# US 11,111,306 B2 · IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia

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- Number: US 11,111,306 B2
- Document ID: US11111306B2
- Status: Granted
- Kind: B2
- Application number: 16/459,396
- Filed: 2019-07-01
- Published: 2019-10-17
- Granted: 2021-09-07
- Earliest claimed: 2015-10-07
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services; University of Maryland, College Park
- Applicants: The United States of America, as represented by the Secretary, Department of Health and Human Services; University of Maryland, College Park
- Inventors: Scott Durum; Julie Hixon; Wen Qing Li; Scott Walsh; Lila Kashi
- Web page: https://patentgrep.com/patent/US11111306B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/02: specific for leukemia
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- G01N 33/57505: of the blood, e.g. leukaemia
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/6869: {Interleukin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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
- G01N 2333/5418: IL-7
- G01N 2333/7155: for interleukins [IL]
- 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)
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Antibodies and antigen binding fragments that specifically bind to IL-7Rα are disclosed. Nucleic acids encoding the antibodies and antigen binding fragments, and vectors including the nucleic acid molecules are also provided. Methods for detecting a ca cancer or a cell that expresses IL-7Rα using the antibodies and antigen binding fragments are disclosed, as is the use of the antibodies and antigen binding fragments to prevent and/or treat a subject with a cancer that expresses IL-7Rα, such as acute lymphoblastic leukemia.

## Claims

### Claim 1

A method of treating a subject with an IL-7Rα positive cancer or with an autoimmune disease, comprising:
administering to the subject a therapeutically effective amount of:
(A) a monoclonal antibody that specifically binds to an extracellular domain of IL-7Rα, the monoclonal antibody comprising:
a heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 of the VH set forth as SEQ ID NO: 1 (4A10 VH) and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the VL set forth as SEQ ID NO: 2 (4A10 VL), or
a VH comprising a HCDR1, a HCDR2, and a HCDR3 of the VH set forth as SEQ ID NO: 3 (2B8 VH) and a VL comprising a LCDR1, a LCDR2, and a LCDR3 of the VL set forth as SEQ ID NO: 4 (2B8 VL);
(B) an antigen binding fragment of the monoclonal antibody; or
(C) a bispecific antibody comprising the monoclonal antibody or the antigen binding fragment; and
administering to the subject a therapeutically effective amount of an additional agent, thereby treating the IL-7Rα positive cancer or the autoimmune disease in the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 comprise the amino acid sequences set forth as SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively (4A10 kabat CDRs) or the amino acid sequences set forth as SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively (2B8 kabat CDRs).

### Claim 3 (depends on 1)

The method of claim 1, wherein the VH and VL comprise the amino acid sequences set forth as SEQ ID NOs: 1 and 2, respectively, or the amino acid sequences set forth as SEQ ID NOs: 3 and 4, respectively.

### Claim 4 (depends on 1)

The method of claim 1, wherein the monoclonal antibody comprises human framework regions and/or a human constant region.

### Claim 5 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is an IgG, IgM, or IgA.

### Claim 6 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is an IgG1 and comprises a human constant region.

### Claim 7 (depends on 6)

The method of claim 6, wherein the monoclonal antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth as SEQ ID NOs: 21 and 22, respectively, or SEQ ID NOs: 23 and 24, respectively.

### Claim 8 (depends on 1)

The method of claim 1, wherein the monoclonal antibody comprises a constant region comprising a modification that increases binding to the neonatal Fc receptor and/or increases antibody-dependent cell cytotoxicity (ADCC).

### Claim 9 (depends on 1)

The method of claim 1, wherein the monoclonal antibody mediates ADCC killing of IL-7Rα positive cells.

### Claim 10 (depends on 1)

The method of claim 1, wherein the monoclonal antibody inhibits IL-7 signaling in IL-7Rα positive cells.

### Claim 11 (depends on 1)

The method of claim 1, comprising treating the subject with the IL-7Rα positive cancer.

