# US 9,518,119 B2 · IL3Rα antibody conjugates and uses thereof

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- Number: US 9,518,119 B2
- Document ID: US9518119B2
- Status: Granted
- Kind: B2
- Application number: 14/632,178
- Filed: 2015-02-26
- Published: 2016-02-04
- Granted: 2016-12-13
- Earliest claimed: 2007-04-13
- Assignees: Stemline Therapeutics, Inc.
- Applicants: Stemline Therapeutics, Inc.
- Inventors: Ivan Bergstein
- Web page: https://patentgrep.com/patent/US9518119B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C12N 9/1048: {Glycosyltransferases (2.4)}
- C12N 9/1077: {Pentosyltransferases (2.4.2)}
- C12N 15/86: Viral vectors
- C12Y 204/02036: NAD(+)--diphthamide ADP-ribosyltransferase (2.4.2.36)
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- C07K 16/18: against material from animals or humans
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/55: containing a fusion with a toxin, e.g. diphteria toxin
- C12N 5/163: {one of the fusion partners being a B or a T lymphocyte}
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- 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)

## Abstract

The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα.

## Claims

### Claim 1

A nucleic acid that encodes a single chain fragment variable (scFv) region of an antibody that binds CD123, wherein said nucleic acid comprises nucleotide sequences that encode the complementarity determining regions (CDRs) of the variable heavy (VH) domain and the variable light (VL) domain of said antibody, and wherein said CDRs comprise the VH domain CDR1 presented in SEQ ID NO: 3, the VH domain CDR2 presented in SEQ ID NO: 4, the VH domain CDR3 presented in SEQ ID NO: 5, the VL domain CDR1 presented in SEQ ID NO: 8, the VL domain CDR2 presented in SEQ ID NO: 9, and the VL domain CDR3 presented in SEQ ID NO: 10.

### Claim 2 (depends on 1)

The nucleic acid of claim 1, wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 1.

### Claim 3 (depends on 1)

The nucleic acid of claim 1, wherein said nucleotide sequence that encodes the CDRs of the VL domain of said antibody comprises SEQ ID NO: 6.

### Claim 4 (depends on 1)

The nucleic acid of claim 1, wherein said nucleotide sequence that encodes the CDRs of the VH domain of said antibody comprises SEQ ID NO: 1 and wherein said nucleotide sequence that encodes the CDRs of the VL domain of said antibody comprises SEQ ID NO: 6.

### Claim 5 (depends on 1)

The nucleic acid of claim 1, wherein said nucleic acid encodes a fusion protein, said fusion protein comprising said anti-CD123 scFv antibody region and a second protein.

### Claim 6 (depends on 5)

An expression vector comprising the nucleic acid of claim 5.

### Claim 7 (depends on 6)

The expression vector of claim 6, wherein said expression vector is a viral vector.

### Claim 8 (depends on 6)

An isolated mammalian cell comprising the expression vector of claim 6.

### Claim 9 (depends on 5)

An isolated mammalian cell engineered to express the nucleic acid of claim 5.

### Claim 10 (depends on 9)

The mammalian cell of claim 9, wherein said mammalian cell is a human cell.

### Claim 11 (depends on 5)

The nucleic acid of claim 5, wherein said second protein is Pseudomonas exotoxin A.

### Claim 12 (depends on 5)

The nucleic acid of claim 5, wherein said second protein is abrin, ricin A, cholera toxin, diphtheria toxin, tumor necrosis factor, α-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, a thrombotic agent, an anti-angiogenic agent, angiostatin, endostatin, a lymphokine, interleukin-1, interleukin-2, interleukin-6, granulocyte macrophage colony stimulating factor, and granulocyte colony stimulating factor, or a growth factor.

### Claim 13 (depends on 1)

An expression vector comprising the nucleic acid of claim 1.

### Claim 14 (depends on 13)

The expression vector of claim 13, wherein said expression vector is a viral vector.

### Claim 15 (depends on 13)

An isolated mammalian cell comprising the expression vector of claim 13.

### Claim 16 (depends on 1)

An isolated mammalian cell engineered to express the nucleic acid of claim 1.

### Claim 17 (depends on 16)

The mammalian cell of claim 16, wherein said mammalian cell is a human cell.

### Claim 18

A nucleic acid that encodes an anti-CD123 single chain fragment variable (scFv) antibody region, wherein said nucleic acid comprises SEQ ID NO: 1 and SEQ ID NO: 6.

### Claim 19 (depends on 18)

The nucleic acid of claim 18, wherein said nucleic acid encodes a fusion protein, said fusion protein comprising said anti-CD123 scFv antibody region and a second protein.

### Claim 20 (depends on 19)

An expression vector comprising the nucleic acid of claim 19.

### Claim 21 (depends on 20)

The expression vector of claim 20, wherein said expression vector is a viral vector.

### Claim 22 (depends on 20)

An isolated mammalian cell comprising the expression vector of claim 20.

### Claim 23 (depends on 19)

An isolated mammalian cell engineered to express the nucleic acid of claim 19.

### Claim 24 (depends on 23)

The mammalian cell of claim 23, wherein said mammalian cell is a human cell.

### Claim 25 (depends on 19)

The nucleic acid of claim 19, wherein said second protein is Pseudomonas exotoxin A.

### Claim 26 (depends on 19)

The nucleic acid of claim 19, wherein said second protein is abrin, ricin A, cholera toxin, diphtheria toxin, tumor necrosis factor, α-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, a thrombotic agent, an anti-angiogenic agent, angiostatin, endostatin, a lymphokine, interleukin-1, interleukin-2, interleukin-6, granulocyte macrophage colony stimulating factor, and granulocyte colony stimulating factor, or a growth factor.

### Claim 27 (depends on 18)

An expression vector comprising the nucleic acid of claim 18.

### Claim 28 (depends on 27)

The expression vector of claim 27, wherein said expression vector is a viral vector.

### Claim 29 (depends on 27)

An isolated mammalian cell comprising the expression vector of claim 27.

### Claim 30 (depends on 18)

An isolated mammalian cell engineered to express the nucleic acid of claim 18.

### Claim 31 (depends on 30)

The mammalian cell of claim 30, wherein said mammalian cell is a human cell.

### Claim 32

A nucleic acid that encodes the variable heavy (VH) domain of monoclonal antibody 26292, wherein said VH domain comprises SEQ ID NO: 2.

### Claim 33 (depends on 32)

The nucleic acid of claim 32, wherein said nucleic acid comprises SEQ ID NO: 1.

### Claim 34 (depends on 33)

The nucleic acid of claim 33, wherein said nucleic acid further comprises a nucleic acid sequence that encodes the variable light (VL) domain of monoclonal antibody 26292, wherein said VL domain comprises SEQ ID NO: 7.

### Claim 35 (depends on 34)

The nucleic acid of claim 34, wherein said nucleic acid sequence that encodes the VL domain of monoclonal antibody 26292 comprises SEQ ID NO: 6.

### Claim 36

A nucleic acid that encodes the variable light (VL) domain of monoclonal antibody 26292, wherein said VL domain comprises SEQ ID NO: 7.

### Claim 37 (depends on 36)

The nucleic acid of claim 36, wherein said nucleic acid comprises SEQ ID NO: 6.