EP0328147A2
Expired / Lapsed
EP
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Anthracycline immunoconjugates having a novel linker and methods for their production
Assignee: Bristol Myers Squibb Co
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Filing: 1989-02-10
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Granted: —
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Expires: 2009-02-10
Abstract
Abstract The present invention relates to novel immunoconjugates, methods for their production, pharmaceutical compositions and method for delivering cytotoxic anthracyclines to a selected population of cells desired to be eliminated. More particularly, the invention relates to immunoconjugates comprised of an antibody reactive with a selected cell population, having a number of anthracycline molecules linked to its structure. Each anthracycline molecule, having a keto group at the C-13 position, is conjugated to the antibody via a linker arm and is bound to that linker arm via an acid-sensitive acylhydrazone bond at the 13-keto position of the anthracycline. The immunoconjugates and methods of the invention are useful in antibody-mediated drug delivery systems for the preferential killing of a selected cell population in the treatment of diseases such as cancers and other tumors, non-cytocidal viral or other pathogenic infections, and autoimmune disorders.
Inventors
- 👤 Robert S. Greenfield
- 👤 Gary R. Braslawsky
- 👤 Lee J. Olech
- 👤 Takushi Kaneko
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-08 01:22
CPC Classifications
A; A61; A61K; A61K39/00; A61K39/395; C; C07; C07H; C07H15/00; C07H15/20; C07H15/24; C07H15/252; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6801; A61K47/6803; A61K47/6807; A61K47/6809; A61K47/6835; A61K47/6881; A61K47/6889; A61P; A61P35/00; H; H10; H10D; H10D84/00; H10D84/01
Claims Analysis
Total Claims: 36
Claim 1
Independent Claim
60 words
An immunoconjugate comprising approximately 4-10 anthracycline molecules linked to an antibody reactive with a selected cell population to be killed, each anthracycline having a keto group at the C-13 position and being attached to the antibody via a linker arm, the linker arm being covalently bound to the anthracycline by an acylhydrazone linkage at the 13-keto position of the anthracycline.
Claim 2
Dependent Claim
60 words
An immunoconjugate comprising approximately 4-10 anthracycline molecules linked to an antibody reactive with a selected cell population to be killed, each anthracycline having a keto group at the C-13 position and being attached to the antibody via a linker arm, the linker arm being covalently bound to the anthracycline by an acylhydrazone linkage at the 13-keto position of the anthracycline.
Claim 3
Dependent Claim
17 words
The immunoconjugate of claim 1, wherein the linker arm additionally contains a disulfide bond or thioether bond.
Claim 4
Dependent Claim
62 words
An immunoconjugate comprising at least one anthracycline molecule having a keto group at the C-13 position attached via a linker arm to an antibody reactive with a selected cell population to be killed, wherein the linker arm is covalently bound to the anthracycline by an acylhydrazone linkage at the 13-keto position of the anthracycline and additionally contains a disulfide or thioether bond.
Claim 5
Dependent Claim
62 words
An immunoconjugate comprising at least one anthracycline molecule having a keto group at the C-13 position attached via a linker arm to an antibody reactive with a selected cell population to be killed, wherein the linker arm is covalently bound to the anthracycline by an acylhydrazone linkage at the 13-keto position of the anthracycline and additionally contains a disulfide or thioether bond.
Claim 6
Dependent Claim
26 words
The immunoconjugate of claim 1, wherein the anthracycline is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, esorubicin, 4′-THP-adriamycin, AD-32 and 3′-deamino-3′-(3-cyano-4-morpholinyl)-doxorubicin.
Claim 7
Dependent Claim
14 words
The immunoconjugate of claim 1 or 3, wherein the anthracycline is adriamycin or daunomycin.
Claim 8
Dependent Claim
15 words
The immunoconjugate of claim 1 or 3, wherein the antibody is reactive with tumor cells.
Claim 9
Dependent Claim
23 words
The immunoconjugate of claim 6, wherein the antibody is reactive with an antigen associated with carcinomas, melanomas, lymphomas, bone or soft tissue sarcomas.
Claim 10
Dependent Claim
21 words
The immunoconjugate of claim 1 or 3, wherein the antibody is reactive with the CD37 antigen found on B cell lymphomas.
Claim 11
Dependent Claim
13 words
The immunoconjugate of claim 1 , wherein the antibody is a monoclonal antibody.
Claim 12
Dependent Claim
25 words
The immunoconjugate of claim 1 or 3, wherein the antibody is the monoclonal antibody 5E9, 3A1, L6, G28.1 or G28.5 and the anthracycline is adriamycin.
Claim 13
Dependent Claim
71 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 14
Dependent Claim
71 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 15
Dependent Claim
69 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 16
Dependent Claim
69 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 17
Dependent Claim
91 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ and R⁷ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R⁴, R⁷ and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 18
Dependent Claim
91 words
A compound having the formula: wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ and R⁷ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R⁴, R⁷ and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive.
Claim 19
Dependent Claim
4 words
Adriamycin 13-{3-(2-pyridyldithio)propionyl}-hydrazone hydrocloride (ADM-HZN).
Claim 20
Dependent Claim
4 words
Adriamycin 13-{3-(2-pyridyldithio)propionyl}-hydrazone hydrocloride (ADM-HZN).
Claim 21
Dependent Claim
2 words
13-{3-(mercaptopropionyl)}adriamycin hydrazone.
Claim 22
Dependent Claim
2 words
13-{3-(mercaptopropionyl)}adriamycin hydrazone.
