DOSAGE REGIMES

Abstract

The present disclosure relates to novel dosage regimes for the treatment of pathological conditions, such as cancer, with Antibody Drug Conjugates (ADCs). In particular, the present disclosure relates to novel dosage regimes for the administration of ADCs which bind to CD25 (CD25-ADCs).

Claims

1-71. (canceled)

72. A method of treating a proliferative disease in a subject, said method comprising administering to a subject a CD25-antibody drug conjugate (ADC), wherein the CD25−ADC comprises as the drug, a pyrrolobenzodiazepine (PBD) dimer, linked to an antibody that binds to CD25, the CD25−ADC having a drug to antibody ratio (DAR) of between 1 and 8, wherein the CD25−ADC is administered to the subject in a dosage regime comprising multiple treatment cycles and wherein the dose of CD25−ADC is reduced following the first or second treatment cycle by about 50% or more.

73. The method of claim 72, wherein the PBD dimer is of formula I: ##STR00047## wherein (a) R.sup.L1′ is a linker for connection to the antibody; (b) (i) R.sup.20 and R.sup.21 either together form a double bond between the nitrogen and carbon atoms to which they are bound; or (ii) R.sup.20 is a capping group R.sup.C, and R.sup.21 is OH; (c) m is 0 or 1; and (d) when there is a double bond between C2 and C3, R.sup.2 is methyl; when there is a single bond between C2 and C3, R.sup.2 is either H or ##STR00048## when there is a double bond between C2′ and C3′, R.sup.12 is methyl; when there is a single bond between C2′ and C3′, R.sup.12 is H or ##STR00049##

74. The method of claim 72, wherein the antibody comprises a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO:3, a VH CDR2 with the amino acid sequence of SEQ ID NO:4, and a VH CDR3 with the amino acid sequence of SEQ ID NO:5, and a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO:6, a VL CDR2 with the amino acid sequence of SEQ ID NO:7, and a VL CDR3 with the amino acid sequence of SEQ ID NO:8.

75. The method of claim 74, wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO:1 and a VL domain having the amino acid sequence of SEQ ID NO:2.

76. The method of claim 73, wherein the PBD is: ##STR00050## wherein R.sup.L1′ is a linker for connection to the antibody.

77. The method of claim 76, wherein the CD25−ADC has the following structure: ##STR00051## wherein Ab is a CD25 antibody comprising: a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO:3, a VH CDR2 with the amino acid sequence of SEQ ID NO:4, and a VH CDR3 with the amino acid sequence of SEQ ID NO:5, and a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO:6, a VL CDR2 with the amino acid sequence of SEQ ID NO:7, and a VL CDR3 with the amino acid sequence of SEQ ID NO:8.

78. The method of claim 77, wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO:1 and a VL domain having the amino acid sequence of SEQ ID NO:2.

79. The method of claim 72, wherein the starting dose of CD25−ADC is reduced no more than once during the dosage regime.

80. The method of claim 72, wherein the starting dose of CD25−ADC is from about 40 μg/kg to about 80 μg/kg.

81. The method of claim 80, wherein the starting dose of CD25−ADC is from about 40 μg/kg to about 50 μg/kg.

82. The method of claim 72, wherein each treatment cycle is about 3 weeks.

83. The method of claim 72, wherein the dose of CD25−ADC is reduced following the second treatment cycle.

84. The method of claim 72, wherein the CD25−ADC is administered in combination with a steroid.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0469] Embodiments and experiments illustrating the principles of the disclosure will now be discussed with reference to the accompanying figures in which:

[0470] FIG. 1. [0471] Sequences

[0472] FIG. 2. [0473] Subcutaeneous Karpas-e007 model—murine xenograft

[0474] FIG. 3. [0475] Systemic Karpas299-e008 model—murine xenograft

[0476] FIG. 4. [0477] ADCx25 Exposure versus Time Following q3w Dosing (n=19) (A) Cycle 1; (B) Cycle 2

[0478] The disclosure includes the combination of the cases and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0479] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0480] Cases and embodiments of the present disclosure will now be illustrated, by way of example, with reference to the accompanying figures. Further cases and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0481] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0482] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.

SOME EMBODIMENTS

[0483] Fractionated Dosage Regimes

[0484] Fractionated dosage regimes in which a partial dose is administered to the subject once per week are specifically contemplated. For example, on days 1, 8, and 15 of a 21 day (3-week) treatment cycle.

[0485] Preferably each partial dose is of equal size, that is, each partial dose delivers the same amount of CD25-ADC to the subject.

[0486] Each partial dose may be 37.5, 40, 42.5, 45, 47.5, or 50 μg/kg. Preferably, each partial dose is about 40 to 60 μg/kg, such as about 45 to 55 μg/kg. Most preferably, each partial dose is about 50 μg/kg.

[0487] Preferably the CD25-ADC is ADCx25 as described herein.

[0488] Preferably the subject is human.

[0489] The use of this type of fractionated dosage regime to treat haematological cancers such as AML and ALL are embodiments of particular interest. Preferably the AML and ALL are CD25+, and may be relapsed or refractory types.

[0490] Administration of ADCx25 in combination with SGN-CD33A for the treatment of AML is envisaged. Administration of ADCx25 in combination with inotuzumab ozogamicin for the treatment of ALL is envisaged.

[0491] Preferably the CD25-ADC is administered in combination with dexamethasone, as described herein.

[0492] Tapered/Elongated Dosage Regimes

[0493] The disclosure provides a method of treating a proliferative disease in a subject, said method comprising administering to a subject a CD25-ADC, wherein the CD25-ADC is administered to the subject in a tapered and/or elongated dosage regimes.

[0494] In some cases the dosage regime comprises dosing about 120 μg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 60 μg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration. Preferably only subjects who have attained at least SD after the second cycle will continue with the reduced dose and increased cycle length.

[0495] In some cases the dosage regime comprises dosing about 150 μg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 60 μg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration. Preferably only subjects who have attained at least SD after the second cycle will continue with the reduced dose and increased cycle length.

[0496] In some particularly preferred cases the dosage regime comprises dosing about 150 μg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 75 μg/kg every 3 weeks, beginning 3 weeks after cycle 2 administration. Preferably only subjects who have attained at least SD after the second cycle will continue with the reduced dose.

[0497] In some cases the dosage regime comprises dosing about 200 μg/kg every 6 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 60 μg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration. Preferably only subjects who have attained at least SD after the second cycle will continue with the reduced dose.

[0498] In some cases the dosage regime comprises dosing about 200 μg/kg every 6 weeks for 1 cycle, then continuing treatment with the second and subsequent cycles at a reduced dose of about 60 μg/kg every 6 weeks, beginning 6 weeks after cycle 1 administration. Preferably only subjects who have attained at least SD after the first cycle will continue with the reduced dose.

[0499] In some cases the dosage regime comprises dosing about 45 μg/kg every 3 weeks for up to 4 treatment cycles, then continuing treatment every 3 weeks at a reduced dose of about 30 μg/kg or about 20 μg/kg (such as 20 to 30 μg/kg). In some cases, the starting dose of 45 μg/kg is administered for only 1 treatment cycle before the dose is reduced. In some cases, the starting dose of 45 μg/kg is administered for only 2 treatment cycles before the dose is reduced. In some cases, the starting dose of 45 μg/kg is administered for only 3 treatment cycles before the dose is reduced. In some cases, the starting dose of 45 μg/kg is administered for 4 treatment cycles before the dose is reduced.

[0500] Preferably the CD25-ADC is administered as single dose on Day 1 of each cycle, unless otherwise specified.

[0501] Preferably the CD25-ADC is ADCx25 as described herein.

[0502] Preferably the proliferative disease is lymphoma, such as a Hodgkin lymphoma or Non Hodgkin Lymphoma. The disease may be relapsed or refractory.

[0503] Administration of ADCx25 in combination with SGN-CD33A for the treatment of AML is envisaged. Administration of ADCx25 in combination with inotuzumab ozogamicin for the treatment of ALL is envisaged.

[0504] Preferably the subject is human.

[0505] Preferably the CD25-ADC is administered in combination with dexamethasone, as described herein.

[0506] A preferred dosage regime for subjects having, suspected of having, or having been diagnosed with Hodgkin's Lymphoma is as follows: [0507] about 40-50 μg/kg (preferably 45 μg/kg) of CD25-ADC Q3W (every 3 weeks) for 3 treatment cycles, followed by [0508] about 25-35 μg/kg (preferably 30 μg/kg) CD25-ADC Q3W (every 3 weeks) until treatment discontinued.

[0509] A preferred dosage regime for subjects having, suspected of having, or having been diagnosed with Acute T-cell lymphoblastic lymphoma (ATLL), is as follows: [0510] about 75-85 μg/kg (preferably 80 μg/kg) of CD25-ADC Q3W (every 3 weeks) until treatment discontinued, optionally wherein [0511] the dose is reduced after the first 2 or 3 treatment cycles to, for example, 40-60 μg/kg.

[0512] A preferred dosage regime for subjects having, suspected of having, or having been diagnosed with a T-cell lymphoma, is as follows: [0513] about 55-65 μg/kg (preferably 60 μg/kg) of CD25-ADC Q3W (every 3 weeks) until treatment discontinued, optionally wherein [0514] the dose is reduced after the first 2 or 3 treatment cycles to, for example, 30-40 μg/kg.

STATEMENTS OF DISCLOSURE

[0515] Fractionated Dosage Regimes

[0516] 1. A method of treating a proliferative disease in a subject, said method comprising administering to a subject a CD25-ADC, wherein the CD25-ADC is administered to the subject in a fractionated dosage regime, and; [0517] wherein the CD25-ADC comprises a conjugate of formula L-(D.sup.L).sub.p, where D.sup.L is of formula I or II:

##STR00019##

[0518] wherein:

[0519] L is an antibody (Ab) which is an antibody that binds to CD25;

[0520] when there is a double bond present between C2′ and C3′, R.sup.12 is selected from the group consisting of:

[0521] (ia) C.sub.5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C.sub.1-7 alkyl, C.sub.3-7 heterocyclyl and bis-oxy-C.sub.1-3 alkylene;

[0522] (ib) C.sub.1-5 saturated aliphatic alkyl;

[0523] (ic) C.sub.3-6 saturated cycloalkyl;

##STR00020##

wherein each of R.sup.21, R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 saturated alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R.sup.12 group is no more than 5;

##STR00021##

wherein one of R.sup.25a and R.sup.25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and

##STR00022##

where R.sup.24 is selected from: H; C.sub.1-3 saturated alkyl; C.sub.2-3 alkenyl; C.sub.2-3 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′,

[0524] R.sup.12 is

##STR00023##

where R.sup.26a and R.sup.26b are independently selected from H, F, C.sub.1-4 saturated alkyl, C.sub.2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C.sub.1-4 alkyl amido and C.sub.1-4 alkyl ester; or, when one of R.sup.26a and R.sup.26b is H, the other is selected from nitrile and a C.sub.1-4 alkyl ester;

[0525] R.sup.6 and R.sup.9 are independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR′, nitro, Me.sub.3Sn and halo;

[0526] where R and R′ are independently selected from optionally substituted C.sub.1-12 alkyl, C.sub.3-20 heterocyclyl and C.sub.5-20 aryl groups;

[0527] R.sup.7 is selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NHRR′, nitro, Me.sub.3Sn and halo;

[0528] R″ is a C.sub.3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NR.sup.N2 (where R.sup.N2 is H or C.sub.1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine;

[0529] Y and Y′ are selected from O, S, or NH;

[0530] R.sup.6′, R.sup.7′, R.sup.9′ are selected from the same groups as R.sup.6, R.sup.7 and R.sup.9 respectively;

[0531] [Formula I]

[0532] R.sup.L1′ is a linker for connection to the antibody (Ab);

[0533] R.sup.11a is selected from OH, OR.sup.A, where R.sup.A is C.sub.1-4 alkyl, and SO.sub.2M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

[0534] R.sup.20 and R.sup.21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0535] R.sup.20 is selected from H and R.sup.C, where R.sup.C is a capping group;

[0536] R.sup.21 is selected from OH, OR.sup.A and SO.sub.2M;

[0537] when there is a double bond present between C2 and C3, R.sup.2 is selected from the group consisting of:

[0538] (ia) C.sub.5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C.sub.1-7 alkyl, C.sub.3-7 heterocyclyl and bis-oxy-C.sub.1-3 alkylene;

[0539] (ib) C.sub.1-5 saturated aliphatic alkyl;

