Extracorporeal affinity adsorption devices which are aimed at the substantial removal of two or more compounds that are etiological in the pathogenesis of diseases in man, provide effective therapeutic intervention means for these diseases. The devices are particularly suitable for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases. Extracorporeal chelation and immunotherapy for artherosclerosis, extracorporeal chelation treatment with on-line regeneration or replacement of chelant, extracorporeal immunotherapy with antibody fragments, and extracorporeal immunoadsorption utilizing antibodies bound to Protein A are also disclosed.

Claims

I claim:

1. An extracorporeal device for treating a disease state having at least two chemical species associated with it, said device including means for drawing from a mammal a fluid, means in said device for exposing at least a portion of the fluid to at least a first binding means and a second affinity binding means for chemically binding at least one of said chemical species in said fluid to the first binding means and for binding at least a second of said chemical species in said fluid to a second binding means, the first chemical species being a metal ion and the first binding means being a chelant, said second affinity binding means binding specifically to a species selected from the group consisting of an anticancer drug and an anticancer drug bound to a targeting antibody, and means for returning to the mammal at least a fraction of said fluid.

2. The device of claim 1 wherein said second binding means binds to a moiety consisting of an anticancer drug and a targeting antibody chemically bound to said anticancer drug directly or through a spacer, said targeting antibody being an intact antibody or a fragment of an antibody.

3. The device of claim 2 in which said specific affinity binding means is an antibody specific to said drug in the drug-targeting antibody moiety or a fragment of such antibody.

4. The device of claim 2 wherein said specific affinity binding means is an antibody specific to a tumor or tissue targeting antibody of the drug targeting antibody moiety, or a fragment of such antibody.

5. The device of claim 2 wherein said specific affinity binding means is tumor antigen, or tissue antigen, or fetal antigen to which the targeting antibody is directed.

6. The device of claim 5 wherein said specific affinity binding means is human-alpha-fetoprotein.

7. The device of claim 2 wherein said drug in the anticancer drug targeting antibody moiety is adriamycin.

8. The device of claim 2 wherein said drug is radioactive.

9. The device of claim 1 wherein said drug is adriamycin.

10. The device of claim 1 wherein said drug is radioactive.

11. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, at least said first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants.

12. The device of claim 11 wherein the first binding means comprises fragments of antibodies to oxidized LDL.

13. The device of claim 12 wherein the first binding means is selected from the group consisting of synthetic fragments of antibodies and enzymatic digestion fragments of antibodies.

14. The device of claim 11 including a semipermeable membrane for preventing the specific affinity adsorbents from entering the body of the mammal.

15. The device of claim 11 wherein said fluid is blood.

16. The device of claim 11 including means for attaching the device into the blood circulatory system of the mammal.

17. The device of claim 11 wherein said fluid is plasma.

18. The device of claim 11 including means for exposing the fluid simultaneously to the first specific affinity binding means and the second specific affinity binding means.

19. The device of claim 11 wherein the second specific affinity binding means is a chelant which binds metal ions.

20. The device of claim 11 wherein the second specific affinity binding means binds a chemical species selected from the group consisting of autoantibodies and immune complexes.

21. The device of claim 11 wherein the second said affinity binding means is a non-immunological chemical affinity adsorbent.

22. The device of claim 11 wherein the first binding means comprises a chelant and the second specific affinity binding means is an antibody to an anticancer drug or a fragment of such antibody.

23. The device of claim 22 wherein said drug is adriamycin.

24. The device of claim 22 wherein said drug is radioactive.

25. The device of claim 11 wherein the first binding means comprises a chelant and the second specific affinity binding means binds to a moiety consisting of an anticancer drug and a targeting antibody chemically bound to said anticancer drug directly or through a spacer, said targeting antibody being an intact antibody or a fragment of an antibody.

26. The device of claim 25 in which the second said specific affinity binding means is an antibody specific to said drug in the drug-targeting antibody moiety or a fragment of such antibody.

27. The device of claim 25 wherein the second specific affinity binding means is an antibody specific to a tumor or tissue targeting antibody of the drug targeting antibody moiety, or a fragment of such antibody.

