Title:  Targeted therapy to a biomedical device

United States Patent:  6,238,872

Assignee:  S.E.T.-Smart Endolumenal Technologies Ltd. (Jerusalem, IL)

Filed:  September 30, 1998

A biomedical device assembly, such as a stent, for the targeted treatment of a tissue, such as the inhibition of restentosis. The stent is coated with an antigen, which is an example of a lock. The antigen can be bound by a labelled antibody, which is an example of a key and an effector. The antibody is preferably labelled with a radioactive source. According to one method of preparing the biomedical device assembly, after the stent has been placed in the blood vessel of the subject, the antibody is injected. The antibody then binds to the antigen on the stent, thereby localizing the radioactive source to the area to be treated, for example for restenosis. Other biomedical devices, such as a coil, an artificial valve or a vascular graft, could also be used in the place of the stent. The biomedical device could be placed in another biological passageway, such as the gastrointestinal tract, an airway or the genitourinary tract.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide localized therapy to a tissue or to a biological passageway.

It is another object of the present invention to provide such localized therapy by targeting an effector to a biomedical device, such that the area surrounding the biomedical device is treated.

It is still another object of the present invention to target the effector to the biomedical device with a lock and key system, in which the key is attached to the effector and the lock is attached to the biomedical device.

It is yet another object of the present invention to provide a method for manufacturing such a biomedical device.

These and other objects of the present invention will become apparent from the following description, claims and figures.

According to the teachings of the present invention, there is provided a biomedical device assembly comprising a biomedical device, wherein the biomedical device features an antigen and an antibody having a label attached, wherein the antigen and the antibody are bound. Preferably, the biological passageway is selected from the group consisting of blood vessel, airway, gastrointestinal tract, intracerebal, bile duct and genitourinary tract. More preferably, the biological passageway is a blood vessel.

Preferably, the antigen is a drug molecule. Also preferably, the biomedical device is selected from the group consisting of coil, artificial valve, vascular graft and stent. More preferably, the biomedical device is a stent.

Preferably, the label is selected from the group consisting of radioactive source and pharmaceutical moiety. More preferably, the label is a radioactive source.

According to another embodiment of the present invention, there is provided a method of substantially inhibiting restenosis in a blood vessel of a subject, comprising the steps of: (a) inserting a stent into the blood vessel of the subject, the stent having an antigen attached; and (b) administering an antibody to the subject, the antibody being capable of binding to the antigen and the antibody having a label attached wherein the label is capable of inhibiting restenosis.

Preferably, the label is selected from the group consisting of radioactive source and pharmaceutical moiety. More preferably, the label is a radioactive source. Preferably, the antigen includes a plurality of different types of antigens, such that the step of administering the antibody is repeated for a plurality of different types of antibodies.

According to another embodiment of the present invention, there is provided a biomedical device assembly for targeted treatment, comprising: (a) a biomedical device; (b) a lock, the lock being attached to the biomedical device; (c) a key for specifically interacting with the lock; and (d) an effector for performing the targeted treatment, the effector being attached to the key.

Preferably, the key and the lock are each individually selected from the group consisting of an antibody, an antigen, a non-regular antibody, a mixed proteinaceous and non-proteinaceous combination, and a non-proteinaceous molecule, and combinations thereof. More preferably, the antibody is selected from the group consisting of a polyclonal immunoglobulin, a monoclonal immunoglobulin, a SFv (single chain antigen binding protein), Fab¹ fragment, a Fab² fragment and a humanized monoclonal immunoglobulin.

Also more preferably, the antigen is selected from the group consisting of a protein, a peptide and fragments thereof, a carbohydrate macromolecule, an oligonucleotide and a pharmaceutical molecule, and combinations thereof. Most preferably, the protein is selected from the group consisting of avidin and biotin.

According to preferred embodiments of the present invention, the non-regular antibody is selected from the group consisting of a macromolecule of IgG, a bifunctional antibody, avidin and biotin. Preferably, the non-proteinaceous molecule is selected from the group consisting of a carbohydrate macromolecule, an oligonucleotide and a bifunctional chelator. Also preferably, the mixed proteinaceous and non-proteinaceous combination is a protein with an attached oligonucleotide.

