Monomethylvaline compounds capable of conjugation to ligands
First Claim
Patent Images
1. A compound having the formula:
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L-(D)p or a pharmaceutically acceptable salt or solvate thereof wherein, L- is a Ligand unit;
p ranges from I to about 20; and
- D is a drug moiety selected from Formulas DE and DF;
wherein, independently at each location;
R2 is selected from H and C1-C8 alkyl;
R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from H and C1-C8 alkyl;
R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—
(C1-C8 alkyl);
R9 is selected from H and C1-C8 alkyl;
R10 is selected from aryl or C3-C8 heterocycle;
Z is O, S, NH, or NR12, wherein R12 is C1-C8 alkyl;
R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —
(R13O)m—
R14, or —
(R13O)m—
CH(R15)2;
m is an integer ranging from 1-1000;
R13 is C2-C8 alkyl;
R14 is H or C1-C8 alkyl;
each occurrence of R15 is independently H, COOH, —
(CH2)n—
N(R16)2, —
(CH2)n—
SO3H, or —
(CH2)n—
SO3—
C1-C8 alkyl;
each occurrence of R16 is independently H, C1-C8 alkyl, or —
(CH2)n—
COOH;
R18 is selected from —
C(R8)2—
(R8)2-aryl, —
C(R8)2—
C(R8)2—
(C3-C8 heterocycle), and —
C(R8)2—
C(R8)2—
(C3-C8 carbocycle); and
n is an integer ranging from 0 to 6.
7 Assignments
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Accused Products
Abstract
Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.
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Citations
221 Claims
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1. A compound having the formula:
-
L-(D)por a pharmaceutically acceptable salt or solvate thereof wherein, L- is a Ligand unit;
p ranges from I to about 20; and
- D is a drug moiety selected from Formulas DE and DF;
wherein, independently at each location;
R2 is selected from H and C1-C8 alkyl;
R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from H and C1-C8 alkyl;
R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—
(C1-C8 alkyl);
R9 is selected from H and C1-C8 alkyl;
R10 is selected from aryl or C3-C8 heterocycle;
Z is O, S, NH, or NR12, wherein R12 is C1-C8 alkyl;
R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —
(R13O)m—
R14, or —
(R13O)m—
CH(R15)2;
m is an integer ranging from 1-1000;
R13 is C2-C8 alkyl;
R14 is H or C1-C8 alkyl;
each occurrence of R15 is independently H, COOH, —
(CH2)n—
N(R16)2, —
(CH2)n—
SO3H, or —
(CH2)n—
SO3—
C1-C8 alkyl;
each occurrence of R16 is independently H, C1-C8 alkyl, or —
(CH2)n—
COOH;
R18 is selected from —
C(R8)2—
(R8)2-aryl, —
C(R8)2—
C(R8)2—
(C3-C8 heterocycle), and —
C(R8)2—
C(R8)2—
(C3-C8 carbocycle); and
n is an integer ranging from 0 to 6. - View Dependent Claims (2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 56, 57, 58, 59, 60, 66, 67, 68, 69, 70, 96, 97, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118)
L-LU-Dor a pharmaceutically acceptable salt or solvate thereof.
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4. The compound of claim 1, wherein the compound is an antibody-drug conjugate having Formula Ia′
- ;
Ab-(Aa-Ww-Yy-D)p
Ia′or a pharmaceutically acceptable salt or solvate thereof, wherein;
Ab is an antibody, A is a Stretcher unit, a is 0 or 1, each W is independently an Amino Acid unit, w is an integer ranging from 0 to 12, Y is a Spacer unit, and y is 0, 1 or 2, p ranges from 1 to about 20, and D is a drug moiety selected from Formulas DE and DF;
wherein, independently at each location;
R2 is selected from H and C1-C8 alkyl;
R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from H and C1-C8 alkyl;
R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—
(C1-C8 alkyl);
R9 is selected from H and C1-C8 alkyl;
R10 is selected from aryl or C3-C8 heterocycle;
Z is O, S, NH, or NR , wherein R is C1-C8 alkyl;
R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —
(R13O)m—
R14, or —
(R13O)m—
CH(R15)2;
m is an integer ranging from 1-1000;
R13 is C2-C8 alkyl;
R14 is H or C1-C8 alkyl;
each occurrence of R15 is independently H, COOH, —
(CH2)n—
N(R16)2, —
(CH2)n—
SO3H, or —
(CH2)n—
SO3—
C1-C8 alkyl;
each occurrence of R16 is independently H, C1-C8 alkyl, or —
(CH2)n—
COOH;
R18 is selected from —
C(R8)2—
C(R8)2-aryl, —
C(R8)2—
C(R8)2—
(C3-C8 heterocycle), and —
C(R8)2—
C(R8)2—
(C3-C8 carbocycle); and
n is an integer ranging from 0 to 6.