### Claim 12 (depends on 1)

The method of claim 1, wherein the monoclonal antibody or antigen binding fragment comprises an Fc domain with one or more glycosylation sites.

### Claim 13 (depends on 12)

The method of claim 12, wherein the monoclonal antibody lacks fucose attached to the Fc domain.

### Claim 14 (depends on 12)

The method of claim 12, wherein the monoclonal antibody comprises fucose from 1% to 80%, as measured by calculating the average amount of fucose within the sugar chain at Asn297 of the CH2 domain of the Fc domain.

### Claim 15 (depends on 12)

The method of claim 12, wherein the monoclonal antibody comprises a biantennary oligosaccharide attached to the Fc region.

### Claim 16 (depends on 12)

The method of claim 12, wherein the monoclonal antibody comprises a galactose in a carbohydrate attached to the Fc domain.

### Claim 17 (depends on 1)

The method of claim 1, comprising treating the subject with the autoimmune disease.

### Claim 18 (depends on 17)

The method of claim 17, wherein the additional agent comprises an adrenocorticosteroid.

### Claim 19 (depends on 18)

The method of claim 18, wherein the adrenocorticosteroid is prednisone.

### Claim 20

A method of treating a subject with an IL-7Rα positive cancer, comprising:
administering to the subject a therapeutically effective amount of:
(A) a monoclonal antibody that specifically binds to an extracellular domain of IL-7Rα, the monoclonal antibody comprising:
a heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 of the VH set forth as SEQ ID NO: 1 (4A10 VH) and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the VL set forth as SEQ ID NO: 2 (4A10 VL), or
a VH comprising a HCDR1, a HCDR2, and a HCDR3 of the VH set forth as SEQ ID NO: 3 (2B8 VH) and a VL comprising a LCDR1, a LCDR2, and a LCDR3 of the VL set forth as SEQ ID NO: 4 (2B8 VL);
(B) an antigen binding fragment of the monoclonal antibody; or
(C) a bispecific antibody comprising the monoclonal antibody or the antigen binding fragment; and
administering to the subject a therapeutically effective amount of an additional agent, wherein the additional agent comprises a chemotherapeutic agent, an alkylating agent, an antimetabolite, a vinca alkaloid, an epipodophyllotoxin, an antibiotic, an adrenocorticosteroid, or a C—X—C chemokine receptor type 4 (CXCR4) antagonist, thereby treating the IL-7Rα positive cancer.

### Claim 21 (depends on 20)

The method of claim 20, wherein the chemotherapeutic agent is vincristine, daunorubicin, fludarabine, doxorubicin, or idarubicin.

### Claim 22 (depends on 20)

The method of claim 20, wherein the IL-7Rα positive cancer comprises a mutation in the IL-7 pathway that increases proliferation of lymphocytes.

### Claim 23 (depends on 22)

The method of claim 22, wherein the mutation is a gain-of-function mutation in the gene encoding IL-7Rα that leads to increased phosphorylation of Stat5b compared to control.

### Claim 24 (depends on 23)

The method of claim 23, wherein the IL-7Rα positive cancer is an acute lymphoblastic leukemia (ALL).

### Claim 25 (depends on 24)

The method of claim 24, wherein the ALL is B-ALL.

### Claim 26 (depends on 25)

The method of claim 25, wherein the ALL is T-ALL.

### Claim 27 (depends on 20)

The method of claim 20, wherein the adrenocorticosteroid is prednisone.

### Claim 28 (depends on 20)

The method of claim 20, wherein the adrenocorticosteroid is prednisone.

### Claim 29 (depends on 20)

The method of claim 20, wherein the vinca alkaloid is L-asparaginase.

### Claim 30 (depends on 20)

The method of claim 20, wherein the alkylating agent is cyclophosphamide.

### Claim 31 (depends on 20)

The method of claim 20, wherein the antimetabolite is methotrexate, cytarabine, mercaptopurine, or thioguanine.