28. The device of claim 25 wherein the second said specific affinity binding means is tumor antigen, or tissue antigen, or fetal antigen to which the targeting antibody is directed.

29. The device of claim 28 wherein said specific affinity binding means is human-alpha-fetoprotein.

30. The device of claim 25 wherein said drug in the anticancer drug targeting antibody moiety is adriamycin.

31. The device of claim 25 wherein said drug is radioactive.

32. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, at least said first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized IDL, oxidized LDL, malondialdehyde LDL, and chelants, said device including means for exposing said fluid sequentially to the first specific affinity binding means and the second specific affinity binding means.

33. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, at least said first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants, at least the second specific affinity binding means binding immunologically.

34. The device of claim 22 wherein the second specific affinity binding means is selected from the group consisting of Protein A, Protein G, and C1q bound to anti-C1q antibody.

35. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, at least said first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants, the second specific affinity binding means binding a species, selected from the group consisting of cholesterol, triglycerides, LDL, oxidized LDL and antibodies to oxidized LDL.

36. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, at least said first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants, one of said first and second binding means being chemically bound to a matrix.

37. The device of claim 36 wherein the binding means is bound to the matrix through a spacer linked to the matrix by a spacer arm.

38. The device of claim 37 wherein the spacer arms comprises from three to thirty carbon atoms.

39. An extracorporeal device including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to a second binding means, means for separating at least said first chemical species from said first binding means to regenerate said device, and means for returning to the mammal at least a fraction of said fluid, at least the first specific affinity binding means being a chelant which binds metal ions and the second specific affinity binding means binding a species selected from the group consisting of cholesterol, triglycerides, LDL, oxidized LDL and antibodies to oxidized LDL.

40. A method for treating a disease state in a living mammal, the disease state being characterized by having at least a first chemical species and a second chemical species which are etiological to the disease state or to its symptoms, the method comprising drawing from the mammal a fluid containing both the chemical species into an extracorporeal device, exposing the fluid to at least a first adsorbent for chemically binding the first chemical species in the device and to a second adsorbent for chemically binding the second chemical species in the device, returning to the mammal at least a fraction of the fluid, and thereafter regenerating the device for further use by connecting a regenerating fluid to the device, and including a further step of administering to the living mammal intravenously at least one plasma component.

41. The method of claim 40 wherein the plasma component is gamma globulin.

42. A method of treating a disease state in a living mammal, comprising connecting into a fluid circulatory system of the mammal an extracorporeal device, exposing at least a portion of the fluid to at least a first and a second specific affinity binding means in the device for chemically binding at least one chemical species in the fluid to the first binding means and for binding at least a second chemical species in the fluid to the second binding means, and returning to the mammal at least a fraction of the fluid, at least the first binding means being selected from the group consisting of antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants.

43. The method of claim 42 wherein the first binding means comprises fragments of antibodies to oxidized LDL.

44. The method of claim 43 wherein the first binding means is selected from the group consisting of synthetic fragments of antibodies and enzymatic digestion fragments of antibodies.

45. The method of claim 42 including a semipermeable membrane for preventing the specific affinity adsorbents from entering the body of the mammal.

46. The method of claim 42 wherein the fluid is blood, the method including attaching the device into the blood circulatory system of the mammal.

47. The method of claim 42 wherein the at least a portion of the fluid is plasma.

48. The method of claim 42 including means for exposing the fluid simultaneously to the first specific affinity binding means and the second specific affinity binding means.

49. The method of claim 42 including means for exposing the fluid sequentially to the first specific affinity binding means and the second specific affinity binding means.

50. A method of treating atherosclerosis comprising a step of placing in an extracorporeal affinity adsorption device at least one affinity adsorbent which binds selectively with a chemical species which is etiological to atherosclerosis, wherein the chemical species is selected from the group consisting of oxidized low density lipoproteins and autoantibodies to oxidized low density lipoproteins, and a step of connecting the device in the blood circulatory system of a mammal to expose at least a portion of the blood of the mammal containing said chemical species to said affinity adsorbent.

