# US 2025/0051476 A1 · Dll3 binding molecules and uses thereof

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- Number: US 2025/0051476 A1
- Document ID: US20250051476A1
- Status: Published application
- Kind: A1
- Application number: 18/927,497
- Filed: 2024-10-25
- Published: 2025-02-13
- Earliest claimed: 2022-08-22
- Assignees: Abdera Therapeutics Inc.
- Applicants: Abdera Therapeutics Inc.
- Inventors: Michael J. ABRAMS; Emma Jane CUMMINS; Adam Daniel JUDGE; Alexander Laurence MANDEL; Raja Solomon VISWAS
- Web page: https://patentgrep.com/patent/US20250051476A1

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/3023: {Lung}
- A61K 35/00: Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K 47/68035: {the drug being a pyrrolobenzodiazepine}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 51/1045: {against animal or human tumor cells or tumor cell determinants}
- A61K 51/1054: {the tumor cell being from lung}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61K 51/1096: {radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications}
- A61P 35/00: Antineoplastic agents
- A61K 2039/505: {comprising antibodies}
- A61K 2121/00: Preparations for use in therapy
- C07K 16/32: against translation products of oncogenes
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/567: Framework region [FR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/77: Internalization into the cell
- 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 2319/00: Fusion polypeptide
- 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

Described herein are heavy chain antibodies that bind to DLL3 and immunoconjugates of DLL3 heavy chain antibodies useful for cancer therapy.

## Claims

### Claim 1

A polypeptide comprising a single domain antibody variable region that binds DLL3, wherein the single domain antibody variable region comprises:
a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 407, a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence of SEQ ID NO: 410, and a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 413.

### Claim 2 (depends on 1)

The polypeptide of claim 1, wherein the single domain antibody variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 401-406.

### Claim 3 (depends on 1)

The polypeptide of claim 1, wherein the single domain antibody variable region comprises the sequence of any one of SEQ ID NOs: 401-406.

### Claim 4 (depends on 1)

The polypeptide of claim 1, wherein the single domain antibody variable region binds to DLL3 with an affinity dissociation constant (KD) of 10 nanomolar or less.

### Claim 5 (depends on 1)

The polypeptide of claim 1, wherein the polypeptide comprises an immunoglobulin heavy chain constant region comprising an immunoglobulin CH2 domain and immunoglobulin CH3 domain.

### Claim 6 (depends on 5)

The polypeptide of claim 5, wherein the immunoglobulin heavy chain constant region is an IgG1 isotype or an IgG4 isotype.

### Claim 7 (depends on 5)

The polypeptide of claim 5, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues relative to wild-type IgG1, and wherein the alteration reduces binding of the immunoconjugate to the neonatal Fc receptor (FcRn) relative to wild-type IgG1.

### Claim 8 (depends on 5)

The polypeptide of claim 5, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues relative to wild-type IgG1, and wherein the alteration reduces complement dependent cytotoxicity (CDC), antibody-dependent cell-cytotoxicity (ADCC), antibody-dependent cell-phagocytosis (ADCP), or a combination thereof relative to wild-type IgG1.

### Claim 9 (depends on 5)

The polypeptide of claim 5, wherein the immunoglobulin heavy chain constant region comprises a hinge region, and wherein the hinge region comprises a C220S alteration per EU numbering relative to wild-type IgG1.

### Claim 10 (depends on 1)

A nucleic acid encoding the polypeptide of claim 1.

### Claim 11

An immunoconjugate comprising a polypeptide that binds to DLL3, wherein the polypeptide that binds to DLL3 is covalently linked to a linker-chelator moiety, or a radionuclide complex thereof, wherein:
the polypeptide comprising a single domain antibody variable region comprising a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 407, a heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence of SEQ ID NO: 410, and a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 413; and
the linker-chelator moiety or the radionuclide complex thereof is conjugated to the polypeptide.

### Claim 12 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the chelator moiety comprises:
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA),
1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A), α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA),
6,6′,6″,6″′-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))tetrakis(methylene))-tetrapicolinic acid (Py4 Pa),
2,2′,2″,2″′-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)-tetraacetic acid (Crown),
6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))-dipicolinic acid (Macropa),
1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid (HEHA),
6,6′-[(1R,2R)-1,2-Cyclohexanediylbis[[(carboxymethyl)imino]methylene]]bis[2-pyridinecarboxylic acid](CHXoctapa),
3,7-Diazabicyclo[3.3.1]nonane-1,5-dicarboxylic acid (Bispa), or
6,6′-(((oxybis(ethane-2,1-diyl))bis((carboxymethyl)azanediyl))-bis(methylene))-dipicolinic acid (Noneunpa).

### Claim 13 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the linker-chelator moiety comprises:

### Claim 14 (depends on 13)

The immunoconjugate of claim 13, or the radionuclide complex thereof, wherein the linker-chelator moiety comprises -p-Bn-DOTA.

### Claim 15 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the single domain antibody variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 401-406.

### Claim 16 (depends on 11)

The immunoconjugate of claim 11, wherein the single domain antibody variable region comprises the sequence of any one of SEQ ID NOs: 401-406.

### Claim 17 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the single domain antibody variable region binds to DLL3 with an affinity dissociation constant (KD) of 10 nanomolar or less.

### Claim 18 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the polypeptide comprises an immunoglobulin heavy chain constant region comprising an immunoglobulin CH2 domain and immunoglobulin CH3 domain.

### Claim 19 (depends on 18)

The immunoconjugate of claim 18, or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region is an IgG1 isotype or an IgG4 isotype.

### Claim 20 (depends on 18)

The immunoconjugate of claim 18, or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises A310, Q435, or both A310 and A435 per EU numbering.

### Claim 21 (depends on 20)

The immunoconjugate of claim 20, or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises A234, E235, A237, S330, and S331 per EU numbering.

### Claim 22 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises a hinge region, and wherein the hinge region comprises S220 per EU numbering.

### Claim 23 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the immunoconjugate is covalently linked to the linker comprises the polypeptide covalently linked to the para position of the benzyl of -p-Bn-DOTA via a thiourea formed by a lysine residue of the polypeptide and the isothiocyane (SCN) of:

### Claim 24 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the immunoconjugate has the following structure:

### Claim 25 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the immunoconjugate has a chelator to polypeptide ratio of 3:1 to 5:1.

### Claim 26 (depends on 11)

The immunoconjugate of claim 11, or the radionuclide complex thereof, wherein the immunoconjugate comprises a linker-chelator radionuclide complex, wherein: the radionuclide is an alpha emitter, beta emitter, or a gamma emitter.

### Claim 27 (depends on 26)

The immunoconjugate of claim 26, wherein the alpha emitter is 225-Ac.

### Claim 28 (depends on 26)

A method of killing a cancer cell expressing DLL3 in an individual having cancer, the method comprising administering the immunoconjugate of claim 26 comprising to the individual, thereby killing the cancer cell.

### Claim 29 (depends on 26)

A method of delivering a radioisotope to a cancer cell or a tumor cell in an individual, the method comprising administering the immunoconjugate of claim 26 comprising to the individual, thereby delivering the radioisotope to the cancer cell or tumor cell.

### Claim 30 (depends on 26)

A method of imaging a cancer cell or a tumor cell in an individual, the method comprising administering the immunoconjugate of claim 26 comprising to the individual, thereby delivering the radioisotope to the cancer cell or tumor cell.