# US 11,298,433 B2 · Radiolabelled antibody fragments for use in treating cancer

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,298,433 B2
- Document ID: US11298433B2
- Status: Granted
- Kind: B2
- Application number: 15/742,161
- Filed: 2016-07-15
- Published: 2018-07-19
- Granted: 2022-04-12
- Earliest claimed: 2015-07-17
- Assignees: Vrije Universiteit Brussel
- Applicants: Vrije Universiteit Brussel
- Inventors: Tony Lahoutte; Matthias D'Huyvetter; Jens De Vos; Nick Devoogdt
- Web page: https://patentgrep.com/patent/US11298433B2

## CPC

- A61K 51/1096: {radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications}
- A61K 51/1051: {the tumor cell being from breast, e.g. the antibody being herceptin}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- 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
- 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)

## Abstract

Provided herein are methods, kits, and compositions for stratifying and treating subjects, e.g., subjects having cancer. In some examples, the methods involve use of a radiolabelled heavy chain variable domain derived from a heavy chain antibody (VHH), or a functional fragment thereof, as both a screening agent and a treatment agent. In some examples, the VHH, or a functional fragment thereof, that is radiolabelled with a radioisotope that is both a γ-emitter and β-emitter.

## Claims

### Claim 1

A method of treating a HER2-expressing cancer, the method comprising:
(a) selecting a subject having cancer for treatment on the basis of detection in the subject of a screening dose of a radiolabelled, heavy chain variable domain derived from a heavy chain antibody (VHH), or a functional fragment thereof, which specifically binds to HER2 that is present on a cancer cell or solid tumor
wherein the VHH or functional fragment thereof comprises
a CDR1 comprising the amino acid sequence of SEQ ID NO:1,
a CDR2 comprising the amino acid sequence of SEQ ID NO:2, and
a CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) administering to the subject a therapeutic dose of the radiolabelled VHH, or functional fragment thereof,
wherein the VHH, or functional fragment thereof, of both the screening dose and the therapeutic dose is radiolabelled with Iodine-131 using N-succinimidyl-4-guanidinomethyl-3-[I-131] iodobenzoate ([I-131]-SGMIB).

### Claim 2 (depends on 1)

The method of claim 1, further comprising:
administering the screening dose to the subject and detecting the presence of the radiolabelled VHH, or functional fragment thereof, at a tumor site in the subject prior to selecting the subject.

### Claim 3 (depends on 2)

The method of claim 2, wherein detecting the presence of the radiolabelled VHH, or functional fragment thereof, comprises imaging the subject.

### Claim 4 (depends on 3)

The method of claim 3, wherein the imaging is gamma camera imaging.

### Claim 5 (depends on 1)

The method of claim 1, wherein the screening dose is between about 37 MBq and about 370 MBq and the therapeutic dose is between about 370 MBq and about 18500 MBq.

### Claim 6 (depends on 1)

The method of claim 1, wherein the radiolabelled VHH, or the functional fragment thereof, has at least 80% amino acid identity with the amino acid sequences of SEQ ID NO:7.

### Claim 7 (depends on 1)

The method of claim 1, wherein the radiolabelled VHH, or functional fragment thereof, is present in a monovalent format.

### Claim 8 (depends on 1)

The method of claim 1, wherein the radiolabelled VHH, or functional fragment thereof, is devoid of a cysteine-containing tag.

### Claim 9 (depends on 1)

The method of claim 1, wherein the cancer is a solid tumor or a hematological cancer.

### Claim 10 (depends on 9)

The method of claim 9, wherein the HER2-expressing cancer is a HER2-expressing solid cancer.

### Claim 11 (depends on 10)

The method of claim 10, wherein the HER2-expressing solid cancer is selected from the group consisting of breast cancer, ovarian cancer and gastric cancer.

### Claim 12 (depends on 9)

The method of claim 9, wherein the HER2-expressing cancer is a HER2-expressing hematological cancer.

### Claim 13 (depends on 10)

The method of claim 10, wherein the HER2-expressing cancer is a HER2-positive breast cancer.

### Claim 14 (depends on 13)

The method of claim 13, wherein the HER2-positive breast cancer is locally advanced or metastatic.

### Claim 15 (depends on 14)

The method of claim 14, wherein the HER2-positive breast cancer is metastatic and present in the brain of the subject.

### Claim 16 (depends on 10)

The method of claim 10, wherein the HER2-expressing cancer is gastric cancer.

### Claim 17 (depends on 16)

The method of claim 16, wherein the gastric cancer is locally advanced or metastatic.

### Claim 18 (depends on 17)

The method of claim 17, wherein the gastric cancer is metastatic and present in the brain of the subject.

