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Last Updated: March 28, 2024

Claims for Patent: 5,525,338


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Summary for Patent: 5,525,338
Title: Detection and therapy of lesions with biotin/avidin conjugates
Abstract:Methods are provided for detecting and/or treating lesions in a patient. The methods use a targeting composition comprised of a biotin and targeting protein conjugate or an avidin and targeting protein conjugate; optionally, a clearing composition comprised of avidin, when the targeting composition is a biotin conjugate, or biotin, when the targeting composition is a avidin conjugate; a detection or therapeutic composition comprised of a conjugate of avidin or biotin with a targeting protein and detection or therapeutic agent; and, optionally, another detection or therapeutic composition comprised of avidin or biotin conjugated to a detection or therapeutic agent. Compositions and kits useful in the methods are also provided.
Inventor(s): Goldenberg; David M. (Short Hills, NJ)
Assignee: Immunomedics, Inc. (Morris Plains, NJ)
Application Number:07/933,982
Patent Claims:1. A method of amplifying the detection or treatment of lesions in a subject, comprising the steps of:

a) parenterally injecting into said subject a targeting composition comprising a targeting protein that specifically binds to a marker substance produced or associated with said lesion compared to non-lesion sites, covalently conjugated to biotin or avidin, and allowing said targeting composition to preferentially accrete at the targeted lesions;

b) optionally parenterally injecting into said subject a clearing composition that is capable both of clearing said targeting composition from said non-lesion sites and binding to said targeting composition accreted at said lesion, said clearing composition comprising avidin when said targeting composition contains biotin and comprising biotin when said targeting composition contains avidin;

c) parenterally injecting into said subject a first detection or therapeutic composition comprising a conjugate composed of covalently linked avidin-targeting protein detection or therapeutic agent, when said targeting composition contains avidin, and composed of covalently linker biotin-targeting protein detection or therapeutic agent when said targeting composition contains biotin, wherein said targeting protein may be the same or different than that of a) above, and allowing said detection or therapeutic composition to preferentially accrete at said lesion;

d) parenterally injecting into said subject, either prior or subsequent to the composition of c) above, a second detection or therapeutic composition comprising a covalent conjugate of avidin-detection or therapeutic agent when said targeting composition of a) above contains biotin and of biotin-detection, or therapeutic agent when said targeting composition of a) above contains avidin;

wherein step d) above is optional if a clearing composition has been administered.

2. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate wherein the targeting specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a first detection or therapeutic composition comprised of

(i) avidin conjugated to a detection or therapeutic agent and allowing the conjugate to accrete at the targeted lesion; and

(c) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and second detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

3. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate,

wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of

(i) avidin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a first detection or therapeutic composition comprised of

(i) avidin conjugated to a detection or therapeutic agent and allowing the conjugate to accrete at the targeted lesion; and

(d) then parenterally injecting a second detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

4. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of

(i) avidin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a first detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion; and

(d) then parenterally injecting second detection or therapeutic composition comprised of

(i) avidin conjugated to a detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion.

5. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of

(i) avidin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a first detection or therapeutic composition comprised of

(i) biotin conjugated to a detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion; and

(d) then parenterally injecting a second detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

6. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of

(i) avidin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion; and

(c) then parenterally injecting a first detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

7. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) a biotin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of

(i) avidin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and first detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion; and

(d) then parenterally injecting another detection or therapeutic composition comprised of

(ii) biotin conjugated to a detection or therapeutic

agent, and allowing the conjugate to accrete at the targeted lesion.

8. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a detection or therapeutic composition comprised of

(i) biotin conjugated to a first detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion; and

(c) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and second detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

9. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of biotin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a detection or therapeutic composition comprised of

(i) biotin conjugated to a first detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion; and

(d) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and second detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

10. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of biotin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and first detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion; and

(d) then parenterally injecting a second detection or therapeutic composition comprised of

(ii) biotin conjugated to a detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion.

11. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of biotin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion; (c) then parenterally injecting a first detection or therapeutic composition comprised of

(i) avidin conjugated to a detection or therapeutic agent and allowing the conjugate to accrete at the targeted lesion; and

(d) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and second detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

12. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of biotin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion; and

(c) then parenterally injecting a detection or therapeutic composition comprised of a conjugate of

(i) avidin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion.

13. The method of claim 1 for detecting or treating lesions in a patient, the method comprising the steps of:

(a) parenterally injecting a subject with a targeting composition comprised of

(i) an avidin-protein conjugate, wherein the targeting protein specifically binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion;

(b) then parenterally injecting a clearing composition comprised of biotin, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion;

(c) then parenterally injecting a first detection or therapeutic composition comprised of a conjugate of

(i) biotin, targeting protein and detection or therapeutic agent,

wherein the targeting protein specifically binds to a marker substance produced by or associated with the targeted lesion and may be the same as the targeting protein of the targeting composition, and allowing the composition to accrete at the targeted lesion; and

(d) then parenterally injecting a second detection or therapeutic composition comprised of

(i) avidin conjugated to a detection or therapeutic agent, and allowing the conjugate to accrete at the targeted lesion.