According to other preferred embodiments of the present invention, the effector is selected from the group consisting of a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T-cell, a toxin, an endothelial cell, a chelate of a radioactive isotope and a bi-component effector. Preferably, the chelate of the radioactive isotope includes a chelator selected from the group consisting of DOTA, DTPA, nitro-benzyl DOTA and a bifunctional chelator. More preferably, the radioactive isotope is selected from the group consisting of yttrium 90 (⁹⁰ Y), lutetium 177 (¹¹⁷ Lu), rhenium 186 (¹⁸⁶ Re), rhenium 188 (¹⁸⁸ Re), bismuth 212 (²¹² Bi), astatine 211 (²¹¹ At), iodine 131 (¹³¹ I), iodine 125 (¹²⁵ I) and copper 67 (⁶⁷ Cu). Preferably, the bi-component effector is an enzyme and a prodrug, wherein the enzyme chemically alters the prodrug to activate the prodrug. Also preferably, the toxin is selected from the group consisting of a plant toxin, a bacterial toxin, a fungal toxin and a synthetic toxin.

According to still other preferred embodiments of the present invention, the lock is attached to a material coating at least a portion of a surface of the biomedical device. Preferably, the material is selected from the group consisting of a derivatizable polymer and a metal. More preferably, the material is the derivatizable polymer and the lock is attached to the derivatizable polymer by a covalent bond. Most preferably, the covalent bond is formed by a chemical reaction between the lock and the derivatizable polymer. Also most preferably, the chemical reaction is activated by exposure of the lock and the derivatizable polymer to ultraviolet light.

Preferably the lock is attached to the derivatizable polymer by a noncovalent bond.

According to yet another embodiment of the present invention, there is provided a method for manufacturing a biomedical device assembly, the method comprising the steps of: (a) providing a biomedical device; (b) attaching a lock to the biomedical device; (c) attaching an effector to a key to form an attached effector; and (d) incubating the lock and the key, such that the lock and the key interact to form the biomedical device assembly.

Preferably, the step of attaching the lock to the biomedical device is performed ex vivo, and the step of incubating the lock and the key to form the biomedical device assembly is performed by first placing the biomedical device with the lock in a subject, and then administering the key with the attached effector to the subject, such that the biomedical device assembly is formed by an interaction of the key and the lock in the subject. Alternatively, and preferably, the step of attaching the lock to the biomedical device is performed ex vivo, and the step of incubating the lock and the key to form the biomedical device assembly is performed ex vivo.

Hereinafter, the terms "radionuclide" and "radioactive isotope" include, but are not limited to, yttrium 90 (⁹⁰ Y), lutetium 177 (¹⁷⁷ Lu), rhenium 186 (¹⁸⁶ Re), rhenium 188 (¹⁸⁸ Re), phosphorous 32 (³² P), bismuth 212 (²¹² Bi), astatine 211 (²¹¹ At), iodine 131 (¹³¹ I), iodine 125 (¹²⁵ I), iridium 192 (¹⁹² Ir), palladium (¹⁰³ Pd) and copper 67 (⁶⁷ Cu).

Hereinafter, the term "DTPA" includes 1,4,7-triazaheptane-N,N',N"-pentaacetic acid) and derivatives thereof. The term "DOTA" includes 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid and derivatives thereof.

Hereinafter, the terms "Sfv" and "single chain antigen binding protein" refer to a type of a fragment of an immunoglobulin, an example of which is sFv CC49 (Larson, S. M. et al., Cancer, 80:2458-68, 1997).

Claim 1 of 12 Claims

What is claimed is:

1. A method of substantially inhibiting restenosis in a blood vessel of a subject, comprising the steps of:

(a) inserting a stent into the blood vessel of the subject, said stent having an antigen attached; and

(b) administering a first antibody to the subject, said first antibody being capable of binding to said antigen and said first antibody having a label attached wherein said label is capable of inhibiting restenosis and wherein said label is a radioactive source.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.