[0540] (ic) C.sub.3-6 saturated cycloalkyl;

##STR00024##

wherein each of R.sup.11, R.sup.12 and R.sup.13 are independently selected from H, C.sub.1-3 saturated alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R.sup.2 group is no more than 5;

##STR00025##

wherein one of R.sup.15a and R.sup.15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and

##STR00026##

where R.sup.14 is selected from: H; C.sub.1-3 saturated alkyl; C.sub.2-3 alkenyl; C.sub.2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;

[0541] when there is a single bond present between C2 and C3,

[0542] R.sup.2 is

##STR00027##

where R.sup.16a and R.sup.16b are independently selected from H, F, C.sub.1-4 saturated alkyl, C.sub.2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C.sub.1-4 alkyl amido and C.sub.1-4 alkyl ester; or, when one of R.sup.16a and R.sup.16b is H, the other is selected from nitrile and a C.sub.1-4 alkyl ester;

[0543] [Formula II]

[0544] R.sup.22 is of formula IIIa, formula IIIb or formula IIIc:

##STR00028##

[0545] where A is a C.sub.5-7 aryl group, and either

[0546] (i) Q.sup.1 is a single bond, and Q.sup.2 is selected from a single bond and —Z—(CH.sub.2).sub.n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or

[0547] (ii) Q.sup.1 is —CH═CH—, and Q.sup.2 is a single bond;

##STR00029##

[0548] where;

[0549] R.sup.C1, R.sup.C2 and R.sup.C3 are independently selected from H and unsubstituted C.sub.1-2 alkyl;

##STR00030##

[0550] where Q is selected from O—R.sup.L2′, S—R.sup.L2′ and NR.sup.N_R.sup.L2′, and R.sup.N is selected from H, methyl and ethyl

[0551] X is selected from the group comprising: O—R.sup.L2′, S—R.sup.L2′, CO.sub.2_R.sup.L2′, CO_R.sup.L2′, NH—C(═O)—R.sup.L2′, NHNH—R.sup.L2′, CONHNH—R.sup.L2′,

##STR00031##

NR.sup.NRL.sup.2′, wherein R.sup.N is selected from the group comprising H and C.sub.1-4 alkyl;

[0552] R.sup.L2′ is a linker for connection to the antibody (Ab);

[0553] R.sup.10 and R.sup.11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0554] R.sup.10 is H and R.sup.11 is selected from OH, OR.sup.A and SO.sub.2M;

[0555] R.sup.30 and R.sup.31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0556] R.sup.30 is H and R.sup.31 is selected from OH, OR.sup.A and SO.sub.2M.

[0557] 2. The method according to statement 1 wherein the CD25-ADC has the chemical structure:

##STR00032##

where the Ab is a CD25 antibody, and the DAR is between 1 and 8.

[0558] 3. The method according to either of statement 1 or statement 2 wherein Ab comprises: a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO. 3, a VH CDR2 with the amino acid sequence of SEQ ID NO. 4, and a VH CDR3 with the amino acid sequence of SEQ ID NO. 5; and, optionally, a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO. 6, a VL CDR2 with the amino acid sequence of SEQ ID NO. 7, and a VL CDR3 with the amino acid sequence of SEQ ID NO. 8.

[0559] 4. The method according to any one of statements 1 to 3 wherein Ab comprises a VH domain having the sequence of SEQ ID NO. 1 and a VL domain having the sequence of SEQ ID NO. 2.

[0560] 5. The method according to any one of statements 1 to 4 wherein the CD25-ADC is ADCx25.

[0561] 6. The method according to any preceding statement wherein the total dose of CD25-ADC administered during the treatment cycle is administered as a series of two or more partial doses during a treatment cycle.

[0562] 7. The method according to any preceding statement wherein the partial doses of CD25 ADC are administered at regularly spaced intervals throughout the treatment cycle.

[0563] 8. The method according to any preceding statement wherein a partial dose of CD25-ADC is administered to the subject once per week.

[0564] 9. The method according to any preceding statement wherein the length of the treatment cycle is 3 weeks.

[0565] 10. The method according to any preceding statement wherein the length of the treatment cycle is 6 weeks.

[0566] 11. The method according to any preceding statement wherein a partial dose of the CD25-ADC is administered once a week in a 3-week treatment cycle.

[0567] 12. The method according to any preceding statement wherein a partial dose of the CD25-ADC is administered on days 1, 8, and 15 of a 3-week treatment cycle.

[0568] 13. The method according to any preceding statement wherein a total dose of about 10 μg/kg CD25-ADC is administered during the treatment cycle.

[0569] 14. The method according to any preceding statement wherein a total dose of about 20 μg/kg CD25-ADC is administered during the treatment cycle.

[0570] 15. The method according to any preceding statement wherein a total dose of about 30 μg/kg CD25-ADC is administered during the treatment cycle.

[0571] 16. The method according to any preceding statement wherein a total dose of about 40 μg/kg CD25-ADC is administered during the treatment cycle.

[0572] 17. The method according to any preceding statement wherein a total dose of about 50 μg/kg CD25-ADC is administered during the treatment cycle.

[0573] 18. The method according to any preceding statement wherein a total dose of about 60 μg/kg CD25-ADC is administered during the treatment cycle.

[0574] 19. The method according to any preceding statement wherein a total dose of about 70 μg/kg CD25-ADC is administered during the treatment cycle.

[0575] 20. The method according to any preceding statement wherein a total dose of about 80 μg/kg CD25-ADC is administered during the treatment cycle.

[0576] 21. The method according to any preceding statement wherein a total dose of about 90 μg/kg CD25-ADC is administered during the treatment cycle.

[0577] 22. The method according to any preceding statement wherein a total dose of about 100 μg/kg CD25-ADC is administered during the treatment cycle.

[0578] 22a. The method according to any preceding statement wherein a total dose of about 112.5 μg/kg CD25-ADC is administered during the treatment cycle.

[0579] 23. The method according to any preceding statement wherein a total dose of about 120 μg/kg CD25-ADC is administered during the treatment cycle.

[0580] 23a. The method according to any preceding statement wherein a total dose of about 127.5 μg/kg CD25-ADC is administered during the treatment cycle.

[0581] 23b. The method according to any preceding statement wherein a total dose of about 135 μg/kg CD25-ADC is administered during the treatment cycle.

[0582] 23c. The method according to any preceding statement wherein a total dose of about 142.5 μg/kg CD25-ADC is administered during the treatment cycle.

[0583] 24. The method according to any preceding statement wherein a total dose of about 150 μg/kg CD25-ADC is administered during the treatment cycle.

[0584] 25. The method according to any preceding statement wherein a total dose of about 200 μg/kg CD25-ADC is administered during the treatment cycle.

[0585] 26. The method according to any preceding statement wherein a total dose of about 250 μg/kg CD25-ADC is administered during the treatment cycle.

[0586] 27. The method according to any preceding statement wherein a total dose of about 300 μg/kg CD25-ADC is administered during the treatment cycle.

[0587] 28. The method according to any preceding statement wherein a total dose of 1 to 10 μg/kg CD25-ADC is administered during the treatment cycle.

[0588] 29. The method according to any preceding statement wherein a total dose of 11 to 20 μg/kg CD25-ADC is administered during the treatment cycle.

[0589] 30. The method according to any preceding statement wherein a total dose of 21 to 30 μg/kg CD25-ADC is administered during the treatment cycle.

[0590] 31. The method according to any preceding statement wherein a total dose of 31 to 40 μg/kg CD25-ADC is administered during the treatment cycle.

[0591] 32. The method according to any preceding statement wherein a total dose of 41 to 50 μg/kg CD25-ADC is administered during the treatment cycle.

[0592] 33. The method according to any preceding statement wherein a total dose of 51 to 60 μg/kg CD25-ADC is administered during the treatment cycle.

[0593] 34. The method according to any preceding statement wherein a total dose of 61 to 70 μg/kg CD25-ADC is administered during the treatment cycle.

[0594] 35. The method according to any preceding statement wherein a total dose of 71 to 80 μg/kg CD25-ADC is administered during the treatment cycle.

[0595] 36. The method according to any preceding statement wherein a total dose of 81 to 90 μg/kg CD25-ADC is administered during the treatment cycle.

[0596] 37. The method according to any preceding statement wherein a total dose of 91 to 100 μg/kg CD25-ADC is administered during the treatment cycle.

[0597] 38. The method according to any preceding statement wherein a total dose of 101 to 120 μg/kg CD25-ADC is administered during the treatment cycle.

[0598] 39. The method according to any preceding statement wherein a total dose of 121 to 140 μg/kg CD25-ADC is administered during the treatment cycle.

[0599] 40. The method according to any preceding statement wherein a total dose of 141 to 160 μg/kg CD25-ADC is administered during the treatment cycle.

[0600] 41. The method according to any preceding statement wherein a total dose of 161 to 180 μg/kg CD25-ADC is administered during the treatment cycle.

[0601] 42. The method according to any preceding statement wherein a total dose of 181 to 200 μg/kg CD25-ADC is administered during the treatment cycle.

[0602] 43. The method according to any preceding statement wherein a total dose of 201 to 220 μg/kg CD25-ADC is administered during the treatment cycle.

[0603] 44. The method according to any preceding statement wherein a total dose of 221 to 240 μg/kg CD25-ADC is administered during the treatment cycle.

[0604] 45. The method according to any preceding statement wherein a total dose of 241 to 260 μg/kg CD25-ADC is administered during the treatment cycle.

[0605] 46. The method according to any preceding statement wherein a total dose of 261 to 280 μg/kg CD25-ADC is administered during the treatment cycle.

[0606] 46. The method according to any preceding statement wherein a total dose of 281 to 300 μg/kg CD25-ADC is administered during the treatment cycle.

[0607] 47. The method according to any preceding statement wherein the partial dose is about 10 μg/kg.

[0608] 48. The method according to any preceding statement wherein the partial dose is about 20 μg/kg.

[0609] 49. The method according to any preceding statement wherein the partial dose is about 30 μg/kg.

[0610] 49a. The method according to any preceding statement wherein the partial dose is about 37.5 μg/kg.

[0611] 50. The method according to any preceding statement wherein the partial dose is about 40 μg/kg.

[0612] 50a. The method according to any preceding statement wherein the partial dose is about 42.5 μg/kg.

[0613] 50b. The method according to any preceding statement wherein the partial dose is about 45 μg/kg.

[0614] 50c. The method according to any preceding statement wherein the partial dose is about 47.5 μg/kg.

[0615] 51. The method according to any preceding statement wherein the partial dose is about 50 μg/kg.

[0616] 52. The method according to any preceding statement wherein the partial dose is about 60 μg/kg.

[0617] 53. The method according to any preceding statement wherein the partial dose is about 70 μg/kg.

[0618] 54. The method according to any preceding statement wherein the partial dose is about 80 μg/kg.

[0619] 55. The method according to any preceding statement wherein the partial dose is about 90 μg/kg.

[0620] 56. The method according to any preceding statement wherein the partial dose is about 100 μg/kg.

[0621] 57. The method according to any preceding statement wherein the partial dose is 1 to 10 μg/kg.

[0622] 58. The method according to any preceding statement wherein the partial dose is 11 to 20 μg/kg.

[0623] 59. The method according to any preceding statement wherein the partial dose is 21 to 30 μg/kg.

[0624] 60. The method according to any preceding statement wherein the partial dose is 31 to 40 μg/kg.

[0625] 61. The method according to any preceding statement wherein the partial dose is 41 to 50 μg/kg.

[0626] 62. The method according to any preceding statement wherein the partial dose is 51 to 60 μg/kg.

[0627] 63. The method according to any preceding statement wherein the partial dose is 61 to 70 μg/kg.

[0628] 64 The method according to any preceding statement wherein the partial dose is 71 to 80 μg/kg.

[0629] 65. The method according to any preceding statement wherein the partial dose is 81 to 90 μg/kg.

[0630] 66. The method according to any preceding statement wherein the partial dose is 91 to 100 μg/kg.

[0631] 67. The method according to any preceding statement wherein the amount of CD25−ADC in each partial dose is the same.

[0632] 68. The method according to any preceding statement wherein the proliferative disease is characterised by the presence of a neoplasm comprising CD25+ve cells

[0633] 69. The method according to any preceding statement wherein the subject has been diagnosed as having the proliferative disease prior to the start of treatment with the CD25-ADC.

[0634] 70. The method according to statement 69, wherein the disease is CD25+ AML.

