Pretargeting kit, method and agents used therein

Patent metadata

Field	Value
Publication number	US-9463256-B2
Application number	US-201113877725-A
Country	US
Kind code	B2
Filing date	Oct 11, 2011
Priority date	Oct 14, 2010
Publication date	Oct 11, 2016
Grant date	Oct 11, 2016

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 an E-cyclooctene which has one or more axial substituents.

First claim

The invention claimed is:

1. A kit for targeted medical imaging and/or therapeutics, comprising at least one Pre-targeting Probe and at least one Effector Probe, which undergo [4+2] cycloaddition in vivo, wherein the Pre-targeting Probe comprises a Primary Targeting Moiety and a first Bio-orthogonal Reactive Group, and wherein the Effector Probe comprises an Effector Moiety and a second Bio-orthogonal Reactive Group, wherein either of the first or second Bio-orthogonal Reactive Groups is a dienophile, and the other of the first and second Bio-orthogonal Reactive Groups is a diene, wherein the dienophile is an 8-member ring dienophile comprising trans-cyclooctene satisfying formula (1):

wherein the position of R is equatorial and the position of R a is axial, wherein each of X, Y, R, and R a independently denotes H, or, in at most six instances, a group selected from alkyl, aryl, O-aryl, O-alkyl, S-aryl, S-alkyl, S(O)-aryl, S(O)-alkyl, S(O) 2 -aryl, S(O) 2 -alkyl, Si-aryl, Si-alkyl, Si-O-alkyl, OCO-alkyl, OCO-aryl, SCO-alkyl, SCO-aryl, OCS-alkyl, OCS-aryl, SCS-alkyl, SCS-aryl, NR′R″ with R′ and R″ each independently being H or alkyl, aryl, C(═O)O-alkyl, C(═O)O-aryl, C(═S)O-alkyl, C(═S)O-aryl, C(═O)S-alkyl, C(═O)S-aryl, C(═S)S-alkyl, C(═S)S-aryl, C(═O)NR′R″ with R′ and R″ each independently being H, aryl or alkyl, NR′CO-alkyl with R′ being H, alkyl or aryl, NR′CO-aryl with R′ being H, alkyl or aryl, NR′C(═O)O-alkyl with R′ being H, alkyl, or aryl, NR′C(═O)O-aryl with R′ being H, alkyl or aryl, OCONR′-alkyl with R′ being H, alkyl or aryl, OCONR′-aryl with R′ being H, alkyl or aryl, NR′CONR″-alkyl with R′ and R″ each independently being H, alkyl or aryl, NR′CONR″-aryl with R′ and R″ each independently being H, alkyl or aryl, NR′CSNR″-alkyl with R′ and R″ each independently being H, alkyl or aryl, and NR′CSNR″-aryl with R′ and R″ each independently being H, alkyl or aryl, CR′NR″ with R′ and R″ each independently being H, alkyl or aryl; with one of R or R a comprised in a Linker Moiety to the Pre-targeting Probe or the Effector Probe; wherein two R or R a moieties together may form a ring; wherein at least one and maximally four of R a is not hydrogen,
wherein the Primary Targeting Moiety is selected from the group of antibodies; antibody fragments selected from Fab2, Fab, scFV and diabodies; polymers which are tumor targeting by virtue of the enhanced permeability and retention (EPR)-effect; proteins; peptides; carbohydrates; monosaccharides; polysaccharides; viruses; whole cells; phage; drugs; chemotherapeutic agents, receptor agonists and antagonists, cytokines, hormones, steroids, and; nucleic acids;
wherein the Effector Moiety is a detectable label selected from the group consisting of MRI-imageable agents being a superparamagnetic particle or a paramagnetic ion selected from Gd, Fe, Mn, Cr, Co, Ni, Cu, Pr, Nd, Yb, Tb, Dy, Ho, Er, Sm, Eu, Ti, Pa, La, Sc, V, Mo, Ru, Ce, Dy, Tl; spin labels; optical labels; an ultrasound-responsive agent being a microbubble, the shell of which is selected from a phospholipid, a (biodegradable) polymer, and human serum albumin; X-ray-responsive agents selected from iodine, barium, barium sulfate, gastrografin, a vesicle filled with iodine compounds and/or barium sulfate, a liposome filled with iodine compounds and/or barium sulfate, and a polymer capsule filled with iodine compounds and/or barium sulfate; radionuclides selected from 3 H, 11 C, 13 N, 15 O, 18 F, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 8O Br, 82 Br, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 97 Ru, 99 Tc, 110 In, 111 In, 113 In, 114 In, 117 Sn, 120 I, 122 Xe, 123 I, 124 I, 125 I, 166 Ho, 167 Tm, 169 Yb, 193 Pt, 195 Pt, 201 Tl, and 203 Pb; FRET-type dyes; (bio)luminescent or fluorescent molecules or tags; biotin; small size organic PET and SPECT labels selected from 18 F, 11 C and 123 I;
and/or wherein the Effector Moiety is a therapeutic moiety, a drug or a radioactive isotope for radiation therapy selected from 24 Na, 32 P, 33 P, 47 Sc, 59 Fe, 67 Cu, 76 As, 77 As, 80 Br, 82 Br, 89 Sr, 90 Nb, 90 Y, 103 Ru, 105 Rh, 109 Pd, 111 Ag, 121 Sn, 127 Te, 131 I, 140 La, 141 Ce, 142 Pr, 143 Pr, 144 Pr, 149 Pm, 149 Tb, 151 Pm, 153 Sm, 159 Gd, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 169 Er, 172 Tm, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 211 At, 211 Bi, 212 Bi, 212 Pb, 213 Bi, 214 Bi, 223 Ra, and 225 Ac.

