Functionally specific antibodies

• US 4,867,962 A
• Filed: 02/26/1988
• Issued: 09/19/1989
• Est. Priority Date: 02/26/1988
• Status: Expired due to Term

• Current Assignee: NeoRx Corporation
• Original Assignee: NeoRx Corporation
• Inventors: Abrams, Paul G.
• Primary Examiner(s): Maples, John S.
• Application Number:
  US07/160,648
• Time in Patent Office: 571 Days
• Field of Search: 424/1.1, 424/9, 424/85
• US Class Current: 424/1.49
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 51/1054 the tumor cell being from lung
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: C07K 16/3023 Lung

Abstract

Diagnostic or therapeutic agents are attached to two or more antibody species having non-overlapping patterns of cross-reactivity to increase the relative amount of the active agent(s) delivered to desired target cells compared to non-target cells. The agents may be attached to monoclonal antibodies which bind to cancer cells so that a higher percentage of the active agent(s) localize on the target cells compared to each type of cross-reactive normal tissue.

Claims

1. A method of delivering one or more diagnostic or therapeutic agents to a target site within a mammalian or human host, comprising administering to said host two or more different antibody species each having one of said agents attached thereto, wherein each of said antibody species is reactive with a different epitope of the target site and wherein the patterns of cross-reactivity for each antibody species are non-overlapping.

2. The method of claim 1 wherein the target site is a cancer site.

3. The method of claims 1, 8, 11, 4, 5, 12, 15, or 7 wherein one antibody species is monoclonal antibody NR-LU-10 or a fragment thereof, and a second antibody species is NR-LU-11 or a fragment thereof.

4. The method of claim 1 wherein an identical therapeutic agent is attached to each of the antibody species.

5. The method of claim 4 wherein the therapeutic agent is ¹⁸⁸ Re in the form of a chelate.

6. The method of claim 1 wherein each of the antibody species is a monoclonal antibody or a fragment thereof.

7. The method of claim 6 wherein each antibody species is a monoclonal antibody, or a fragment thereof, which binds to cancer cells.

8. The method of claim 1 wherein an identical diagnostic agent is attached to each of the antibody species.

9. The method of claim 8 wherein the diagnostic agent is a diagnostically effective radionuclide.

10. The method of claim 9 wherein the diagnostic agent is selected from the group consisting of ^99m Tc, ¹³¹ I, ¹¹¹ In, and ¹²³ I, ⁷⁶ Br, and ¹⁸ F.

11. The method of claim 10 wherein the diagnostic agent is ^99m Tc in the form of a chelate.

12. The method of claim 1 wherein different therapeutic agents are attached to each of the antibody species.

13. The method of claim 12 wherein the target site is a cancer site, a sensitizing drug is attached to one antibody species, and a therapeutically effective radionuclide is attached to a second antibody species.

14. The method of claim 12 wherein the target site is a cancer site, a sensitizing drug is attached to one antibody species, and an anti-cancer drug is attached to a second antibody species.

15. The method of claim 14 wherein the sensitizing drug is buthionine sulfoximine and the anti-cancer drug is doxorubicin.

16. The method of claim 1, 4, or 12 wherein each therapeutic agent is selected from the group consisting of therapeutically effective radionuclides, drugs, toxins, sensitizers, and biological response modifiers.

17. The method of claim 16 wherein the radionuclide is selected from the group consisting of ¹⁸⁸ Re, ¹⁸⁶ Re, ²⁰³ Pb, ²¹² Pb, ²¹² Bi, ¹⁰⁹ Pd, ⁶⁴ Cu, ⁶⁷ Cu, ¹³¹ I, ²¹¹ At, ⁹⁷ Ru, ¹⁰⁵ Rh, ¹⁹⁸ Au, and ¹⁹⁹ Ag.

18. The method of claim 16 wherein the toxin is selected from the group consisting of ricin, abrin, diphtheria toxin, Pseudomonas exotoxin A, ribosomal inactivating proteins, mycotoxins, trichothecenes, and therapeutically effective fragments thereof.

