Patent US1963138A successfully refreshed from Google Patents.
Patent EP0302473A2 successfully refreshed from Google Patents.
EP0302473A2
Expired / Lapsed
EP
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Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells
Assignee: Bristol Myers Squibb Co
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Filing: 1988-08-03
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Granted: —
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Expires: 2008-08-03
Abstract
Abstract This invention relates to a novel method for the delivery of cytotoxic drugs to tumor cells by the administration of a tumor-specific antibody-enzyme conjugate that binds to the tumor cells, and the additional administration of a prodrug that is converted at the tumor site, in the presence of the antibody-bound enzyme, to an active cytotoxic drug. According to preferred embodiments of this invention, antibody-enzyme conjugates containing the enzyme, alkaline phosphatase ("AP"), have been used in conjunction with the novel prodrug, etoposide-4′-phosphate or 7-(2′-aminoethyl phosphate)mitomycin or a combination thereof, to effect killing of tumor cells. According to another embodiment of the invention, an antibody-enzyme conjugate containing the enzyme, penicillin V amidase ("PVA"), has been used. in conjunction with a novel prodrug, N-( p -hydroxyphenoxyacetyl)adriamycin to effect killing of tumor cells. Still another embodiment of the invention relates to the use of an antibody-enzyme conjugate containing the enzyme, cytosine deaminase ("CD"), in combination with the prodrug, 5-fluorocytosine, to effect killing of tumor cells. The methods, antibody-enzyme conjugates, prodrugs, pharmaceutical compositions and combinations of this invention provide for enhanced selective killing of tumor cells and are thus useful in the treatment of cancers and other tumors.
Inventors
- 👤 Peter D. Senter
- 👤 Mark G. Saulnier
- 👤 Joseph P. Brown
- 👤 David E. Kerr
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 09:22
CPC Classifications
A; A61; A61K; A61K39/00; A61K39/395; A61K39/44; B; B82; B82Y; B82Y5/00; A61K38/00; A61K38/01; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6891; A61K47/6899; A61P; A61P35/00; A61P43/00; C; C07; C07H; C07H15/00; C07H15/20; C07H15/24; C07H15/252
Claims Analysis
Total Claims: 40
Claim 1
Independent Claim
65 words
The use of at least one prodrug that is weakly cytotoxic to tumor cells compared to its corresponding parent drug and of at least one antibody-enzyme conjugate comprising an antibody reactive with an antigen on the surface of tumor cells conjugated to an enzyme capable of converting said prodrug into the more cytotoxic parent drug, for preparing a pharmaceutical composition for the treatment of tumors.
Claim 2
Dependent Claim
65 words
The use of at least one prodrug that is weakly cytotoxic to tumor cells compared to its corresponding parent drug and of at least one antibody-enzyme conjugate comprising an antibody reactive with an antigen on the surface of tumor cells conjugated to an enzyme capable of converting said prodrug into the more cytotoxic parent drug, for preparing a pharmaceutical composition for the treatment of tumors.
Claim 3
Dependent Claim
20 words
The use of claim 1, wherein the antibody is selected from the group consisting of polyclonal, monoclonal or chimeric antibodies.
Claim 4
Dependent Claim
21 words
The use of claim 1, wherein the antibody is selected from the group consisting of monoclonal antibodies L6, 96,5 and 1F5.
Claim 5
Dependent Claim
29 words
The use of claim 1, wherein the enzyme is selected from the group consisting of alkaline phosphatase, penicillin amidases, arylsulfatases, cytosine deaminases, proteases, D-alanyl carboxypeptidases, carbohydrate-cleaving enzymes and β-lactamases.
Claim 6
Dependent Claim
17 words
The use of claim 1, wherein the enzyme is alkaline phosphatase, penicillin V amidase, or cytosine deaminase.
Claim 7
Dependent Claim
36 words
The use of claim 1, wherein the parent drug is selected from the group consisting of etoposide, teniposide, adriamycin, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycins, cis-platinum and cis-platinum analogues, bleomycins, esperamicins, 5-fluorouracil, melphalan and other nitrogen mustards.
Claim 8
Dependent Claim
15 words
The use of claim 1, wherein the parent drug is etoposide, mitomycin, adriamycin, or 5-fluorouracil.
Claim 9
Dependent Claim
38 words
The use of claim 1, wherein the prodrug is selected from the group consisting of phosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, D-amino acid modified prodrugs, optionally substituted phenoxyacetamide-containing prodrugs and optionally substituted phenylacetamide-containing prodrugs.