[0635] 71. The method according to statement 69, wherein the disease is CD25+ ALL.

[0636] 72. The method according to any preceding statement wherein the method comprises the step of selecting a subject for treatment based on expression of CD25.

[0637] 73. The method according to statement 72, wherein a subject is selected if at least 5% of neoplasm cells express CD25.

[0638] 74. The method according to any preceding statement wherein the proliferative disease is Hodgkin's lymphoma or non-Hodgkin's lymphoma, optionally wherein the non-Hodgkin's lymphoma is selected from: Peripheral T-cell Lymphoma; Cutaneous T-cell Lymphoma; Diffuse Large B-cell Lymphoma; Follicular Lymphoma; Mantle-cell Lymphoma; Chronic Lymphocytic Leukemia; Anaplastic Large-cell Lymphoma; Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ ALL) or Philadelphia chromosome-negative ALL (Ph−ALL).

[0639] 75. The method according to any preceding statement wherein the proliferative disease is CD25+ AML.

[0640] 76. The method according to any preceding statement wherein the proliferative disease is CD25+ ALL.

[0641] 77. The method according to any preceding statement wherein the proliferative disease is resistant, relapsed or refractory.

[0642] 78. The method according to any preceding statement wherein the subject is human.

[0643] 79. The method according to any preceding statement wherein the CD25−ADC is administered intravenously.

[0644] 80. The method according to any preceding statement further comprising administering a chemotherapeutic agent in combination with the CD25−ADC.

[0645] 81. The method according to statement 80, wherein the chemotherapeutic agent is inotuzumab ozogamicin.

[0646] 82. The method according to statement 80, wherein the chemotherapeutic agent is inotuzumab SGN-CD33A.

[0647] 83. The method according to any one of statements 80 to 82, wherein the chemotherapeutic agent is administered to the subject before, at the same time, or after the CD25−ADC.

[0648] 84. The method according to any preceding statement, wherein the CD25−ADC is administered in combination with a steroid.

[0649] 85. The method according to statement 84, wherein a first dose of steroid is administered on the same day as the ADC.

[0650] 86. The method according to statement 85, wherein the first dose of steroid is administered at least 2 hours before the ADC.

[0651] 87. The method according to either one of statements 85 or 86, wherein a second dose of steroid is administered the day after the ADC.

[0652] 88. The method according to statement 84, wherein a first dose of steroid is administered the day before the ADC.

[0653] 89. The method according to statement 88, wherein a second dose of steroid is administered on the same day as the ADC.

[0654] 90. The method according to statement 89, wherein the second dose of steroid is administered at least 2 hours before the ADC.

[0655] 91. The method according to either one of statements 89 or 90, wherein a third dose of steroid is administered the day after the ADC.

[0656] 92. The method according to any one of statements 84 to 91, wherein the steroid or steroid doses are administered only in conjunction with the first administration of ADC in each treatment cycle.

[0657] 93. The method according to any one of statements 84 to 92, wherein the steroid is administered orally.

[0658] 94. The method according to any one of statements 84 to 93, wherein each dose of steroid is 8 mg.

[0659] 95. The method according to any one of statements 84 to 94, wherein each dose of steroid is 16 mg.

[0660] 96. The method according to any one of statements 84 to 95, wherein each dose of steroid is administered as two equal, partial doses.

[0661] 97. The method according to any one of statements 84 to 96, wherein each partial dose is 4 mg.

[0662] 98. The method according to any one of statements 84 to 97, wherein each partial dose is 8 mg.

[0663] 99. The method according to any one of statements 84 to 98, wherein the steroid is dexamethasone.

[0664] 100. The method according to statement 84, wherein 4 mg dexamethasone is administered orally twice daily: (i) the day before ADC administration on week 1, day 1 of the treatment cycle, (ii) the day of ADC administration on week 1, day 1 of the treatment cycle, and (iii) the day after ADC administration on week 1, day 1 of the treatment cycle.

[0665] 101. The method according to statement 84, wherein 4 mg dexamethasone is administered orally twice daily: (i) the day of ADC administration on week 1, day 1 of the treatment cycle, and (ii) the day after ADC administration on week 1, day 1 of the treatment cycle.

[0666] 102. The method according to either one of statements 100 and 101, wherein the dexamethasone administered on the same day as the ADC is administered at least two hours before the ADC.

[0667] 103. The method according to any one of statements 100 to 102, wherein the dexamethasone is administered only in conjunction with the first administration of ADC in each treatment cycle.

[0668] 104. The method according to any preceding statement wherein the fractionated dosage regime has lower toxicity than a single-dose dosage regime having the same total dose administered and length of treatment cycle.

[0669] 105. The method according to statement 104, wherein the the incidence of TEAE with the fractionated dosage regime is no more than 50% of the incidence of TEAE in the single-dose regime.

[0670] 106. The method according to statement 104, wherein the incidence of SAE with the fractionated dosage regime is no more than 50% of the incidence of SAE in the single-dose regime.

[0671] 107. The method according to statement 104, wherein the incidence of DLT with the fractionated dosage regime is no more than 50% of the incidence of DLT in the single-dose regime.

[0672] 108. The method according to any preceding statement wherein the fractionated dosage regime has greater efficacy than a single-dose dosage regime having the same total dose administered and length of treatment cycle.

[0673] 109. The method according to statement 108, wherein the proportion of subjects achieving at least PR with the fractionated dosage regime is at least 150% of the proportion of subjects achieving at least a partial response [PR] in the single dose regime.

[0674] 110. The method according to any preceding statement, wherein the subject undergoes a neurological examination prior to treatment with the ADC.

[0675] 111. The method according to any preceding statement, wherein the subject undergoes a neurological examination after administration of the ADC.

[0676] 112. The method according to any preceding statement, wherein the subject undergoes a neurological examination after each administration of the ADC.

[0677] 113. The method according to any preceding statement, wherein the subject undergoes a neurological examination if they experience a neurologic toxicity following administration of the ADC.

[0678] 114. The method according to any one of statements 110 to 111, wherein the neurological examination includes tests of strength, sensation, and/or deep-tendon reflexes.

[0679] 115. The method according to any preceding statement, wherein treatment with the ADC is reduced, suspended, or permanently discontinued if the subject has a neurological disorder or experiences a neurologic toxicity.

[0680] 116. The method according to any preceding statement, wherein treatment with the ADC is reduced or suspended if the subject experiences a grade 1 neurologic toxicity.

[0681] 117. The method according to any preceding statement, wherein treatment with the ADC is permanently discontinued if the subject experiences a grade 2 neurologic toxicity.

[0682] 118. The method according to any one of statements 115 to 117, wherein treatment with the ADC is reduced by reducing the dose of ADC that is administered to the subject in each subsequent treatment cycle, and/or by increasing the length of each subsequent treatment cycle.

[0683] 119. A method of selecting a subject for treatment by a method according to any one of statements 1 to 118, which method comprises determining if the subject has, or recently had, a neurologic disorder, wherein the subject is determined to be not suitable for treatment with the ADC if they have, or have recently had, a neurologic disorder.

[0684] 120. A method of selecting a subject for treatment by a method according to any one of statements 1 to 118, which method comprises determining if the subject has, or recently had, an infection caused by a pathogen that may be associated with neurologic and/or immune-related disease; wherein the subject is determined to be not suitable for treatment with the ADC if they have, or have recently had, such an infection and/or immune-related disease.

[0685] 121. The method according to any one of statements 113 to 120, wherein the neurologic disorder or neurological toxicity is polyradiculopathy, acute inflammatory demyelinating (AIDP), Guillain-Barre syndrome (GBS), myasthenia gravis, or a neurologic disorder that is linked to or is an early indicator of polyradiculitis, GBS, or myasthenia gravis, such as ascending sensory loss and/or motor weakness.

[0686] 122. The method according to any one of statements 113 to 120, wherein the neurologic disorder or neurological toxicity is Guillain-Barre syndrome (GBS).

[0687] 123. A method of reducing the toxicity and/or side effects associated with administration of a CD25−ADC to a subject, the method comprising administering the CD25−ADC according to the method of any preceding statement.

[0688] 124. A method of increasing the treatment efficacy associated with administration of a CD25−ADC to a subject, the method comprising administering the CD25−ADC according to the method of any preceding statement.

[0689] 125. A method of selecting a subject for treatment by a method according to any one of statements 1 to 122, which method comprises selecting for treatment subjects that express CD25 in a tissue of interest.

[0690] 126. The method according to statement 125 wherein subjects are selected if at least 5% of cells in a sample of the tissue of interest express CD25.

[0691] 127. The method according to either one of statements 123 and 124 wherein the tissue of interest is lymphoid tissue or tumour tissue.

[0692] 128. The method according to any one of statements 125 to 127, wherein the subject has experienced a DLT in a single-dose dosage regime of a CD25−ADC.

[0693] 129. A packaged pharmaceutical product comprising a CD25−ADC as defined in any one of statements 1 to 5, in combination with a label or insert advising that the CD25−ADC should be administered according to the method of any one of statements 1 to 122.

[0694] 130. A kit comprising:

[0695] a first medicament comprising a CD25−ADC as defined in any one of statements 1 to 5; and, optionally,

[0696] a package insert or label comprising instructions for administration of the CD25−ADC according to the method of any one of statements 1 to 122.

[0697] 131. A CD25−ADC as defined in any one of statements 1 to 5 for use in a method of any one of statements 1 to 122.

[0698] 132. A pharmaceutical composition comprising a CD25−ADC as defined in any one of statements 1 to 5, optionally in combination with a pharmaceutically acceptable excipient, for use in a method of any one of statements 1 to 122.

[0699] 133. Use of a CD25−ADC as defined in any one of statements 1 to 5 in the preparation of a medicament for use in a method of any one of statements 1 to 122.

[0700] Tapered/Elongated Dosage Regimes

[0701] 1. A method of treating a proliferative disease in a subject, said method comprising administering to a subject a CD25−ADC, wherein the CD25−ADC is administered to the subject in a tapered and/or elongated dosage regime, and; [0702] wherein the CD25−ADC comprises a conjugate of formula L-(D.sup.L).sub.p, where D.sup.L is of formula I or II:

##STR00033##

[0703] wherein:

[0704] L is an antibody (Ab) which is an antibody that binds to CD25; [0705] when there is a double bond present between C2′ and C3′, R.sup.12 is selected from the group consisting of:

[0706] (ia) C.sub.5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C.sub.1-7 alkyl, C.sub.3-7 heterocyclyl and bis-oxy-C.sub.1-3 alkylene;

[0707] (ib) C.sub.1-5 saturated aliphatic alkyl;

[0708] (ic) C.sub.3-6 saturated cycloalkyl;

##STR00034##

##STR00035##

wherein one of R.sup.25a and R.sup.25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and

##STR00036##

[0709] when there is a single bond present between C2′ and C3′,

[0710] R.sup.12 is

##STR00037##

[0711] R.sup.6 and R.sup.9 are independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR′, nitro, Me.sub.3Sn and halo;

[0712] where R and R′ are independently selected from optionally substituted C.sub.1-12 alkyl, C.sub.3-20 heterocyclyl and C.sub.5-20 aryl groups;

[0713] R.sup.7 is selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NHRR′, nitro, Me.sub.3Sn and halo;

[0714] R″ is a C.sub.3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NR.sup.N2 (where R.sup.N2 is H or C.sub.1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine;

[0715] Y and Y′ are selected from O, S, or NH;

[0716] R.sup.6′, R.sup.7′, R.sup.9′ are selected from the same groups as R.sup.6, R.sup.7 and R.sup.9 respectively;

[0717] [Formula I]

[0718] R.sup.L1′ is a linker for connection to the antibody (Ab);

[0719] R.sup.11a is selected from OH, OR.sup.A, where R.sup.A is C.sub.1-4 alkyl, and SO.sub.2M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

[0720] R.sup.20 and R.sup.21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0721] R.sup.20 is selected from H and R.sup.C, where R.sup.C is a capping group;

[0722] R.sup.21 is selected from OH, OR.sup.A and SO.sub.2M;

[0723] when there is a double bond present between C2 and C3, R.sup.2 is selected from the group consisting of:

[0724] (ia) C.sub.5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C.sub.1-7 alkyl, C.sub.3-7 heterocyclyl and bis-oxy-C.sub.1-3 alkylene;

[0725] (ib) C.sub.1-5 saturated aliphatic alkyl;

[0726] (ic) C.sub.3-6 saturated cycloalkyl;

##STR00038##

##STR00039##

wherein one of R.sup.15a and R.sup.15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and

##STR00040##

[0727] when there is a single bond present between C2 and C3,

[0728] R.sup.2 is

##STR00041##

[0729] [Formula II]

[0730] R.sup.22 is of formula IIIa, formula IIIb or formula IIIc:

##STR00042##

[0731] where A is a C.sub.5-7 aryl group, and either

[0732] (i) Q.sup.1 is a single bond, and Q.sup.2 is selected from a single bond and —Z—(CH.sub.2).sub.n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or

[0733] (ii) Q.sup.1 is —CH═CH—, and Q.sup.2 is a single bond;

##STR00043##

[0734] where;

[0735] R.sup.C1, R.sup.C2 and R.sup.C3 are independently selected from H and unsubstituted C.sub.1-2 alkyl;

##STR00044##

[0736] where Q is selected from O—R.sup.L2′, S—R.sup.L2′ and NR.sup.N_R.sup.L2′, and R.sup.N is selected from H, methyl and ethyl

[0737] X is selected from the group comprising: O—R.sup.L2′, S—R.sup.L2′, CO.sub.2R.sup.L2′, CO—R.sup.L2′, NH—C(═O)—R.sup.L2′, NHNH—R.sup.L2′, CONHNH—R.sup.L2′,

##STR00045##

NR.sup.NR.sup.L2′, wherein R.sup.N is selected from the group comprising H and C.sub.1-4 alkyl;

[0738] R.sup.L2′ is a linker for connection to the antibody (Ab);

[0739] R.sup.10 and R.sup.11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0740] R.sup.10 is H and R″ is selected from OH, OR.sup.A and SO.sub.2M;

[0741] R.sup.30 and R.sup.31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;

[0742] R.sup.30 is H and R.sup.31 is selected from OH, OR.sup.A and SO.sub.2M.