19. The method of claim 16 wherein said target site is a cancer site and the drug is an anti-cancer drug.

20. The method of claim 19 wherein the drug is an anti-cancer antibiotic.

21. The method of claim 20 wherein the drug is doxorubicin.

22. A method of producing additive accumulation of two or more immunoconjugates on a target tissue within a human or mammalian host while minimizing additive accumulation of the immunoconjugates on non-target tissues, comprising:

a) administering a first immunoconjugate comprising a first antibody species to the host;

administering one or more additional immunoconjugates each comprising a different antibody species to the host, wherein each of the antibody species reacts with a different epitope of the target tissue and the different antibody species have non-overlapping patterns of cross-reactivity wherein each of said first and additional immunoconjugates comprise a therapeutic or diagnostic agent attached to an antibody species.

23. The method of claim 22 wherein each immunoconjugate comprises a diagnostic agent attached to an antibody species.

24. The method of claim 23 wherein the diagnostic agent is a diagnostically effective radionuclide.

25. The method of claim 24 wherein the diagnostic agent is selected from the group consisting of ^99m Tc, ¹³¹ I, ¹¹¹ In, ¹²³ I, ⁷⁶ Br, and ¹⁸ F.

26. The method of claim 22, 23, or 29 wherein the target tissue comprises cancer cells.

27. The method of claim 26 wherein each antibody species is a monoclonal antibody, or a fragment thereof, which binds to the cancer cells.

28. The method of claim 27 wherein one antibody species is monoclonal antibody NR-LU-10 or a fragment thereof, and a second antibody species is NR-LU-11 or a fragment thereof.

29. The method of claim 22 wherein each immunoconjugate comprises a therapeutic agent attached to an antibody species.

30. The method of claim 29 wherein different therapeutic agents are attached to each of the antibody species.

31. The method of claim 29 or 30 wherein each therapeutic agent is selected from the group consisting of therapeutically effective radionuclides, drugs, sensitizers, toxins, and biological response modifiers.

32. The method of claim 31 wherein each radionuclide is selected from the group consisting of ¹⁸⁸ Re, ¹⁸⁶ Re, ²⁰³ Pb, ²¹² Pb, ²¹² Bi, ¹⁰⁹ Pd, ⁶⁴ Cu, ¹³¹ I, ²¹¹ At, ⁹⁷ Ru, ¹⁰⁵ Rh, ¹⁹⁸ Au, and ¹⁹⁹ Ag.

33. The method of claim 31 wherein each toxin is selected from the group consisting of ricin, abrin, diphtheria toxin, Pseudomonas exotoxin A, ribosomal inactivating proteins, mycotoxins, trichothecenes, and therapeutically effective fragments thereof.

34. The method of claim 31 wherein said target tissue comprises cancer cells and each drug is an anti-cancer drug.

35. The method of claim 31 wherein the target tissue comprises cancer cells, a sensitizer is attached to one antibody species, and a therapeutically effective radionuclide or anti-cancer drug is attached to a second antibody species.

40. The method of claim 29 wherein one antibody species is monoclonal antibody NR-LU-10 or a fragment thereof, and a second antibody species is NR-LU-11 or a fragment thereof.

36. A method of administering two or more different therapeutic agents to a human or mammalian host to eradicate target cells, wherein each therapeutic agent is administered at its maximum tolerated dose to the host, while minimizing toxicity toward non-target tissues, comprising attaching each different therapeutic agent to a different antibody species, wherein each, antibody species, reacts with a different epitope of the target cells, and wherein the patterns of cross-reactivity for each antibody species are non-overlapping, and administering each of the resulting immunoconjugates at the maximum tolerated dose to the host.

37. The method of claim 36 wherein each therapeutic agent is selected from the group consisting of therapeutically effective radionuclides, drugs, toxins, and biological response modifiers.

38. The method of claim 36 wherein the target cells are cancer cells.

39. The method of claim 38 wherein each of the antibody species is a monoclonal antibody, or a fragment thereof, which binds to the cancer cells.