US4867973A
Expired / Lapsed
US
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Antibody-therapeutic agent conjugates
Assignee: Cytogen Corp
•
Filing: 1984-09-13
•
Granted: 1989-09-19
•
Expires: 2004-09-13
Abstract
Abstract This invention relates to antibody-therapeutic agent conjugates having a therapeutic agent covalently attached to an antibody or antibody fragment. Also described are methods for intermediates in the preparation of antibody conjugates. Therapeutic in vivo methods utilizing such antibody-therapeutic agent conjugates are described.
Inventors
- 👤 John W. F. Goers
- 👤 Hurley D. King
- 👤 Chyi Lee
- 👤 Daniel J. Coughlin
- 👤 Vernon L. Alvarez
- 👤 John D. Rodwell
- 👤 Thomas J. McKearn
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 18:22
CPC Classifications
G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/53; G01N33/531; G01N33/532; A; A61; A61K; A61K41/00; A61K41/0042; A61K41/0057; A61K41/0071; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/10; A61K51/1093; C; C07; C07K; C07K5/00; C07K5/04; C07K5/08; C07K5/0802; C07K5/0804; G01N33/534; A61K2121/00; Y; Y10; Y10S; Y10S530/00; Y10S530/827; Y10S530/828; Y10S530/863; Y10S530/864; Y10S530/866
Claims Analysis
Total Claims: 89
Claim 1
Independent Claim
171 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a therapeutic agent containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thio-semicarbazide groups, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 2
Independent Claim
171 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a therapeutic agent containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thio-semicarbazide groups, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 3
Dependent Claim
13 words
The method according to claim 1, wherein the oxidizing agent is an enzyme.
Claim 4
Dependent Claim
14 words
The method according to claim 1, wherein the oxidizing agent is an oxygen acid.
Claim 5
Dependent Claim
26 words
The method according to claim 1, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 6
Dependent Claim
21 words
The method according to claim 1, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 7
Dependent Claim
23 words
The method according to claim 1, wherein the antibody-therapeutic agent conjugate is stabilized by exposure to an effective amount of a reducing agent.
Claim 8
Independent Claim
186 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of the linker portion of a linker-therapeutic agent intermediate comprising a linker portion, containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, covalently attached to a therapeutic agent, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 9
Independent Claim
186 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of the linker portion of a linker-therapeutic agent intermediate comprising a linker portion, containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, covalently attached to a therapeutic agent, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 10
Dependent Claim
13 words
The method according to claim 7, wherein the oxidizing agent is an enzyme.
Claim 11
Dependent Claim
14 words
The method according to claim 7, wherein the oxidizing agent is an oxygen acid.
Claim 12
Dependent Claim
26 words
The method according to claim 7, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 13
Dependent Claim
21 words
The method according to claim 7, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 14
Dependent Claim
23 words
The method according to claim 7, wherein the antibody-therapeutic agent conjugate is stabilized by exposure to an effective amount of a reducing agent.
Claim 15
Dependent Claim
13 words
The method according to claim 7, wherein the linker is a branched linker.
Claim 16
Dependent Claim
16 words
The method according to claim 7, wherein the linker is susceptible to cleavage by activated complement.
Claim 17
Dependent Claim
19 words
The method according to claim 7, wherein the linker is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 18
Independent Claim
126 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: covalently attaching the linker portion of an antibody-linker intermediate comprising a linker portion covalently attached to an oxidized carbohydrate moiety of an antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment, to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration, and combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 19
Independent Claim
126 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: covalently attaching the linker portion of an antibody-linker intermediate comprising a linker portion covalently attached to an oxidized carbohydrate moiety of an antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment, to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration, and combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 20
Dependent Claim
26 words
The method according to claim 16, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 21
Dependent Claim
21 words
The method according to claim 16, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 22
Dependent Claim
22 words
The method according to claim 16, wherein the antibody-linker intermediate is stabilized by exposure to an effective amount of a reducing agent.
Claim 23
Dependent Claim
13 words
The method according to claim 16, wherein the linker is a branched linker.
Claim 24
Dependent Claim
16 words
The method according to claim 16, wherein the linker is susceptible to cleavage by activated complement.
Claim 25
Dependent Claim
19 words
The method according to claim 16, wherein the linker is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 26
Independent Claim
207 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a linker containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-linker intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the linker portion of the antibody-linker intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugated in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 27
Independent Claim
207 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a linker containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-linker intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the linker portion of the antibody-linker intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugated in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 28
Dependent Claim
13 words
The method according to claim 23, wherein the oxidizing agent is an enzyme.
Claim 29
Dependent Claim
14 words
The method according to claim 23, wherein the oxidizing agent is an oxygen acid.
Claim 30
Dependent Claim
26 words
The method according to claim 23, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 31
Dependent Claim
21 words
The method according to claim 23, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 32
Dependent Claim
22 words
The method according to claim 23, wherein the antibody-linker intermediate is stabilized by exposure to an effective amount of a reducing agent.
Claim 33
Dependent Claim
13 words
The method according to claim 23, wherein the linker is a branched linker.
