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Last Updated: March 29, 2024

Claims for Patent: 6,358,490


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Summary for Patent: 6,358,490
Title: Three-step pretargeting methods and compounds
Abstract:Methods, compounds, compositions and kits that relate to pretargeted delivery of diagnostic and therapeutic agents are disclosed. In particular, three-step pretargeting methods are described.
Inventor(s): Theodore; Louis J. (Lynnwood, WA), Reno; John M. (Brier, WA), Gustavson; Linda M. (Seattle, WA)
Assignee: NeoRx Corporation (Seattle, WA)
Application Number:09/316,452
Patent Claims:1. A method of enhancing active agent localization at a target site in a mammalian recipient, which method comprises:

administering to the recipient a first conjugate comprising an antibody or antigen-binding antibody fragment and a biotin, whereupon the first conjugate localizes to the target site;

administering to the recipient avidin or streptavidin; and

thereupon administering to the recipient a second conjugate comprising biotin, a linker resistant to biotinidase cleavage and an active agent, wherein second conjugate localization at the target site is enhanced as a result of prior localization of the first conjugate and wherein the active agent is an anti-tumor agent or chemotherapeutic drug,

and further wherein the linker is selected from the group consisting of:

1) a D-amino acid-containing linker of the formula ##STR47##

2) a linker of the formula ##STR48##

3) a linker of the formula ##STR49##

4) a linker of the formula ##STR50##

wherein L' is selected from the group consisting of:

a) --NH--CO--(CH.sub.2).sub.n --O--;

b) --NH--; ##STR51##

d) --NH--CS--NH--; and

e) --NH--CO--(CH.sub.2).sub.n --NH--;

wherein R.sup.1 is hydrogen, lower alkyl; lower alkyl substituted with one or more hydrophilic groups, selected from the group consisting of (CH.sub.2).sub.m --OH, (CH.sub.2).sub.m --OSO.sub.3, (CH.sub.2).sub.m --SO.sub.3, and ##STR52##

where m is 1 or 2;

glucuronide-substituted amino acids;

R.sup.2 is hydrogen; lower alkyl; substituted lower alkyl having one or more substituents selected from the group consisting of hydroxy, sulfate, and phosphonate; or a hydrophilic moiety;

R.sup.3 is hydrogen; an amine; a lower alkyl; a hydroxy-, sulfate- or phosphonate-substituted lower alkyl; a glucuronide; or a glucuronide-derivatized amino acid;

R.sup.4 is hydrogen or lower alkyl;

R' is hydrogen, --(CH.sub.2).sub.2 --OH or a sulfate or phosphonate derivative thereof; or ##STR53##

R" is a bond or --(CH.sub.2).sub.n --CO--NH; and

n ranges from 0-5.

2. A method of claim 1 wherein the antibody is a monoclonal antibody, or a monovalent antigen-binding fragment thereof.

3. A method of claim 2 wherein the monoclonal antibody is a human, a humanized or a chimeric monoclonal antibody.

4. A method of claim 3 wherein the monoclonal antibody or fragment thereof is reactive with an antigen recognized by the antibody NR-LU-10.

5. A method of claim 1 wherein the anti-tumor agent is a cytokine.

6. A method of claim 5 wherein the cytokine is tumor necrosis factor.

7. A method of claim 1 wherein the cytokine is an interleukin.

8. A method of claim 1 wherein the anti-tumor agent or chemotherapeutic drug is selected from the group consisting of asparaginase, bleomycin, carboplatin, cisplatinum, cyclophosphamide, cytarabine, doxorubicin, 5-fluorouracil, fludarabine, ifosfamide, levamisole, melphalan, mercaptopurine, methotrexate, mitoxantrone, paclitaxel, pentostatin, teniposide, 6-thioguanine, and vinblastine.

9. A method of claim 1 wherein the step of administering the second conjugate is conducted by intralesional or intraarterial injection.

10. A method of claim 9 wherein the second conjugate is administered via an artery supplying target site tissue.

11. A method of claim 9 wherein the second conjugate is administered via an artery selected from the group consisting of hepatic artery, carotid artery, bronchial artery and renal artery.

12. A method of claim 1 wherein the second conjugate is administered intravenously.

13. A method of claim 1 wherein the linker is a D-amino acid-incorporating linker of the formula ##STR54##

14. A method of claim 13 wherein R.sup.1 is CH.sub.3 and R.sup.2 is H.

15. A method of claim 1 wherein the linker is a linker of the formula ##STR55##

16. A method of claim 15 wherein R.sup.3 is hydrogen; R.sup.4 is CH.sub.3 ; and n is 4.

17. A method of claim 15 wherein R.sup.3 is hydrogen; R.sup.4 is CH.sub.3 ; and n is 0.

18. A method of claim 1 wherein the linker is a linker of the formula ##STR56##

wherein L' is selected from the group consisting of:

a) --NH--CO--(CH.sub.2).sub.n --O--;

b) --NH--; ##STR57##

d) --NH--CS--NH--; and

e) --NH--CO--(CH.sub.2).sub.n --NH.

19. A method of enhancing active agent localization at a target site in a mammalian recipient, which method comprises:

administering to the recipient a first conjugate comprising an antibody or an antigen-binding antibody fragment thereof and a biotin, whereupon the first conjugate localizes to the target site;

administering to the recipient avidin or streptavidin; and

thereupon administering to the recipient a second conjugate comprising biotin, a linker resistant to biotinidase cleavage and an active agent, wherein second conjugate localization at the target site is enhanced as a result of prior localization of the first conjugate and wherein the active agent is an anti-tumor agent or chemotherapeutic drug,

and further wherein the linker has the formula ##STR58##

wherein R.sup.3 is hydrogen, R.sup.4 is CH.sub.3 and n is 4; or R.sup.3 is hydrogen, R.sup.4 is CH.sub.3 and n is 0.

20. A method of enhancing active agent localization at a target site in a mammalian recipient, which method comprises:

administering to the recipient a first conjugate comprising an antibody or an antigen-binding antibody fragment thereof and a biotin, whereupon the first conjugate localizes to the target site;

administering to the recipient avidin or streptavidin; and

thereupon administering to the recipient a second conjugate comprising biotin, a linker resistant to biotinidase cleavage and an active agent, wherein second conjugate localization at the target site is enhanced as a result of prior localization of the first conjugate and wherein the active agent is an anti-tumor agent or chemotherapeutic drug,

and further wherein the linker is a D-amino acid incorporating a linker of the formula ##STR59##

wherein R.sup.1 is CH.sub.3 and R.sup.2 is H.

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