2. A kit according to claim 1 , wherein the dienophile of formula 1 satisfies one or more of the following requirements:
a) X is H or methyl
b) Y is H or methyl;
c) one or more substituents R 2 a , R 3 a , R 4 a , R 5 a are O-alkyl;
d) one or more substituents R 2 a , R 3 a , R 4 a , R 5 a are O-aryl;
e) one or more substituents R 2 a , R 3 a , R 4 a , R 5 a are alkyl; and
f) one or more substituents R 2 a , R 3 a , R 4 a , R 5 a are aryl.

3. A kit according to claim 1 , wherein the diene is selected from the group consisting of compounds of the formulae (2), (3), (4), and (5) as defined below:

wherein R 1 is selected from the group consisting of H, alkyl, aryl, CF 3 , CF 2 —R′, OR′, SR′, C(═O)R′, C(═S)R′, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, NR′C(═O)NR″R′″, NR′C(═S)N′R″R′″ with R′, R″, and R″ each independently being H, aryl or alkyl; A and B each independently are selected from the group consisting of alkyl-substituted carbon, aryl substituted carbon, nitrogen, N + O − , N + R with R being alkyl, with the proviso that A and B are not both carbon; X is selected from the group consisting of O, N-alkyl, and C═O, and Y is CR with R being selected from the group consisting of H, alkyl, aryl, C(═O)OR′, C(═O)SR′, C(═S)OR′, C(═S)SR′, C(═O)NR′R″ with R′ and R″ each independently being H, aryl or alkyl;

wherein R 1 and R 2 each independently are selected from the group consisting of H, alkyl, aryl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S)NR′R″, SC(═S)NR′R″, NR′C(═O)NR′R″, NR′C(═S)N′R′R″ with R′ and R″ each independently being H, aryl or alkyl, and R′″ independently being aryl or alkyl; A is selected from the group consisting of N-alkyl, N-aryl, C═O, and CN-alkyl; B is O or S; X is selected from the group consisting of N, CH, C-alkyl, C-aryl, CC(═O)R′, CC(═S)R′, CS(═O)R′, CS(═O) 2 R′″, CC(═O)O—R′, CC(═O)S—R′, CC(═S)O—R′, CC(═S)S—R′, CC(═O)NR′R″, CC(═S)NR′R″, R′ and R″ each independently being H, aryl or alkyl and R′″ independently being aryl or alkyl; Y is selected from the group consisting of CH, C-alkyl, C-aryl, N, and N + O − ;

wherein R 1 and R 2 each independently are selected from the group consisting of H, alkyl, aryl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′

Assignees

• Lub Johan
• Ten Hoeve Wolter
• Rossin Raffaella
• Van Den Bosch Sandra Martina
• Robillard Marc Stefan
• Koninklijke Philips Nv

Inventors

• Lub Johan
• Ten Hoeve Wolter
• Rossin Raffaella
• Van Den Bosch Sandra Martina
• Robillard Marc Stefan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title