Claim 34
Dependent Claim
16 words
The method according to claim 23, wherein the linker is susceptible to cleavage by activated complement.
Claim 35
Dependent Claim
19 words
The method according to claim 23, wherein the linker is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 36
Independent Claim
226 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a spacer portion of a linker, said linker comprising a spacer element covalently attached to a cleavable element and said spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-linker intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the cleavable element of the antibody-linker intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 37
Independent Claim
226 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a spacer portion of a linker, said linker comprising a spacer element covalently attached to a cleavable element and said spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-linker intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the cleavable element of the antibody-linker intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 38
Dependent Claim
13 words
The method according to claim 32, wherein the oxidizing agent is an enzyme.
Claim 39
Dependent Claim
14 words
The method according to claim 32, wherein the oxidizing agent is an oxygen acid.
Claim 40
Dependent Claim
26 words
The method according to claim 32, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 41
Dependent Claim
21 words
The method according to claim 32, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 42
Dependent Claim
22 words
The method according to claim 32, wherein the antibody-linker intermediate is stabilized by exposure to an effective amount of a reducing agent.
Claim 43
Dependent Claim
13 words
The method according to claim 32, wherein the linker is a branched linker.
Claim 44
Dependent Claim
17 words
The method according to claim 32, wherein the cleavable element is susceptible to cleavage by activated complement.
Claim 45
Dependent Claim
20 words
The method according to claim 32, wherein the cleavable element is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 46
Independent Claim
202 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment , in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; and (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a linker-therapeutic agent intermediate, said linker-therapeutic agent intermediate comprising a spacer element covalently attached to a cleavable element which is covalently attached to a therapeutic agent, and said amine group located on said spacer element and selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 47
Independent Claim
202 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment , in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; and (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with an amine group of a linker-therapeutic agent intermediate, said linker-therapeutic agent intermediate comprising a spacer element covalently attached to a cleavable element which is covalently attached to a therapeutic agent, and said amine group located on said spacer element and selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form a soluble antibody-therapeutic agent conjugate characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (c) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 48
Dependent Claim
13 words
The method according to claim 44, wherein the oxidizing agent is an enzyme.
Claim 49
Dependent Claim
14 words
The method according to claim 41, wherein the oxidizing agent is an oxygen acid.
Claim 50
Dependent Claim
26 words
The method according to claim 41, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 51
Dependent Claim
20 words
The method according to claim 41, wherein the antibody or antibody fragment is monoclonal antibody or a monoclonal antibody fragment.
Claim 52
Dependent Claim
23 words
The method according to claim 41, wherein the antibody-therapeutic agent conjugate is stabilized by exposure to an effective amount of a reducing agent.
Claim 53
Dependent Claim
13 words
The method according to claim 41, wherein the linker is a branched linker.
Claim 54
Dependent Claim
17 words
The method according to claim 41, wherein the cleavable element is susceptible to cleavage by activated complement.
Claim 55
Dependent Claim
20 words
The method according to claim 41, wherein the cleavable element is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 56
Independent Claim
212 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with a spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-spacer element intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the spacer element of the antibody-spacer element intermediate to a cleavable element of a cleavalbe element-therapeutic agent intermediate, to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 57
Independent Claim
212 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody fragment with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with a spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-spacer element intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the spacer element of the antibody-spacer element intermediate to a cleavable element of a cleavalbe element-therapeutic agent intermediate, to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (d) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 58
Dependent Claim
13 words
The method according to claim 50, wherein the oxidizing agent is an enzyme.
Claim 59
Dependent Claim
14 words
The method according to claim 50, wherein the oxidizing agent is an oxygen acid.
Claim 60
Dependent Claim
26 words
The method according to claim 50, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 61
Dependent Claim
21 words
The method according to claim 50, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 62
Dependent Claim
23 words
The method according to claim 50, wherein the antibody-spacer element intermediate is stabilized by exposure to an effective amount of a reducing agent.
Claim 63
Dependent Claim
15 words
The method according to claim 50, wherein the spacer element is a branched spacer element.
Claim 64
Dependent Claim
17 words
The method according to claim 50, wherein the cleavable element is susceptible to cleavage by activated complement.
Claim 65
Dependent Claim
20 words
The method according to claim 50, wherein the cleavable element is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 66
Independent Claim
229 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate, composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody conjugate with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with a spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-spacer element intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the spacer element of the antibody-spacer element intermediate to a cleavable element to form an antibody-spacer element-cleavable element intermediate; (d) covalently attaching the cleavable element of the antibody-spacer element-cleavable element intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (e) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 67
Independent Claim
229 words
A method for preparing a pharmaceutical antibody-therapeutic agent conjugate, composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: (a) reacting an antibody or antibody conjugate with an oxidizing agent to form an aldehyde group in a carbohydrate moiety of the antibody or antibody fragment, in which the carbohydrate moiety is located outside the antigen binding region of the antibody or antibody fragment; (b) reacting the aldehyde group of the resultant oxidized carbohydrate moiety of the antibody or antibody fragment with a spacer element containing an amine group selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups, to form an antibody-spacer element intermediate having substantially the same immunospecificity as the unconjugated antibody or antibody fragment; (c) covalently attaching the spacer element of the antibody-spacer element intermediate to a cleavable element to form an antibody-spacer element-cleavable element intermediate; (d) covalently attaching the cleavable element of the antibody-spacer element-cleavable element intermediate to a therapeutic agent to form a soluble antibody-therapeutic agent conjugate in which the antibody-therapeutic conjugate is characterized by (i) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (ii) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration; and (e) combining a therapeutically effective amount of the soluble antibody-therapeutic agent conjugate with a pharmaceutical carrier.