- ;
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5. The antibody-drug conjugate compound of claim 4 wherein D is Formula DF:
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6. The antibody-drug conjugate compound of claim 4 wherein D is Formula DE:
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7. The antibody-drug conjugate compound of claim 1 having the formula:
-
Ab-(D)pwherein a, w, and y are each 0.
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8. The antibody-drug conjugate compound of claim 4,wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
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9. The antibody-drug conjugate compound of claim 8 wherein p is 2 to 5.
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10. The antibody-drug conjugate compound of claim 4 wherein p is 2 to 8.
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11. The antibody-drug conjugate compound of claim 4 wherein p is 2 to 5.
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12. The antibody-drug conjugate compound of claim 4 or 8 having the formula:
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13. The antibody-drug conjugate compound of claim 12 having the formula:
-
14. The antibody-drug conjugate compound of claim 12 having the formula:
-
15. The antibody-drug conjugate compound of claim 14 wherein D is Formula DE.
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16. The antibody-drug conjugate compound of claim 15 wherein Formula DE has the formula:
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17. The antibody-drug conjugate compound of claim 14 wherein D is Formula DF.
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18. The antibody-drug conjugate compound of claim 17 wherein Formula DF has the formula:
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19. The antibody-drug conjugate compound of claim 4 having the formula:
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20. The antibody-drug conjugate compound of claim 4 having the formula:
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21. The antibody-drug conjugate compound of claim 4 having the formula:
-
22. The antibody-drug conjugate compound of claim 21 wherein D is Formula DE.
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23. The antibody-drug conjugate compound of claim 22 wherein Formula DE has the formula:
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24. The antibody-drug conjugate compound of claim 21 wherein D is Formula DF.
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25. The antibody-drug conjugate compound of claim 24 wherein Formula DF has the formula:
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26. The antibody-drug conjugate compound of claim 4 having the formula:
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27. The antibody-drug conjugate compound of claim 4 wherein w is an integer ranging from 2 to 12.
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28. The antibody-drug conjugate compound of claim 4 wherein w is 2.
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29. The antibody-drug conjugate compound of claim 28 wherein Ww is -valine-citrulline-.
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30. The antibody-drug conjugate compound of claim 27 wherein Ww is 5-aminovaleric acid, homo phenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalanine lysine, isonepecotic acid lysine, beta-alanine lysine, glycine serine valine glutamine and isonepecotic acid.
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31. The antibody-drug conjugate compound of claim 4, 6 or 7 wherein D has the formula:
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32. The antibody-drug conjugate compound of claim 4, 5 or 7 wherein D has the formula:
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33. The antibody-drug conjugate compound of claim 5 wherein D has the formula:
-
34. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
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35. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
-
36. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
-
37. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
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38. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
-
39. The antibody-drug conjugate compound of claim 5, wherein D has the formula:
-
40. The antibody-drug conjugate compound of claim 5 wherein D has the formula:
-
41. The antibody-drug conjugate compound of claim 5 wherein D has the formula:
-
42. The antibody-drug conjugate compound of claim 4, wherein the antibody is a monoclonal antibody.
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43. The antibody-drug conjugate compound of claim 4, wherein the antibody is a bispecific antibody.
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44. The antibody-drug conjugate compound of claim 4, wherein the antibody is a chimeric antibody.
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45. The antibody-drug conjugate compound of claim 4, wherein the antibody is a humanized antibody.
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46. The antibody-drug conjugate compound of claim 4, wherein the antibody is an antibody fragment.
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47. The antibody-drug conjugate compound of claim 46, wherein the antibody fragment is a Fab fragment.
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48. The antibody-drug conjugate compound of claim 4, wherein a substantial amount of the drug moiety is not cleaved from the antibody until the antibody-drug conjugate compound enters a cell with a cell-surface receptor specific for the antibody of the antibody-drug conjugate, and the drug moiety is cleaved from the antibody when the antibody-drug conjugate does enter the cell.