Claim 10
Dependent Claim
40 words
The use of claim 1, wherein the prodrug is selected from the group consisting of etoposide phosphates, etoposide thiophosphates, etoposide sulfates, teniposide phosphates, teniposide thiophosphates, teniposide sulfates, adriamycin phosphates, adriamycin sulfates, N⁷-C₁₋₈ alkyl mitomycin phosphates and N⁷-C₁₋₈ alkyl mitomycin sulfates.
Claim 11
Dependent Claim
24 words
The use of claim 1, wherein the prodrug is etoposide-4′-phosphate or a pharmaceutically acceptable salt thereof, or 7-(2′-aminoethylphosphate)mitomycin or a pharmaceutically acceptable salt thereof.
Claim 12
Dependent Claim
23 words
The method of claim 1, wherein the prodrug is selected from the group consisting of N-(p-hydroxyphenoxyacetyl)adriamycin, N-(phenoxyacetyl)adriamycin, N-(p-hydroxyphenylacetyl)adriamycin, N-(phenylacetyl)adriamycin, 5-fluorouridine monophosphate and 5-fluorocytosine.
Claim 13
Dependent Claim
18 words
The use of claim 1, wherein the antibody-enzyme conjugate is L6-AP, 96,5-AP, 1F5-AP, L6-PVA, 1F5-PVA, L6-CD or 1F5-CD.
Claim 14
Dependent Claim
24 words
The use of claim 1, wherein the antibody-enzyme conjugate is L6-AP and the prodrug is etoposide-4′-phosphate, N⁷-C₁₋₈-alkyl mitomycin phosphate or pharmaceutically acceptable salts thereof.
Claim 15
Dependent Claim
24 words
The use of claim 1, wherein the antibody-enzyme conjugate is L6-PVA and the prodrug is selected from the group consisting of N-(p-hydroxyphenoxyacetyl)adriamycin and N-(phenoxyacetyl)adriamycin.
Claim 16
Dependent Claim
16 words
The use of claim 1, wherein the antibody-enzyme conjugate is L6-CD and the prodrug is 5-fluorocytosine.
Claim 17
Dependent Claim
30 words
The use of claim 1, wherein the tumor cells are of an origin selected form the group consisting of carcinomas, melanomas, lymphomas, bone and soft tissue sarcomas and other tumors.
Claim 18
Dependent Claim
30 words
The use of anyone of the preceding claims wherein more than one prodrug is used, each of which is weakly cytotoxic to tumor cells compared to its corresponding parent drug
Claim 19
Dependent Claim
11 words
The use of claim 17, wherein the enzyme is alkaline phosphatase.
Claim 20
Dependent Claim
46 words
The use of claim 17, wherein the prodrugs are selected from the gorup consisting of etoposide phosphates, etoposide thiophosphates, etoposide sulfates, teniposide phosphates, teniposide thiophosphates, teniposide sulfates, adriamycin phosphate, adriamycin sulfates, N-phenoxyacetyl derivatives of adriamycin, N-phenylacetyl derivatives of adriamycin, N⁷-C₁₋₈-alkyl-mitomycin phosphates and N⁷-C₁₋₈ alkyl mitomycin sulfates.
Claim 21
Dependent Claim
15 words
The use of claim 17, wherein one of the prodrugs is 5-fluorocytosine or 5-fluorouridine monophosphate.
Claim 22
Dependent Claim
19 words
The use of claim 17, wherein the prodrugs are etoposide-4′-phosphate, N⁷-C₁₋₈ alkyl mitomycin phosphate or pharmaceutically acceptable salts thereof.
Claim 23
Dependent Claim
20 words
The use of claim 17, wherein the antibody-enzyme conjugate is selected from the group consisting of L6-AP, 96,5-AP and 1F5-AP.
Claim 24
Dependent Claim
25 words
The use of claim 17, wherein the antibody-enzyme conjugate is L6-AP and the prodrugs are etoposide-4′-phosphate and N⁷-C₁₋₈alkyl mitomycin phosphate or pharmaceutically acceptable salts thereof.
Claim 25
Dependent Claim
74 words
The use of claim 1, wherein more than antibody-enzyme conjugate is used, wherein the antibody of each conjugate is reactive with the same or a different antigen located on the surface of said tumor cells and the enzyme of each conjugate is the same or different and is capable of converting at least one prodrug, that is weakly cytotoxic to tumor cells compared to its corresponding parent drug, into the more cytotoxic parent drug.
