Means and methods of combating myeloproliferative disorders or lymphoproliferative disorders
By binding human AML-specific antibodies to AML cells, independent of ADCC and CDC, the problem of high GvHD complications and relapse rates in allogeneic SCT has been solved, achieving effective treatment of AML and protection of immunocompromised patients.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- KLING BIOTHERAPEUTICS BV
- Filing Date
- 2014-12-17
- Publication Date
- 2026-06-09
AI Technical Summary
Existing allogeneic stem cell transplantation for the treatment of acute myeloid leukemia (AML) has high rates of graft-versus-host disease (GvHD) complications and relapse. Existing antibodies have significant side effects and limited efficacy in individuals lacking immunity.
It provides human AML-specific antibodies that reduce AML cell proliferation by binding to AML cells and exerting toxic effects in vivo, independent of ADCC, CDC, and immune cells, utilizing antibodies generated by the patient's innate immune defense after allogeneic SCT.
It effectively inhibits AML cell proliferation, reduces GvHD complications, improves treatment success rate, and lowers the risk of relapse. It is suitable for AML patients with weakened immune systems.
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Abstract
Claims
1. An isolated, synthetic, or recombinant antibody or its functional portion thereof, said antibody or its functional portion being capable of binding to snRNP200 in acute myeloid leukemia (AML) cells; and The antibody or its functional portion thereof includes: The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences, respectively, as defined by SEQ ID NO: 1, 14, 27, 40, 53, and 66; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined in SEQ ID NO: 2, 15, 28, 41, 54, and 67, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 7, 20, 33, 46, 59, and 72, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 9, 22, 35, 48, 61, and 74, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 11, 24, 37, 50, 63, and 76, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences are defined by SEQ ID NO: 13, 26, 39, 52, 65, and 78, respectively.
2. The antibody or functional portion according to claim 1, wherein the antibody or functional portion is capable of inducing the death of primary AML blast cells.
3. The antibody or functional portion according to claim 1 or 2, wherein the antibody or functional portion is capable of reducing the proliferation of AML cells in vitro within 3 days.
4. The antibody or functional part of claim 1 or 2, wherein, The AML cells belong to the French American British (FAB) category within the group consisting of M5, M0, M1, M2, M3, and M4.
5. The antibody or functional part of claim 1 or 2, wherein, The AML cells belong to FAB category M5, M1, M0, or M4.
6. The antibody of claim 1 or 2, wherein, The AML cells belong to FAB category M5.
7. The antibody or functional portion according to claim 1, wherein the antibody or functional portion is capable of binding to cell surface components of at least two different AML cell types of FAB.
8. The antibody or functional portion according to claim 7, wherein the antibody or functional portion is capable of binding to cell surface components of at least three different AML cell types of FAB.
9. The antibody or functional portion according to claim 7 or 8, wherein the antibody or functional portion is capable of binding to cell surface components of at least four different AML cell types of FAB.
10. The antibody or functional part of claim 1 or 2, wherein, The antibody is an IgG isotype.
11. The antibody or functional part of claim 10, wherein, The antibody belongs to the IgG1 or IgG3 isotype.
12. The antibody or functional part according to claim 1 or 2, comprising a heavy chain variable region sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 79, 80, 85, 87, 89 and 91.
13. The antibody or functional portion of claim 12, comprising a light chain variable region sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 92, 93, 98, 100, 102 and 104.
14. The antibody or functional part of claim 1 or 2, which is linked to another compound, wherein, The other compound is a detectable marker.
15. A chimeric antigen receptor (CAR) T cell, said CAR T cell specifically binding to snRNP200 and comprising a chimeric antigen receptor, said chimeric antigen receptor comprising: The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences, respectively, as defined by SEQ ID NO: 1, 14, 27, 40, 53, and 66; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined in SEQ ID NO: 2, 15, 28, 41, 54, and 67, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 7, 20, 33, 46, 59, and 72, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 9, 22, 35, 48, 61, and 74, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences as defined by SEQ ID NO: 11, 24, 37, 50, 63, and 76, respectively; or The heavy chain CDR1, CDR2, and CDR3 sequences and the light chain CDR1, CDR2, and CDR3 sequences are defined by SEQ ID NO: 13, 26, 39, 52, 65, and 78, respectively.
16. A nucleic acid molecule or functional equivalent or vector, said nucleic acid molecule or functional equivalent or vector encoding at least the heavy chain variable region sequence and the light chain variable region sequence of the antibody or functional portion according to any one of claims 1 to 14.
17. The nucleic acid molecule or functional equivalent or vector according to claim 16, comprising a sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 105, 106, 111, 113, 115, 117-119, 124, 126, 128, 130-132, 137, 139, 141, 143-145, 150, 152, 154, 156-158, 163, 165, 167, 169-171, 176, 178, 180 and 182.
18. The nucleic acid molecule or functional equivalent or vector according to claim 16 or 17, comprising a sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 183, 184, 189, 191, 193 and 195, and / or comprising a sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 196, 197, 202, 204, 206 and 208.