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49. The antibody-drug conjugate compound of claim 4, wherein the bioavailability of the compound or an intracellular metabolite of the compound in a mammal is improved when compared to a drug compound comprising the drug moiety of the antibody-drug conjugate compound.
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50. The antibody-drug conjugate compound of claim 4 wherein the bioavailability of the compound or an intracellular metabolite of the compound in a mammal is improved when compared to an analog of the compound not having the drug moiety.
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51. The antibody-drug conjugate compound of claim 4 wherein the drug moiety is intracellularly cleaved in a mammal from the antibody of the compound, or an intracellular metabolite of the compound.
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54. A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate compound of claim 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
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55. The pharmaceutical composition of claim 54 further comprising a therapeutically effective amount of chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.
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56. A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating tumor cells or cancer cells with an amount of the antibody-drug conjugate compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, being effective to kill or inhibit the proliferation of the tumor cells or cancer cells.
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57. A method for treating cancer comprising administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 4, said amount being effective to treat cancer.
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58. The method of claim 57 further comprising administering an effective amount of an additional anticancer agent, an immunosuppressant agent or an anti-infectious agent.
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59. A method for treating an autoimmune disease, comprising administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 4, the amount being effective to treat the autoimmune disease.
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60. A method for treating an infectious disease, comprising administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 4, the amount being effective to treat the infectious disease.
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66. The method of claim 57, wherein the antibody-drug conjugate compound is formulated in a unit dosage injectable form.
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67. An assay for detecting cancer cells comprising:
exposing cells to an antibody drug conjugate compound of claim 4 and determining the extent of binding of the antibody-drug conjugate compound to the cells.
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68. The assay of claim 67 wherein the extent of binding is determined by immunohistochemistry (IHC).
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69. An article of manufacture comprising
an antibody drug conjugate compound of claim 4; -
a container; and
a package insert or label indicating that the compound can be used to treat cancer characterized by the overexpression of at least one of CD30, CD40, CD70 and Lewis Y.
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70. The compound of claim 2, wherein the Linker Unit (LU) comprises:
-
-Aa-Ww-Yy-wherein -A- is a Stretcher unit, a is 0 or 1, each -W- is independently an Amino Acid unit, w is an integer ranging from 0 to 12, -Y- is a Spacer unit, and y is 0, 1 or 2.
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96. The compound or pharmaceutically acceptable salt or solvate of the compound of claim 1 wherein the Ligand unit is an antibody.
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97. The compound or pharmaceutically acceptable salt or solvate of the compound of claim 2 wherein the Ligand unit is an antibody.
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100. The compound of claim 1 having the formula
-
101. A method for killing or inhibiting the multiplication of a tumor cell or cancer cell comprising administering to a patient an amount of a compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1, 2, 4, 72, or 85-97, said amount being effective to kill or inhibit the multiplication of a tumor cell or cancer cell.
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102. A method for treating cancer comprising administering to a patient an amount of the compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 2, 72, or 85-97, said amount being effective to treat cancer.
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103. A method for treating an autoimmune disease, comprising administering to a patient an amount of the compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 2, 4, 72, or 85-97, said amount being effective to treat an autoimmune disease.
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104. A method for treating an infectious disease, comprising administering to a patient an amount of a compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 2, 72, or 85-97, said amount being effective to treat an infectious disease.
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105. The method of claim 101, further comprising administering an effective amount of an additional anticancer agent.
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106. The method of claim 102, further comprising administering a therapeutically effective amount of an additonal anticancer agent.
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107. The method of claim 103, further comprising administering a therapeutically effective amount of an immunosuppressant agent.
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108. The method of claim 104, further comprising administering a therapeutically effective amount of an anti-infectious agent.
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109. The compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 2, 472, or 85-97 that is in isolated and purified form.
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110. The method of claim 101, wherein the patient is a human.
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111. The method of claim 102, wherein the patient is a human.
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112. The method of claim 103, wherein the patient is a human.
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113. The method of claim 104, wherein the patient is a human.
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114. The antibody-drug conjugate compound of claim 4 wherein the antibody binds to CD30, CD40, Lewis Y, and CD70.
