# US 2015/0147271 A1 · Targets for diagnosis, prognosis and therapy of acute myeloid leukemia and myelodysplastic syndromes

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- Number: US 2015/0147271 A1
- Document ID: US20150147271A1
- Status: Published application
- Kind: A1
- Application number: 14/236,118
- Filed: 2012-08-09
- Published: 2015-05-28
- Earliest claimed: 2011-08-11
- Assignees: Albert Einstein College of Medicine of Yeshiva University
- Inventors: Ulrich G. Steidl; Laura Barreyro De Pujato; Britta Will
- Web page: https://patentgrep.com/patent/US20150147271A1

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 35/15: Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells (presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00)
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 47/6843: {the antibody targeting a material from animals or humans}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 51/1018: {against material from animals or humans}
- A61K 51/1021: {against cytokines, e.g. growth factors, VEGF, TNF, lymphokines or interferons}
- A61K 51/1027: {against receptors, cell-surface antigens or cell-surface determinants}
- A61K 51/1033: {against receptors for cytokines, lymphokines or interferons}
- C07K 16/244: {Interleukins [IL]}
- G01N 33/6869: {Interleukin}
- A61K 2039/505: {comprising antibodies}
- C07K 14/5421: {IL-8}
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/158: Expression markers
- C12Q 2600/16: Primer sets for multiplex assays
- G01N 2333/7155: for interleukins [IL]
- G01N 2333/914: Hydrolases (3)
- G01N 2500/10: involving cells
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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)
- 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)
- 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

Methods are disclosed for diagnosis, prognosis and therapy of acute myeloid leukemia and myelodysplastic syndromes using interleukin 1 receptor accessory protein and other targets.

## Claims

### Claim 1

A method for determining the prognosis of a subject having acute myeloid leukemia (AML) comprising determining the level of expression of Interleukin 1 Receptor Accessory Protein (IL1RAP) in early stem or progenitor cells of the subject, wherein a subject with a high level of IL1RAP expression has a poorer likelihood of survival than a subject with a low level of IL expression, wherein a subject is defined as having a high level of IL1RAP expression if the level of IL1RAP expression in early stem or progenitor cells of the subject is equal to or greater than 1.5 (log 2 scale) the level of IL1RAP expression in early stem or progenitor cells from a control population of subjects without AML or a myelodysplastic syndrome (MDS).

### Claim 2 (depends on 1)

The method of claim 1, wherein the level of expression of IL1RAP mRNA is determined.

### Claim 3 (depends on 1)

The method of claim 1, wherein the level of expression of IL1RAP protein is determined.

### Claim 4

A method for predicting whether a subject with a myelodysplastic syndrome (MDS) is likely to progress to acute myeloid leukemia (AML), the method comprising testing whether CD34+ stem or progenitor cells from the subject express Interleukin 1 Receptor Accessory Protein (IL1RAP) protein, wherein expression of IL protein in a greater percentage of CD34+ cells in the subject compared to a control population of subjects without MDS or AML indicates that the subject with MDS is at high risk for progressing to acute myeloid leukemia (AML).

### Claim 5 (depends on 4)

The method of claim 4, wherein expression of IL1RAP protein in at least 10% of CD34+ cells indicates that the subject is at high risk for progressing to acute myeloid leukemia (AML).

### Claim 6 (depends on 4)

The method of claim 4, wherein expression of IL1RAP protein in less than 2% of CD34+ cells indicates that the subject is at low risk for progressing to acute myeloid leukemia (AML).

### Claim 7 (depends on 4)

The method of claim 4, wherein the CD34+ cells are CD34+/CD38− cells.

### Claim 8

A method for treating a subject having acute myeloid leukemia (AML) comprising administering to the subject an amount of an agent effective to inhibit expression or activity of Interleukin 1 Receptor Accessory Protein (IL1RAP) in early stem or progenitor cells.

### Claim 9 (depends on 8)

The method of claim 8, wherein treatment with the agent inhibits division of AML cells.

### Claim 10 (depends on 8)

The method of claim 8, wherein the agent is a shRNA.

### Claim 11

A method for identifying an agent for treating acute myeloid leukemia (AML), the method comprising determining whether or not the agent inhibits expression or activity of Interleukin 1 Receptor Accessory Protein (IL1RAP) in early stem or progenitor cells,
wherein an agent that inhibits expression or activity of Interleukin 1 Receptor Accessory Protein (IL1RAP) in early stem or progenitor cells is identified as a candidate agent for treating acute myeloid leukemia (AML), and
wherein an agent that does not inhibit expression or activity of Interleukin 1 Receptor Accessory Protein (IL1RAP) in early stem or progenitor cells is not identified as a candidate agent for treating acute myeloid leukemia (AML).

### Claim 12 (depends on 11)

The method of claim 11, the agent treats AML by inhibiting division of AML cells.

### Claim 13

A method for treating a subject having acute myeloid leukemia (AML) or a high risk myelodysplastic syndrome (MDS) comprising administering to the subject an agent that binds to Interleukin 1 Receptor Accessory Protein (IL1RAP) protein expressed on the surface of AML cells in a subject with AML or on the surface of early stem or progenitor cells in a subject with high risk MDS, wherein the agent is an antibody or aptamer that illicits an immune response or wherein the agent is an aptamer or antibody conjugated to a cytotoxic agent.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cytotoxic agent is a radioisotope or chemotherapeutic agent.

