NZ736010B2 - Site-specific antibody-drug conjugates - Google Patents

Site-specific antibody-drug conjugates

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Publication number
NZ736010B2
NZ736010B2 NZ736010A NZ73601016A NZ736010B2 NZ 736010 B2 NZ736010 B2 NZ 736010B2 NZ 736010 A NZ736010 A NZ 736010A NZ 73601016 A NZ73601016 A NZ 73601016A NZ 736010 B2 NZ736010 B2 NZ 736010B2
Authority
NZ
New Zealand
Prior art keywords
group
seq
alkyl
amino acid
antibody
Prior art date
Application number
NZ736010A
Other versions
NZ736010A (en
Inventor
Philip Wilson Howard
Berkel Patricius Hendrikus Cornelis Van
Original Assignee
Adc Therapeutics Sa
Medimmune Limited
Filing date
Publication date
Priority claimed from GBGB1506402.5A external-priority patent/GB201506402D0/en
Application filed by Adc Therapeutics Sa, Medimmune Limited filed Critical Adc Therapeutics Sa
Publication of NZ736010A publication Critical patent/NZ736010A/en
Publication of NZ736010B2 publication Critical patent/NZ736010B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Site-specific antibody-drug conjugates are described, in particular conjugates comprising pyrrolobenzodiazepines (PBDs) having a labile protecting group in the form of a linker. The site of conjugation, along with modification of the antibody moiety, allows for improved safety and efficacy of the ADC.

Claims (27)