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115. The antibody-drug conjugate compound of claims 4 or 52 wherein the antibody is not an antibody which binds to an ErbB receptor or which binds to one or more of receptors (1)-(35):
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(1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession no. NM—
001203);
(2) E16 (LAT1, SLC7A5, Genbank accession no. NM—
003486);
(3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank accession no. NM—
012449);
(4) 0772P (CA125, MUC16, Genbank accession no. AF361486);
(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession no. NM—
005823);
(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession no. NM—
006424);
(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession no. AB040878);
(8) PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession no. AY358628);
(9) ETBR (Endothelin type B receptor, Genbank accession no. AY275463);
(10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession no. NM—
017763);
(11) STEAP2 (HGNC—
8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank accession no. AF455138);
(12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM—
017636);
(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession no. NP—
003203 or NM—
003212);
(14) CD21 (CR2 (Complement receptor
2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792 Genbank accession no. M26004);
(15) CD79b (IGb (immunoglobulin-associated beta), B29, Genbank accession no. NM—
000626);
(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession no. NM—
030764);
(17) HER2 (Genbank accession no. M11730);
(18) NCA (Genbank accession no. M18728);
(19) MDP (Genbank accession no. BC017023);
(20) IL20Ra (Genbank accession no. AF184971);
(21) Brevican (Genbank accession no. AF229053);
(22) Ephb2R (Genbank accession no. NM—
004442);
(23) ASLG659 (Genbank accession no. AX092328);
(24) PSCA (Genbank accession no. AJ297436);
(25) GEDA (Genbank accession no. AY260763);
(26) BAFF-R (Genbank accession no. NP—
443177.1);
(27) CD22 (Genbank accession no. NP—
001762.1);
(28) CD79a (CD79A, CD79a, immunoglobulin-associated alpha, Genbank accession No. NP—
001774.1);
(29) CXCR5 (Burkitt'"'"'s lymphoma receptor 1, Genbank accession No. NP—
001707.1);
(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank accession No. NP—
002111.1);
(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, Genbank accession No. NP—
002552.2);
(32) CD72 (B-cell differentiation antigen CD72, Lyb-2, Genbank accession No. NP—
001773.1);
(33) LY64 (Lymphocyte antigen 64 (RP105), type 1 membrane protein of the leucine rich repeat (LRR) family, Genbank accession No. NP—
005573.1);
(34) FCRH1 (Fc receptor-like protein 1, Genbank accession No. NP—
443170.1); and
(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2Genbank accession No. NP—
112571.1).
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117. The antibody-drug conjugate compound of claim 28 wherein Ww is -phenylalanine-lysine-.
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118. The antibody-drug conjugate compound of claim 28 wherein Ww is —
- N-methyl valine-citrulline-.
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3. A compound having the formula:
-
LU-Dor a pharmaceutically acceptable salt or solvate thereof wherein, -LU- is a Linker Unit; and
-D is a drug moiety selected from Formulas DE and DF;
wherein, independently at each location;
R2 is selected from H and C1-C8 alkyl;
R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from H and C1-C8 alkyl;
R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—
(C1-C8 alkyl);
R9 is selected from H and C1-C8 alkyl;
R10 is selected from aryl or C3-C8 heterocycle;
Z is O, S, NH, or NR12, wherein R12 is C1-C8 alkyl;
R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —
(R13O)m—
R14 or —
(R13O)m—
CH(R15)2;
m is an integer ranging from 1-1000;
R13 is C2-C8 alkyl;
R14 is H or C1-C8 alkyl;
each occurrence of R15 is independently H, COOH, —
(CH2)n—
N(R16)2, —
(CH2)n—
SO3H, or —
(CH2)n—
SO3—
C1-C8 alkyl;
each occurrence of R16 is independently H, C1-C8 alkyl, or —
(CH2)n—
COOH;
R18 is selected from —
C(R8)2—
C(R8)2-aryl, —
C(R8)2—
C(R8)2—
(C3-C8 heterocycle), and —
C(R8)2—
C(R8)2—
(C3-C8 carbocycle); and
n is an integer ranging from 0 to 6. - View Dependent Claims (71)
-Aa-Ww-Yy-wherein -A- is a Stretcher unit, a is 0 or 1, each -W- is independently an Amino Acid unit, w is an integer ranging from 0 to 12, -Y- is a Spacer unit, and y is 0, 1 or 2.
