# US 11,306,038 B2 · Preparation of 212Pb labeled monoclonal antibodies

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- Number: US 11,306,038 B2
- Document ID: US11306038B2
- Status: Granted
- Kind: B2
- Application number: 16/307,811
- Filed: 2017-06-23
- Published: 2019-06-27
- Granted: 2022-04-19
- Earliest claimed: 2016-06-24
- Assignees: Sciencons AS
- Applicants: Sciencons AS
- Inventors: Roy Hartvig Larsen
- Web page: https://patentgrep.com/patent/US11306038B2

## CPC

- C07B 59/008: {Peptides; Proteins}
- A61K 51/1051: {the tumor cell being from breast, e.g. the antibody being herceptin}
- 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
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- 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 relates to the generation of lead-212 for therapeutic use. Specifically, are methods related to the generation of lead-212 based radio labelled proteins, such as radioimmunoconjugates, embodiments of the present invention.

## Claims

### Claim 1

A method for generating a radionuclide labeled protein, the method comprising:
a) providing an raw aqueous solution comprising 224Ra and 212Pb, and an aqueous solution comprising a protein conjugated with a chelator,
b) mixing and incubating the solutions provided in a) to provide a reaction solution comprising a 212Pb-labelled protein,
c) purifying the reaction solution by gel filtration chromatography to remove 224Ra, and
d) recovering the 212Pb-labelled protein from the purification in step c).

### Claim 2 (depends on 1)

The method according to claim 1, wherein the protein is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, an antibody fragment, a synthetic protein, and a peptide.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the protein has a size of 500-500,000 Dalton.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the solution comprising 224Ra and 212Pb in step a) has a radioactivity generated from 224Ra and 212Pb of 1 to 10 000 MBq.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the activity ratio in MBq between 212Pb to 224Ra in the aqueous solution in step a) is between 0.5 and 2.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the antibody conjugated with a chelator recovered in step d) is present in amount of 0.05-50 mg.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the solution in step a) is in a volume of 100 μL to 1000 mL.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the solution comprising an antibody conjugated with a chelator in step a) has a concentration of 0.1 to 4 mg/ml.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the mixing and incubating in step b) is done in 1-180 minutes.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the gel filtration chromatography in step c) is selected from the group consisting of desalting purification, desalting and buffer exchange, and desalting gel exclusion separation.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the desalting is repeated for enhancement of the purity.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the purification in step c) is driven by a method selected from the group consisting of centrifugation, pressure, vacuum, and gravitation.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the chelator is TCMC.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the antibody is selected from the group consisting of trastuzumab, rituximab, HH1, cetuximab, bevacizumab, daratumumab, alemtuzumab, Pembrolizumab, Epratuzumab, L19, F8, F16, Galiximab, Toralizumab, Alemtuzumab, Ofatumumab, Veltuzumab, Afutuzumab, Tositumomab, Reditux and Ibritumomab.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the protein is an antibody that is specific for an antigen selected from the group consisting of CD19, CD20, CD22, CD33, CD37, CD38, CD45, CD74, CD138, PSMA, HER-2, EGFR, MUC-1, MUC-18, CEA, FBP, NG2, EPCAM, Syndecan-1, Ca-125, LK-26, HMFG, CS-1, and BCMA.