Patent Application

App. No. 16/806,910

Abstract

Claims (138)

1 .- 124 . (canceled)

125 . A method of treating CD25+ve acute myeloid leukemia (AML) in a subject, said method comprising administering to a subject a conjugate of formula L-(D L ) p wherein D L is of formula I or IL

and further wherein:

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

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

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

(ib) C 1-5 saturated aliphatic alkyl;

(ic) C 3-6 saturated cycloalkyl;

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

wherein one of R 25a and R 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

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

R 12 is

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

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

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

R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;

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

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

R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;

R L1′ is a linker for connection to the antibody (Ab);

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

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

R 20 is selected from H and R C , where R C is a capping group;

R 21 is selected from OH, OR A and SO z M;

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

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

(ib) C 1-5 saturated aliphatic alkyl;

(ic) C 3-6 saturated cycloalkyl;

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

wherein one of R 15a and R 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

where R 14 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 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,

R 2 is

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

R 22 is of formula IIIa, formula IIIb or formula IIIc:

where A is a C 5-7 aryl group, and either

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

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

where;

R C1 , R C2 and R C3 are independently selected from H and unsubstituted C 1-2 alkyl;

where Q is selected from O—R L2′ , S—R L2′ and NR N —R L2′ , and R N is selected from H, methyl and ethyl

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

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

R L2′ is a linker for connection to the antibody (Ab);

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

R 10 is H and R 11 is selected from OH, OR A and SO z M;

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

R 30 is H and R 31 is selected from OH, OR A and SO z M;

optionally wherein the CD25+ve Acute Myeloid Leukemia comprises both CD25+ve and CD25-ve cells;

and/or the CD25+ve Acute Myeloid Leukemia (AML) is:

(i) refractory AML; or

(ii) relapsed AML.

126 . The method of claim 125 , wherein:

R 7 is a C 1-4 alkyloxy group, Y is O, R″ is C 3-7 alkylene, R 9 is H, and/or R 6 is selected from H and halo.

127 . The method of claim 125 , wherein:

(A) there is a double bond between C2′ and C3′, and R 12 is:

(i) a C 5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or

(ii) methyl, ethyl or propyl; or

(iii) cyclopropyl; or

(iv) a group of formula:

wherein the total number of carbon atoms in the R 12 group is no more than 4; or

(v) the group:

or

(iv) a group of formula:

wherein R 24 is selected from H and methyl.

OR

(B) there is a single bond between C2′ and C3′, R 12 is R

and:

(i) R 26a and R 26b are both H; or

(ii) R 26a and R 26b are both methyl; or

(iii) one of R 26a and R 26b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.

128 . The method of claim 125 , wherein:

(A) there is a double bond between C2 and C3, and R 2 is:

(i) a C 5-7 aryl group which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or

(ii) methyl, ethyl or propyl; or

(iii) cyclopropyl; or

(iv) a group of formula:

wherein the total number of carbon atoms in the R 2 group is no more than 4; or

(v) the group:

or

(vi) a group of formula:

wherein R 14 is selected from H and methyl;

OR

(B) there is a single bond between C2 and C3, R 2 is

and:

(i) R 16a and R 16b are both H; or

(ii) R 16a and R 16b are both methyl; or

(iii) one of R 16a and R 16b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.

129 . The method of claim 125 , wherein R 20 is R C , wherein R C is a group:

where the asterisk indicates the point of attachment to the N10 position, G 2 is a terminating group, L 3 is a covalent bond or a cleavable linker L 1 , L 2 is a covalent bond or together with OC(═O) forms a self-immolative linker.

130 . The method of claim 125 , wherein:

(a) R 22 is of formula IIIa, and A is phenyl, Q 1 is a single bond, and Q 2 is a single bond; or

(b) R 22 is of formula IIIb, and R C1 , R C2 and R C3 are all H; and

X is NH—R L2′ .

131 . The method of claim 125 , wherein:

(A) R 6′ , R 7′ , R 9′ , and Y′ are the same as R 6 , R 7 , R 9 , and Y;

and/or

(B) L-R L1′ or L-R L2′ is a group:

where the asterisk indicates the point of attachment to the PBD, Ab is the antibody, L 1 is a cleavable linker, A is a connecting group connecting L to the antibody, L 2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker;

optionally wherein,

(i) L 1 comprises a dipeptide and the group —X 1 -X 2 — in dipeptide, —NH—X 1 -X 2 —CO—, is selected from:

-Phe-Lys-,

-Val-Ala-,

-Val-Lys-,

-Ala-Lys-,

-Val-Cit-,

-Phe-Cit-,

-Leu-Cit-,

-Ile-Cit-,

-Phe-Arg-,

-Trp-Cit-,

or

(ii) C(═O)O and L 2 together form the group:

where the asterisk indicates the point of attachment to the PBD, the wavy line indicates the point of attachment to the linker L, Y is NH, O, C(═O)NH or C(═O)O, and n is 0 to 3.

132 . The method of claim 125 , wherein D L is selected from the group comprising:

133 . The method of claim 125 , wherein the antibody comprises:

(A) 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, and/or

(B) a VH domain having the sequence according to SEQ ID NO. 1,

and, optionally further comprises a VL domain having the sequence according to SEQ ID NO. 2.

134 . The method of claim 125 , wherein:

the drug loading (p) of drugs (D) to antibody (Ab) is an integer from 1 to about 8;

the drug loading (p) of drugs (D) to antibody (Ab) is 1, 2, 3, or 4; or

the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

135 . The method of claim 125 , wherein the conjugate is ADCT-301.

136 . The method of claim 125 , wherein the method further comprises a step of screening a subject to identify the presence of CD25+ve acute myeloid leukemia;

optionally, wherein said screening is performed by means of a companion diagnostic which identifies CD25+ve cells by means of immunohistochemistry.

137 . The method of claim 125 , wherein said method further comprises:

(i) identifying the presence in the subject of CD25+ve acute myeloid leukemia,

optionally wherein said identifying is performed by means of a companion diagnostic which identifies CD25+ve cells by means of immunohistochemistry; and

(ii) administering to the subject the antibody-drug conjugate compound.

138 . The method of claim 125 , wherein:

(i) said 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; Acute lymphoblastic leukemia;

(ii) the neoplasm or neoplastic cells are, or are present in, a non-hematological cancer;

(iii) said neoplasm or neoplastic cells are, or are present in, a solid tumor;

(iv) said neoplasm or neoplastic cells are malignant; or

(v) said neoplasm or neoplastic cells are metastatic.

Assignments (9)