Genetically modified non-human animal with human or chimeric LAG-3

Patent metadata

Field	Value
Publication number	US-10925264-B2
Application number	US-201916409683-A
Country	US
Kind code	B2
Filing date	May 10, 2019
Priority date	Nov 11, 2016
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

The present disclosure relates to the genetically modified non-human animals that express a human or chimeric (e.g., humanized) Lymphocyte Activation Gene 3 (LAG-3), and methods of use thereof.

First claim

What is claimed is:

1. A genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a chimeric Lymphocyte Activation Gene 3 (LAG-3), wherein the chimeric LAG-3 comprises an amino acid sequence that is identical to SEQ ID NO: 31.

2. The animal of claim 1 , wherein the sequence encoding the chimeric LAG-3 is operably linked to an endogenous regulatory element at the endogenous LAG-3 gene locus in the at least one chromosome.

3. The animal of claim 1 , wherein the chimeric LAG-3 consists of an amino acid sequence that is identical to SEQ ID NO: 31.

4. The animal of claim 1 , wherein the animal is a rodent.

5. The animal of claim 1 , wherein the animal is a mouse.

6. The animal of claim 1 , wherein the animal does not express endogenous LAG-3.

7. The animal of claim 1 , wherein the animal has one or more cells expressing the chimeric LAG-3.

8. The animal of claim 1 , wherein the animal further comprises a sequence encoding an additional human or chimeric protein.

9. The animal of claim 8 , wherein the additional human or chimeric protein is programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), B And T Lymphocyte Associated (BTLA), Programmed Cell Death 1 Ligand 1 (PD-L1), TNF Receptor Superfamily Member 9 (4-1BB), CD27, CD28, CD47, T-Cell Immunoreceptor With Ig And ITIM Domains (TIGIT), CD27, Glucocorticoid-Induced TNFR-Related Protein (GITR), or TNF Receptor Superfamily Member 4 (OX40).

10. A method of determining effectiveness of an anti-LAG-3 antibody for treating cancer, comprising:
administering the anti-LAG-3 antibody to the animal of claim 1 , wherein the animal has a tumor; and
determining inhibitory effects of the anti-LAG-3 antibody to the tumor.

11. The method of claim 10 , wherein the tumor comprises one or more human cancer cells that are injected into the animal.

12. The animal of claim 1 , wherein the animal is modified and the modification is performed by CRISPR associated protein 9 (Cas9) with sgRNAs that target SEQ ID NO: 5 and SEQ ID NO: 12.

Assignees

• Biocytogen Pharmaceuticals Beijing Co Ltd

Inventors

• Shen Yuelei
• Guo Yanan
• Guo Chaoshe
• Bai Yang
• Yao Jiawei
• Zhao Lei
• Huang Rui

Classifications

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A01K2217/072

  maintaining or altering function, i.e. knock in · CPC title

• C07K14/70503

  Immunoglobulin superfamily · CPC title

• C12N2810/10

  Vectors comprising a non-peptidic targeting moiety · CPC title

• C12N9/22 Primary

  Ribonucleases {[RNase]; Deoxyribonucleases [DNase]} · CPC title