14. The method of claim 1, wherein the lesion is cancerous, cardiovascular, infectious or inflammatory.

15. The method of claim 14, wherein the cardiovascular lesion is a thrombus, embolus, infarct or atherosclerotic plaque.

16. The method of claim 14, wherein the cancerous lesion is a carcinoma, melanoma, sarcoma, neuroblastoma, leukemia, lymphoma, glioma or myeloma.

17. The method of claim 14, wherein the lesion is infectious or inflammatory.

18. The method of claim 1, wherein the targeting protein is a peptide, polypeptide, hormone, lymphokine, growth factor, albumin, cytokine, enzyme, immune modulator, receptor protein, antibody or antibody fragment.

19. The method of claim 1, wherein the protein of the targeting composition and the detection or therapeutic composition are the same.

20. The method of claim 1, wherein the protein of the targeting composition and the detection or therapeutic composition are different.

21. The method of claim 20, wherein the different proteins specifically bind to differing epitopes or molecules of the same marker substance.

22. The method of claim 18, wherein the targeting protein is a monoclonal antibody, or a specific binding fragment thereof.

23. The method of claim 22, wherein the fragment is a Fv, single chain antibody, Fab, Fab', F(ab).sub.2 or F(ab').sub.2.

24. The method of claim 23, wherein the fragment is Fab, Fab', F(ab).sub.2 or F(ab').sub.2.

25. The method of claim 22, wherein the antibody is multispecific.

26. The method of claim 25, wherein the antibody is multispecific to differing epitopes or molecules of a marker substance.

27. The method of claim 18, wherein the targeting protein has a specific immunoreactivity to a marker substance of at least 60% and a cross-reactivity to other antigens or non-target substances of less than 35%.

28. The method of claim 1, wherein the method is for detection of a lesion.

29. The method of claim 28, wherein the method is external imaging or internal detection.

30. The method of claim 29, wherein internal detection is during an operative, intravascular or endoscopic procedure.

31. The method of claim 28, wherein the detection agent is a radionuclide, mri enhancing agent, photoactivated dye or differentiation agent.

32. The method of claim 31, wherein the radionuclide is a gamma-, positron-, x-ray or fluorescence-emitter.

33. The method of claim 31, wherein the differentiation agent is a vitamin, cytokine, autocrine, hormone or drug.

34. The method of claim 31, wherein the radionuclide has an energy between 10 and 5000 keV.

35. The method of claim 34, wherein the radionuclide has an energy between 50 and 500 keV.

36. The method of claim 31, wherein the radionuclide used for imaging is Iodine-123, Iodine-131, Indium-111, Gallium-67, Ruthenium-97, Technetium-99m, Cobalt-57, Cobalt-58, Chromium-51, Iron-59, Selenium-75, Thallium-201, or Ytterbium-169.

37. The method of claim 30, wherein the radionuclide used is Iodine-125, Iodine-123, Iodine-131, Indium-111, Technetium-99m or Gallium-67.

38. The method of claim 31, wherein the mri enhancing agent is a species of Gadolinium, Iron, Manganese, Rhenium, Europium, Lanthanium, Holmium, or Ferbium.

39. The method of claim 1, wherein the method is for treating a lesion.

40. The method of claim 39, wherein the therapeutic agent is an isotope, drug, toxin, fluorescent dye activated by nonionizing radiation, hormone, hormone antagonist, receptor antagonist, autocrine or cytokine.

41. The method of claim 39, wherein the therapeutic agent is an electron- or neutron-capturing agent.

42. The method of claim 40, wherein the isotope is Iodine-125, Iodine-131, Rhenium-186, Rhenium-188, Silver-111, Platinum-197, Palladium-109, Copper-67, Phosphorus-32, Phosphorus-33, Yttrium-90, Scandium-47, Samarium-153, Lutetium-177, Rhodium-105, Praseodymium-142, Praseodymium-143, Terbium-161, Holmium-166, or Gold-199.

43. The method of claim 39, wherein the therapeutic agent is an anti-DNA, anti-RNA, anti-protein or anti-chromatin cytoxic or antimicrobial agent.

44. The method of claim 39, wherein the drug is taxol, mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, thiotepa, busulfan, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, fluorouracil, cytarabine, azaribine, mercaptopurine, thioguanine, vinblastine, vincristine, dactinomycin, daunorubicin, doxorubicin, bleomycin, mithramycin, mitomycin, L-asparaginase, cisplatin, hydroxyurea, procarbazine, mitotane, prednisone, hydroxyprogesterone caproate, medroprogesterone acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate and fluoxymesterone.

45. The method of claim 39, wherein the toxin is abrin, alpha toxin, diphtheria toxin, exotoxin, gelonin, pokeweed antiviral protein, ricin, or saporin.

46. The method of claim 39, wherein the drug is puromycin, cycloheximide or ribonuclease.

47. The method of claim 1, wherein the immunogenicity of avidin or of the therapeutic agent conjugate is reduced by coupling the avidin or therapeutic moiety of the conjugate with carbohydrate polymer or polyol groups.

48. The method of claim 1, wherein the immunogenicity of the targeting composition is reduced by coupling with a carbohydrate polymer or polyol groups.

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