells of the animal expresses a human or chimeric CD98HC.
  14. 14 . The animal of claim 12 or 13 , wherein the animal does not express endogenous CD98HC or expresses a decreased level of endogenous CD98HC as compared to CD98HC expression level in a wild-type animal.
  15. 15 . The animal of any one of claims 12-14 , wherein the replaced sequence encodes all or a portion of the extracellular region of CD98HC.
  16. 16 . The animal of any one of claims 12-15 , wherein the animal has one or more cells expressing a chimeric CD98HC having an extracellular region, a transmembrane region, and a cytoplasmic region, wherein the extracellular region comprises a sequence that is at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% identical to the extracellular region of human CD98HC (NP_002385.3 (SEQ ID NO: 2)).
  17. 17 . The animal of claim 16 , wherein the extracellular region of the chimeric CD98HC has a sequence that has at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 410, or 416 contiguous amino acids that are identical to a contiguous sequence present in the extracellular region of human CD98HC (e.g., amino acids 215-630 of SEQ ID NO: 2).
  18. 18 . The animal of claim 16 , wherein the chimeric CD98HC has a sequence that is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 111, 112, 113, or 114 contiguous amino acids that are identical to a contiguous sequence present in the cytoplasmic region of endogenous CD98HC (e.g., amino acids 1-114 of SEQ ID NO: 1).
  19. 19 . The animal of any one of claims 12-18 , wherein the sequence encoding a region of endogenous CD98HC comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, and/or exon 10, or a part thereof, of the endogenous CD98HC gene.
  20. 20 . The animal of claim 19 , wherein the animal is a mouse.

Description

CLAIM OF PRIORITY This application claims the benefit of Chinese Patent Application App. No. 202111550049.0, filed on Dec. 17, 2021. The entire contents of the foregoing application are incorporated herein by reference. TECHNICAL FIELD This disclosure relates to genetically modified animal expressing human or chimeric (e.g., humanized) CD98HC, and methods of use thereof. BACKGROUND The traditional drug research and development typically use in vitro screening approaches. However, these screening approaches cannot provide the body environment (such as tumor microenvironment, stromal cells, extracellular matrix components and immune cell interaction, etc.), resulting in a higher rate of failure in drug development. In addition, in view of the differences between humans and animals, the test results obtained from the use of conventional experimental animals for in vivo pharmacological test may not reflect the real disease state and the interaction at the targeting sites, resulting in that the results in many clinical trials are significantly different from the animal experimental results. Therefore, the development of humanized animal models that are suitable for human antibody screening and evaluation will significantly improve the efficiency of new drug development and reduce the cost for drug research and development. SUMMARY This disclosure is related to an animal model with human CD98HC or chimeric CD98HC. The animal model can express human CD98HC or chimeric CD98HC (e.g., humanized CD98HC) protein in its body. It can be used in the studies on the function of CD98HC gene, and can be used in the screening and evaluation of anti-human CD98HC antibodies or drugs targeting CD98HC. In addition, the animal models prepared by the methods described herein can be used in drug screening, pharmacodynamics studies, treatments for immune-related diseases, and cancer therapy for human CD98HC target sites; they can also be used to facilitate the development and design of new drugs, and save time and cost. In summary, this disclosure provides a powerful tool for studying the function of CD98HC protein and a platform for screening cancer drugs. In one aspect, the disclosure is related to a genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric cluster of differentiation 98 heavy chain (CD98HC). In some embodiments, the sequence encoding the human or chimeric CD98HC is operably linked to an endogenous regulatory element at the endogenous CD98HC gene locus in the at least one chromosome. In some embodiments, the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to human CD98HC (NP_002385.3 (SEQ ID NO: 2)). In some embodiments, the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 11. In some embodiments, the sequence encoding a human or chimeric CD98HC comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to amino acids 215-630 of SEQ ID NO: 2. In some embodiments, the animal is a mammal, e.g., a monkey, a rodent, a mouse, or a rat. In some embodiments, the animal is a mouse. In some embodiments, the animal does not express endogenous CD98HC or expresses a decreased level of endogenous CD98HC as compared to CD98HC expression level in a wild-type animal. In some embodiments, the animal has one or more cells expressing human or chimeric CD98HC. In some embodiments, the animal has one or more cells expressing human or chimeric CD98HC, and the expressed human or chimeric CD98HC can interact with a human integrin, activating downstream signaling pathways. In some embodiments, the animal has one or more cells expressing human or chimeric CD98HC, and the expressed human or chimeric CD98HC can interact with an endogenous integrin, activating downstream signaling pathways. In one aspect, the disclosure is related to a genetically-modified, non-human animal, wherein the genome of the animal comprises a replacement of a sequence encoding a region of endogenous CD98HC with a sequence encoding a corresponding region of human CD98HC at an endogenous CD98HC gene locus. In some embodiments, the sequence encoding the corresponding region of human CD98HC is operably linked to an endogenous regulatory element at the endogenous CD98HC locus, and one or more cells of the animal expresses a human or chimeric CD98HC. In some embodiments, the animal does not express endogenous CD98HC or expresses a decreased level of endogenous CD98HC as compared to CD98HC expression level in a wild-type animal. In some embodiments, the replaced sequence encodes all or a portion of the extracellular region of CD98HC. In some embodiments, the animal has one or more cells