[0743] 2. The method according to statement 1 wherein the CD25−ADC has the chemical structure:

##STR00046##

where the Ab is a CD25 antibody, and the DAR is between 1 and 8.

[0744] 3. The method according to either of statement 1 or statement 2 wherein Ab comprises: [0745] a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO. 3, a VH CDR2 with the amino acid sequence of SEQ ID NO. 4, and a VH CDR3 with the amino acid sequence of SEQ ID NO. 5; and, optionally, [0746] a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO. 6, a VL CDR2 with the amino acid sequence of SEQ ID NO. 7, and a VL CDR3 with the amino acid sequence of SEQ ID NO. 8.

[0747] 4. The method according to any one of statements 1 to 3 wherein Ab comprises a VH domain having the sequence of SEQ ID NO. 1 and a VL domain having the sequence of SEQ ID NO. 2.

[0748] 5. The method according to any one of statements 1 to 4 wherein the CD25−ADC is ADCx25.

[0749] 6. The method according to any preceding statement wherein the starting dose of CD25−ADC is reduced no more than twice during the dosage regime.

[0750] 7. The method according to any preceding statement wherein the starting dose of CD25−ADC is reduced no more than once during the dosage regime.

[0751] 8. The method according to any preceding statement wherein the dose is reduced following the first treatment cycle.

[0752] 9. The method according to any preceding statement wherein the dose is reduced following the second treatment cycle.

[0753] 10. The method according to any preceding statement wherein the dose is reduced following the third treatment cycle.

[0754] 11. The method according to any preceding statement wherein the dose is reduced following the fourth treatment cycle.

[0755] 12. The method according to any preceding statement wherein the dose is reduced only if the subject has attained at least Stable Disease [SD] at the end of the preceding treatment cycle.

[0756] 13. The method according to any preceding statement wherein the starting dose is at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 μg/kg.

[0757] 14. The method according to any preceding statement wherein the starting dose is about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120, 150, 200, 250, 300, 350, 400, 450, 500, 550, or 600 μg/kg.

[0758] 15. The method according to any preceding statement wherein the starting dose is 1 to 10 μg/kg, 11 to 20 μg/kg, 21 to 30 μg/kg, 31 to 40 μg/kg, 41 to 50 μg/kg, 51 to 60 μg/kg, 61 to 70 μg/kg, 71 to 80 μg/kg, 81 to 90 μg/kg, 91 to 100 μg/kg, 101 to 120 μg/kg, 121 to 140 μg/kg, 141 to 160 μg/kg, 161 to 180 μg/kg, 181 to 200 μg/kg, 201 to 220 μg/kg, 221 to 240 μg/kg, 241 to 260 μg/kg, 261 to 280 μg/kg, 281 to 300 μg/kg, 301 to 320 μg/kg, 321 to 340 μg/kg, 341 to 360 μg/kg, 361 to 380 μg/kg, 381 to 400 μg/kg, 401 to 420 μg/kg, 421 to 440 μg/kg, 441 to 460 μg/kg, 461 to 480 μg/kg, 481 to 500 μg/kg, 501 to 520 μg/kg, 521 to 540 μg/kg, 541 to 560 μg/kg, 561 to 580 μg/kg, or 581 to 600 μg/kg.

[0759] 16. The method according to any preceding statement wherein the starting dose is 40 to 50 μg/kg, such as about 45 μg/kg.

[0760] 17. The method according to any preceding statement wherein the starting dose is 55 to 65 μg/kg, such as about 60 μg/kg.

[0761] 18. The method according to any preceding statement wherein the starting dose is 75 to 85 μg/kg, such as about 80 μg/kg.

[0762] 19. The method according to any preceding statement wherein the starting dose is at least 120 μg/kg.

[0763] 20. The method according to any preceding statement wherein the starting dose is about 120 μg/kg.

[0764] 21. The method according to any preceding statement wherein the starting dose is at least 150 μg/kg.

[0765] 22. The method according to any preceding statement wherein the starting dose is about 140 to 160 μg/kg, such as 150 μg/kg.

[0766] 23. The method according to any preceding statement wherein the starting dose is at least 200 μg/kg.

[0767] 24. The method according to any preceding statement wherein the starting dose is about 200 μg/kg.

[0768] 25. The method according to any preceding statement wherein the reduced dose is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, or 300 μg/kg.

[0769] 26. The method according to any preceding statement wherein the reduced dose is 1 to 10 μg/kg, 11 to 20 μg/kg, 21 to 30 μg/kg, 31 to 40 μg/kg, 41 to 50 μg/kg, 51 to 60 μg/kg, 61 to 70 μg/kg, 71 to 80 μg/kg, 81 to 90 μg/kg, 91 to 100 μg/kg, 101 to 120 μg/kg, 121 to 140 μg/kg, 141 to 160 μg/kg, 161 to 180 μg/kg, 181 to 200 μg/kg, 201 to 220 μg/kg, 221 to 240 μg/kg, 241 to 260 μg/kg, 261 to 280 μg/kg, or 281 to 300 μg/kg.

[0770] 27. The method according to any preceding statement wherein the reduced dose is 15 to 35 μg/kg, such as about 20 μg/kg or about 30 μg/kg.

[0771] 28. The method according to any preceding statement wherein the reduced dose is 25 to 35 μg/kg, such as about 30 μg/kg.

[0772] 29. The method according to any preceding statement wherein the reduced dose is 35 to 45 μg/kg, such as about 40 μg/kg.

[0773] 30. The method according to any preceding statement wherein the reduced dose is 45 to 55 μg/kg, such as about 50 μg/kg.

[0774] 31. The method according to any preceding statement wherein the reduced dose is 55 to 65 μg/kg, such as about 60 μg/kg.

[0775] 32. The method according to any preceding statement wherein the reduced dose is about 60 μg/kg.

[0776] 33. The method according to any preceding statement wherein the reduced dose is about 70 to 80 μg/kg, such as 75 μg/kg.

[0777] 34. The method according to any preceding statement wherein each treatment cycle is the same length.

[0778] 35. The method according to statement 34, wherein each treatment cycle is 3 weeks.

[0779] 36. The method according to statement 35, wherein about 140 to 160 μg/kg of CD25-ADC are administered for two, 3-week treatment cycles, [0780] followed by subsequent 3-week cycles of 70 to 80 μg/kg beginning 3 weeks after the cycle 2 administration.

[0781] 37. The method according to statement 36, wherein about 150 μg/kg of CD25−ADC are administered for two, 3-week treatment cycles, followed by subsequent 3-week cycles of 75 μg/kg beginning 3 weeks after the cycle 2 administration.

[0782] 38. The method according to statement 35, wherein about 40 to 50 μg/kg of CD25−ADC are administered for three, 3-week treatment cycles, followed by subsequent 3-week cycles of 25 to 35 μg/kg beginning 3 weeks after the cycle 3 administration.

[0783] 37. The method according to statement 38, wherein about 45 μg/kg of CD25−ADC are administered for three, 3-week treatment cycles, [0784] followed by subsequent 3-week cycles of 30 μg/kg beginning 3 weeks after the cycle 3 administration.

[0785] 38. The method according to statement 34, wherein each treatment cycle is 6 weeks.

[0786] 39. The method according to statement 38, wherein about 200 μg/kg of CD25−ADC are administered for two, 6-week treatment cycles, [0787] followed by subsequent 6-week cycles of 60 μg/kg beginning 6 weeks after the cycle 2 administration.

[0788] 40. The method according to statement 38, wherein about 200 μg/kg of CD25−ADC are administered for one, 6-week treatment cycle, [0789] followed by subsequent 6-week cycles of 60 μg/kg beginning 6 weeks after the cycle 1 administration.

[0790] 41. The method according to any one of statements 1 to 33, wherein the treatment cycle length is increased no more than twice during the dosage regime.

[0791] 42. The method according to any one of statements 1 to 33 or 41, wherein the treatment cycle length is increased no more than once during the dosage regime.

[0792] 43. The method according to any one of statements 1 to 33 or 41 to 42, wherein the treatment cycle length is increased following the first treatment cycle.

[0793] 44. The method according to any one of statements 1 to 33 or 41 to 43, wherein the treatment cycle length is increased following the second treatment cycle.

[0794] 45. The method according to any one of statements 1 to 33 or 41 to 44, wherein the cycle length is increased only if the subject has attained at least Stable Disease [SD] at the end of the preceding treatment cycle.

[0795] 46. The method according to any one of statements 1 to 33 or 41 to 45, wherein ‘Day 1’ of the first treatment cycle of increased length is delayed so that the time elapsed between ‘Day 1’ of the final shorter treatment cycle and ‘Day 1’ of the first treatment cycle of increased length is equal in length to the increased treatment cycle.

[0796] 47. The method according to any one of statements 1 to 33 or 41 to 46, wherein the starting length is 3 weeks.

[0797] 48. The method according to any one of statements 1 to 33 or 41 to 47, wherein the increased length is 6 weeks.

[0798] 49. The method according to statement 48, wherein about 150 μg/kg of CD25−ADC are administered for two, 3-week treatment cycles, [0799] followed by subsequent 6-week cycles of 60 μg/kg beginning 6 weeks after the cycle 2 administration.

[0800] 50. The method according to statement 48, wherein about 120 μg/kg of CD25−ADC are administered for two, 3-week treatment cycles, [0801] followed by subsequent 6-week cycles of 60 μg/kg beginning 6 weeks after the cycle 2 administration.

[0802] 51. The method according to any preceding statement, wherein the CD25−ADC is administered as a single dose.

[0803] 52. The method according to any preceding statement, wherein the dose of CD25−ADC is administered on Day 1 of the treatment cycle.

[0804] 53. The method according to any preceding statement wherein the proliferative disease is characterised by the presence of a neoplasm comprising CD25+ve cells

[0805] 54. The method according to any preceding statement wherein the subject has been diagnosed as having the proliferative disease prior to the start of treatment with the CD25-ADC.

[0806] 55. The method according to any preceding statement wherein the method comprises the step of selecting a subject for treatment based on expression of CD25.

[0807] 56. The method according to statement 57, wherein a subject is selected if at least 5% of neoplasm cells express CD25.

[0808] 57. The method according to any preceding statement wherein the proliferative disease is lymphoma.

[0809] 58. The method according to statement 57 wherein the proliferative disease is Hodgkin's lymphoma.

[0810] 59. The method according to statement 57, wherein the lymphoma is Non-Hodgkin Lymphoma (NHL).