Claims
1. A ate comprising a compound of formula I or II: 9 L1' 21 R20 R9' R R 11a R R N Y' Y N H R'' H I C2' N 7' 7 N C2 12 R R 2 R 6' 6 R C3' O R R O C3 R 9' 9 10 31 R R R 11 R R H N Y' Y N H C2' N 7' 7 12 R R N R 6' 6 R C3' O R R O and an antibody (Ab) which binds CD22, and which comprises: heavy chains comprising an amino acid substitution of each of HC226 and HC229 according to the EU index as set forth in Kabat, light chains each having an amino acid substitution of the interchain cysteine residue ?LC214 or ?LC213 according to the EU index as set forth in Kabat, and heavy chains each retaining the unsubstituted interchain cysteine HC220 according to the EU index as set forth in Kabat; wherein: when there is a double bond present between C2’ and C3’, R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, y, ester, C1-7 alkyl, C3-7 heterocyclyl and y-C1-3 ne; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl; (id) R21 , wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; (ie) R25a , wherein one of R25a and R25b is H and the other is ed from: , which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if) R24 , where R24 is selected from: H; C 1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2’ and C3’, * R26a R12 is R26b , where R26a and R26b are ndently ed from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are ally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR’, nitro, Me3Sn and halo; where R and R’ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is ed from H, R, OH, OR, SH, SR, NH2, NHR, NHRR’, nitro, Me3Sn and halo; R? is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. e or pyridine; Y and Y’ are selected from O, S, or NH; R6’, R7’, R9’ are selected from the same groups as R6, R7 and R9 respectively; RL1’ is a linker for connection to the antibody (Ab); R11a is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R20 and R21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R20 is selected from H and RC, where RC is a capping group; R21 is selected from OH, ORA and SOzM; when there is a double bond present between C2 and C3, R2 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl; (id) R , wherein each of R11, R12 and R13 are independently selected from H, C1-3 ted alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; (ie) , wherein one of R15a and R15b is H and the other is selected from: , which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if) R , where R14 is ed from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, , methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3, R2 is R , where R16a and R16b are ndently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; R22 is of a IIIa, formula IIIb or formula IIIc: 1 A 2 X (a) Q Q IIIa where A is a C5-7 aryl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond; C1 C3 (b) R R where; RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl; Q IIIc where Q is selected from O-RL2’, S-RL2’ and NRN-RL2’, and RN is selected from H, methyl and ethyl X is selected from the group comprising: , S-RL2’, CO2-RL2’, CO-RL2’, NH-C(=O)-RL2’, L2' L2' N R N N R NHNH-RL2’, CONHNH-RL2’, , , NRNRL2’, wherein RN is selected from the group comprising H and C1-4 alkyl; RL2’ is a linker for connection to the antibody (Ab); R10 and R11 either together form a double bond n the en and carbon atoms to which they are bound or; R10 is H and R11 is selected from OH, ORA and SOzM; R30 and R31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R30 is H and R31 is selected from OH, ORA and SOzM; n the conjugation of the drug moiety to the dy is at HC220 according to the EU index as set forth in Kabat.
2. The conjugate according to claim 1, wherein the number of compounds of formula I or II conjugated to the antibody is 1 or 2.
3. The conjugate according to claim 1 or 2, wherein: (i) R7 is a C1-4 alkyloxy group; and/or (ii) Y is O and R’’ is C3-7 alkylene.
4. The conjugate according to any one of claims 1 to 3, wherein R6 and R9 are H.
5. The conjugate according to any one of claims 1 to 4, wherein there is a double bond between C2’ and C3’, and R12 is: (a) a C5-7 aryl group, which may bear one to three tuent groups selected from methoxy, ethoxy, fluoro, , cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or (b) methyl, ethyl or propyl; or (c) ropyl; or (d) a group of formula: R21 , wherein the total number of carbon atoms in the R12 group is no more than 4; Or (e) the group: (f) a group of formula: R24 , wherein R24 is selected from H and methyl.
6. The conjugate according to any one of claims 1 to 4, wherein there is a single bond * R26a between C2’ and C3’, R12 is R26b and: (a) R26a and R26b are both H; or (b) R26a and R26b are both methyl; or (c) one of R26a and R26b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
7. The conjugate according to any one of claims 1 to 6, wherein there is a double bond between C2 and C3, and R2 is: (a) a C5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or (b) methyl, ethyl or propyl; or (c) ropyl; or (d) a group of formula: R , wherein the total number of carbon atoms in the R2 group is no more than 4; or (e) the group: (f) a group of formula: R , n R14 is selected from H and methyl.
8. The conjugate according to any one of claims 1 to 6, n there is a single bond between C2 and C3, R2 is R and: (a) R16a and R16b are both H; or (b) R16a and R16b are both methyl; or (c) one of R16a and R16b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
