Patent application EP19305816A (EP), filed 2019-06-21
Publication number: EP3753954A1
Title: ANTI-CD123 ANTIBODIES, ANTI-CD123 CHIMERIC ANTIGEN RECEPTORS AND ANTI-CD123 CHIMERIC ANTIGEN RECEPTORS T CELLS
Abstract: [0001]    The invention is relative to monoclonal anti-CD123 antibodies, or fragments thereof that specifically bind to the alpha chain of the human interleukin 3 (IL3) receptor. Further, the invention is relative to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antibody or an antibody fragment which includes an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least a stimulatory domain, polypeptides encoded by said nucleic acid molecule as well as an isolated chimeric antigen receptor (CAR) molecules comprising such an antibody or antibody fragment. The invention is also relative to a vector comprising a nucleic acid molecule encoding a CAR, as well as a T cell comprising said vector, and to the use of a T cell expressing a CAR molecule for a treatment of a proliferative disease in a mammal, such as cancer.
IPC codes: A61K  39/    00            A I
A61P  35/    00            A I
C07K  16/    28            A I
Claims: number: 1
text: Antibody that binds specifically to antigen CD123, wherein said antibody is selected from the group consisting of AB1, AB2, AB3, AB4, AB5 and AB6, said antibody having a K<D> value of not more than 9.5 x 10<-9> M, an antibody dissociation rate k<off> of not more than 9.0 x 10<-4> s<-1>, and an antibody association rate k<on> of at least 7 x 10<4> Ms<-1>, and wherein
number: 2
text: The antibody according to claim 1, wherein
number: 3
text: The antibody according to any of the preceding claims, wherein
number: 4
text: The antibody according to one of the preceding claims,
wherein the heavy chain of AB1 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 37, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 38, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 39, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 40, and wherein the light chain of AB1 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 61, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 62, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 63, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 64 ;
wherein the heavy chain of AB2 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 41, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 42, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 43, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 44, and wherein the light chain of AB2 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 65, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 66, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 67, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 68 ;
wherein the heavy chain of AB3 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 45, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 46, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 47, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 48, and wherein the light chain of AB3 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 69, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 70, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 71, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 72 ;
wherein the heavy chain of AB4 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 49, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 50, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 51, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 52, and wherein the light chain of AB4 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 73, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 74, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 75, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 76 ;
wherein the heavy chain of AB5 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 53, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 54, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 55, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 56, and wherein the light chain of AB5 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 77, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 78, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 79, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 80 ;
wherein the heavy chain of AB6 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 57, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 58, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 59, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 60, and wherein the light chain of AB6 has a variable region comprising a first framework region (FR1) consisting of amino acid sequence SEQ ID NO : 81, a second framework region (FR2) consisting of amino acid sequence SEQ ID NO : 82, a third framework region (FR3) consisting of amino acid sequence SEQ ID NO : 83, and a fourth framework region (FR4) consisting of amino acid sequence SEQ ID NO : 84.
number: 5
text: An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antibody or antibody fragment which includes an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least a stimulatory domain, and wherein said anti-CD123 binding domain comprises:
number: 6
text: The isolated nucleic acid molecule according to claim 5, wherein the anti-CD123 binding domain is selected from the group consisting of an antibody, a Fv, a scFv, a Fab, or another antibody fragment, preferably a scFv.
number: 7
text: The isolated nucleic acid molecule according to any of claims 5 or 6, wherein the intracellular signaling domain is CD3-zeta (CD3ζ), optionally comprising a costimulatory domain selected from the group consisting of CD28, 4.1BB, Inducible T-cell COStimulator (ICOS), OX-40 or a combination thereof.
number: 8
text: An isolated polypeptide molecule encoded by the nucleic acid molecule of any one of claims 5 to 7.
number: 9
text: An isolated chimeric antigen receptor (CAR) molecule comprising an antibody or antibody fragment which includes an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least a stimulatory domain, and wherein said anti-CD123 binding domain comprises:
number: 10
text: An isolated chimeric antigen receptor (CAR) molecule, wherein the said CAR is as defined in any one of claims 6 or 7.
number: 11
text: An expression vector comprising a nucleic acid molecule as defined in any of claims 5 to 7, wherein the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, an adenoviral vector, or a retrovirus vector.
number: 12
text: An engineered immune cell comprising the nucleic acid molecule of any of claims 5 to 7 or the vector of claim 11.
number: 13
text: The cell according to claim 12 for use as a medicament.
number: 14
text: The cell according to claim 12 or 13 for use in the treatment of a proliferative disease in a mammal, preferably a human, wherein the proliferative disease is a disease associated with CD123 overexpression, preferably Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).
number: 15
text: A pharmaceutical composition comprising the engineered immune cell according to any of claims 12 to 14 and a pharmaceutical excipient.
Office action: search_report, dated 2020-12-23
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Final disposition: pending (2020-12-23)