Bio-orthogonal drug activation

Patent metadata

Field	Value
Publication number	US-9931408-B2
Application number	US-201214117655-A
Country	US
Kind code	B2
Filing date	May 16, 2012
Priority date	May 16, 2011
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The invention relates to a Prodrug activation method, for therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention also relates to a Prodrug kit comprising at least one Prodrug and at least one Activator, wherein the Prodrug comprises a Drug and a first Bio-orthogonal Reactive Group (the Trigger), and wherein the Activator comprises a second Bio-orthogonal Reactive Group. The invention also relates to targeted therapeutics used in the above-mentioned method and kit. The invention particularly pertains to antibody-drug conjugates and to bi- and trispecific antibody derivatives.

First claim

The invention claimed is:

1. A prodrug kit comprising a prodrug compound and an activator compound, wherein the prodrug compound comprises a drug moiety D D linked to a trigger moiety T R either directly or via a linker L D , wherein the trigger moiety comprises a dienophile and the activator compound comprises a diene that can react with the dienophile, the dienophile comprising a structure according to formula (1a):

wherein T, G each independently is H, or a substituent selected from the group consisting of alkyl, F, Cl, Br or I;
A and P each independently are CR a 2 or CR a X D , provided that at least one is CR a X D ;
wherein X D is (O—C(O)) p -(L D ) n -(D D ), S—C(O)-(L D ) n -(D D ), O—C(S)-(L D ) n -(D D ), S—C(S)-(L D ) n -(D D ), or O—S(O)-(L D ) n -(D D ), wherein p=0 or 1; wherein (L D ) n is a linker, and n=0 or 1, wherein L D is linear and/or branched, and when p=0, L D or D D is bound to T R via O, S or aromatic N;
Y, Z, Q, X together form a four-membered aliphatic moiety;
each R a independently is selected from the group consisting of H, alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O) 2 R′″, S(═O) 2 NR′R″, Si—R′″, Si—O—R′″, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, F, Cl, Br, I, N 3 , SO 2 H, SO 3 H, SO 4 H, PO 3 H, PO 4 H, NO, NO 2 , CN, OCN, SCN, NCO, NCS, CF 3 , CF 2 —R′, NR′R″, C(═O)R′, C(═S)R′, C(═O)O—R′, C(═S)O—R′, C(═O)S—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═O)O—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, NR′C(═S)S—R′″, OC(═O)NR′—R′″, SC(═O)NR′—R′″, OC(═S)NR′—R′″, SC(═S)NR′—R′″, NR′C(═O)NR″—R″, NR′C(═S)NR″—R″, CR′NR″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl;
D D is one or more therapeutic moieties or drugs, linked via S, N, NH, or O, wherein these atoms are part of the therapeutic moiety;
wherein L D is selected from

X═O or S or NH or NR with R=alkyl or aryl

wherein
=attached Trigger or D D
=attached T T or S P -T T or M M or S P -M M

wherein at least one of the linker L D and the trigger moiety comprises a targeting agent T T or a masking moiety M M ;
wherein S P is an alkyl, a polyethylene glycol, a peptide or a polylactide spacer, T T is an antibody, antibody fragment, protein or peptide targeting agent, and M M is a protein, peptide, polymer, polyethylene glycol, or carbohydrate masking moiety;
wherein the drug moiety D D is selected from the group of antibodies, antibody fragments, antibody fragments Fab2, antibody fragments Fab, antibody fragments scFV, diabodies, triabodies, antibody fragment fusions, bi-specific mAb fragments, trispecific mAb fragments, proteins, aptamers, oligopeptides, oligonucleotides, oligosaccharides, peptides, peptoids, steroids, organic drug compounds, toxins, hormones, viruses, phage, immunotoxins of ricin A, diphtheria toxin, cholera toxin, auristatins, maytansines, calicheamicin, duocarmycin, maytansinoids DM1 and DM4, auristatin MMAE, CC1065, camptothecin, SN-38, antiproliforative/antitumor agents, antibiotics, cytokines, anti-inflammatory agents, anti-viral agents, antihypertensive agents, chemosensitizing agents, and radiosensitizing agents, dihydrofolatc reductase inhibitors, and thymidylate synthase inhibitors, DNA alkylators, radiation sensitizers, DNA intercalators, DNA cleavers, anti-tubulin agents, topoisomerases inhibitors, platinum-based drugs, anthracyclines, vinca drugs, initomycins, bleomycins, cytotoxic nucleosides, taxanes, lexitropsins, pteridines, diynenes, podophyllotoxins, dolastatins, maytansinoids, differentiation inducers, taxols, methotrexate, methopterin, dichloromethotrexate, 5-fluorouracil, DNA minor groove binders, 6-mercaptopurinc, cytosine arabinoside, melphalan, leurosine, leurosideine, actinomycin, duanorubicin, doxorubicin, mitomycin C, mitomycin A, caminomycin, aminopterin, tallysomycin, podophyllotoxin, podophyllotoxins, etoposide, etoposide phosphate, vinblastine, vincristine, vincristine, vindesine, taxol, taxotere, retinoic acid, butyric acid, N8-acetyl spermidine, camptothecin, esperamicin, ene-diynes, mitomycin, anthracyclines, A1-(2-chloroethyl)l, 2-djmethanesulfonyl hydrazide, cytarabine, anguidine, and 6-mecaptopurine;
wherein the activator comprises a diene selected from the dienes according to Formula (4)

wherein R 1 and R 2 each independently are selected from the group consisting of H, alkyl, aryl, CF 3 , CF 2 —R′, NO, NO 2 , OR′, SR′, CN, 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 OR′, PO 3 R′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)NR″R″ with each R′ and each R″ independently being H, aryl or alkyl, and R′″ independently being aryl or alkyl; wherein A is N; B is N; X is N; and Y is N.

2. A prodrug kit according to claim 1 , wherein (O—C(O)) p -(L D ) n -(D D ), wherein p=0 or 1, and n=0 or 1.

3. A prodrug kit according to claim 1 , wherein the dienophile has a structure according to formula (1b):

wherein each R d is independently selected from the group consisting of H, alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O) 2 R′″, Si—O—R′″, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, F, Cl, Br, I, N 3 , SO 2 H, SO 3 H, PO 3 H, NO, NO 2 , CN, CF 3 , CF 2 —R′, C(═O)R′, C(═S)R′, C(═O)O—R′, C(═S)O—R′, C(═O)S—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═O)O—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, NR′C(═S)S—R′″, NR′C(═O)NR″—R″, NR′C(═S)NR″—R″, CR′NR″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl; wherein two R a,d moieties together may form a ring.

4. A prodrug kit according to claim 3 , wherein the dienophile is selected from the following structures:

=rest of attached T T or S P -T T or M M or S P -M M
=rest of attached D D , L D -D D , optionally comprising T T or S P -T T or M M or S P -M M

=rest of attached T T or S P -T T or M M or S P -M M
=rest of attached D D , L D -D D , optionally comprising T T or S P -T T or M M or S P -M M

Assignees

• Robillard Marc Stefan
• Janssen Hendricus Marie
• Ten Hoeve Wolter
• Versteegen Ronny Mathieu
• Rossin Raffaella
• Koninklijke Philips Nv

Inventors

• Robillard Marc Stefan
• Janssen Hendricus Marie
• Ten Hoeve Wolter
• Versteegen Ronny Mathieu
• Rossin Raffaella

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/05

  Dipeptides · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K47/6897

  Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies · CPC title