### Claim 19 (depends on 4)

The method of claim 4, wherein the gamma camera imaging is selected from the group consisting of one or any combination of planar gamma camera imaging, single photon emission computed tomography and positron emission tomography.

### Claim 20 (depends on 4)

The method of claim 4, wherein the imaging is selected from the group consisting of one or any combination of X-ray imaging, computed tomography and magnetic resonance imaging.

### Claim 21 (depends on 8)

The method of claim 8, wherein the radiolabelled VHH, or functional fragment thereof, is devoid of a GGC-tag.

### Claim 22 (depends on 8)

The method of claim 8, wherein the radiolabeled VHH, or functional fragment thereof, is untagged.

### Claim 23 (depends on 1)

The method of claim 1, wherein the therapeutic dose is between about 3000 MBq and about 20000 MBq, between about 10000 MBq and about 20000 MBq, or between about 3000 MBq and about 10000 MBq.

### Claim 24 (depends on 1)

The method of claim 1, wherein the radiolabelled VHH comprises the amino acid sequence of SEQ ID NO: 7.

### Claim 25

A method of treating a HER2-expressing cancer, the method comprising:
(a) selecting a subject having breast cancer for treatment on the basis of detection in the subject of a screening dose of between about 37 MBq and about 370 MBq of a radiolabelled, heavy chain variable domain derived from a heavy chain antibody (VHH), or a functional fragment thereof, which specifically binds to HER2 that is present on the cancer
wherein the VHH or functional fragment thereof comprises
a CDR1 comprising the amino acid sequence of SEQ ID NO:1,
a CDR2 comprising the amino acid sequence of SEQ ID NO:2, and
a CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) administering to the subject a therapeutic dose of between about 3000 MBq and about 20000 MBq of the radiolabelled VHH, or functional fragment thereof,
wherein the radiolabelled VHH, or functional fragment thereof, of both the screening dose and the therapeutic dose comprises N-succinimidyl-4-guanidinomethyl-3[I-131]iodobenzoate ([I-131]-SGMIB).

### Claim 26 (depends on 25)

The method of claim 25, wherein the HER2-expressing cancer is a solid tumor.

### Claim 27 (depends on 25)

The method of claim 25, wherein HER2 expression is detected in the cancer.

### Claim 28 (depends on 27)

The method of claim 27, wherein HER2 expression is detected in the cancer by in situ hybridization or by immunohistochemistry.

### Claim 29 (depends on 25)

The method of claim 25, wherein the VHH comprises the amino acid sequence of SEQ ID NO: 7.

### Claim 30

A method of treating a HER2-expressing breast cancer, the method comprising:
(a) selecting a subject having breast cancer for treatment on the basis of detection in the subject of a screening dose of between about 37 MBq and about 370 MBq of a radiolabelled, heavy chain variable domain derived from a heavy chain antibody (VHH), or a functional fragment thereof, which specifically binds to HER2 that is present on the breast cancer;
wherein the VHH or functional fragment thereof comprises
a CDR1 comprising the amino acid sequence of SEQ ID NO:1,
a CDR2 comprising the amino acid sequence of SEQ ID NO:2, and
a CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) administering to the subject a therapeutic dose of between about 3000 MBq and about 20000 MBq of the radiolabelled VHH, or functional fragment thereof,
wherein the radiolabelled VHH, or functional fragment thereof, of both the screening dose and the therapeutic dose comprises N-succinimidyl-4-guanidinomethyl-3[I-131]iodobenzoate ([I-131]-SGMIB).

### Claim 31 (depends on 30)

The method of claim 30, wherein the VHH comprises the amino acid sequence of SEQ ID NO: 7.

### Claim 32

A method of treating a HER2-expressing gastric cancer, the method comprising:
(a) selecting a subject having gastric cancer for treatment on the basis of detection in the subject of a screening dose of between about 37 MBq and about 370 MBq of a radiolabelled, heavy chain variable domain derived from a heavy chain antibody (VHH), or a functional fragment thereof, which specifically binds to HER2 that is present on the gastric cancer
wherein the VHH or functional fragment thereof comprises
a CDR1 comprising the amino acid sequence of SEQ ID NO:1,
a CDR2 comprising the amino acid sequence of SEQ ID NO:2, and
a CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) administering to the subject a therapeutic dose of between about 3000 MBq and about 20000 MBq of the radiolabelled VHH, or functional fragment thereof,
wherein the radiolabelled VHH, or functional fragment thereof, of both the screening dose and the therapeutic dose comprises N-succinimidyl-4-guanidinomethyl-3-[I-131]iodobenzoate ([I-131]-SGMIB).

### Claim 33 (depends on 32)

The method of claim 32, wherein the VHH comprises the amino acid sequence of SEQ ID NO: 7.