Targeting CLL1 chimeric antigen receptor and application thereof
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A chimeric antigen receptor and targeting technology, applied in the field of biomedicine
Active Publication Date: 2021-08-10
GUANGZHOU BIO GENE TECH CO LTD
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Embodiment 1
[0104] The source of embodiment 1 anti-CLL1 antibody
[0105] In this example, anti-CLL1 antibodies 19C1, 23D7, 27H4, humanized 27H4 (H27H4) and 1075.7 (patent US8536310B2) were selected as antigen-binding domains for the construction of CAR molecules, wherein 19C1 includes SEQ ID NO: 1-2 23D7 includes the variable region shown in SEQ ID NO:3~4, 27H4 includes the variable region shown in SEQ ID NO:5~6, H27H4 includes the variable region shown in SEQ ID NO:7~8 The variable region, 1075.7 includes the variable region shown in SEQ ID NO: 11-12.
Embodiment 2
[0106] Example 2 Expression of CLL1 by tumor cells
[0107] In this example, FITC anti-human CD371 (CLL1) antibody (biolegend) was used to co-incubate target cells Jurkat and KG-1a, and the expression of CLL1 by target cells was detected by flow cytometry.
[0108] The result is as figure 1 As shown, THP-1, U937 and HL-60 are CLL1 positive cells, Jurkat and KG-1a are CLL1 negative cells.
Embodiment 3
[0109] Example 3 Design of Chimeric Antigen Receptor
[0110] In this example, a chimeric antigen receptor targeting CLL1 is designed, and the structure diagram is shown in figure 2 , including CD8α signal peptide, single-chain antibody specifically binding to CLL1 antigen (Anti-CLL1scFv), CD8α hinge region (Hinge) and transmembrane region (Transmembrane), 4-1BB co-stimulatory domain and CD3ζ signaling domain, The specific CAR molecule is:
[0111]①19C1-CAR: CD8α signal peptide, Anti-CLL1scFv (19C1), CD8αHinge+TM, 4-1BB and CD3ζ;
[0112] ②23D7-CAR: CD8α signal peptide, Anti-CLL1scFv (23D7), CD8αHinge+TM, 4-1BB and CD3ζ;
[0113] ③27H4-CAR: CD8α signal peptide, Anti-CLL1scFv (27H4), CD8αHinge+TM, 4-1BB and CD3ζ;
[0114] ④H27H4-CAR: IgGκ light chain signal peptide, Anti-CLL1scFv (H27H4), CD8αHinge+TM, 4-1BB and CD3ζ;
[0115] ⑤1075.7-CAR: CD8α signal peptide, Anti-CLL1scFv (1075.7), CD8αHinge+TM, 4-1BB and CD3ζ;
[0116] Wherein, the amino acid sequence of the CD8α signa...
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Abstract
The invention provides a targeting CLL1 chimeric antigen receptor and an application thereof. The targeting CLL1 chimeric antigen receptor comprises an antigen binding structural domain, a hinge region, a transmembrane structural domain and a signal transduction structural domain, and the antigen binding structural domain is an anti-CLL1 antibody. The anti-CLL1 antibody is adopted as an antigen binding structural domain to construct a chimeric antigen receptor molecule, the targeted CLL1 chimeric antigen receptor has a specific targeting effect on CLL1 positive tumor cells, the in-vivo and in-vitro killing effect of immune cells expressing the targeted CLL1 chimeric antigen receptor is remarkable, a large number of cell factors IFN-gamma are secreted after co-culture with the CLL1 positive tumor cells, and the product has a specific removal effect on CLL1 positive tumor cells.
Description
technical field [0001] The invention belongs to the technical field of biomedicine, and relates to targeting CLL1 chimeric antigen receptor and its application. Background technique [0002] C-type lectin-like molecule 1 (CLL1), also known as C-type lectin domain family 12 member A (CLEC12A), is a type II transmembrane protein. Studies have shown that CLL1 is limitedly expressed on hematopoietic cells, mainly including myeloid-derived cells in peripheral blood and bone marrow, such as monocytes, dendritic cells, granulocytes and most acute myeloid leukemia (AML) cells. It is worth noting that although CLL1 is abundantly expressed on myeloid cells in peripheral blood and bone marrow, it is not expressed on myeloid-derived cells in peripheral tissues, such as tissue macrophages and tissue dendritic cells. . Studies have also found that CLL1 is expressed on AML stem cells (CD34+ / CD38-) and a small number of hematopoietic progenitor cells (CD34+ / CD38+ or CD34+ / CD33+), but in n...
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