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US 5,851,527 AGranted
Method for antibody targeting of therapeutic agents
AssigneeImmunomedics, Inc.
InventorHans John Hansen
Life of this patent
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Abstract
The targeting capability of an antibody is enhanced using an antibody-enzyme conjugate and a separate soluble substrate-agent conjugate, wherein the targeted enzyme catalyzes the conversion of a soluble substrate, bearing at least one therapeutic or diagnostic agent, to a product comprising the agent, which accumulates at the target site for effective treatment or diagnosis. This method is useful for targeting any type of agent to a site to which an antibody can selectively bind, including use for imaging, e.g., tumors, infectious lesions, fibrin clots, myocardial infarctions, non-cancerous cells, damaged normal cells, atherosclerotic plaque, lymphocyte autoreactive clones, and for therapy, e.g., with drugs, toxins, immune modulators, radioisotopes or antibiotics.
Claims26
A method for targeting a cytotoxic agent to a target site, comprising the steps of:
- (a) injecting a mammal parenterally with an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope on an enzyme, wherein binding to said epitope does not interfere with enzyme activity;
- (b) subsequently injecting said mammal parenterally with an effective amount for enzyme activity of said enzyme, such that said bispecific antibody or antibody fragment binds said enzyme to form an antibody-enzyme conjugate in situ;
- and
- (c) after a sufficient period of time for localization of said antibody-enzyme conjugate at the target site and for unbound antibody-enzyme conjugate to clear from the circulatory system of the mammal, further injecting said mammal parenterally with an effective amount for deposition at said site of a serum soluble polymer substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising a cytotoxic agent that is relatively insoluble in serum in vivo, wherein the cytotoxic agent partitions out once the substrate-agent conjugate is acted upon by the enzyme component of the targeted antibody-enzyme conjugate, so that the agent then accretes at the target site to a significantly greater extent than the substrate-agent conjugate would accrete in the absence of the enzyme, said polymer substrate-agent conjugate comprising a polymer substrate for said enzyme, wherein either (1) a plurality of molecules of said agent are linked to said polymer substrate, or (2) said polymer substrate is a coating on the agent, which agent is one that is attracted to the target site in the absence of such coating, such that cleavage by the enzyme liberates the agent;
- wherein said enzyme is selected from the group consisting of dextranase, cellulase and beta-glucosidase.
2 more elements
A sterile injectable preparation, for targeting a cytotoxic agent to a target site, comprising;
- (a) a first sterile injectable solution containing an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope of an enzyme, wherein binding to said epitope does not interfere with enzyme activity, said antibody or antibody fragment being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- (b) a second sterile injectable solution containing an effective amount for enzyme activity at said target site of said enzyme, said enzyme being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- and
- (c) a third sterile injectable solution containing an effective amount, for deposition at said site, of a serum soluble polymer substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising at least one cytotoxic agent that is relatively insoluble in serum in vivo, said polymer substrate-agent conjugate comprising a polymer substrate for said enzyme, wherein either (1) a plurality of molecules of said agent are linked to said polymer substrate, or (2) said polymer substrate is a coating on the agent, which agent is one that is attracted to the target site in the absence of such coating, such that cleavage by the enzyme liberates the agent, said polymer substrate-agent conjugate being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- wherein said enzyme is selected from the group consisting of dextranase, cellulase, and beta-glucosidase.
2 more elements
A kit, for targeting a cytotoxic agent to a target site, comprising;
- (a) a first sterile container containing an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope of an enzyme which does not interfere with enzyme activity;
- (b) a second sterile container containing an effective amount for enzyme activity at said target site of said enzyme;
- and
- (c) a third sterile container containing an effective amount for deposition at said site of a serum soluble polymer substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising a cytotoxic agent that is relatively insoluble in serum in vivo, said polymer substrate-agent conjugate comprising a polymer substrate for said enzyme, wherein either (1) a plurality of molecules of said agent are linked to said polymer substrate, or (2) said polymer substrate is a coating on the agent, which agent is one that is attracted to the target site in the absence of such coating, such that cleavage by the enzyme liberates the agent;
- wherein said enzyme is selected from the group consisting of dextranase, cellulase, and beta-glucosidase.
2 more elements
A method for targeting a cytotoxic agent to a target site, comprising the steps of:
- (a) injecting a mammal parenterally with an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope on an enzyme, wherein binding to said epitope does not interfere with enzyme activity;
- (b) subsequently injecting said mammal parenterally with an effective amount for enzyme activity of said enzyme, such that said bispecific antibody or antibody fragment binds said enzyme to form an antibody-enzyme conjugate in situ;
- and
- (c) after a sufficient period of time for localization of said antibody-enzyme conjugate at the target site and for unbound antibody-enzyme conjugate to clear from the circulatory system of the mammal, further injecting said mammal parenterally with an effective amount for deposition at said site of a serum soluble substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising a cytotoxic agent that is relatively insoluble in serum in vivo, wherein the cytotoxic agent partitions out once the substrate-agent conjugate is acted upon by the enzyme component of the targeted antibody-enzyme conjugate, so that the agent then accretes at the target site to a significantly greater extent than the substrate-agent conjugate would accrete in the absence of the enzyme;
- wherein said enzyme is glucuronidase.
2 more elements
A sterile injectable preparation, for targeting a cytotoxic agent to a target site, comprising;
- (a) a first sterile injectable solution containing an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope of an enzyme, wherein binding to said epitope does not interfere with enzyme activity, said antibody or antibody fragment being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- (b) a second sterile injectable solution containing an effective amount for enzyme activity at said target site of said enzyme, said enzyme being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- and
- (c) a third sterile injectable solution containing an effective amount, for deposition at said site, of a serum soluble substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising at least one cytotoxic agent that is relatively insoluble in serum in vivo, said substrate-agent conjugate comprising a substrate for said enzyme, wherein cleavage by the enzyme liberates serum soluble cytotoxic agent in situ, said substrate-agent conjugate being dissolved in a pharmaceutically acceptable sterile injection vehicle;
- wherein said enzyme is glucuronidase.
2 more elements
A kit for targeting a cytotoxic agent to a target site, comprising;
- (a) a first sterile container containing an effective amount for targeting of a bispecific antibody or antibody fragment having a first binding site specific for an antigen present at a target site and a second binding site specific for an epitope of an enzyme which does not interfere with enzyme activity;
- (b) a second sterile container containing an effective amount for enzyme activity at said target site of said enzyme;
- and
- (c) a third sterile container containing an effective amount for deposition at said site of a soluble substrate-agent conjugate which is capable of transformation by said enzyme to form a product comprising a cytotoxic agent, said substrate-agent conjugate comprising a substrate for said enzyme, wherein cleavage by the enzyme liberates soluble cytotoxic agent in situ,
- wherein said enzyme is glucuronidase.
2 more elements
Dependencies are inferred from the claim text.