[0811] 60. The method according to statement 59, wherein the non-Hodgkin's lymphoma is either: [0812] (a) a B-cell lineage lymphoma such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL); or [0813] (b) a T-cell lineage lymphoma, such as Extranodal T cell lymphoma, Cutaneous T-cell lymphomas (Sezary syndrome and Mycosis fungoides), Anaplastic large cell lymphoma, T-cell lymphoblastic lymphoma, including acute T-cell lymphoblastic lymphoma (ATLL), and Angioimmunoblastic T-cell lymphoma.

[0814] 61. The method according to statement 59, wherein the non-Hodgkin's lymphoma is acute T-cell lymphoblastic lymphoma (ATLL).

[0815] 62. The method according to statement 59, wherein the non-Hodgkin's lymphoma is a T-cell lineage lymphoma.

[0816] 63. The method according to any one of statements 1 to 56 wherein the proliferative disease is a T-cell lineage leukaemia, such as Large granular lymphocytic leukaemia, adult T-cell leukaemia, or T-cell prolymphocytic leukaemia.

[0817] 64. The method according to any preceding statement wherein the proliferative disease is resistant, relapsed or refractory.

[0818] 65. The method according to any preceding statement wherein the subject is human.

[0819] 66. The method according to any preceding statement wherein the CD25−ADC is administered intravenously.

[0820] 67. The method according to any preceding statement, further comprising administering a chemotherapeutic agent in combination with the CD25−ADC; optionally wherein the chemoptherpeutic agent is inotuzumab ozogamicin, inotuzumab SGN-CD33A, or a checkpoint inhibitor, such as ibrutinib and durvalumab.

[0821] 68. The method according to statement 67, wherein the chemotherapeutic agent is administered to the subject before, at the same time, or after the CD25−ADC.

[0822] 69. The method according to any preceding statement, wherein the CD25−ADC is administered in combination with a steroid.

[0823] 70. The method according to statement 69, wherein a first dose of steroid is administered on the same day as the ADC.

[0824] 71. The method according to statement 60, wherein the first dose of steroid is administered at least 2 hours before the ADC.

[0825] 72. The method according to either one of statements 69 or 70, wherein a second dose of steroid is administered the day after the ADC.

[0826] 73. The method according to statement 69, wherein a first dose of steroid is administered the day before the ADC.

[0827] 74. The method according to statement 73, wherein a second dose of steroid is administered on the same day as the ADC.

[0828] 75. The method according to statement 74, wherein the second dose of steroid is administered at least 2 hours before the ADC.

[0829] 76. The method according to either one of statements 74 or 75, wherein a third dose of steroid is administered the day after the ADC.

[0830] 77. The method according to any one of statements 69 to 76, wherein the steroid or steroid doses are administered only in conjunction with the first administration of ADC in each treatment cycle.

[0831] 78. The method according to any one of statements 69 to 77, wherein the steroid is administered orally.

[0832] 79. The method according to any one of statements 69 to 78, wherein each dose of steroid is 8 mg.

[0833] 80. The method according to any one of statements 69 to 79, wherein each dose of steroid is 16 mg.

[0834] 81. The method according to any one of statements 69 to 80, wherein each dose of steroid is administered as two equal, partial doses.

[0835] 82. The method according to any one of statements 69 to 81, wherein each partial dose is 4 mg.

[0836] 83. The method according to any one of statements 69 to 82, wherein each partial dose is 8 mg.

[0837] 84. The method according to any one of statements 69 to 83, wherein the steroid is dexamethasone.

[0838] 85. The method according to statement 69, wherein 4 mg or 8 mg dexamethasone is administered orally twice daily: (i) the day before ADC administration on week 1, day 1 of the treatment cycle, (ii) the day of ADC administration on week 1, day 1 of the treatment cycle, and (iii) the day after ADC administration on week 1, day 1 of the treatment cycle.

[0839] 86. The method according to statement 69, wherein 4 mg or 8 mg dexamethasone is administered orally twice daily: (i) the day of ADC administration on week 1, day 1 of the treatment cycle, and (ii) the day after ADC administration on week 1, day 1 of the treatment cycle.

[0840] 87. The method according to either one of statements 85 and 86, wherein the dexamethasone administered on the same day as the ADC is administered at least two hours before the ADC.

[0841] 88. The method according to any one of statements 85 to 87, wherein the dexamethasone is administered only in conjunction with the first administration of ADC in each treatment cycle.

[0842] 89. The method according to any preceding statement wherein the tapered and/or elongated dosage regime has lower toxicity than a single-dose dosage regime a dosage regime having constant dosage level and cycle length, optionally wherein the constant dose level and cycle length of the comparator regime is the same as the starting dose and starting length of the tapered and/or elongated regime.

[0843] 90. The method according to statement 89, wherein the the incidence of TEAE with the tapered and/or elongated dosage regime is no more than 50% of the incidence of TEAE in the constant dose level and cycle length regime.

[0844] 91. The method according to statement 90, wherein the incidence of SAE with the tapered and/or elongated dosage regime is no more than 50% of the incidence of SAE in the constant dose level and cycle length regime.

[0845] 92 The method according to statement 89, wherein the incidence of DLT with the tapered and/or elongated dosage regime is no more than 50% of the incidence of DLT in the constant dose level and cycle length regime.

[0846] 93. The method according to any preceding statement wherein the tapered and/or elongated dosage regime has greater efficacy than a dosage regime having constant dosage level and cycle length, optionally wherein the constant dose level and cycle length of the comparator regime is the same as the starting dose and starting length of the tapered and/or elongated regime.

[0847] 94. The method according to statement 93, wherein the proportion of subjects achieving at least PR with the tapered and/or elongated dosage regime is at least 150% of the proportion of subjects achieving at least a partial response [PR] in the constant dose level and cycle length regime.

[0848] 95. The method according to any preceding statement, wherein the subject undergoes a neurological examination prior to treatment with the ADC.

[0849] 96. The method according to any preceding statement, wherein the subject undergoes a neurological examination after administration of the ADC.

[0850] 97. The method according to any preceding statement, wherein the subject undergoes a neurological examination after each administration of the ADC.

[0851] 98. The method according to any preceding statement, wherein the subject undergoes a neurological examination if they experience a neurologic toxicity following administration of the ADC.

[0852] 99. The method according to any one of statements 95 to 98, wherein the neurological examination includes tests of strength, sensation, and/or deep-tendon reflexes.

[0853] 100. The method according to any preceding statement, wherein treatment with the ADC is reduced, suspended, or permanently discontinued if the subject has a neurological disorder or experiences a neurologic toxicity.

[0854] 101. The method according to any preceding statement, wherein treatment with the ADC is reduced or suspended if the subject experiences a grade 1 neurologic toxicity.

[0855] 102. The method according to any preceding statement, wherein treatment with the ADC is permanently discontinued if the subject experiences a grade 2 neurologic toxicity.

[0856] 103. The method according to any one of statements 100 to 102, wherein treatment with the ADC is reduced by reducing the dose of ADC that is administered to the subject in each subsequent treatment cycle, and/or by increasing the length of each subsequent treatment cycle.

[0857] 104. A method of selecting a subject for treatment by a method according to any one of statements 1 to 103, which method comprises determining if the subject has, or recently had, a neurologic disorder, wherein the subject is determined to be not suitable for treatment with the ADC if they have, or have recently had, a neurologic disorder.

[0858] 105. A method of selecting a subject for treatment by a method according to any one of statements 1 to 103, which method comprises determining if the subject has, or recently had, an infection caused by a pathogen that may be associated with neurologic and/or immune-related disease; wherein the subject is determined to be not suitable for treatment with the ADC if they have, or have recently had, such an infection and/or immune-related disease.

[0859] 106. The method according to any one of statements 98 to 105, wherein the neurologic disorder or neurological toxicity is polyradiculopathy, acute inflammatory demyelinating (AIDP), Guillain-Barre syndrome (GBS), myasthenia gravis, or a neurologic disorder that is linked to or is an early indicator of polyradiculitis, GBS, or myasthenia gravis, such as ascending sensory loss and/or motor weakness.

[0860] 107. The method according to any one of statements 98 to 105, wherein the neurologic disorder or neurological toxicity is Guillain-Barre syndrome (GBS).

[0861] 108. A method of reducing the toxicity and/or side effects associated with administration of a CD25−ADC to a subject, the method comprising administering the CD25−ADC according to the method of any preceding statement.

[0862] 109. A method of increasing the treatment efficacy associated with administration of a CD25−ADC to a subject, the method comprising administering the CD25−ADC according to the method of any preceding statement.

[0863] 110. A method of selecting a subject for treatment by a method according to any one of statements 1 to 107, which method comprises selecting for treatment subjects that express CD25 in a tissue of interest.

[0864] 111. The method according to statement 110 wherein subjects are selected if at least 5% of cells in a sample of the tissue of interest express CD25.

[0865] 112. The method according to either one of statements 110 and 101 wherein the tissue of interest is lymphoid tissue or tumour tissue.

[0866] 113. The method according to any one of statements 110 to 112, wherein the subject has experienced a DLT in a constant dose and or constant cycle length dosage regime of a CD25−ADC.

[0867] 114. A packaged pharmaceutical product comprising a CD25−ADC as defined in any one of statements 1 to 5, in combination with a label or insert advising that the CD25−ADC should be administered according to the method of any one of statements 1 to 113.

[0868] 115. A kit comprising: [0869] a first medicament comprising a CD25−ADC as defined in any one of statements 1 to 5; and, optionally, [0870] a package insert or label comprising instructions for administration of the CD25−ADC according to the method of any one of statements 1 to 113.

[0871] 116. A CD25−ADC as defined in any one of statements 1 to 5 for use in a method of any one of statements 1 to 113.

[0872] 117. A pharmaceutical composition comprising a CD25−ADC as defined in any one of statements 1 to 5, optionally in combination with a pharmaceutically acceptable excipient, for use in a method of any one of statements 1 to 113.

[0873] 118. Use of a CD25−ADC as defined in any one of statements 1 to 5 in the preparation of a medicament for use in a method of any one of statements 1 to 113.

EXAMPLES

Example 1: Efficacy of ADCx25 Treatment in Mouse Xenograft in Vivo Model

[0874] Subcutaeneous Karpas-e007 Model

[0875] Female severe combined immunodeficient mice (Fox Chase SCID®, C.B-17/lcr-Prkdcscid, Charles River) were eight weeks old with a body weight (BW) range of 16.5 to 21.3 grams on Day 1 of the study.

[0876] On the day of tumor implant, each test mouse received 1×107 Karpas-299 cells (0.1 mL cell suspension in PBS) implanted subcutaneously in the right flank. Tumor growth was monitored as the average size approached the target range of 100 to 150 mm3. Twelve days after tumor implantation, designated as Day 1 of the study, the animals were sorted into groups, each consisting of ten mice, with individual tumor volumes of 88 to 196 mm3 and group mean tumor volumes of 122 to 137 mm3. Tumors were measured in two dimensions using calipers, and volume was calculated using the formula:

Tumor Volume (mm3)=w2×l/2

[0877] where w=width and l=length, in mm, of the tumor. Tumor weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumor volume.

[0878] All treatments were administered intraveneously (i.v.). The dosing volume was 0.2 mL per 20 grams of body weight (10 mL/kg), and was scaled to the body weight of each individual animal. Tumors were measured using calipers twice per week, and each animal was euthanized when its tumor reached the endpoint volume of 2000 mm3 or at the end of the study (Day 63), whichever came first.

[0879] In one group of animals, 0.6 mg/kg ADCx25 was administered as a single dose on day 1 (qd×1).

[0880] In the other group, the same dose of ADCx25 was administered as 3 fractionated doses i.e. 3 doses each of 0.2 mg/kg at 1 week intervals (qwk×3).

[0881] It was observed that in the group receiving the fractionated dose, tumour size grew steadily throughout the study. In contrast, the group receiving the single dose on day 1 showed no significant tumour mass until ˜ day 30 (see FIG. 2).

[0882] Systemic Karpas299-e008 Model

[0883] Female severe combined immunodeficient mice (Fox Chase SCID®, C.B-17/lcr-Prkdcscid, Charles River) were eight weeks old with a body weight (BW) range of 15.5 to 23.6 grams on Day 1 of the study.

[0884] On the day of tumor implantation, Karpas 299 cells were harvested during mid-log phase growth and resuspended in PBS. The mice each received 1×107 cells (0.2 mL cell suspension) via a bolus tail vein injection. Twelve days after tumor cell injection, the mice were randomized into nine groups (n=10/group) and dosing was initiated. The first day of dosing was designated as Day 1 of the study. Each ADC and the PBS vehicle were administered intraveneously (i.v.). The dosing volume of 0.2 mL/20 g mouse (10 mL/kg) was scaled to the last recorded weight of each animal.

