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US 2026/0242735 A1Published application
Discernible cell surface protein variants of cd33 for use in cell therapy
AssigneesUniversitäT Basel, Cimeio Therapeutics AG
InventorsStefanie URLINGER, Rosalba LEPORE, Mathilde TESTUT, Lukas JEKER, Anna CAMUS, Thomas BURGOLD, Simon GARAUDE, Astrid BEERLAGE
Life of this patent
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Abstract
The present disclosure relates to the use of cells having discernible surface protein with engineered or naturally occurring mutation(s) but functional surface protein for use in therapy. The present invention also relates to the use of cells having discernible CD33 surface protein variants but functional surface protein for use in therapy, in particular adoptive cell therapy.
Claims20
1:
- A mammalian cell or a population of cells expressing a first isoform of CD33 for use in a medical treatment in a patient in need thereof, said patient having cells expressing a second isoform of CD33,
- wherein said cell expressing said first isoform comprises a polymorphism or genetically engineered allele that is not present in the genome of the patient having cells expressing said second isoform of CD33, wherein said first and second isoform are substantially functionally identical and/or are expressed at the same level or substantially the same level, and
- wherein said polymorphic or genetically engineered allele is characterized by at least one substitution of an amino acid at position N20, F21, W22, Q24, F43, F44, H45, P48, Y49 and/or Y50 of SEQ ID NO:
- 1.
1 more element
2:
- The mammalian cell or population of cells for use according to claim 1, wherein said polymorphic or genetically engineered allele is characterized by at least one substitution of an amino acid at position N20, F21, W22 and/or Y50 of SEQ ID NO:
- 1.
3:
- The mammalian cell or population of cells for use according to claim 1, wherein said function is the binding to sialic acids, the stimulation by sialic acids, phosphorylation upon binding to sialic acids, the capability to act as a docking site for Src homology 2 (SH2) domain-containing proteins and/or are the capability to trigger the inhibition of phagocytosis.
4:
- The mammalian cell or population of cells for use according to claim 3, wherein said residue N20 is substituted with G, S, D, E, K, V, R or H, and/or residue F21 is substituted with V, L, I, S, M, N Q or H, and/or residue W22 is substituted with S, T, E, R, D, K or H, and/or Q24 is substituted with R, and/or F43 is substituted with S, and/or F44 is substituted with P or S, and/or H45 is substituted with Y, and/or residue P48 is substituted with F, D or S, and/or residue Y49 is substituted with A, and/or residue Y50 is substituted with S, L, R, D, E, A, K or H.
5:
- The mammalian cell or population of cells for use according to claim 1, wherein said first isoform of CD33 is obtained by in vivo or ex vivo modifying the nucleic acid sequence encoding said first isoform of CD33 by gene editing, preferably by introducing into a cell a gene editing enzyme capable of inducing site-specific mutations(s) within a target sequence encoding a surface protein region involved in the binding of agent comprising at least a first antigen-binding region.
6:
- The mammalian cell or population of cells according to claim 1 wherein said medical treatment comprises administering a therapeutically efficient amount of said cell or population of cells expressing said first isoform of CD33 to said patient in need thereof, in combination with a therapeutically efficient amount of a depleting agent comprising at least a first antigen-binding region that binds specifically to said second isoform of CD33 to specifically deplete patient cells expressing said second isoform of CD33.
7:
- The mammalian cell or population of cells for use according to claim 6, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including the amino acids N20, F21 and/or W22 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 4, VHCDR2 is SEQ ID NO:
- 5 and VHCDR3 is SEQ ID NO:
- 6;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 7, VLCDR2 is SEQ ID NO:
- 8, VLCDR3 is SEQ ID NO:
- 9.
8 more elements
8:
- The mammalian cell or population of cells for use according to claim 6, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including the amino acids N20, F21 and/or W22 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 20, VHCDR2 is SEQ ID NO:
- 21 and VHCDR3 is SEQ ID NO:
- 22;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 23, VLCDR2 is SEQ ID NO:
- 8, VLCDR3 is SEQ ID NO:
- 24.