-
- 52. An antibody-drug conjugate compound having the formula:
- 61. The method of 57, wherein the antibody-drug conjugate compound is a formulation comprising a pharmaceutically acceptable diluent, carrier or excipient.
- 72. A compound having the formula:
- 74. A compound having the formula:
- 85. A compound having the formula:
-
119. An antibody-drug conjugate compound comprising an antibody covalently attached to one or more drug moieties, the compound having Formula Ic:
-
Ab-(Aa-Ww-Yy-D)p
Icor a pharmaceutically acceptable salt or solvate thereof, wherein;
Ab is an antibody which binds to one or more tumor-associated antigens (1)-(35);
(1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession no. NM—
001203);
(2) E16 (LAT1, SLC7A5, Genbank accession no. NM—
003486);
(3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank accession no. NM—
012449);
(4) 0772P (CA125, MUC16, Genbank accession no. AF361486);
(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession no. NM—
005823);
(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession no. NM—
006424);
(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession no. AB040878);
(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession no. AY358628);
(9) ETBR (Endothelin type B receptor, Genbank accession no. AY275463);
(10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession no. NM—
017763);
(11) STEAP2 (HGNC—
8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank accession no. AF455138);
(12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM—
017636);
(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession no. NP—
003203 or NM—
003212);
(14) CD21 (CR2 (Complement receptor
2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792 Genbank accession no. M26004);
(15) CD79b (IGb (immunoglobulin-associated beta), B29, Genbank accession no. NM—
000626);
(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession no. NM—
030764);
(17) HER2 (Genbank accession no. M11730);
(18) NCA (Genbank accession no. M18728);
(19) MDP (Genbank accession no. BC017023);
(20) IL20Ra (Genbank accession no. AF184971);
(21) Brevican (Genbank accession no. AF229053);
(22) Ephb2R (Genbank accession no. NM—
004442);
(23) ASLG659 (Genbank accession no. AX092328);
(24) PSCA (Genbank accession no. AJ297436);
(25) GEDA (Genbank accession no. AY260763);
(26) BAFF-R (Genbank accession no. NP—
443177.1);
(27) CD22 (Genbank accession no. NP-001762.1);
(28) CD79a (CD79A, CD79α
, immunoglobulin-associated alpha, Genbank accession No. NP—
001774.1);
(29) CXCR5 (Burkitt'"'"'s lymphoma receptor 1, Genbank accession No. NP—
001707.1);
(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank accession No. NP—
002111.1);
(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, Genbank accession No. NP—
002552.2);
(32) CD72 (B-cell differentiation antigen CD72, Lyb-2, Genbank accession No. NP—
001773.1);
(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family, Genbank accession No. NP—
005573.1);
(34) FCRH1 (Fc receptor-like protein 1, Genbank accession No. NP—
443170.1); and
(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2Genbank accession No. NP—
112571.1),A is a Stretcher unit, a is 0 or 1, each W is independently an Amino Acid unit, w is an integer ranging from 0 to 12, Y is a Spacer unit, and y is 0, 1 or 2, p ranges from 1 to 20, and D is a drug moiety selected from Formulas DE and DF;
wherein the wavy line of DE and DF indicates the covalent attachment site to A, W, or Y, and independently at each location;
R2 is selected from H and C1-C8 alkyl;
R3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from H and C1-C8 alkyl;
R7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—
(C1-C8 alkyl);
R9is selected from H and C1-C8 alkyl;
R10 is selected from aryl or C3-C8 heterocycle;
Z is O, S, NH, or NR12, wherein R12 is C1-C8 alkyl;
R11 is selected from H, C1-C20 alkyl, aryl, C3-C8 heterocycle, —
(R13O)m—
R14, or —
(R13O)m—
CH(R15)2;
m is an integer ranging from 1-1000;
R13 is C2-C8 alkyl;
R14 is H or C1-C8 alkyl;
each occurrence of R15 is independently H, COOH, —
(CH2)n—
N(R16)2, —
(CH2)n—
SO3H, or —
(CH2)n—
SO3—
C1-C8 alkyl;
each occurrence of R16 is independently H, C1-C8 alkyl, or —
(CH2)n—
COOH;
R18 is selected from —
C(R8)2—
C(R8)2-aryl, —
C(R8)2—
C(R8)2—
(C3-C8 heterocycle), and —
C(R8)2—
C(R8)2—
(C3-C8 carbocycle); and
n is an integer ranging from 0 to 6. - View Dependent Claims (120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221)
-
-
121. The antibody-drug conjugate compound of claim 119, wherein D is Formula DF:
-
122. The antibody-drug conjugate compound of claim 119 having the formula:
-
Ab-(D)pwherein a, w, and y are each 0.
