# US 11,897,961 B2 · Anti-CD123 antibodies and conjugates and derivatives thereof

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- Number: US 11,897,961 B2
- Document ID: US11897961B2
- Status: Granted
- Kind: B2
- Application number: 17/711,518
- Filed: 2022-04-01
- Published: 2022-11-24
- Granted: 2024-02-13
- Earliest claimed: 2015-06-29
- Assignees: ImmunoGen, Inc.
- Applicants: Immunogen, Inc.
- Inventors: Yelena Kovtun; Daniel J. Tavares; Lingyun Rui; Thomas Chittenden
- Web page: https://patentgrep.com/patent/US11897961B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/68033: {the drug being a maytansine}
- A61K 47/68035: {the drug being a pyrrolobenzodiazepine}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6883: {Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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: 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

## Abstract

The present invention generally relates to antibodies, antigen-binding fragments thereof, polypeptides, and immunoconjugates that bind to CD123 antigen (the α chain of the interleukine 3 receptor, or IL-3Rα). The present invention also relates to methods of using such CD123-binding molecules for diagnosing and treating diseases, such as B-cell malignancies.

## Claims

### Claim 1

An immunoconjugate having the following formula:
CBACyL1)wL,
wherein:
WL is an integer from 1 to 20; and
CyL1 is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H or a (C1-C4)alkyl; and when it is a single bond, X is —H or an amine protecting moiety, and Y is —OH or —SO3M;
wherein M is H+ or a cation;
L′ is represented by the following formula:
—NR5—P—C(═O)—(CRaRb)m—C(═O)— (B1′);
R5 is —H or a (C1-C3)alkyl;
P is an amino acid residue or a peptide containing between 2 to 20 amino acid residues;
Ra and Rb, for each occurrence, are each independently —H, (C1-C3)alkyl, or a charged substituent or an ionizable group Q, wherein Q is —SO3M; and
m is an integer from 1 to 6; and
CBA is an anti-CD123 antibody or antigen-binding fragment thereof that is covalently linked through a lysine residue to CyL1, wherein the antibody or antigen-binding fragment thereof comprises:
a) a heavy chain variable region CDR1 having the amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, and 12; a heavy chain variable region CDR2 having the amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 6-10, 13, and 14; and a heavy chain variable region CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 4, 11, 15, and 70; and
b) a light chain variable region CDR1 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 16, 19, 20, 23 and 72; a light chain variable region CDR2 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 17, 21, 24 and 71; and a light chain variable region CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 18, 22, and 25;
wherein the antibody or antigen-binding fragment thereof binds an epitope within amino acids 101 to 346 of human CD123 or IL3-Rα antigen and inhibits IL3-dependent proliferation in antigen-positive TF-1 cells.

### Claim 2 (depends on 1)

The immunoconjugate of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:
a) an immunoglobulin heavy chain variable region comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 5, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 11; and
b) an immunoglobulin light chain variable region comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 22.

### Claim 3 (depends on 1)

The immunoconjugate of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:
a) an immunoglobulin heavy chain variable region (VH) having the amino acid sequence set forth in SEQ ID NO: 39 or 40; and b) an immunoglobulin light chain variable region (VL) having the amino acid sequence set forth in SEQ ID NO: 41; or
a) an immunoglobulin heavy chain variable region (VH) having the amino acid sequence set forth in SEQ ID NO: 34; and b) an immunoglobulin light chain variable region (VL) having the amino acid sequence set forth in SEQ ID NO: 35; wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 34, is Phe or Val.

### Claim 4 (depends on 3)

The immunoconjugate of claim 3 wherein the antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 35.

### Claim 5 (depends on 1)

The immunoconjuate of claim 1, wherein the antibody comprises:
a) an immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO: 50 and
b) an immunoglobulin light chain having the amino acid sequence set forth in SEQ ID NO: 51.

### Claim 6 (depends on 1)

The immunoconjugate of claim 1, wherein Ra and Rb are both H; and R5 is H or Me.

### Claim 7 (depends on 1)

The immunoconjugate of claim 1, wherein P is a peptide containing 2 to 5 amino acid residues.

### Claim 8 (depends on 1)

The immunoconjugate of claim 1, wherein P is selected from Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Phe-N9-tosyl-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu (SEQ ID NO: 55), β-Ala-Leu-Ala-Leu (SEQ ID NO: 57), Gly-Phe-Leu-Gly (SEQ ID NO: 73), Val-Arg, Arg-Val, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala-Met, and Met-Ala.

### Claim 9 (depends on 8)

The immunoconjugate of claim 8, wherein P is Gly-Gly-Gly, Ala-Val, Ala-Ala, Ala-D-Ala, D-Ala-Ala, or D-Ala-D-Ala.

### Claim 10 (depends on 1)

The immunoconjugate of claim 1, wherein the immunoconjugate is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein WL is an integer from 1 to 10; the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H; and when it is a single bond, X is —H, and Y is —OH or —SO3M.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the immunoconjugate of claim 1, and a pharmaceutically acceptable carrier.