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1. (WO2017137458) ANTIBODY-CONJUGATES WITH IMPROVED THERAPEUTIC INDEX FOR TARGETING CD30 TUMOURS AND METHOD FOR IMPROVING THERAPEUTIC INDEX OF ANTIBODY-CONJUGATES
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Claims

1. Antibody-conjugate comprising an antibody AB connected to a target molecule D via a linker L, obtainable by:

(i) contacting a glycoprotein comprising 1 - 4 core /V-acetylglucosamine moieties with a compound of the formula S(F )x-P in the presence of a catalyst, wherein S(F )X is a sugar derivative comprising x functional groups F capable of reacting with a functional group Q\ x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F )X moiety to the core-GlcNAc moiety, to obtain a modified antibody according to Formula (24):

AB-

(24)

wherein S(F )X and x are as defined above; AB represents an antibody; GlcNAc is N- acetylglucosamine; Fuc is fucose; b is 0 or 1 ; and y is 1 , 2, 3 or 4; and

(ii) reacting the modified antibody with a linker-conjugate comprising a functional group Q capable of reacting with functional group F and a target molecule D connected to Q via a linker L2 to obtain the antibody-conjugate wherein linker L comprises S-Z3-L2 and wherein Z3 is a connecting group resulting from the reaction between Q and F\

wherein antibody AB is capable of targeting CD30-expressing tumours and target molecule D is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, maytansinoids, calicheamycins and enediynes, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins, pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof.

The antibody-conjugate according to claim 1 , wherein the antibody is capable of targeting CD30-expressing tumours and is selected from Ki-2, Ki-4, Ki-6, Ki-7, HRS-1 , HRS-4, Ber-H8, Ber-H2, 5F11 , Ki-1 , Ki-5, M67, Ki-3, M44, HeFi-1 , AC10, cAC10, and functional analogues thereof.

3. The antibody-conjugate according to claim 1 or 2, wherein linker L2 comprises a group according to formula (1 ) or a salt thereof:


1

wherein:

- a is 0 or 1 ; and

- R3 is selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups, the Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S or NR33 wherein R33 is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups, or R3 is an additional target molecule D, wherein the target molecule is optionally connected to N via a spacer moiety.

The antibody-conjugate according to any one of claims 1 to 3, wherein antibody AB is brentuximab and target molecule D is selected from the group of auristatins consisting of MMAD, MMAE and MMAF, preferably D = MMAD or MMAE.

The antibody-conjugate according to any one of claims 1 to 4, wherein:

(I) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-S(0)2-NH-(CH2-CH2-0)2-CO-Val-Cit- PABC-, D = MMAE;

(II) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-(CH2)3-CO-NH-S(0)2-NH-(CH2-CH2-0)2- CO-Val-Cit-PABC- D = MMAE;

(III) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-(CH2-CH2-0)4-CO-Val-Cit-PABC-, D = MMAE;

(IV) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-(CH2-CH2-0)4-CO-N(CH2-CH2-0-CO-Val- Cit-PABC-D)2, each occurrence of D = MMAE;

(V) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-S(0)2-NH-(CH2-CH2-0)2-CO-N(CH2-CH2- 0-CO-Val-Cit-PABC-D)2, each occurrence of D = MMAE;

(VI) AB = iratumumab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N292, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-(CH2-CH2-0)4-CO-Val-Cit-PABC-, D = MMAE; or

(VII) AB = brentuximab, wherein S(F )X is connected to the core-GlcNAc linked to amino acid N297, S(F )X = 6-azido-6-deoxy-A/-acetylgalactosamine, Q is according to formula (9q), L2 = CH2-0-C(0)-NH-S(0)2-NH-(CH2-CH2-0)2-CO-Val-Cit- PABC-, D = MMAD.

Use of a mode of conjugation for increasing the therapeutic index of a bioconjugate, wherein the mode of conjugation is being used to connect a biomolecule B with a target molecule D via a linker L, wherein the mode of conjugation comprises:

(ii) contacting a glycoprotein comprising 1 - 4 core /V-acetylglucosamine moieties with a compound of the formula S(F ))cP in the presence of a catalyst, wherein S(F )X is a sugar derivative comprising x functional groups F capable of reacting with a functional group Q , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F )X moiety to the core-GlcNAc moiety, to obtain a modified glycoprotein according to Formula (24):


(24)

wherein S(F )X and x are as defined above; AB represents an antibody; GlcNAc is N- acetylglucosamine; Fuc is fucose; b is 0 or 1 ; and y is 1 , 2, 3 or 4; and

(ii) reacting the modified glycoprotein with a linker-conjugate comprising a functional group Q capable of reacting with functional group F and a target molecule D connected to Q via a linker L2 to obtain the antibody-conjugate wherein linker L comprises S-Z3-L2 and wherein Z3 is a connecting group resulting from the reaction between Q and F .