-
-
123. The antibody-drug conjugate compound of claim 119, wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
-
124. The antibody-drug conjugate compound of claim 123, wherein p is 1 to 4.
-
125. The antibody-drug conjugate compound of claim 119 wherein p is 2 to 8.
-
126. The antibody-drug conjugate compound of claim 119 wherein p is 2 to 5.
-
127. The antibody-drug conjugate compound of claim 123 having the formula:
-
128. The antibody-drug conjugate compound of claim 127 having the formula:
-
129. The antibody-drug conjugate compound of claim 128 wherein D is Formula DE.
-
130. The antibody-drug conjugate compound of claim 129 wherein Formula DE has the formula:
-
131. The antibody-drug conjugate compound of claim 128 wherein D is Formula DF.
-
132. The antibody-drug conjugate compound of claim 131 wherein Formula DF has the formula:
-
133. The antibody-drug conjugate compound of claim 119 having the formula:
-
134. The antibody-drug conjugate compound of claim 133 having the formula:
-
135. The antibody-drug conjugate compound of claim 134 having the formula:
-
136. The antibody-drug conjugate compound of claim 135 wherein D is Formula DE.
-
137. The antibody-drug conjugate compound of claim 136 wherein Formula DE has the formula:
-
138. The antibody-drug conjugate compound of claim 134 wherein D is Formula DF.
-
139. The antibody-drug conjugate compound of claim 138 wherein Formula DF has the formula:
-
140. The antibody-drug conjugate compound of claim 119 having the formula:
-
141. The antibody-drug conjugate compound of claim 119 wherein w is an integer ranging from 2 to 12.
-
142. The antibody-drug conjugate compound of claim 119 wherein w is 2.
-
143. The antibody-drug conjugate compound of claim 142 wherein Ww is -valine-citrulline-.
-
144. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
145. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
146. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
147. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
148. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
149. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
150. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
151. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
152. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
153. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
154. The antibody-drug conjugate compound of claim 119 wherein D has the formula:
-
155. The antibody-drug conjugate compound of claim 119 wherein the antibody specifically binds to a HER2 receptor.
-
156. The antibody-drug conjugate compound of claim 155 which specifically binds to the extracellular domain of the HER2 receptor and inhibits growth of tumor cells which overexpress HER2 receptor.
-
157. The antibody-drug conjugate compound of claim 119 wherein the antibody is a monoclonal antibody.
-
158. The antibody-drug conjugate compound of claim 119 wherein the antibody is a bispecific antibody.
-
159. The antibody-drug conjugate compound of claim 119 wherein the antibody is a chimeric antibody.
-
160. The antibody-drug conjugate compound of claim 119 wherein the antibody is a humanized antibody.
-
161. The antibody-drug conjugate compound of claim 160 wherein the humanized antibody is selected from huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (trastuzumab).
-
162. The antibody-drug conjugate compound of claim 161 wherein the antibody is huMAb4D5-8 (trastuzumab).
-
163. The antibody-drug conjugate compound of claim 119 wherein the antibody is an antibody fragment.
-
164. The antibody-drug conjugate compound of claim 163 wherein the antibody fragment is a Fab fragment.
-
165. The antibody-drug conjugate compound of claim 119 wherein a substantial amount of the drug moiety is not cleaved from the antibody until the antibody-drug conjugate compound enters a cell with a cell-surface receptor specific for the antibody of the antibody-drug conjugate, and the drug moiety is cleaved from the antibody when the antibody-drug conjugate does enter the cell.
-
166. The antibody-drug conjugate compound of claim 119 wherein the bioavailability of the antibody-drug conjugate compound or an intracellular metabolite of the compound in a mammal is improved when compared to a drug compound comprising the drug moiety of the antibody-drug conjugate compound.