19. A nucleic acid molecule or its functional equivalent or carrier, encoding an antibody or functional portion according to any one of claims 1 to 14.
20. The nucleic acid molecule or its functional equivalent or carrier according to claim 16 or 17, wherein the nucleic acid molecule comprises cDNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), or DNA / RNA helix.
21. An isolated or recombinant cell comprising a nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20.
22. A composition comprising an antibody or functional portion according to any one of claims 1 to 14, or a CAR T cell according to claim 15, or a nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20, or a cell according to claim 21.
23. The composition of claim 22, wherein, The composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient.
24. The composition according to claim 22 or 23, wherein the composition comprises at least two antibodies or functional portions according to any one of claims 1 to 14.
25. The use of an antibody or functional portion according to any one of claims 1 to 14, or a CAR-T cell according to claim 15, or a nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20, or a cell according to claim 21, or a composition according to any one of claims 22 to 24 in the preparation of a medicament or preventative agent for at least part of the treatment or prevention of acute myeloid leukemia (AML).
26. The use of an antibody or functional portion according to any one of claims 1 to 14, or a nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20, or the use of a cell according to claim 21 in the preparation of a diagnostic reagent for acute myeloid leukemia (AML).
27. The use of the antibody or functional portion according to any one of claims 1 to 14, or the nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20, or the cell according to claim 21, in the preparation of a kit for determining whether a sample includes AML cells.
28. A method for producing an antibody or functional portion according to any one of claims 1 to 14, the method comprising providing a cell having a nucleic acid molecule or functional equivalent or carrier according to any one of claims 16 to 20, and allowing the cell to translate the nucleic acid molecule or functional equivalent or carrier to produce an antibody or functional portion according to any one of claims 1 to 14.
29. The method of claim 28, further comprising harvesting, purifying and / or separating the antibody or functional portion according to any one of claims 1 to 14.
30. The use of the antibody or functional portion according to any one of claims 1 to 14 in the preparation of a kit for determining the presence of cells expressing snRNP200 on their cell surface in a sample, wherein the method for determination comprises: Contact the sample with the antibody or functional portion according to any one of claims 1 to 14, and If cells expressing snRNP200 on their cell surface are present, the antibody or functional portion is allowed to bind to the cells expressing snRNP200 on their cell surface. The presence of cells expressing snRNP200 on their cell surface in the sample is determined by whether the cells bind to the antibody or functional portion.
31. The use of the antibody or functional portion according to any one of claims 1 to 14 in the preparation of a kit for determining the presence of AML cells in a sample, wherein the method for determination comprises: Contact the sample with the antibody or functional portion according to any one of claims 1 to 14, and If AML cells are present, the antibody or functional portion or binding compound is allowed to bind to the AML cells, and Determining whether AML cells bind to the antibody or functional portion determines the presence of AML cells in the sample.
32. The use of the antibody or functional portion according to any one of claims 1 to 14 in the preparation of a kit for determining whether an individual has AML, wherein the method for determination comprises: Contact the sample from said individual with the antibody or functional portion according to any one of claims 1 to 14, and If AML cells are present, the antibody or functional portion is allowed to bind to the AML cells, and Determining whether AML cells bind to the antibody or functional portion determines whether the individual has AML.
33. The antibody or functional portion according to any one of claims 1 to 14, or the composition according to any one of claims 22 to 24, or the application according to any one of claims 25 to 27 and 30 to 32, or the method according to claims 28 to 29, wherein, The antibody is selected from the group consisting of: An antibody comprising a heavy chain variable domain sequence as defined in SEQ ID NO: 79 and a light chain variable domain sequence as defined in SEQ ID NO: 92; or An antibody comprising a heavy chain variable domain sequence as defined in SEQ ID NO: 80 and a light chain variable domain sequence as defined in SEQ ID NO: 93; or An antibody comprising a heavy chain variable domain sequence as defined in SEQ ID NO: 85 and a light chain variable domain sequence as defined in SEQ ID NO: 98; or An antibody comprising a heavy chain variable domain sequence as defined in SEQ ID NO: 87 and a light chain variable domain sequence as defined in SEQ ID NO: 100; or An antibody comprising a heavy chain variable domain sequence as defined in SEQ ID NO: 89 and a light chain variable domain sequence as defined in SEQ ID NO: 102; or An antibody comprising a heavy chain variable domain sequence defined by SEQ ID NO: 91 and a light chain variable domain sequence defined by SEQ ID NO: 104; And their functional parts.
34. Use of the antibody or functional portion according to any one of claims 1 to 14 in the preparation of a kit for determining whether an AML patient has graft-versus-leukemia effect.
35. The use of the antibody or functional portion thereof according to any one of claims 1 to 14, or the nucleic acid molecule or its functional equivalent or carrier according to any one of claims 16 to 20, or the cell according to claim 21 in the preparation of a kit for determining whether a sample contains AML cells.
36. A method for detecting AML cells in vitro using an antibody or functional portion according to any one of claims 1 to 14, wherein, The method described herein is for non-diagnostic purposes.