[0885] The study endpoint was death or moribundity due to disseminated Karpas 299 lymphoma progression.

[0886] Animals were weighed twice weekly for the duration of the study, starting on Day 1, and were frequently examined for overt signs of tumor progression such as ocular proptosis and loss of hind limb function.

[0887] Animals were euthanized if they were unable to ambulate or were moribund. Each animal found dead, or euthanized, because of tumor progression was recorded as a death on survival study (DSS). The day of death or euthanasia represented the time to endpoint (TTE). Animals that did not reach the endpoint were euthanized at the end of the study, and assigned a TTE value equal to the last day (63 days).

[0888] In one group of animals, 0.6 mg/kg ADCx25 was administered as a single dose on day 1 (qd×1).

[0889] In two other groups, the same dose of ADCx25 was administered as 3 fractionated doses i.e. 3 doses each of 0.2 mg/kg. In one group the doses were administered at 1 week intervals (qwk×3), in the second group the doses were administered at 4-day intervals (day 1, 5, 9).

[0890] It was observed that in both groups receiving the fractionated dose, mortality rates were higher and occurred sooner in the study, with the effect more pronounced in the weekly dosing than the 4-day dosing (see FIG. 3).

Example 2: Myeloblast Count of AML Patients

[0891] ADCx25 was administered to 25 patients with relapsed or refractory CD25+ acute myeloid leukemia (AML) comprising 8 dose cohorts (3, 6, 12, 22, 32, 52, 72, and 92 μg/kg), using a 3-week treatment cycle with a single-dose administered on day 1.

[0892] Two patients were observed to have transient significant decrease in their peripheral myeloblast count (>70% to 2% in one patient and 38 to 1% in the other) but the percentage of myeloblasts in the peripheral blood increased prior to the scheduled subsequent dose (three-week intervals between doses). No dose-limiting toxicities (DLTs) or significant toxicities were reported.

[0893] The full clinical study protocol for the 3-week treatment cycle with a single-dose administered on day 1 is publically available at www.clinical trials.gov, having the ClinicalTrials.gov unique identifier: NCT02588092 (27 Apr. 2017 update).

Example 3: Pharmokinetics of ADCx25

[0894] Preliminary pharmacokinetic (PK) information was obtained from 12 patients on a 3-week treatment cycle with a single-dose administered on day 1 (3 patients each at 6, 12, 22 and 32 μg/kg). Collection of data was done in the standard manner (see full clinical study protocol NCT02588092 referenced above for more details).

[0895] The data suggests that peak exposure is dose-related. ADCx25 is rapidly cleared, with concentrations less than the lower limit of quantification for most patients through the 22 μg/kg dose group by Day 7.

Example 4: Synopsis of Fractionated Dosage Protocol

[0896] Indication

[0897] Patients with relapsed or refractory cluster of differentiation 25 (CD25)-positive acute myeloid leukemia (AML) or CD25-positive acute lymphoblastic leukemia (ALL) who have failed, or are intolerant to, any established therapy known to provide clinical benefit at current state of disease. Patients with myelodysplastic syndrome who have received treatment with hypomethylating agents and subsequently present with CD25+ AML and who failed, or are ineligible for standard induction therapy, are eligible for treatment with ADCx25.

[0898] Objectives

[0899] Primary Objectives:

[0900] The primary objectives for Part 1 (dose-escalation) and Part 2 (expansion) of the study are: [0901] Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of ADCX25 in patients with CD25-positive relapsed or refractory AML and CD25-positive ALL (Part 1). [0902] Determine the recommended dose of ADCX25 for Part 2. [0903] Evaluate the safety and tolerability of ADCX25 in Part 2 at the dose level recommended in Part 1.

[0904] Secondary Objectives:

[0905] The secondary objectives for Part 1 and Part 2 of the study are: [0906] Evaluate the clinical activity of ADCX25, based on the patient's response to treatment (complete response [CR], CR with incomplete blood count recover [CRi], partial response [PR], progressive disease [PD], no response [NR]) and determination of the overall duration of response (DOR), overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). [0907] Characterize the pharmacokinetic (PK) profile of ADCX25 (total antibody, drug-to-antibody ratio [DAR]>0), PBD-conjugated antibody (DAR >1), and free warhead SG3199. [0908] Evaluate anti-drug antibodies (ADAs) to ADCX25 in blood before, during, and after treatment with ADCX25.

[0909] Efficacy Assessment

[0910] Assessment of response to treatment with ADCX25 will be based on bone marrow samples (aspirate or biopsy, if aspirate unattainable). The activity of ADCX25 will be evaluated based on the Investigator's evaluation of the patient's response to ADCX25 as CR, CRi, PR, PD, or NR as defined herein.

[0911] PK Assessment

[0912] The PK profile of ADCX25 (total antibody; drug-to-antibody ratio [DAR]>0), PBD-conjugated antibody (DAR >1), and free warhead will be assessed. Additional PK, ADA, cytokines, and serum CD25 (sCD25); blood samples will be collected at the discretion of the Investigator during any visit where toxicity is observed. A PK, ADA, cytokines, and sCD25 sample will also be collected concurrently with any other blood draw to assess safety (e.g., Unscheduled Visit), if possible. The PK profile will include determination of standard PK parameters (e.g., maximum concentration [Cmax], time to Cmax [Tmax], AUC0-last, AUC0-T, AUC0-∞, AI, Vss, MRT, Az, t½, CL, and Vz.).

[0913] Safety Assessment

[0914] Safety will be assessed based on AEs, serious AEs (SAEs), treatment discontinuations due to AEs, DLTs (as defined herein) measurements of cytokines in serum, periodic 12-lead electrocardiogram (ECG) recordings, physical examinations, vital signs measurements, ECOG performance status, and hematology, biochemistry, coagulation panel, pregnancy testing (for women of child-bearing potential) and urinalysis test results. Adverse events will be graded according to CTCAE Version 4.0 (v4.03, published Jun. 14, 2010; NIH Publication No. 09-5410).

[0915] Product Dosage and Mode of Administration

[0916] ADCX25 is a sterile formulation containing PBD-conjugated HuMax®-TAC (DAR >1), HuMax®-TAC (DAR=0), and SG3249. It is provided pre-formulated in 10-mL glass vials containing approximately 30 mg of ADCX25 per vial (deliverable volume 5.4 mL at 6 mg/mL). The appropriate quantity of ADCX25 will be diluted in 50 mL of 5% dextrose in water (D5W).

[0917] Patients will receive a 1-hour intravenous (IV) infusion of ADCX25 on Day 1 of Cycle 1. If ADCX25 is well tolerated after the first infusion, the infusion duration may be shortened to 30 minutes for subsequent cycles for that patient, at the Investigator's discretion.

[0918] The investigational product administration schedule is as follows:

[0919] Patients will be given ADCX25 (weekly [QW]) on Days 1, 8, and 15 of each 3-week (21-day) treatment cycle.

[0920] A patient will maintain the same treatment schedule throughout the duration of the trial.

[0921] Once a patient achieves CR/CRi, frequency or dose may be adjusted by the DESC based on emerging safety, efficacy, and PK profile.

[0922] The trial will be continuously monitored for emerging safety, efficacy and/or PK profile, and the DESC will determine if it is appropriate to maintain a QW schedule, revert to an every 3-week (Q3W) schedule, or test other dosing regimens.

[0923] Dose Escalation Design

[0924] Dose-escalation (Part 1) will be conducted according to a 3+3 design. The initial dose of ADCX25 will be 3 μg/kg (Dose Level 1), and the highest allowed dose will be 300 μg/kg.

[0925] The DLT observation period for dose-escalation will be 1 cycle. The first patient at each new dose level must be observed for 7 days for occurrence of AEs prior to treating the second patient at that dose level. Patients will be entered sequentially to each dose level.

[0926] For each dose level, if none of the first 3 patients at that level experiences a DLT, new patients may be entered at the next higher dose level. If 1 of 3 patients experiences a DLT, up to 3 more patients are to be treated at that same dose level. If none of the additional 3 patients at that dose level experiences a DLT, new patients may then be entered at the next higher dose level. However, if 1 or more of the additional 3 patients experience a DLT, then no further patients are to be started at that dose level and the preceding dose is identified as the MTD. The MTD; therefore, is defined as the highest dose level at which none of the first 3 treated patients, or no more than 1 of the first 6 treated patients, experiences a DLT.

[0927] No intra-patient dose-escalation is allowed.

[0928] The number of dose levels will depend on the emergent toxicity profile of ADCX25 and will be decided by the DESC; PK and PD evaluations may also inform decision making. During Part 1 (dose-escalation), the DESC may expand enrolment at doses below the current dose level as part of the dose-escalation process.

[0929] Additional patients may only be added at a lower dose level provided there is at least 1 patient who has achieved a PR or better (Section 7.1). No more than 10 patients in total can be treated at any dose level unless >3 of the 10 patients have achieved a PR or better.

[0930] Patients will be given ADCX25 (QW) on Days 1, 8 and 15 of each 3-week treatment cycle.

[0931] The first dose level for the weekly fractionated dosage regime/3 week treatment cycle (QW) dosing will be based on the safety and tolerability of patients who have been treated on the single dose/3-week treatment cycle schedule(Q3W). The first 3 patients will be given a cumulative dose each cycle that is comparable to (but not higher than) the highest dose tested at the Q3W dose schedule at which 3 patients completed the DLT observation period without a DLT. For example, if the highest Q3W dose tested at which 3 patients did not experience a DLT was cohort 92 μg/kg, the first cohort to receive QW dosing will receive 30 μg/kg each week for 3 weeks.

[0932] When the dose is escalated, the dose may increase by 50% if no DLTs are observed at the current level. Once a DLT is observed at a given dose level, the next dose may only increase by 25%. The dose may never increase by more than 50%, or more than an absolute value of 20 μg/kg/week, whichever is less. During Part 1, the DESC may expand enrolment at doses below the current dose level as part of the dose-escalation process. Additional patients may only be added at a lower dose level provided there is at least 1 patient who has achieved a partial response (PR or better). No more than 10 patients in total can be treated at any dose level unless >3 of the 10 patients have achieved a PR or better.

[0933] During Part 2 (dose expansion), patients will be monitored for safety using the same DLT criteria employed during dose-escalation. If during the treatment period, >30% of patients experience safety events that would meet the criteria that define a DLT in the dose-escalation phase of the study, enrolment in the expansion cohort(s) may be paused and the study data reviewed to determine whether additional monitoring or other action (such as alternate dose levels) should be evaluated prior to further enrolment.

[0934] A maximum of 80 patients (up to 50 patients in Part 1 and up to 30 patients in Part 2) may be enrolled at approximately 10 study sites in Part 1 and 10 study sites in Part 2.

Example 5: Summary of ADCx25 Treatment Safety and Efficacy Studies

[0935] Study Design

[0936] Phase 1, open-label, multicenter dose-escalation (part 1) and dose-expansion (part 2) study in patients with R/R CD25+ AML or ALL.

[0937] Patients receive ADCx25 as an intravenous (IV) infusion with a starting dose cohort at 3 μg/kg every 3 weeks (q3w).

[0938] In part 1, patients are assigned to treatment using a 3+3 dose-escalation design, based on assessment of dose-limiting toxicities (DLTs) during Cycle 1, to determine the MTD.

[0939] Dose frequency in subsequent cohorts may increase to once weekly (qw) based on emerging safety, efficacy, and PK profile.

[0940] Part 2 will further evaluate safety, tolerability, PK, and clinical activity at the dose recommended from part 1.

TABLE-US-00006 Key patient inclusion criteria Key patient exclusion criteria Age 18 years or older Active graft-versus-host disease Histologically confirmed relapsed or Evidence of myelodysplasia or myeloid refractory lymphoma, including stage ≥lb leukemia cutaneous T-cell lymphoma Failed, or intolerant to, any established Known history of positive serum human anti- therapy known to provide clinical benefit at drug antibody, or known allergy to any current state of disease component of ADCx25 Eastern Cooperative Oncology Group History of symptomatic autoimmune disease performance status 0 to 2 WBC count <15,000 cells/μL prior to Cycle 1, Major surgery, chemotherapy, systemic Day 1. Patients with WBC >15,000 cells/uL therapy, or radiotherapy within 14 days prior could receive hydroxyurea to lower WBC to Day 1 treatment count. Autologous or allogenic transplant within the 60 days prior to screening

[0941] Results

[0942] Patient Characteristics

[0943] As of Oct. 31, 2017, 33 patients have been treated with ADCx25. Baseline CD25 expression was present in 5% to 100% of local blast cells.