### Claim 15

A method for diagnosing a subject as having acute myeloid leukemia (AML) comprising testing early stem or progenitor cells from the subject for expression of two or more of the following genes: ankyrin repeat domain 36B (ANKRD36B), B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB (BDP1), CD97 molecule (CD97), chemokine (C—X—C motif) ligand 2 (CXCL2), coiled-coil domain containing 88A (CCDC88A), cyclin T1 (CCNT1), eukaryotic translation initiation factor 5B (EIF5B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), protein phosphatase 1, regulatory subunit 15A (PPP1R15A), 6-pyruvoyltetrahydropterin synthase (PTS), RAS guanyl releasing protein 3 (RASGRP3), SH2 domain protein 1A (SH2D1A), solute carrier family 38, member 1 (SLC38A1), spermidine/spermine N1-acetyltransferase 1 (SAT1), UPF2 regulator of nonsense transcripts homolog, aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), brain expressed, X-linked 5 (BEX5), carbonic anhydrase I (CA1), desmoglein 2 (DSG2), deoxynucleotidyltransferase, terminal (DNTT), hemoglobin, beta (HBB), immunoglobulin J polypeptide (IGJ), insulin-like growth factor 1 receptor (IGF1R), LOC401097, nuclear factor I/A (NFIA), nudix (nucleoside diphosphate linked moiety X)-type motif 11 (NUDT11), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), ribosomal protein L39-like (RPL39L), serpin peptidase inhibitor, clade E, member 2 (SERPINE2), small nucleolar RNA, H/ACA box 42 (SNORA42), small nucleolar RNA, C/D box 46 (SNORD46), small nucleolar RNA, and C/D box 36B (SNORD36B);
wherein the subject is diagnosed as having acute myeloid leukemia (AML) when expression of two or more of the tested genes is changed compared to the level of expression in a control population without AML or a myelodysplastic syndrome (MDS);
wherein the following genes are overexpressed in a subject with AML compared to the level of expression in the control population: ankyrin repeat domain 36B (ANKRD36B), B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB (BDP1), CD97 molecule (CD97), chemokine (C—X—C motif) ligand 2 (CXCL2), coiled-coil domain containing 88A (CCDC88A), cyclin T1 (CCNT1), eukaryotic translation initiation factor 5B (EIF5B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), protein phosphatase 1, regulatory subunit 15A (PPP1R15A), 6-pyruvoyltetrahydropterin synthase (PTS), RAS guanyl releasing protein 3 (RASGRP3), SH2 domain protein 1A (SH2D1A), solute carrier family 38, member 1 (SLC38A1), spermidine/spermine N1-acetyltransferase 1 (SAT1), and UPF2 regulator of nonsense transcripts homolog; and
wherein the following genes are underexpressed in a subject with AML compared to the level of expression in the control population: aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), brain expressed, X-linked 5 (BEX5), carbonic anhydrase I (CA1), desmoglein 2 (DSG2), deoxynucleotidyltransferase, terminal (DNTT), hemoglobin, beta (HBB), immunoglobulin J polypeptide (IGJ), insulin-like growth factor 1 receptor (IGF1R), LOC401097, nuclear factor I/A (NFIA), nudix (nucleoside diphosphate linked moiety X)-type motif 11 (NUDT11), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), ribosomal protein L39-like (RPL39L), serpin peptidase inhibitor, clade E, member 2 (SERPINE2), small nucleolar RNA, H/ACA box 42 (SNORA42), small nucleolar RNA, C/D box 46 (SNORD46), small nucleolar RNA, and C/D box 36B (SNORD36B).

### Claim 16 (depends on 15)

The method of claim 15 comprising testing early stem or progenitor cells from the subject for expression of two or more of the following genes: ankyrin repeat domain 36B (ANKRD36B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), RAS guanyl releasing protein 3 (RASGRP3), spermidine/spermine N1-acetyltransferase 1 (SAT1), brain expressed, X-linked 5 (BEX5), insulin-like growth factor 1 receptor (IGF1R), LOC401097, and nuclear factor I/A (NFIA);
wherein the subject is diagnosed as having acute myeloid leukemia (AML) when expression of two or more of the tested genes is changed compared to the level of expression in a control population without AML or a myelodysplastic syndrome (MDS);
wherein the following genes are overexpressed in a subject with AML compared to the level of expression in the control population: ankyrin repeat domain 36B (ANKRD36B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), RAS guanyl releasing protein 3 (RASGRP3), and spermidine/spermine N1-acetyltransferase 1 (SAT1); and
wherein the following genes are underexpressed in a subject with AML compared to the level of expression in the control population: brain expressed, X-linked 5 (BEX5), insulin-like growth factor 1 receptor (IGF1R), LOC401097, and nuclear factor I/A (NFIA).

### Claim 17 (depends on 15)

The method of claim 15, wherein mRNA expression is tested.