-
167. The antibody-drug conjugate compound of claim 119 wherein the bioavailability of the antibody-drug conjugate compound or an intracellular metabolite of the compound in a mammal is improved when compared to an analog of the antibody-drug conjugate compound not having the drug moiety.
-
168. The antibody-drug conjugate compound of claim 119 wherein the drug moiety is intracellularly cleaved in a mammal from the antibody of the antibody-drug conjugate compound, or an intracellular metabolite of the antibody-drug conjugate compound.
-
169. The antibody-drug conjugate compound of claim 119 selected from the formulae:
-
170. The antibody-drug conjugate compound of claim 169 wherein the antibody is huMAb4D5-8 (trastuzumab).
-
171. A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate compound of claim 119 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
-
172. The pharmaceutical composition of claim 171 further comprising a therapeutically effective amount of chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.
-
173. A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating tumor cells or cancer cells with an amount of the antibody-drug conjugate compound of claim 119 or a pharmaceutically acceptable salt or solvate thereof, being effective to kill or inhibit the proliferation of the tumor cells or cancer cells.
-
174. A method for treating cancer comprising administering to a patient with a hyperproliferative disorder an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 119, said amount being effective to treat cancer.
-
175. The method of claim 174 further comprising administering an effective amount of an additional anticancer agent.
-
176. The method of claim 174 further comprising administering an effective amount of an immunosuppressant agent.
-
177. The method of claim 174 further comprising administering an effective amount of an anti-infectious agent.
-
178. A method for treating an autoimmune disease, comprising administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 119, said amount being effective to treat an autoimmune disease.
-
179. A method for treating an infectious disease, comprising administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof of claim 119, said amount being effective to treat an infectious disease.
-
180. A method of inhibiting cellular proliferation comprising:
-
exposing mammalian cells in a cell culture medium to the antibody drug conjugate compound of claim 119, and measuring a cytotoxic activity of the antibody-drug conjugate compound, whereby proliferation of the cells is inhibited.
-
-
181. The method of claim 180 further comprising culturing the cells for a period from about 6 hours to about 5 days.
-
182. The method of claim 180 wherein the mammalian cells have HER2 receptor proteins to the antibody-drug conjugate compound.
-
183. The method of claim 180 wherein the mammalian cells are SK-BR-3 breast tumor cells.
-
184. The method of claim 180 wherein the cytotoxic activity of the antibody-drug conjugate compound is more than twice that of a drug compound consisting essentially of the drug moiety of the antibody-drug conjugate compound.
-
185. A method of treating cancer comprising administering to a patient a formulation of an antibody-drug conjugate compound of claim 119 and a pharmaceutically acceptable diluent, carrier or excipient.
-
186. The method of claim 185 wherein the antibody-drug conjugate compound specifically binds to a receptor encoded by an ErbB2 gene.
-
187. The method of claim 185 wherein the amount of antibody-drug conjugate compound administered to the patient is in the range of about 0.1 to about 10 mg/kg of patient weight.
-
188. The method of claim 185 wherein the antibody-drug conjugate is administered at about three week intervals.
-
189. The method of claim 185 wherein said antibody-drug conjugate compound is administered parenterally.
-
190. The method of claim 189 wherein said antibody-drug conjugate compound is formulated with a pharmaceutically acceptable parenteral vehicle.
-
191. The method of claim 185 wherein said antibody-drug conjugate compound is formulated in a unit dosage injectable form.
-
192. The method of claim 185 wherein said antibody-drug conjugate compound is administered intravenously.
-
193. The method of claim 185 further comprising the administration of a second antibody which binds a tumor-associated antigen selected from (1)-(35).
-
194. The method of claim 193 wherein said second antibody is conjugated with a cytotoxic agent.
-
195. A method of inhibiting the growth of tumor cells that overexpress a tumor-associated antigen comprising administering to a patient an antibody drug conjugate compound of claim 119 which binds specifically to said tumor-associated antigen, and a chemotherapeutic agent wherein said antibody drug conjugate and said chemotherapeutic agent are each administered in amounts effective to inhibit growth of tumor cells in the patient.
-
196. The method of claim 195 wherein said antibody drug conjugate compound sensitizes the tumor cells to said chemotherapeutic agent.
-
197. A method for the treatment of a human patient susceptible to or diagnosed with a disorder characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of a combination of an antibody drug conjugate compound of claim 119, and a chemotherapeutic agent.