8 more elements
9:
- The mammalian cell or population of cells for use according to claim 6, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including amino acid P48 and/or Y50 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 27, VHCDR2 is SEQ ID NO:
- 28 and VHCDR3 is SEQ ID NO:
- 29;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 30, VLCDR2 is SEQ ID NO:
- 31, VLCDR3 is SEQ ID NO:
- 32.
8 more elements
10:
- A pharmaceutical composition comprising the mammalian cell or population of cells of claim 1 and a pharmaceutically acceptable carrier.
11:
- A depleting agent for use in preventing or reducing the risk of severe side effects in a patient having received a cell expressing a first isoform of CD33, wherein said patient's native cells express a second isoform of CD33, and wherein said depleting agent comprises at least a second antigen-binding region which binds specifically to said first isoform of CD33 and does not bind or binds substantially weaker to said second isoform of CD33.
12:
- A depleting agent for use in selectively depleting host cells in a patient in need thereof wherein said patient's host cells express a second isoform of CD33 and wherein said depleting agent comprises at least a first antigen-binding region which binds specifically to said second isoform of CD33, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including the amino acids N20, F21 and/or W22 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 4, VHCDR2 is SEQ ID NO:
- 5 and VHCDR3 is SEQ ID NO:
- 6;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 7, VLCDR2 is SEQ ID NO:
- 8, VLCDR3 is SEQ ID NO:
- 9.
8 more elements
13:
- A depleting agent for use in selectively depleting host cells in a patient in need thereof wherein said patient's host cells express a second isoform of CD33 and wherein said depleting agent comprises at least a first antigen-binding region which binds specifically to said second isoform of CD33, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including the amino acids N20, F21, and/or W22 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 20, VHCDR2 is SEQ ID NO:
- 21 and VHCDR3 is SEQ ID NO:
- 22;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 23, VLCDR2 is SEQ ID NO:
- 8, VLCDR3 is SEQ ID NO:
- 24.
8 more elements
14:
- A depleting agent for use in selectively depleting host cells in a patient in need thereof wherein said patient's host cells express a second isoform of CD33 and wherein said depleting agent comprises at least a first antigen-binding region which binds specifically to said second isoform of CD33, wherein said first antigen-binding region of said depleting agent binds specifically to an epitope including amino acid Y50 of SEQ ID NO:
- 1, and wherein said first antigen-binding region comprises an antigen binding region which has the same epitope specificity as an antigen binding region comprising:
- a) an antibody heavy chain variable domain (VH) comprising the three CDRs VHCDR1, VHCDR2 and VHCDR3 wherein VHCDR1 is SEQ ID NO:
- 27, VHCDR2 is SEQ ID NO:
- 28 and VHCDR3 is SEQ ID NO:
- 29;
- and
- b) an antibody light chain variable domain (VL) comprising the three CDRs VLCDR1, VLCDR2 and VLCDR3 wherein VLCDR1 is SEQ ID NO:
- 30, VLCDR2 is SEQ ID NO:
- 31, VLCDR3 is SEQ ID NO:
- 32.
8 more elements
15:
- The mammalian cell or population of cells for use according to claim 1 comprising hematopoietic stem cells.
16:
- The mammalian cell or population of cells for use according to claim 6 which restores normal haematopoiesis after immunotherapy in the treatment of hematopoietic disease.
17:
- The mammalian cell or population of cells for use according to claim 16 wherein the hematopoietic disease is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), blastic plasmacytoid dendritic cell neoplasm (BPDCN) or another myeloproliferative neoplasm.
18:
- The mammalian cell or population of cells for use according to claim 6 wherein said depleting agent is an antibody, antibody-drug conjugate or an immune cell.
19:
- The mammalian cell or population of cells for use according to claim 6 wherein said depleting agent a T-cell bearing a chimeric antigen receptor (CAR) comprising a first antigen-binding region which binds specifically to said second isoform and does not bind or binds substantially weaker to said first isoform.
20:
- The pharmaceutical composition of claim 10 further comprising a depleting agent comprising at least a first antigen-binding region that binds specifically to said second isoform of CD33 to specifically deplete patient cells expressing said second isoform of CD33.