[0944] Safety Data

[0945] No DLTs were observed up to the highest evaluated q3w dose of 92 μg/kg.

[0946] Upon switching to weekly dosing, one DLT (maculopapular rash) was reported in the 30 μg/kg dose group.

[0947] During exposure, a total of 391 treatment-emergent adverse events (TEAEs) were reported in 31/33 (94%) patients.

[0948] Most common TEAEs were fatigue (n=10) and nausea (n=8) followed by febrile neutropenia and pneumonia (both n=7).

[0949] A summary of Grade >3 TEAEs that occurred in >10% patients are presented in the table below.

[0950] Summary of Grade >3 Treatment-Emergent Adverse Events (TEAEs):

TABLE-US-00007 Dose Escalation q3w qw 3 6 12 22 32 52 72 92 30 37.5 Total μg/kg μg/kg μg/kg μg/kg μg/kg μg/kg μg/kg μg/kg μg/kg μg/kg N = 33 N = 4 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 4 N = 6 N = 1 (%) Any TEAE for 1 2 3 3 3 3 3 3 6 0 27 Grade ≥3 (81.8) Febrile 0 0 2 0 1 0 1 0 3 0 7 neutropenia (21.2) Thrombocytopenia 0 0 1 1 0 0 1 0 2 0 5 (15.2) Fatigue 0 0 0 1 0 1 1 1 0 0 4 (12.1) Neutrophil count 0 1 0 0 0 1 1 0 1 0 4 decreased (12.1) Pneumonia 0 1 1 0 0 0 1 0 1 0 4 (12.1)

[0951] Grade ≥3 TEAEs were reported by 27/33 (81.8%) patients

[0952] Eight deaths from TEAEs were recorded (disease progression and AML [both n=3], and cardiac arrest and pneumonia [both n=1]). One case each of increased QTc and palpitations was evaluated to be infusion-related by the investigator. Four patients experienced TEAEs leading to a dose delay or reduction (2 cases of skin rash, 1 case each of pericarditis and supraventricular tachycardia). Three patients discontinued treatment due to Grade 2 and 3 skin rash (1 and 2 cases, respectively) and 1 patient due to Grade 3 gamma-glutamyltransferase increase. In 6 patients who underwent prior allogeneic stem cell transplantation, no cases of graft-versus-host disease were observed.

[0953] In a separate study of ADCx25 in patients with Hodgkin lymphoma, there have been 2 reports of Guillain-Barre syndrome and 1 report of polyradiculopathy. To date, no such cases have been observed in patients with leukemia treated with ADCx25.

[0954] Efficacy Data

[0955] One patient had complete response with incomplete blood count recovery.

[0956] Transient CD25+ blast clearance in 2 patients who received 2 and 7 cycles, respectively, of ADCx25 32 μg/kg q3w, was observed, supporting on-target activity of ADCx25. One patient had 6.25% CD25+ blasts in the marrow prior to Cycle 1, which was reduced to 0% after 2 cycles of ADCx25, despite overall disease progression.

[0957] A Second Patient had 10% CD25+ Blasts in the Marrow Prior to Cycle 1, which was Reduced to 0% after 2 cycles, with a total marrow blast count of 5%. CD25+ blasts remained at 0% until after cycle 7 when the patient had disease progression with CD25+ blasts.

[0958] PK data

[0959] PK data show increasing concentrations of PBD-conjugated antibody with dose (see FIG. 4).

[0960] No drug accumulation is apparent with a q3w regimen. Rapid systemic clearance of the drug with levels below limit of quantitation suggests that q3w dosing may be insufficient for therapeutic efficacy.

[0961] Conclusions

[0962] In this ongoing Phase 1 study in patients with CD25+R/R AML or ALL, single-agent ADCx25 has shown an acceptable safety profile thus far.

[0963] The study is continuing to explore the safety profile of weekly dosing.

Example 6: Pharmokinetics of ADC in Patients

[0964] At least one dose of ADC was administered to 48 patients with Relapsed or Refractory Non Hodgkin Lymphoma (4 at 15 μg/kg, 4 at 30 μg/kg, 4 at 60 μg/kg, 5 at 90 μg/kg, 12 at 120 μg/kg, 3 at 150 μg/kg and 17 at 200 μg/kg). Cohorts at 120 μg/kg and 200 μg/kg were expanded to further explore the early efficacy signals seen at those dose levels.

[0965] Emerging safety, pharmacokinetic and efficacy data suggest that repetitive dosing every three weeks is not well tolerated or necessary at doses of 120 μg/kg and higher. Twelve patients have been treated at 120 μg/kg (10 DLBCL, 1 FL and 1 MCL) with 4 patients attaining complete remission (CR) and 2 partial remission (PR). The 6 responding patients have received 3-7 infusions of ADC with 4 of these patients having at least one dose delay due to adverse events (fatigue (2), edema (3), muscle pain (2), rash (1), Elevated GGT and alkaline phosphatase (1)). Two patients were discontinued from treatment due to adverse events in this cohort (both had attained CR).

[0966] At 150 μg/kg, the three initial patients received either 2 or 3 cycles of ADCT before side effects necessitated dose delay which eventually led to removal from the study since the toxicities were slow to resolve.

[0967] The first six evaluable patients treated on the 200 μg/kg cohort with dose administered every three weeks attained CR(5) or PR(1) on first restaging scans at the end of Cycle 2 (after second dose). However, all patients had some evidence of toxicity at the end of Cycle 2 (4 patients) or cycle 3 (1 patient). The pharmacokinetic profiles for the first two cycles for the initial 3 patients treated on the 200 μg/kg cohort indicated that the AUC and Cmax at the 200 μg/kg dose level are significantly higher than seen at lower doses. The trough levels at the end of Cycle 1 appear to be in the range of 500-1000 ng/ml.

[0968] In view of the emerging safety profile, it is proposed to modify the dosage regimes for future subjects at doses of 120 μg/kg or higher so that they are tapered and/or elongated dosage regimes as described herein. In particular, the following tapered and elongated dosage regimes will be utilised: [0969] A. 120 μg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [0970] B. 150 μg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [0971] C. 200 μg/kg: Dosing every 6 weeks for 2 cycles. For patients with at least SD 6 weeks after Cycle 2, continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [0972] D. 200 μg/kg: Dosing every 6 weeks. For patients with at least SD 6 weeks after Cycle 1, continue treatment at a reduced dose of 60 μg/kg every 6 weeks beginning 6 weeks after Cycle 1 infusion.

[0973] A full clinical study protocol for the 3-week treatment cycle with a single-dose of ADCx25 administered on day 1 is publically available at www.clinical trials.gov, having the ClinicalTrials.gov unique identifier: NCT02432235 (27 Apr. 2017 update).

Example 7: Synopsis of Tapered and/or Elongated Dosage Protocol

[0974] Indication

[0975] Patients with relapsed or refractory non-Hodgkin Lymphoma (NHL) who have failed, or are intolerant to, any established therapy; or for whom no other treatment options are available, in the opinion of the Investigator.

[0976] The Dose Escalation Steering Committee (DESC) will determine which histologic sub-types will be investigated in Part 2 of the study based on the emerging efficacy and tolerability profile from part 1.

[0977] NHL defined as: [0978] Diffuse large B-cell lymphoma (DLBCL) [0979] Follicular lymphoma (FL) [0980] Chronic lymphocytic leukemia (CLL) [0981] Mantle cell lymphoma (MCL) [0982] Marginal Zone B-cell Lymphoma (MZBCL) [0983] Burkitt's lymphoma (BL) [0984] Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]).

[0985] Objectives

[0986] Primary Objectives: [0987] Evaluate the safety and tolerability, and determine, as appropriate, the maximum tolerated dose (MTD) of ADC in patients with relapsed or refractory NHL (Part 1). [0988] Determine the recommended dose(s) of ADC for Part 2 (expansion). [0989] Evaluate the safety and tolerability of ADC in Part 2 (expansion) at the dose level(s) recommended in Part 1.

[0990] Secondary Objectives: [0991] Evaluate the clinical activity of ADC as measured by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). [0992] Characterize the pharmacokinetic (PK) profile of ADC (total antibody; drug to-antibody ratio [DAR]>0), PBD-conjugated antibody (DAR >1), and free warhead. [0993] Evaluate anti-drug antibodies (ADAs) in blood before, during, and after treatment with ADC.

[0994] Efficacy Assessment

[0995] Disease assessments will be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (i.e., Cycles 8, 11, 14, etc.), until disease progression, or more frequently, if clinically indicated. The same methods used at Screening which identify sites of disease should be used uniformly for all subsequent assessments. If PET-CT is positive, subsequent diagnostic CT and MRI are not needed unless clinically indicated. PET-CT is not required if a PET-CT examination at Screening was negative.

[0996] For patients who have reduced dosing frequency and are following a 6 week schedule, disease assessments should occur approximately 6 weeks and 12 weeks after Cycle 1 Day 1, and thereafter at least every 12 weeks. It is understood that there will be a ±6 day window for restaging of these patients.

[0997] The patient's response to treatment will be determined by the Investigator as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), based on the 2014 Lugano Classification Criteria.

[0998] PK Assessment

[0999] The PK profile of ADC (total antibody; DAR >0), PBD-conjugated antibody (DAR >1), and free warhead will be assessed using measures from validated bioanalytical methods. The PK profile will include determination of standard PK parameters (e.g., maximum concentration [Cmax], time to Cmax [Tmax]).

[1000] The following pharmacodynamic and other exploratory assessments will be performed at various time points in the study: [1001] Immunohistochemistry (archival tumor tissue or pre-treatment tumor biopsies in consenting patients) for CD25 protein expression [1002] Level of ADAs against ADC in serum. [1003] Analysis of peripheral WBC populations and CD marker panel expression (CD25, CD20, CD21, CD22), before, during, and after treatment with ADC (US only). [1004] Serum concentrations of ADC and free warhead will be determined. The QTc interval will also be measured.

[1005] Safety Assessment

[1006] Safety will be assessed based on the evaluation of adverse events (AEs), serious AEs (SAEs), treatment discontinuations due to AEs, dose limiting toxicity(s) (DLTs), periodic 12-lead electrocardiogram (ECG) recordings, physical examinations, vital signs measurements, ECOG performance status, and hematology, coagulation panel and pregnancy testing (for women of child-bearing potential), biochemistry, and urinalysis test results obtained at various timepoints during the study. Adverse events will be graded according to CTCAE Version 4.0 (v4.03, published Jun. 14, 2010; NIH Publication No. 09-5410).

[1007] Product Dosage and Mode of Administration

[1008] ADC is a sterile formulation containing PBD-conjugated humanized monoclonal IgG1 antibody (DAR ≥1), humanized monoclonal IgG1 antibody (DAR=0), and drug-linker. It is provided pre-formulated in 10 mL single-use, glass vials containing approximately 16 mg ADC per vial (deliverable volume 3.2 mL, with an additional 0.3 mL overfill at 5 mg/mL). Patients will receive a 1-hour intravenous (IV) infusion of ADC on Day 1 of Cycle 1. If ADC is well tolerated after the first infusion, the infusion duration may be shortened to 30 minutes for subsequent cycles for that patient, at the Investigator's discretion.

[1009] Dose Escalation Design

[1010] In Part 1, patients will be assigned to treatment with ADCx25 at escalating doses according to a 3+3 study design. The initial dose of ADCx25 will be 15 μg/kg (Dose Level 1), and the highest allowed dose will be 300 μg/kg.

[1011] Further dose levels and schedules evaluated include the following: [1012] A. 120 μg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [1013] B. 150 μg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [1014] C. 200 μg/kg: Dosing every 6 weeks for 2 cycles. For patients with at least SD 6 weeks after Cycle 2, continue treatment at a reduced dose of 60 μg/kg q6 weeks, beginning 6 weeks after Cycle 2 infusion. [1015] D. 200 μg/kg: Dosing every 6 weeks. For patients with at least SD 6 weeks after Cycle 1, continue treatment at a reduced dose of 60 μg/kg every 6 weeks beginning 6 weeks after Cycle 1 infusion.

[1016] The first patient enrolled into the study at 15 μg/kg (Dose Level 1) must be observed for 7 days for occurrence of AEs prior to treating the second patient in the study. The DLT observation period for dose escalation is 1 cycle.

