# US 2024/0197879 A1 · Antigen recognizing receptors targeting cd33 and uses thereof

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- Number: US 2024/0197879 A1
- Document ID: US20240197879A1
- Status: Published application
- Kind: A1
- Application number: 18/591,191
- Filed: 2024-02-29
- Published: 2024-06-20
- Earliest claimed: 2021-09-02
- Assignees: Memorial Sloan Kettering Cancer Center; Sloan-Kettering Institute for Cancer Research; Memorial Hospital for Cancer and Allied Diseases; Tri-Institutional Therapeutics Discovery Institute, Inc.
- Applicants: Memorial Sloan-Kettering Cancer Center; Sloan-Kettering Institute for Cancer Research; Memorial Hospital for Cancer and Allied Diseases; Tri-Institutional Therapeutics Discovery Institute, Inc.
- Inventors: Anthony Daniyan; Renier J. BRENTJENS; Ivo C. LORENZ; Abdul KHAN
- Web page: https://patentgrep.com/patent/US20240197879A1

## CPC

- A61K 40/421: {Immunoglobulin superfamily}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/32: T-cell receptors [TCR]
- A61P 35/02: specific for leukemia
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70514: {CD4}
- C07K 14/70517: {CD8}
- C07K 14/70521: {CD28, CD152}
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C12N 5/0636: {T lymphocytes}
- A61K 2239/10: characterized by the structure of the chimeric antigen receptor [CAR]
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C12N 2740/10041: Use of virus, viral particle or viral elements as a vector
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The presently disclosed subject matter provides for antigen-recognizing receptors that specifically target CD33 and cells comprising such CD33-targeted antigen-recognizing receptors. The presently disclosed subject matter further provides uses of the CD33-targeted antigen-recognizing receptors for treatment.

## Claims

### Claim 1

An antigen-recognizing receptor, comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen-binding domain specifically binds to CD33, wherein the extracellular antigen-binding domain comprises a heavy chain variable region and a light chain variable region, wherein:
(a) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7;
(b) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 16, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 17;
(c) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24 the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27;
(d) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 34 the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27;
(e) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 42;
(f) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51;
(g) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 57, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 58; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61;
(h) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 66, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 69, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 70, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 71;
(i) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 57, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80; or
(j) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 85, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 87; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 42.

### Claim 2 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv), a Fab, or a F(ab)2.

### Claim 3 (depends on 2)

The antigen-recognizing receptor of claim 2, wherein one or more of the scFv, Fab and F(ab)2 are comprised in a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

### Claim 4 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein
(a) the heavy chain variable region comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% homologous or identical to the amino acid sequence selected set forth in SEQ ID NO: 8, SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 35, SEQ ID NO: 43, SEQ ID NO: 52, SEQ ID NO: 62, SEQ ID NO: 72, SEQ ID NO: 81, or SEQ ID NO: 88; and
(b) the light chain variable region comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO: 29, SEQ ID NO: 44, SEQ ID NO: 53, SEQ ID NO: 63, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 89, or SEQ ID NO: 92.

### Claim 5 (depends on 4)

The antigen-recognizing receptor of claim 4, wherein
(a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8, SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 35, SEQ ID NO: 43, SEQ ID NO: 52, SEQ ID NO: 62, SEQ ID NO: 72, SEQ ID NO: 81, or SEQ ID NO: 88; and
(b) the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO: 29, SEQ ID NO: 44, SEQ ID NO: 53, SEQ ID NO: 63, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 89, or SEQ ID NO: 92.

### Claim 6 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein
(a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9;
(b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 18, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 19;
(c) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 29;
(d) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 35, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 29;
(e) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 44;
(f) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 52, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 53;
(g) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 62, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 63;
(h) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 72, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73;
(i) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 81, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 82;
(j) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 88, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 89; or
(k) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 93.

### Claim 7 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain comprises a linker between the heavy chain variable region and the light chain variable region.

### Claim 8 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein a signal peptide is covalently joined to the 5′ terminus of the extracellular antigen-binding domain.

### Claim 9 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, or a combination thereof.

### Claim 10 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the intracellular signaling domain comprises a CD3ζ polypeptide.

### Claim 11 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the intracellular signaling domain further comprises at least one co-stimulatory signaling region.

### Claim 12 (depends on 11)

The antigen-recognizing receptor of claim 11, wherein the at least one co-stimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof.

### Claim 13 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the antigen-recognizing receptor is a chimeric antigen receptor (CAR), or a T-cell like fusion protein.

### Claim 14 (depends on 1)

The antigen-recognizing receptor of claim 1, wherein the antigen-recognizing receptor is recombinantly expressed or expressed from a vector.

### Claim 15 (depends on 1)

A cell comprising the antigen-recognizing receptor of claim 1.

### Claim 16 (depends on 15)

The cell of claim 15, wherein the antigen-recognizing receptor is constitutively expressed on the surface of the cell.

### Claim 17 (depends on 15)

The cell of claim 15, wherein the cell is an immunoresponsive cell, a cell of the lymphoid lineage, or a cell of the myeloid lineage.

### Claim 18 (depends on 15)

The cell of claim 15, wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a stem cell from which a lymphoid cell may be differentiated.

### Claim 19 (depends on 18)

The cell of claim 18, wherein the cell is a T cell.

### Claim 20 (depends on 19)

The cell of claim 19, wherein the T cell is a cytotoxic T lymphocyte (CTL) or a regulatory T cell.

### Claim 21 (depends on 18)

The cell of claim 18, wherein the stem cell is a pluripotent stem cell, an embryoid stem cell, or an induced pluripotent stem cell.

### Claim 22 (depends on 1)

A nucleic acid encoding the antigen-recognizing receptor of claim 1.

### Claim 23 (depends on 22)

A vector comprising the nucleic acid of any one of claim 22.

### Claim 24 (depends on 22)

A host cell expressing the nucleic acid of claim 22.

### Claim 25 (depends on 15)

A composition comprising the cell of claim 15.

### Claim 26 (depends on 22)

A lipid nanoparticle comprising the nucleic acid of claim 22.

### Claim 27 (depends on 26)

A composition comprising the lipid nanoparticle of claim 26.

### Claim 28 (depends on 15)

A method of treating or ameliorating a disease or disorder in a subject, reducing tumor burden in a subject, treating and/or preventing a tumor in a subject, and/or increasing or lengthening survival of a subject having a tumor comprising administering to the subject the cell of claim 15.

### Claim 29 (depends on 28)

The method of claim 28, wherein the tumor is hematological cancer or solid tissue cancer.

### Claim 30 (depends on 28)

The method of claim 28, wherein the tumor is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasms (MPNs), and chronic myeloid neoplasms.

### Claim 31 (depends on 30)

The method of claim 30, wherein the tumor is acute myeloid leukemia (AML).

### Claim 32 (depends on 28)

The method of claim 28, wherein the subject is a human.

### Claim 33 (depends on 15)

A kit for treating or ameliorating a disease or disorder in a subject, reducing tumor burden in a subject, treating and/or preventing a tumor in a subject, and/or increasing or lengthening survival of a subject having a tumor, comprising the cell of claim 15.

### Claim 34 (depends on 1)

A method for producing a CD33-targeted antigen-recognizing receptor of any one of claim 1, comprising introducing into the cell a nucleic acid that encodes the antigen-recognizing receptor.