9. The conjugate according to any one of claims 1 to 8, wherein R20 is RC, wherein RC is a group: L3 O * G2 L2 where the asterisk indicates the point of attachment to the N10 position, G2 is a terminating group, L3 is a covalent bond or a cleavable linker L1, L2 is a covalent bond or together with OC(=O) forms a self-immolative linker.
10. The conjugate according to any one of claims 1 to 6, wherein: (a) R22 is of formula iiia, A is phenyl, Q1 is a single bond, Q2 is a single bond; or (b) R22 is of a iiib, and RC1, RC2 and RC3 are all H; And X is NH-RL2’.
11. The conjugate according to any one of claims 1 to 10, wherein R6’, R7’, R9’, and Y’ are the same as R6, R7, R9, and Y.
12. The conjugate according to any one of claims 1 to 11 wherein, wherein L-RL1’ or L-RL2’ is a group: Ab 1 L 2 O * A L Where the asterisk indicates the point of attachment to the PBD, Ab is the antibody, L1 is a cleavable linker, A is a connecting group connecting L1 to the antibody, L2 is a covalent bond or er with -OC(=O)- forms a self-immolative linker.
13. The conjugate of claim 12, wherein L1 comprises a dipeptide and the group -X1-X2- in dipeptide, -NH-X1-X2-CO-, is selected from: -Phe-Lys-, -Val-Ala-, -Val-Lys-, -Ala-Lys-, -Val-Cit-.
14. The conjugate ing to claim 13, wherein C(=O)O and L2 together form the group: O * where the asterisk indicates the point of attachment to the PBD, the wavy line indicates the point of ment to the linker L1, Y is NH, O, H or C(=O)O, and n is 0 to 3.
15. A conjugate ing to claim 1 of formula ConjA: ConjA ConjB: ConjB ConjC: ConjC ConjD: O N O O O O Ab H H N N O O O O N O O N H H N O O N O O ConjD ConjE: O N Ab NH O O O O O O O H H N N O O O O N O O N H H N O O N O O ConjE ; ConjF: ConjF ConjG: O O N NH O O O O O O O N O O N H H N OMe MeO N O O H ConjG N N N N O H H N O ConjH: O O NH O O O O O O O O O O O O H H H H N N N N N N H H O O O O O O O O OH O H N O O N H H N O O N O O ConjH .
16. The conjugate according to any one of claims 1 to 15 wherein the antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO.110, or fragment thereof, wherein each of the cysteines at positions 109 and 112 in SEQ ID NO: 110, if present, is substituted by an amino acid that is not cysteine; a light chain comprising, (i) the amino acid sequence of SEQ ID NO. 150, or fragment thereof, wherein the cysteine at on 105, if present, is tuted by an amino acid that is not ne; or (ii) the amino acid sequence of SEQ ID NO. 160, or fragment thereof, wherein the cysteine at position 102, if present, is substituted by an amino acid that is not cysteine; wherein the drug moiety is conjugated to the ne at position 103 of SEQ ID NO.110.
17. The ate according to any one of claims 1 to 15 wherein the antibody comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO.113 or SEQ ID NO.114, and a light chain comprising the amino acid sequence of SEQ ID NO.151, SEQ ID NO.152, SEQ ID NO.153, SEQ ID , SEQ ID NO.162, or SEQ ID NO.163; wherein the drug moiety is conjugated to the cysteine at position 103 of SEQ ID NO.113 or SEQ ID NO.114; or (ii) a heavy chain comprising an amino acid sequence with 99% or more sequence identity to the amino acid sequence of SEQ ID NO.114, and a light chain comprising the amino acid ce of SEQ ID NO.151, SEQ ID NO.152, SEQ ID NO.153, SEQ ID NO.161, SEQ ID NO.162, or SEQ ID NO.163; wherein the drug moiety is conjugated to the cysteine at position 103 of SEQ ID NO.114.
18. The ate according to any one of claims 1 to 17 wherein the antibody comprises a heavy chain having a substitution of the amino acid at position 234 in the EU index set forth in Kabat and/or a substitution of the residue at position 235 in the EU index set forth in Kabat, optionally wherein the substituted amino acids are replaced by alanine, e, valine, or isoleucine.
19. The conjugate according to any one of claims 1 to 18 wherein the antibody comprises a VH domain having the amino acid sequence of SEQ ID NO. 1.
20. The conjugate according to claim 19 n the antibody further comprises a VL domain having the amino acid sequence of SEQ ID NO. 2.
21. The conjugate according to any one of the preceding claims wherein the dy in an intact antibody, optionally wherein the antibody is humanised, nised or resurfaced.
22. The conjugate ing to any one of the preceding claims wherein the number of compounds of formula I or II conjugated to the antibody (Ab) is 2.
23. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 22 and a ceutically acceptable diluent, carrier or excipient; optionally wherein the composition comprises a mixture of the conjugates of any one of claims 1 to 22 and the average number of compounds of formula I or II per antibody is in the range from 1 to 2.
24. The ceutical composition of claim 23 further comprising a therapeutically effective amount of a chemotherapeutic agent.
25. Use of a conjugate according to any one of claims 1 to 22 in the preparation of a medicament for use in the treatment of a proliferative disease associated with CD22 expressing cells in a subject.
26. The use according to claim 25 wherein the proliferative e is cancer.
27. The conjugate of claim 1, substantially as herein described with nce to any one of the examples thereof and/or
NZ736010A 2016-04-15 Site-specific antibody-drug conjugates NZ736010B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1506402.5A GB201506402D0 (en) 2015-04-15 2015-04-15 Site-specific antibody-drug conjugates
PCT/EP2016/058379 WO2016166307A1 (en) 2015-04-15 2016-04-15 Site-specific antibody-drug conjugates

Publications (2)

Publication Number Publication Date
NZ736010A NZ736010A (en) 2025-03-28
NZ736010B2 true NZ736010B2 (en) 2025-07-01

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