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In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents

A technology of click chemical reaction and therapeutic agent, applied in the field of 18F or 19F labeled peptide or other molecules

Inactive Publication Date: 2013-07-24
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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Method used

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  • In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents
  • In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents
  • In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1. Peptide IMP272 18 F mark

[0193] prepare and use 18The first peptide labeled with F is IMP272: DTPA-Gln-Ala-Lys(HSG)-D-Tyr-Lys(HSG)-NH 2 (SEQ ID NO: 3).

[0194] Acetate buffer solution - 1.509 g of acetic acid was diluted in ~160 mL of water and the pH was adjusted by adding 1M NaOH, then diluted to 250 mL to make a 0.1 M solution at pH 4.03.

[0195] Aluminum acetate buffer solution - by adding 0.1028g of AlCl 3 The aluminum solution was prepared by diluting the hexahydrate in 42.6 mL DI water. A 4 mL aliquot of the aluminum solution was mixed with 16 mL of a pH 4 0.1 M NaOAc solution to provide a 2 mM Al stock solution.

[0196] IMP272 acetate buffer solution-peptide, 0.0011g, 7.28×10 -7 mol IMP272 was dissolved in 364 μL of 0.1 M pH 4 acetate buffer solution to obtain a 2 mM peptide stock solution.

[0197] F-18 Labeling of IMP272 - Place 3 µL aliquots of aluminum stock solution in REACTI-VIAL TM medium and with 50μL 18 F (as received) was mixed...

Embodiment 2

[0198] Example 2. Peptide IMP272 with other metals 18 F mark

[0199] Aliquot 3 μL metal stock solution (6 × 10 -9 mol) was placed in a polypropylene conical flask and mixed with 75 μL 18 F (as received) was mixed, incubated at room temperature for ~2min, and then mixed with 20μL of 2mM (4×10 -8 mol) IMP272 solution mixed. The solution was heated in a heating block at 100°C for 15 min and analyzed by reverse phase HPLC. IMP272 (not shown) was labeled with indium (24%), gallium (36%), zirconium (15%), lutetium (37%) and yttrium (2%). These results demonstrate that, 18 F metal labeling techniques are not limited to aluminum ligands, but other metals can be utilized as well. Depending on the metal ligand, different chelating moieties can be utilized to optimize binding of the F-18-metal conjugate.

Embodiment 3

[0200] Example 3. Serum stable 18 Generation and use of the F-labeled peptide IMP449

[0201] IMP449

[0202] NOTA-ITCBenzyl-D-Ala-D-Lys(HSG)-D-Tyr-D-Lys(HSG)-NH 2 (SEQ ID NO:4)

[0203] On Sieber amide resin, peptide IMP448D-Ala-D-Lys(HSG)-D-Tyr-D-Lys(HSG)-NH was prepared by adding the following amino acids to the resin in the order indicated 2 (SEQID NO:5): Aloc-D-Lys(Fmoc)-OH, Trt-HSG-OH, cut Aloc, Fmoc-D-Tyr(But)-OH, Aloc-D-Lys(Fmoc)-OH, Trt -HSG-OH, cleaves Aloc, Fmoc-D-Ala-OH, and finally Fmoc to make the desired peptide. The peptide was then cleaved from the resin and purified by HPLC to generate IMP448, which was then coupled to ITC-benzyl NOTA.

[0204] Make IMP448 (0.0757g, 7.5×10 -5 mol) and 0.0509g (9.09×10 -5 mol) ITC benzyl NOTA was mixed and dissolved in 1 mL of water. Anhydrous potassium carbonate (0.2171 g) was then added slowly to the stirred peptide / NOTA solution. The pH of the reaction solution after all the carbonate addition was 10.6. The reacti...

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Abstract

The present application discloses compositions and methods of synthesis and use involving click chemistry reactions for in vivo or in vitro formation of therapeutic and / or diagnostic complexes. Preferably, the diagnostic complex is of use for 18F imaging, while the therapeutic complex is of use for targeted delivery of chemotherapeutic drugs or toxins. More preferably, a chelating moiety or targetable construct may be conjugated to a targeting molecule, such as an antibody or antibody fragment, using a click chemistry reaction involving cyclooctyne, nitrone or azide reactive moieties. In most preferred embodiments, the click chemistry reaction occurs in vivo. In vivo click chemistry is not limited to 18F labeling but can be used for delivering a variety of therapeutic and / or diagnostic agents.

Description

[0001] Related applications [0002] This application claims priority to US Patent Application No. 12 / 958,889, filed December 2, 2010, and US Patent Application No. 61 / 419,082, filed December 2, 2010. Each priority application is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing which has been filed in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 17, 2011, is named IMM310WO.txt and is 24,970 bytes in size. [0005] field [0006] The present invention relates to the use, for example, of PET or NMR imaging useful in vivo 18 F or 19 F Methods of Labeling Peptides or Other Molecules. Preferably, via a chelating moiety that can be covalently linked to a protein, peptide or other molecule 18 F or 19 F is linked to aluminum or another metal to form a conjugate [complex]. Using the techniques described here, high specific act...

Claims

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Application Information

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IPC IPC(8): A61K51/10A61K51/08A61K47/48A61K101/02
CPCC07K1/13C07K2317/31A61K51/082A61K51/083C07K16/3092A61K47/4823C07K16/3007C07B59/008C07D255/02C07K16/18A61K51/088C07K2317/55A61K51/0459A61K51/0497A61K51/0491A61K47/48215A61K49/14C07K2317/24A61K47/60A61K47/61A61P9/10A61P31/04A61P31/12
Inventor W·J·麦克布赖德C·A·德索扎D·M·戈德堡
Owner IMMUNOMEDICS INC
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