### Claim 18 (depends on 15)

The method of claim 15, wherein protein expression is tested.

### Claim 19 (depends on 15)

The method of claim 15, wherein the subject is diagnosed as having acute myeloid leukemia (AML) when expression of all of the tested genes is changed compared to the level of expression in a control population without AML or a myelodysplastic syndrome (MDS).

### Claim 20

A method for treating a subject having acute myeloid leukemia (AML) comprising administering to the subject an amount of one or more agents effective to
i) inhibit expression or activity of one or more of the following in early stem or progenitor cells: ankyrin repeat domain 36B (ANKRD36B), B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB (BDP1), CD97 molecule (CD97), chemokine (C—X—C motif) ligand 2 (CXCL2), coiled-coil domain containing 88A (CCDC88A), cyclin T1 (CCNT1), eukaryotic translation initiation factor 5B (EIF5B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), protein phosphatase 1, regulatory subunit 15A (PPP1R15A), 6-pyruvoyltetrahydropterin synthase (PTS), RAS guanyl releasing protein 3 (RASGRP3), SH2 domain protein 1A (SH2D1A), solute carrier family 38, member 1 (SLC38A1), spermidine/spermine N1-acetyltransferase 1 (SAT1), or UPF2 regulator of nonsense transcripts homolog; and/or
ii) increase expression or activity of one or more of the following in early stem or progenitor cells: aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), brain expressed, X-linked 5 (BEX5), carbonic anhydrase I (CA1), desmoglein 2 (DSG2), deoxynucleotidyltransferase, terminal (DNTT), hemoglobin, beta (HBB), immunoglobulin J polypeptide (IGJ), insulin-like growth factor 1 receptor (IGF1R), LOC401097, nuclear factor I/A (NFIA), nudix (nucleoside diphosphate linked moiety X)-type motif 11 (NUDT11), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), ribosomal protein L39-like (RPL39L), serpin peptidase inhibitor, clade E, member 2 (SERPINE2), small nucleolar RNA, H/ACA box 42 (SNORA42), small nucleolar RNA, C/D box 46 (SNORD46), small nucleolar RNA, or C/D box 36B (SNORD36B).

### Claim 21 (depends on 20)

The method of claim 20 comprising administering to the subject an amount of one or more agents effective to
i) inhibit expression or activity of one or more of the following in early stem or progenitor cells: ankyrin repeat domain 36B (ANKRD36B), interleukin 8 (IL8), interleukin 1 receptor accessory protein (IL1RAP), leucine rich repeat (in FLII) interacting protein 1 (LRRFIP1), microRNA21 (mir-21), RAS guanyl releasing protein 3 (RASGRP3), or spermidine/spermine N1-acetyltransferase 1 (SAT1); and/or
ii) increase expression or activity of one or more of the following in early stem or progenitor cells: brain expressed, X-linked 5 (BEX5), insulin-like growth factor 1 receptor (IGF1R), LOC401097, or nuclear factor I/A (NFIA).

### Claim 22

A method for treating a subject having acute myeloid leukemia (AML) or a high risk myelodysplastic syndrome (MDS) comprising administering to the subject one or more agents that binds to ankyrin repeat domain 36B (ANKRD36B), CD97 molecule (CD97), SH2 domain protein 1A (SH2D1A) or solute carrier family 38, member 1 (SLC38A1) expressed on the surface of AML cells in a subject with AML or on the surface of early stem or progenitor cells in a subject with high risk MDS, or that binds to chemokine (C—X—C motif) ligand 2 (CXCL2) or interleukin 8 (IL8) secreted though the cell surface, wherein the agent is an antibody or aptamer that illicits an immune response or wherein the agent is an aptamer or antibody conjugated to a cytotoxic agent.

### Claim 23 (depends on 22)

The method of claim 22, wherein the cytotoxic agent is a radioisotope or chemotherapeutic agent.

### Claim 24

A method for determining the prognosis of a subject having acute myeloid leukemia (AML) comprising determining the kinetics of the frequency of Interleukin 1 Receptor Accessory Protein (IL1RAP)-positive cells within early stem or progenitor cells of the subject, wherein a subject with an increase of IL1RAP-positive stem cells (>2-fold) has a higher likelihood of disease progression.

### Claim 25

A method for predicting whether a subject with a myelodysplastic syndrome (MDS) is likely to progress to acute myeloid leukemia (AML), the method comprising serial testing in a time course of disease or treatments whether Lin−CD34+ stem or progenitor cells from the subject express Interleukin 1 Receptor Accessory Protein (IL1RAP) protein, wherein expression of IL1RAP protein in more than a 2-fold percentage of Lin−CD34+ cells in the subject compared to a percentage determined at an earlier time point indicates that the subject with MDS is at high risk for progressing to acute myeloid leukemia (AML).

### Claim 26

A method for treating a subject having acute myeloid leukemia (AML) or a high risk myelodysplastic syndrome (MDS) comprising administering to the subject dendritic cells that have been engineered to present Interleukin 1 Receptor Accessory Protein (IL1RAP) protein or immunogenic parts of IL1RAP protein on their surface.