Claim 23
Independent Claim
182 words
A method of preparing a compound having the formula wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ and R⁷ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R⁴, R⁷ and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive, comprising: a) reacting an N-hydroxysuccinimido ester of ω-(R²dithio)carboxylic acid with hydrazine to form ω-(R²dithio)carboxylic acid hdyrazide, wherein R² is as defined above; and b) reacting said hydrazide with an anthracycline of the formula: wherein: R¹ is COCH₃, COCH₂OH, COCH₂OCOCH(OC₂H₅)₂ or COCH₂OCO(CH₂)₃CH₃; R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP.
Claim 24
Independent Claim
182 words
A method of preparing a compound having the formula wherein: R¹ is CH₃, CH₂OH, CH₂OCO(CH₂)₃CH₃ or CH₂OCOCH(OC₂H₅)₂; R² is R³ is OCH₃, OH or hydrogen; R⁴ and R⁷ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R⁴, R⁷ and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP; and n is an integer from 1 to 10, inclusive, comprising: a) reacting an N-hydroxysuccinimido ester of ω-(R²dithio)carboxylic acid with hydrazine to form ω-(R²dithio)carboxylic acid hdyrazide, wherein R² is as defined above; and b) reacting said hydrazide with an anthracycline of the formula: wherein: R¹ is COCH₃, COCH₂OH, COCH₂OCOCH(OC₂H₅)₂ or COCH₂OCO(CH₂)₃CH₃; R³ is OCH₃, OH or hydrogen; R⁴ is NH₂, NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R⁵ is OH, O-THP or hydrogen; R⁶ is OH or hydrogen, provided that R⁶ is not OH when R⁵ is OH or O-THP.
Claim 25
Dependent Claim
23 words
The method of claim 16, comprising the additional step of treating the compound with a reducing agent to form a 13-{3-(mercaptopropionyl)} anthracycline hydrazone.
Claim 26
Independent Claim
26 words
A method of preparing ADM-HZN comprising the steps of: a) reacting SPDP with hydrazine to form a 3-(2-pyridylthio)propionyl hydrazide; and b) reacting adriamycin-hydrocloride with said hydrazide.
Claim 27
Independent Claim
26 words
A method of preparing ADM-HZN comprising the steps of: a) reacting SPDP with hydrazine to form a 3-(2-pyridylthio)propionyl hydrazide; and b) reacting adriamycin-hydrocloride with said hydrazide.
Claim 28
Dependent Claim
38 words
A method of preparing the immunoconjugate of claim 1 or 3, comprising the steps of: a) reacting the antibody with a thiolating agent; and b) reacting the thiolated antibody with an acylhydrazone of claim 11, 12 or 13.
Claim 29
Dependent Claim
10 words
The method of claim 19, wherein the acylhydrazone is ADM-HZN.
Claim 30
Dependent Claim
13 words
The method of claim 19, wherein the thiolating agent is SPDP or 2-IT.
Claim 31
Dependent Claim
58 words
A method of preparing the immunoconjugate of claim 1 or 3, comprising the steps of: a) reacting the SPDP with hydrazine to form a 3-(2-pyridylthio)propionyl hydrazide; b) reacting adriamycin-hydrochloride with said hydrazide to form ADM-HZN; and c) reacting ADM-HZN with an antibody reactive with a selected cell population to be killed to which thiol groups have been attached.
Claim 32
Dependent Claim
70 words
A method of preparing the immunoconjugate of claim 1 or 3, comprising the steps of: a) reacting SPDP with hydrazine to form a 3-(2-pyridylthio)propionyl hydrazide; b) reacting adriamaycin-hydrochloride with said hydrazide to form ADM-HZN; c) treating said ADM-HZN with a reducing agent to form 13-{3-(mercaptopropionyl)}adriamycin hydrazone; and d) reacting said hydrazone with an antibody reactive with a selected cell population to be killed to which maleimide groups have been attached.
Claim 33
Dependent Claim
57 words
The use of at least one immunoconjugate according to anyone of claims 1 to 10 for preparing a pharmaceutical composition for delivering anthracyclines to a selected cell population to be killed, for treating mammalian diseases selected from the group consisting of cancers, non-malignant tumors, non-cytocidal viral or pathogenic infections and autoimmune disorders and for treating mammalian tumors.
Claim 34
Dependent Claim
94 words
The use of more than one immunoconjugate, wherein an antibody reactive with a selected cell population to be killed is linked to at least one anthracycline molecule via a linker arm attached to th e anthracycline by an acylhydrazone linkage at t he 13-ketoposition of the anthracycline, the antibody of each conjugate being reactive with the same or a different antigen or epitope associated with said cell population and the anthracycline of each conjugate being the same or different, for preparing a pharmaceutical composition for delivering a combination of anthracyclines to said cell population.
Claim 35
Dependent Claim
94 words
The use of more than one immunoconjugate, wherein an antibody reactive with a selected cell population to be killed is linked to at least one anthracycline molecule via a linker arm attached to th e anthracycline by an acylhydrazone linkage at t he 13-ketoposition of the anthracycline, the antibody of each conjugate being reactive with the same or a different antigen or epitope associated with said cell population and the anthracycline of each conjugate being the same or different, for preparing a pharmaceutical composition for delivering a combination of anthracyclines to said cell population.
Claim 36
Dependent Claim
48 words
A pharmaceutically acceptable composition useful in the treatment of disease in particular of cancers, non-malignant tumors, non-cytocidal viral or pathogenic infections, and autoimmune disorders, which comprises a pharmaceutically effective amount of at least one immunoconjugate according to anyone of claims 1 to 10 and a pharmaceutically acceptable carrier.
References Cited (Backward Citations)
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