Use according to claim 6, wherein the antibody AB is capable of targeting tumours that express an antigen selected from Axl, 5T4 (TPBG), av-integrin/ITGAV, BCMA, C4.4a, cadherin-6 (CDH6), CA-IX, CD19, CD19b, CD22, CD25, CD30, CD33, CD37, CD40, CD43, CD56, CD70, CD74, CD79b, CD123, CD352, c-KIT (CD117), CD138/SDC1 , CEACAM5 (CD66e), Cripto, CS1 , DLL3, EFNA4, EGFR, EGFRvlll, Endothelin B Receptor (ETBR),

ENPP3 (AGS-16), EpCAM, EphA2, FGFR2, FGFR3, FLT3, FOLR1 (folate receptor a), gpNMB, guanyl cyclase C (GCC), HER2 (Erb-B2), HER3 (Erb-B3), Lamp-1 , Lewis Y antigen, LIV-1 (SLC39A6, ZIP6), Mesothelin (MSLN), MUC1 (CA6, huDS6), MUC16/EA-125, NaPi2b, Nectin-4, Notch3, P-cadherin, PSMA/FOLR1 , PTK7, SLITRK6 (SLC44A4), STEAP1 , TF (CD142), Trop-1 , Trop-2/EGP-1 , Trop-3, Trop-4, preferably CD30-expressing tumours.

8. Use according to claim 6 or 7, wherein increasing the therapeutic index of an antibody- conjugate is selected from:

(a) increasing the therapeutic efficacy of the antibody-conjugate; and/or

(b) increasing the tolerability of the antibody-conjugate.

9. Use according to any one of claims 6 to 8, wherein the reaction of step (ii) is a(n) (cyclo)alkyne-azide conjugation reaction to from a connecting moiety Z3 that is represented by (10e), (10i)


wherein cycle A is a 7-10-membered (hetero)cyclic moiety.

10. Use according to any one of claims 6 to 9, wherein one of F is an azide moiety, Q is an (cyclo)alkyne moiety, and Z3 is a triazole moiety.

1 1. Use according to any one of claims 6 to 10, wherein x is 1 or 2, preferably wherein x is 1.

12. Use according to any one of claims 6 to 1 1 , wherein S(F )X is 6-azido-6-deoxy-/V- acetylgalactosamine.

13. Use according to any one of claims 6 to 12, wherein the antibody-conjugate is represented by Formula (40) or (40b):


(40)


(40b),

wherein:

R3 is independently selected from the group consisting of hydrogen, halogen, -OR35, -NO2, -CN, -S(0)2R35, Ci - C24 alkyl groups, Ce - C24 (hetero)aryl groups, C7 - C24 alkyl(hetero)aryl groups and C7 - C24 (hetero)arylalkyl groups and wherein the alkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, wherein two substituents R3 may be linked together to form an annelated cycloalkyl or an annelated (hetero)arene substituent, and wherein R35 is independently selected from the group consisting of hydrogen, halogen, Ci - C24 alkyl groups, Ce - C24 (hetero)aryl groups, C7 - C24 alkyl(hetero)aryl groups and C7 - C24 (hetero)arylalkyl groups;

X is C(R3 )2, O, S or NR32, wherein R32 is R3 or L3(D , wherein L3 is a linker, and D is as defined in claim 1 ;

r is 1 - 20;

q is 0 or 1 , with the proviso that if q is 0 then X is N-L2(D)r;

aa is 0, 1 , 2, 3, 4, 5, 6, 7 or 8;

aa' is 0,1 , 2, 3, 4, 5, 6, 7 or 8; and

aa+aa' < 10.

b is 0 or 1 ;

pp is 0 or 1 ;

M is -N(H)C(0)CH2-, -N(H)C(0)CF2-, -CH2-, -CF2- or a 1 ,4-phenylene containing 0 - 4 fluorine substituents, preferably 2 fluorine substituents which are preferably positioned on C2 and C6 or on C3 and C5 of the phenylene;

y is 1 - 4;

Fuc is fucose.

14. The use according to any one of claims 6 to 13, wherein D is an active substance, preferably an anti-cancer agent.

15. Method for targeting CD30-expressing cells, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is obtainable by:

0) contacting a glycoprotein comprising 1 - 4 core /V-acetylglucosamine moieties with a compound of the formula S(F )x-P in the presence of a catalyst, wherein S(F )X is a sugar derivative comprising x functional groups F capable of reacting with a functional group Q , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F )X moiety to the core-GlcNAc moiety, to obtain a modified antibody according to Formula (24):


AB

(24)

wherein S(F )X and x are as defined above; AB represents an antibody; GlcNAc is N- acetylglucosamine; Fuc is fucose; b is 0 or 1 ; and y is 1 , 2, 3 or 4; and

(ii) reacting the modified antibody with a linker-conjugate comprising a functional group Q capable of reacting with functional group F and a target molecule D connected to Q via a linker L2 to obtain the antibody-conjugate wherein linker L comprises S-Z3-L2 and wherein Z3 is a connecting group resulting from the reaction between Q and F\

wherein antibody AB is capable of targeting CD30-expressing tumours.

The method according to claim 15, wherein the targeting CD30-expressing cells includes one or more of treating, imaging, diagnosing, preventing the proliferation of, containing and reducing CD30-expressing cells, in particular CD30-expressing tumours.

The method according to claim 15 or 16, wherein the subject suffers from a disorder selected from lymphoma, such as Hodgkin's lymphoma (HL), non-Hodgkin lymphoma (NHL), anaplastic large-cell lymphoma (ALCL), large B-cell lymphoma, paediatric lymphoma, T-cell lymphoma and enteropathy-associated T-cell lymphoma (EATL), leukaemia, such as acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and mast cell leukaemia, germ cell cancer, graft-versus-host disease (GvHD) and lupus, in particular systemic lupus erythematosus (SLE).

18. The method according to any one of claims 15 - 17, wherein target molecule D is an anticancer agent, preferably a cytotoxin.