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Pretargeting kit, method and agents used therein

A kit, pre-targeting technology, used in non-bioreactive chemical groups, nuclear imaging and radiotherapy, pre-targeting kits, pre-targeting reagents, can solve problems such as long circulation time and high concentration

Active Publication Date: 2012-03-28
タグワークスファーマシューティカルスビーブイ
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this is often problematic: for example, imaging studies in humans have shown that maximal concentrations of radiolabeled antibodies at tumor sites can be reached within 24 hours, but additional days are required for the labeled antibodies to circulate in the system. The concentration of the antibody drops low enough for successful imaging to occur
In particular, this means that the effector probes require relatively long circulation times and / or high concentrations in order to bind sufficiently to the pre-targeting probes

Method used

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  • Pretargeting kit, method and agents used therein
  • Pretargeting kit, method and agents used therein
  • Pretargeting kit, method and agents used therein

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0121] Such as Figure 3a As an example of linking a tetrazine-derived moiety to an antibody, molecule 1 was prepared (see Figure 4 ). An example of the corresponding probe 2 (derived from E-cyclooctene) is in Figure 5shown in . Both molecules contain PEG chains. Molecule 1 comprises an N-hydroxysuccinimidyl moiety for coupling the molecule to an amino group present in the antibody. The DOTA-derived moieties in 2 can be used to carry rare earth metal ions such as Gd for MR imaging or Lu-177 for nuclear imaging and therapy (SPECT).

[0122] Figure 4 The synthesis of 1 is shown in . The starting tetrazine-derived molecule 5 was prepared according to Blackman et al. (Blackman, ML; Royzen, M; Fox, JM, Journal of The American Chemical Society, 2008, 130 (41), 13518-19). It is converted to acid 6 by reaction with succinic anhydride, followed by its N-hydroxysuccinimidyl ester 7. This N-hydroxysuccinimidyl ester was used to form acid 9 which in turn was converted to its hy...

Embodiment 2

[0125] Compared to Example 1, this example illustrates the opposite molecular pair, namely 1) the E-cyclooctene derivative 3 that will form the pre-targeting moiety after attachment to the antibody and, 2) the E-cyclooctene derivative 3 derived from the Probe 4 for tetrazine / DOTA, which can be used as Figure 3b Effector probes shown in , respectively, in Image 6 with 7 shown in .

[0126] Commercially available (IRIS biochem) PEG derivative 8 with N-hydroxysuccinimidyl ester 14 (see Figure 5 ) to form the acid 19, followed by the N-hydroxysuccinimidyl derivative derived from this acid to form the E-cyclooctene derivative 3.

[0127] Figure 7 The synthesis of probe 4 derived from tetrazine / DOTA is shown in . By amine 18 derived from DOTA and PEG (see Figure 5 ) with N-hydroxysuccinimidyl ester 7 (see Figure 4 ) reaction to prepare this probe.

Embodiment 3

[0128] Example 3: In Vivo Imaging

[0129] All reagents and solvents were obtained from commercial sources (reagents from Sigma-Aldrich, Acros, ABCR, Invitrogen, and Merck, conventional and deuterated solvents from Biosolve, Merck, and Cambridge Isotope Laboratories) and were not further prepared unless otherwise stated. The purification is ready to use. 1-amino-3,6,9,12,15,18,21,24,27,30,33,36-dodeoxanonacosane-39-oic acid (S11) and (35-amino-3 , 6, 9, 12, 15, 18, 21, 24, 27, 30, 33-tert-butyl undecaoxapentacyl) carbamate (S3) were purchased from Polypure (Norway) and Iris Biotech (Germany )get. 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10 -tetraazacyclododecane-1,4,7-triyl)triacetic acid (S6) as with HPF 6 and about 3 equivalents of trifluoroacetic acid (TFA) were obtained from Macrocyclics (USA). Rituximab solution (MabThera®) was purchased from Roche (Switzerland). [ 111 In] indium chloride and [ 125 I] Sodium iodide solution was purchased...

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Abstract

Described is a pretargeting method, and related kits, for targeted medical imaging and / or therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention involves the use of [4+2] inverse electron demand (retro) Diels- Alder chemistry in providing the coupling between a Pre-targeting Probe and an Effector Probe. To this end one of these probes comprises an electron-deficient tetrazine or other suitable diene, and the other a cyclooctene or cyclooctyne.

Description

technical field [0001] The present invention relates to a pretargeting method for targeted medical imaging and / or therapy in which abiotic reactive chemical groups showing bio-orthogonal reactivity with each other are used . The present invention also relates to a pre-targeting kit (kit) containing at least one pre-targeting probe and at least one effector probe, wherein the pre-targeting probe comprises A primary targeting moiety and a first bioorthogonal reactive group, and wherein the effector probe comprises an effector moiety, such as a label or a pharmaceutically active compound, and a second bioorthogonal reactive group. The present invention also relates to pre-targeting reagents for use in the above methods and kits. The invention particularly relates to nuclear imaging and radiation therapy. Background technique [0002] In many areas of medical diagnosis and treatment, it is desirable to selectively deliver agents, such as therapeutic (drugs) or diagnostic (eg,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K51/04
CPCA61K47/48746A61K51/0495B82Y5/00A61K47/6897
Inventor M.S.罗比拉尔德R.罗辛J.卢布P.雷纳特弗柯克D.伯丁斯基
Owner タグワークスファーマシューティカルスビーブイ