Claim 68
Dependent Claim
13 words
The method according to claim 59, wherein the oxidizing agent is an enzyme.
Claim 69
Dependent Claim
14 words
The method according to claim 59, wherein the oxidizing agent is an oxygen acid.
Claim 70
Dependent Claim
26 words
The method according to claim 59, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 71
Dependent Claim
21 words
The method according to claim 59, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 72
Dependent Claim
23 words
The method according to claim 59, wherein the antibody-spacer element intermediate is stabilized by exposure to an effective amount of a reducing agent.
Claim 73
Dependent Claim
15 words
The method according to claim 59, wherein the spacer element is a branched spacer element.
Claim 74
Dependent Claim
17 words
The method according to claim 59, wherein the cleavable element is susceptible to cleavage by activated complement.
Claim 75
Dependent Claim
20 words
The method according to claim 59, wherein the cleavable element is susceptible to cleavage by an enzyme having proteolytic activity.
Claim 76
Dependent Claim
96 words
A pharmaceutical composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: a therapeutically effective amount of an antibody-therapeutic agent conjugate in which: a therapeutic agent is attached via a covalent bond to an oxidized carbohydrate moiety outside the antigen binding region of an antibody or antibody fragment to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and a pharmaceutical carrier.
Claim 77
Dependent Claim
96 words
A pharmaceutical composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: a therapeutically effective amount of an antibody-therapeutic agent conjugate in which: a therapeutic agent is attached via a covalent bond to an oxidized carbohydrate moiety outside the antigen binding region of an antibody or antibody fragment to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and a pharmaceutical carrier.
Claim 78
Dependent Claim
25 words
The pharmaceutical composition according to claim 68, wherein the covalent bond is an imine, enamine, hydrazone, oxime, phenylhydrazone, semicarbazone, thiosemicarbazone, or a reduced form thereof.
Claim 79
Dependent Claim
27 words
The pharmaceutical composition according to claim 68, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 80
Dependent Claim
22 words
The pharmaceutical composition according to claim 68, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 81
Dependent Claim
103 words
A pharmaceutical composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: a therapeutically effective amount of an antibody-therapeutic agent conjugate in which: a therapeutic agent is attached via a covalent bond to a linker which is covalently attached to an oxidized carbohydrate moiety outside the antigen binding region of an antibody or antibody fragment to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and a pharmaceutical carrier.
Claim 82
Dependent Claim
103 words
A pharmaceutical composition suitable for in vivo administration and for the in vivo delivery of a therapeutic agent, comprising: a therapeutically effective amount of an antibody-therapeutic agent conjugate in which: a therapeutic agent is attached via a covalent bond to a linker which is covalently attached to an oxidized carbohydrate moiety outside the antigen binding region of an antibody or antibody fragment to form a soluble antibody-therapeutic agent conjugate characterized by (a) substantially the same immunospecificity as the unconjugated antibody or antibody fragment; and (b) aqueous solubility such that the antibody-therapeutic agent conjugate is suitable for in vivo administration and a pharmaceutical carrier.
Claim 83
Dependent Claim
25 words
The pharmaceutical composition according to claim 72, wherein the covalent bond is an imine, enamine, hydrazone, oxime, phenylhydrazone, semicarbazone, thiosemicarbazone, or a reduced form thereof.
Claim 84
Dependent Claim
27 words
The pharmaceutical composition according to claim 72, wherein the antibody fragment is selected from the group consisting of Fab fragments, (Fab') 2 fragments and half antibody molecules.
Claim 85
Dependent Claim
22 words
The pharmaceutical composition according to claim 72, wherein the antibody or antibody fragment is a monoclonal antibody or a monoclonal antibody fragment.
Claim 86
Dependent Claim
14 words
The pharmaceutical composition according to claim 72, wherein the linker is a branched linker.
Claim 87
Dependent Claim
18 words
The pharmaceutical composition according to claim 72, wherein the linker comprises a spacer element and a cleavable element.
Claim 88
Dependent Claim
17 words
The pharmaceutical composition according to claim 77, wherein the cleavable element is susceptible to cleavage to complement.
Claim 89
Dependent Claim
21 words
The pharmaceutical composition according to claim 77, wherein the cleavable element is susceptible to cleavage by an enzyme having proteolytic activity.
References Cited (Backward Citations)
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1992-09-18 | 1993-03-20 | 1993-09-19 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1996-09-18 | 1997-03-20 | 1997-09-19 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2000-09-18 | 2001-03-20 | 2001-09-19 | $7700.00 | Window Closed / Lapsed |