[1017] For each dose level, if none of the first 3 patients at that level experiences a DLT, new patients may be entered at the next higher dose level. If 1 of 3 patients experiences a DLT, up to 3 more patients are to be treated at that same dose level. If none of the additional 3 patients at that dose level experiences a DLT, new patients may then be entered at the next higher dose level. However, if 1 or more of the additional 3 patients experiences a DLT, then no further patients are to be started at that dose level and the preceding dose is identified as the MTD. The MTD is therefore defined as the highest dose level at which none of the first 3 treated patients, or no more than 1 of the first 6 treated patients, experiences a DLT.

[1018] The study will be continuously monitored for safety and early stopping for successful identification of the MTD.

[1019] Dose Expansion Design

[1020] In Part 2, (expansion), patients will be assigned to dose level(s) and/or schedule(s) of ADCx25 identified in Part 1 based on evolving safety, efficacy and pharmacokinetic data.

[1021] The population in Part 2 expansion may be restricted to specific histologies based on both signals of activity and the safety observed in Part 1.

[1022] Further, dose levels and schedules evaluated in Part 2 may include the regimes A, B, C. and D as described for Part 1, above.

Example 8: Summary of ADCx25 Treatment Safety and Efficacy Studies

[1023] Study Design

[1024] In this Phase 1, open-label, multicenter study, eligible patients (see table below) with R/R HL or NHL receive 1-hour intravenous infusions of ADCx25 every 3 weeks (=1 treatment cycle).

TABLE-US-00008 Key patient inclusion criteria Key patient exclusion criteria Age 18 years or older Active graft-versus-host disease Histologically confirmed relapsed or Evidence of myelodysplasia or myeloid refractory lymphoma, including stage ≥lb leukemia cutaneous T-cell lymphoma Failed, or intolerant to, any established Known history of positive serum human anti- therapy known to provide clinical benefit at drug antibody, or known allergy to any current state of disease component of ADCx25 Eastern Cooperative Oncology Group History of symptomatic autoimmune disease performance status 0 to 2 Major surgery, chemotherapy, systemic therapy, or radiotherapy within 14 days prior to Day 1 treatment

[1025] In part 1, the initial cohort received a starting dose of 3 μg/kg, with subsequent cohorts enrolled at escalating doses up to a maximum of 300 μg/kg according to a continual reassessment method, which allows expansion at different doses for different lymphoma subtypes.

[1026] The dose-limiting toxicity (DLT) observation period is Cycle 1, with cumulative DLTs occurring through Cycle 3 incorporated into the adaptive dose-escalation algorithm No more than 10 patients can be treated at any dose level unless at least 3/10 patients have documented a partial response or better

[1027] The MTD will be the highest dose that has at least a 60% probability of the DLT rate being <30%.

[1028] Part 2 will further evaluate safety, tolerability, PK.

[1029] Results

[1030] Patient Characteristics

[1031] As of Nov. 1, 2017, 86 patients have been treated with ADCx25.

[1032] Median number of cycles: 2 [min, max: 1, 15], with a median treatment duration of 43 days [min, max: 7, 375]

[1033] 71 patients have been treated with doses ranging from 3 to 150 μg/kg during part 1.15 patients have been treated with dose 45 μg/kg in part 2. Histological subtypes treated include HL, n=50 and NHL, n=36.

[1034] Safety Data

[1035] DLTs have been reported in 4 patients: Oral mucositis and small bowel enteritis at 20 μg/kg, Elevated creatine phosphokinase at 30 μg/kg, Maculopapular rash and pruritus at 30 μg/kg, Lip ulceration and skin infection at 45 μg/kg.

[1036] The most common treatment-emergent adverse events (TEAEs) were fatigue, rash, elevated gamma-glutamyltransferase and pyrexia. The most common Grade 23 TEAEs were elevated gamma-glutamyltransferase, decreased platelet count, elevated alanine aminotransferase, anemia and rash.

[1037] Drug dose was delayed or reduced following a TEAE for 28/86 patients (32.6%). TEAEs leading to treatment discontinuation occurred in 12/86 patients (14.0%). There have been 3 cases of autoimmune neurotoxicity: Two cases of Guillain-Barre syndrome (GBS); one case of polyradiculopathy in a patient with concurrent thyroiditis.

[1038] The MTD has not been reached, but no further dose escalation is planned for patients with HL.

[1039] Any Grade TEAEs (safety analysis set; N=86):

TABLE-US-00009 ADCx25 dose (μg/kg) q3w TEAEs (any grade) reported by ≥20% of ≤30 μg/kg patients, n % (n = 16) 45a(n = 30) 60(n = 20) 80(n = 15) 100(n = 3) 150(n = 2) Total (N = 86) Patients with 15 26 20 15 3 2 81 TEAE (any (93.8) (86.7) (100) (100) (100) (100) (94.2) grade) Fatigue 4 7 9 5 1 0 26 (25.0) (23.3) (45.0) (33.3) (33.3) (30.2) Rash 6 5 7 4 0 0 22 maculopapular (37.5) (16.7) (35.0) (26.7) (25.6) Gamma- 3 4 5 5 1 1 19 glutamyltransferase (18.8) (13.3) (25.0) (33.3) (33.3) (50.0) (22.1) increased Pyrexia 2 5 6 5 0 0 18 (12.5) (16.7) (30.0) (33.3) (20.9)

[1040] Grade≥3 TEAEs (safety analysis set; N=86):

TABLE-US-00010 ADCx25 dose (μg/kg) g3w TEAEs (Grade ≥3) reported by ≥5% of ≤30 μg/kg patients, n (%) (n = 16) 45a(n = 30) 60(n = 20) 80(n = 15) 100(n = 3) 150(n = 2) Total (N = 86) Patients with 10 12 11 13 3 2 51 TEAE Grade (62.5) (40.0) (55.0) (86.7) (100) (100) (59.3) ≥3 Gamma- 2 1 3 4 0 1 11 glutamyltransferase (12.5) (3.3) (15.0) (26.7) (50.0) (12.8) increased Platelet 1 1 2 2 1 1 8 count (6.3) (3.3) (10.0) (13.3) (33.3) (50.0) (9.3) decreased Alanine 0 1 2 1 0 1 5 aminotransferase (3.3) (10.0) (6.7) (50.0) (5.8) increased Anemia 2 1 0 2 0 0 5 (12.5) (3.3) (13.3) (5.8) Rash 4 0 0 1 0 0 5 maculopapular (25.0) (6.7) (5.8)

[1041] Efficacy Data

[1042] Response data for 35 patients with HL give ORR for all doses was 71.4% (25/35 patients).

[1043] 27 patients with HL have been treated with doses >45 μg/kg in part 1, with an ORR of 77.8% (21/27) that comprises a CR rate of 44.4% (12/27) and PR rate of 33.3% (9/27).

[1044] Of the 12 patients with HL who have been treated with dose 45 μg/kg in parts 1 and 2, 6 patients each have achieved a CR or PR, respectively, resulting in an ORR of 100% (12/12).

[1045] In part 1 and 2 at doses >45 μg/kg, a CR or PR was achieved by: [1046] 21/27 patients (77.8%) with prior brentuximab vedotin [1047] 13/18 patients (72.2%) with prior checkpoint inhibitor [1048] 9/14 patients (64.3%) who had prior stem cell transplantation [1049] 4/8 patients (50.0%) who had received all three of the above treatments.

[1050] Median duration of response was 5.1 months.

[1051] Responses were also seen in patients with NHL (all doses; partial response: 18.2% [6/33]; complete response: 6.1% [2/33]).

[1052] Dose escalation will continue for patients with NHL.

[1053] Best overall responses (efficacy analysis set):

TABLE-US-00011 HL NHL Part t Parts 1 & only: 2; Parts 1 & 2: ≥45 μg/kg All doses 45 μg/kg T-cell lymphoma n (%) (n = 27) (n = 35) (n = 12) (n = 12) B-cell lymphoma (n = 21) OR 21 (77.8) 25 (71.4) 12 ( 00) 4 (33.3) 4 (19 9) CR 12 (44.4) 14 (40.0) 6 (50) 0 2 (9 5) PR 9 (33.3) 11 (31.4) 6 (50) 4 (33.3) 2 (9.5) SD 1 (3 7) 4 (1:4) 0 1 (8.3) 0 RD 4 (14.8) 4 (11 4) 0 6 (50.0) 15 (71.4) NE 1 (3.7) 2 (5 71 0 1 (8.3) 2 (9.5)

[1054] Conclusions

[1055] In patients with R/R HL, ADCx25 was active with the safety profile as described during dose escalation and expansion.

[1056] The ORR in this heavily pretreated population is very promising and HL expansion cohorts are underway.

[1057] Dose escalation will continue to identify the MTD in NHL, with planned subtype-specific expansion cohorts at the MTD.

[1058] ADCx25 has shown high levels of activity in HL, T- and B-cell lymphomas.

[1059] Characterization of the dosing regimen is ongoing to maximize the therapeutic window for Phase 2 in HL.

Example 9: Pharmacometric Characterization for Safety of ADCx25 in Patients with Hematologic Malignancies in a Phase 1 Trial

[1060] Aims

[1061] To optimize future studies of ADCx25, the relationship between drug exposure and treatment emergent adverse events (TEAE) was analysed.

[1062] Methods

[1063] Exposure was determined using a population pharmacokinetic (PPK) model of conjugated antibody (cAb) and total antibody (tAb) disposition, comprising shared terms for clearance (linear and non-linear, time-dependent) and volume. The model was fitted by first order conditional estimation using NONMEM v7.3.0 (ICON Solutions). Parameters for peak (C.sub.max) and average (C.sub.avg) exposure were derived for each patient and associated to occurrence and severity of TEAE categories for autoimmune-mediated, edema/effusion, fatigue, liver function test (LFT), neurological, pain, and skin. Kaplan-Meier curves for event-free time (EFT) to TEAE were drawn for patients grouped according to low and high exposure. Testing for significance of covariates included sex, race, age, weight, disease subtype, body mass index, body surface area, performance status (ECOG), tumor size and number of prior therapies, and was performed using Kaplan-Meier and the associated log rank test.

[1064] Results

[1065] Measures of cAb (n=938) and tAb (n=963) in serum were assessed from 77 patients given intravenous Cami-T doses of 3-150 μg/kg Q3W. Unconjugated PBD toxin levels were below the 10 μg/mL lower limit of quantification for most patients and not used in analysis. Modeling yielded a linear clearance of 0.674 L/day, deconjugation clearance of 0.210 L/day, and nonlinear terms for V.sub.max=0.319 mg/day, K.sub.m=0.169 μg/mL, and K.sub.des=0.00113 day.sup.−1. For TEAEs grade ≥1, significant differences in EFT by cAb exposure (high/low) during Cycle 1 or at any time were observed for LFT (Cycle 1), pain (Cycle 1), and skin-related toxicities (any cycle) (Table 1).

TABLE-US-00012 TABLE 1 Log Rank Test (p-value) and mEFT for treatment emergent adverse events (TEAEs) Grade ≥1 and conjugated antibody (cAb) Exposure TEAEs cAb exposure mEFT for high mEFT for low grade ≥1 (high vs low) p-value exposure (days) exposure (days) LFT Cycle 1 C.sub.avg 0.027 146 NR LFT Cycle 1 C.sub.max 0.036 NR NR Pain Cycle 1 C.sub.avg 0.048 NR NR Skin max C.sub.avg 0.024 37 234 Skin max C.sub.max 0.0096 35 234 Edema/Effusion max C.sub.avg 0.081 NR NR LFT, liver function test; mEFT, median event-free time; NR, not reached

[1066] Potentially clinically important, but not significant was edema/effusion. Covariates with a significant effect on TEAEs grade ≥1 included ECOG (0 vs >1) on autoimmune-mediated toxicity (p=0.007, median EFTs [mEFTs] not reached), race effect (White vs non-White) on edema/effusion (p=0.035, mEFTs not reached) and on neurological toxicity (p=0.042, mEFTs not reached). For TEAEs grade ≥3, no significant differences in EFT by cAb exposure were observed.

[1067] Conclusion

[1068] Using an integrated PPK model, individual patient drug exposures were obtained and used as drivers of observed safety effects in an exposure-response analysis. Data indicated apparent exposure relatedness to mild severities of LFT, pain, and skin-related toxicities following ADCx25 treatment of patients with R/R lymphomas. Development of a parametric model to predict time-to-event for various dosage regimens is planned to optimize the benefit/risk ratio in these patients.

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