-
198. An assay for detecting cancer cells comprising:
exposing cells to an antibody drug conjugate compound of claim 119, and determining the extent of binding of the antibody-drug conjugate compound to the cells.
-
199. The assay of claim 198 wherein the cells are breast tumor cells.
-
200. The assay of claim 198 wherein the extent of binding is determined by measuring levels of tumor-associated antigen-encoding nucleic acid by fluorescent in situ hybridization (FISH).
-
201. The assay of claim 198 wherein the extent of binding is determined by immunohistochemistry (IHC).
-
202. An article of manufacture comprising:
-
an antibody drug conjugate compound of claim 119;
a container; and
a package insert or label indicating that the compound can be used to treat cancer characterized by the overexpression of an ErbB2 receptor.
-
-
203. The article of manufacture of claim 202 wherein said package insert of label indicates that the compound can be used to treat cancer characterized by the overexpression of an ErbB2 receptor.
-
204. The article of manufacture of claim 202 wherein the cancer is breast cancer.
-
205. The article of manufacture of claim 204 wherein the cancer is characterized by the overexpression of an ErbB2 receptor at a 2+ level or above.
-
206. A method for the treatment of cancer in a mammal, wherein the cancer is characterized by the overexpression of an ErbB2 (HER2) receptor and does not respond, or responds poorly, to treatment with an anti-ErbB2 antibody, comprising administering to the mammal a therapeutically effective amount of an antibody drug conjugate compound of claim 119.
-
207. The method of claim 206 wherein the mammal is human.
-
208. The method of claim 206 wherein the antibody of the antibody-drug conjugate compound is a growth inhibitory antibody.
-
209. The method of claim 206 wherein the antibody-drug conjugate compound induces cell death.
-
210. The method of claim 206 wherein the antibody-drug conjugate compound induces apoptosis.
-
211. The method of claim 206 wherein the cancer is selected from the group consisting of breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, colorectal, thyroid, pancreatic, prostate and bladder cancer.
-
212. The method of claim 211 wherein the cancer is breast cancer and the breast cancer overexpresses ErbB2 at a 2+ level or more.
-
213. The method of claim 211 wherein the breast cancer overexpresses ErbB2 at a 3+ level.
-
214. The method of claim 206 wherein the antibody of the antibody-drug conjugate compound has a biological characteristic of a 4D5 monoclonal antibody.
-
215. The method of claim 206 wherein the antibody of the antibody-drug conjugate compound binds essentially the same epitope as a 4D5 monoclonal antibody.
-
216. The method of claim 206 wherein the antibody of the antibody-drug conjugate compound is the monoclonal antibody 4D5 (ATCC CRL 10463).
-
217. The method of claim 216 wherein the antibody is humanized.
-
218. The method of claim 217 wherein the antibody is selected from the group consisting of humanized antibodies huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (trastuzumab).
-
219. The method of claim 218 wherein the antibody is humanized antibody huMAb4D5-8 (trastuzumab).
-
220. The method of claim 206 wherein the antibody of the antibody-drug conjugate compound is an antibody fragment.
-
221. The method of claim 220 wherein the antibody fragment is a Fab fragment.
Specification
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Current AssigneeSeagen Inc. (Pfizer Inc.)
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Original AssigneeSeattle Genetics Incorporated (Pfizer Inc.)
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InventorsPolakis, Paul, Doronina, Svetlana O., Senter, Peter D., Toki, Brian E., Spencer, Susan D., Ebens, Allen J., Sliwkowski, Mark X., Kline, Toni Beth
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current424/178.100
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CPC Class CodesA61K 2039/505 comprising antibodiesA61K 38/00 Medicinal preparations cont...A61K 47/68031 the drug being an auristatinA61K 47/6811 the drug being a protein or...A61K 47/6849 the antibody targeting a re...A61K 47/6851 the antibody targeting a de...A61K 47/6855 the tumour determinant bein...A61K 47/6889 Conjugates wherein the anti...A61P 31/00 Antiinfectives, i.e. antibi...A61P 31/04 Antibacterial agentsA61P 31/12 AntiviralsA61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 43/00 Drugs for specific purposes...C07K 16/32 against translation product...C07K 2317/24 containing regions, domains...C07K 7/02 Linear peptides containing ...View All