51. A method of treating atherosclerosis comprising a step of placing in an extracorporeal affinity adsorption device at least one affinity adsorbent which binds selectively with a chemical species which is etiological to atherosclerosis, wherein the affinity adsorbent is selected from the group consisting of oxidized low density lipoproteins, malondialdehyde low density lipoproteins, antibodies to oxidized low density lipoproteins, antibodies to cholesterol, Protein A, and Protein G, and a step of connecting the device in the blood circulatory system of a mammal to expose at least a portion of the blood of the mammal containing the chemical species to the affinity adsorbent.

52. A method of treating atherosclerosis in a living mammal, comprising connecting into a fluid circulatory system of the mammal an extracorporeal device, exposing at least a portion of the fluid to at least a first and a second affinity binding means in the device for binding LDL in the fluid to the first binding means and for immunologically binding a second chemical species etiological to atherosclerosis in the fluid to the second binding means, and returning to the mammal at least a fraction of the fluid.

53. The method of claim 52 wherein the second species is selected from the group consisting of cholesterol, triglycerides, oxidized LDL, antibodies to oxidized LDL, and metal ion oxidants.

54. The method of claim 53 wherein the second species is selected from the group consisting of oxidized LDL and antibodies to oxidized LDL.

55. The method of claim 52 wherein the first adsorbent is a specific binding adsorbent which binds LDL selectively.

56. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, said first binding means being selected from the group consisting of antibodies to LDL, antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants, and said second species being selected from the group consisting of cholesterol, triglycerides, LDL, and oxidized LDL.

57. An extracorporeal device, including means for drawing fluid from a mammal, means in said device for exposing at least a portion of the fluid to at least a first and a second specific affinity binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to the second binding means, and means for returning to the mammal at least a fraction of said fluid, said first binding means being selected from the group consisting of antibodies to LDL, antibodies to cholesterol, antibodies to oxidized LDL, oxidized LDL, malondialdehyde LDL, and chelants, and said second specific affinity binding means binds immunologically.

58. An extracorporeal device including means for drawing fluid from a mammal; exposure means in said device for exposing at least a portion of the fluid to a binding means for chemically binding at least one chemical species in said fluid to the binding means, the binding means comprising an adsorbent bound to a matrix or a polymerized antibody, the exposure means comprising a first semipermeable membrane for preventing the adsorbent from entering the body of the mammal; regeneration means for regenerating said device, the regeneration means comprising a second semipermeable membrane, the second semipermeable membrane being nonpermeable to the matrix or polymerized antibody; and means for returning to the mammal at least a fraction of said fluid.

59. An extracorporeal device including means for drawing fluid from a mammal; exposure means in said device for exposing at least a portion of the fluid to at least a first and a second binding means for chemically binding at least one chemical species in said fluid to the first binding means and for binding at least a second chemical species in said fluid to a second binding means, at least one of the first and second binding means comprising either an adsorbent bound to a matrix or a polymerized antibody; regeneration means for regenerating said device, the regeneration means comprising a semipermeable membrane distinct from the matrix; and means for returning to the mammal at least a fraction of said fluid.

60. The device of claim 59 wherein the exposure means comprises a second semipermeable membrane for preventing the first and second binding means from entering the body of the mammal.

61. The device of claim 59 wherein at least one of the binding means is a chelant which binds metal ions.

62. The device of claim 59 wherein at least one of the binding means binds a species selected from the group consisting of cholesterol, LDL, oxidized LDL and antibodies to oxidized LDL.

63. The device of claim 62 wherein the other binding means binds a chemical species selected from the group consisting of autoantibodies and immune complexes.

64. The device of claim 59 wherein at least one of the binding means binds immunologically.

65. The device of claim 64 wherein at least one of the binding means is selected from the group consisting of Protein A, Protein G, and C1q bound to anti-C1q antibody.

66. The device of claim 59 wherein at least the first said affinity binding means is a non-immunological chemical affinity adsorbent.

67. The device of claim 59 wherein one of said binding means is an antibody to an anticancer drug.

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