Claim 26
Dependent Claim
11 words
The antibody-enzyme conjugate L6-AP, 96,5-AP, 1F5-AP, L6-PVA, 1F5-PVA, L6-CD, or 1F5-CD.
Claim 27
Dependent Claim
11 words
The antibody-enzyme conjugate L6-AP, 96,5-AP, 1F5-AP, L6-PVA, 1F5-PVA, L6-CD, or 1F5-CD.
Claim 28
Dependent Claim
59 words
A compound having the formula: wherein: R¹ is H, and R³ is OH or OCH₃; or R¹ is OH and R³ is OCH₃; and R² is H or OH; or a compound having the formula wherein: R¹ is H, and R³ is OH or OCH₃; or R¹ is OH and R³ is OCH₃; and R² is H or OH.
Claim 29
Dependent Claim
59 words
A compound having the formula: wherein: R¹ is H, and R³ is OH or OCH₃; or R¹ is OH and R³ is OCH₃; and R² is H or OH; or a compound having the formula wherein: R¹ is H, and R³ is OH or OCH₃; or R¹ is OH and R³ is OCH₃; and R² is H or OH.
Claim 30
Dependent Claim
3 words
N-(p-hydroxyphenoxyacetyl)adriamycin or N-(phenoxyacetyl)adriamycin.
Claim 31
Dependent Claim
3 words
N-(p-hydroxyphenoxyacetyl)adriamycin or N-(phenoxyacetyl)adriamycin.
Claim 32
Dependent Claim
26 words
A pharmaceutically acceptable composition useful in the treatment of tumors which comprises a pharmaceutically effective amount of at least one antibody-enzyme conjugate according to claim 1.
Claim 33
Dependent Claim
35 words
A combination of at least one antibody-enzyme conjugate and at least one prodrug that is weakly cytotoxic to tumor cells compared to its corresponding parent drug, as defined in anyone of claims 1 to 24.
Claim 34
Dependent Claim
20 words
The combination of claim 29, wherein the antibody-enzyme conjugate is selected from the group consisting of L6-AP, L6-PVA and L6-CD.
Claim 35
Dependent Claim
47 words
The combination of claim 29, wherein the prodrug is selected from the group consisting of etoposide phosphates, etoposide thiophosphates, etoposide sulfates, teniposide phosphates, teniposide thiophosphates, teniposide sulfates, adriamycin phosphates, adriamycin sulfates, N-phenoxyacetyl derivatives of adriamycin, N-phenylacetyl derivatives of adriamycin, mitomycin phosphates, mitomycin sulfates, 5-fluorouridine monophosphates and 5-fluorocytosine.
Claim 36
Dependent Claim
25 words
The combination of claim 29, wherein the antibody-enzyme conjugate is L6-AP and the prodrug is etoposide-4′-phosphate, N⁷-C₁₋₈ alkyl mitomycin phosphate or pharmaceutically acceptable salts thereof.
Claim 37
Dependent Claim
68 words
The use of anyone of claims 1 to 24, wherein the antibody-enzyme conjugate is a fusion protein comprising at least the antigen binding region of an antibody reactive with a tumor-associated antigen linked to at least a functionally active portion of an enzyme capable of converting at least one weakly cytotoxic prodrug into its more cytotoxic parent drug, and the administration of an effective amount of said prodrug.
Claim 38
Dependent Claim
88 words
A process for the preparation of the compounds of claims 26 and 27, characterized in that, a compound of the general formula a) is reacted with p-hydroxy phenoxy acetic acid or phenoxy acetic acid, or an activated derivative therefrom, preferably activated with N-hydroxysuccinimide or dicyclo hexylcarbodiimide, to form a compound of the general formula (I); or b) is reacted with phenyl acetic acid or hydroxyphenyl acetic acid or an activated derivative therefrom, preferably activated with N-hydroxysuccinimide or dicyclo hexylcarbodiimide, to form a compound of the general formula (II).
Claim 39
Dependent Claim
27 words
A process for preparing the pharmaceutical composition of claim 29 which comprises providing at least one antibody-enzyme conjugate according to claim 1 in a suitable dosage form.
Claim 40
Dependent Claim
21 words
A process for preparing the combinations of claims 31 to 34 which comprises combining said antibody enzyme conjugate and said prodrug.
References Cited (Backward Citations)
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