Effective targeting of primary human leukemia using anti-CD123 chimeric antigen receptor engineered T cells

Patent metadata

Field	Value
Publication number	US-11028177-B2
Application number	US-201715400096-A
Country	US
Kind code	B2
Filing date	Jan 6, 2017
Priority date	Feb 20, 2013
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

The invention provides compositions and methods for treating leukemia, for example, acute myeloid leukemia (AML) and B-cell acute lymphoid leukemia (B-ALL). The invention also relates to at least one chimeric antigen receptor (CAR) specific to CD123, vectors comprising the same, and recombinant T cells comprising the CD123 CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a CD123 binding domain. The invention also includes methods of bone marrow ablation for use in treatments necessitating bone marrow reconditioning or transplant.

First claim

What is claimed is:

1. A method of eradicating at least a portion of existing CD123-expressing cells in the bone marrow in a subject, the method comprising administering to the subject an effective amount of T cells expressing a chimeric antigen receptor (CAR) molecule comprising an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain, thereby eradicating at least a portion of the existing CD123-expressing cells in the bone marrow in a subject, wherein said anti-CD123 binding domain comprises:
(a) a light chain variable region comprising:

a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 22, and
a heavy chain variable region comprising:

a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 16, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 17, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 18; or
(b) a light chain variable region comprising:

a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 28, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 29, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 30, and
a heavy chain variable region comprising:

a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 24, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 25, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 26; or
(c) a light chain variable region comprising:

a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 87, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 88, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 89, and
a heavy chain variable region comprising:

a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 84, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 85, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 86.

2. A method of treating a subject having cancer, the method comprising
administering to the subject an amount of T cells expressing a chimeric antigen receptor (CAR) molecule effective to eradicate at least a portion of existing CD123-expressing cells in the bone marrow in a subject, wherein said CAR molecule comprises an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain,
thereby treating the subject having cancer, wherein said anti-CD123 binding domain comprises:
(a) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 22, and
a heavy chain variable region comprising:
a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 16, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 17, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 18; or
(b) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 28, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 29, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 30, and
a heavy chain variable region comprising:
a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 24, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 25, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 26; or
(c) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 87, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 88, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 89, and
a heavy chain variable region comprising:
a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 84, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 85, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 86.

3. A method of treating a subject having a disease, disorder or condition that is treatable with a bone marrow transplant or bone marrow reconditioning, the method comprising
administering to the subject an amount of T cells expressing a chimeric antigen receptor (CAR) molecule effective to eradicate at least a portion of existing CD123-expressing cells in the bone marrow in a subject, wherein said CAR molecule comprises an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain,
thereby treating the subject having a disease, disorder or condition that is treatable with a bone marrow transplant or bone marrow reconditioning, wherein said anti-CD123 binding domain comprises:
(a) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 20, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 21, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 22, and
a heavy chain variable region comprising:
a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 16, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 17, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 18; or
(b) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 28, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 29, and a light chain complementarity determining region 3 (LC CDR3) comprising the sequence of SEQ ID NO: 30, and
a heavy chain variable region comprising:
a heavy chain complementarity determining region 1 (HC CDR1) comprising the sequence of SEQ ID NO: 24, a heavy chain complementarity determining region 2 (HC CDR2) comprising the sequence of SEQ ID NO: 25, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence of SEQ ID NO: 26; or
(c) a light chain variable region comprising:
a light chain complementarity determining region 1 (LC CDR1) comprising the sequence of SEQ ID NO: 87, a light chain complementarity determining region 2 (LC CDR2) comprising the sequence of SEQ ID NO: 88, and a light chain complementarity determining region 3

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Brogdon Jennifer
• Gill Saar
• June Carl H
• Kalos Michael D
• Loew Andreas
• Scholler John

Classifications

• A61K40/4224

  Molecules with a "CD" designation not provided for elsewhere · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title