Functional immunoassay

Abstract

Compositions, methods, and functional immunoassays for measuring functioning of organs, receptors, and biological processes in a subject are provided. Functional immunoassay combines pharmacokinetics of xenobiotics after administering one or more of the compositions to a subject by quantifying the xenobiotic in samples taken from the subject. The method provides a xenobiotic that is processed principally by a single organ system with minimal metabolism and involves administering the xenobiotic to the subject, measuring its concentration in samples of biological material obtained over time, calculating a kinetic parameter that describes change in concentration over time, and associating this parameter with the functioning of the target organ. Functional immunoassay is used for measuring, for example, kidney, brain, lung, cardiovascular, gastrointestinal, and immune system function; progression of cancer and infectious disease; and diabetes and inflammatory disease status. Xenobiotics include, for example, drugs, ligands, hormone analogs, substrates, polysaccharides, and nucleic acids and respective analogs.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a set of graphs showing comparison of three different methods to measure glomerular filtration rate. FIG. 1, panel A is a comparison of the radioactive method to the neutron activation method, and shows that these methods are linearly correlated over the ranges of the xenobiotics on the axes. FIG. 1, panel B is a comparison of the neutron activation method to the functional immunoassay method, and shows that these methods are linearly correlated over the ranges of the xenobiotics on the axes.

FIG. 2 is a set of graphs showing comparison of the three different methods of measuring effective renal blood flow. FIG. 2, panel A is a comparison of the radioactive method to the neutron activation method, and shows that these methods are linearly correlated over the ranges of the xenobiotics on the axes. FIG. 2, panel B is a comparison of the neutron activation method to the functional immunoassay method, and shows that these methods are linearly correlated over the ranges of the xenobiotics on the axes.

FIG. 3 is a graph showing a comparison of two different methods of measuring filtration fraction of the kidney. The functional immunoassay method is directly compared to traditional radioactive method, and the two methods are shown to be linearly correlated over the ranges shown on the axes.

Claims

1. A composition comprising a first antibody selected from the group comprising anti-iohexol, anti-iothalamate, anti-ioversol, anti-gadolinium-DTPA, anti-gadolinium-DOTA, anti-GdHP-D03A, anti-chromium-EDTA, and anti-inulin; and a second antibody selected from the group comprising anti-para-aminohippuric acid, anti-iodohippurate and anti-mercaptoacetyltriglycine-rhenium (MAG3-Re).

2. The composition according to claim 1, wherein a first immunoassay comprising the first antibody measures glomerular filtration rate and a second immunoassay comprising the second antibody measures effective renal blood flow, and wherein the composition is a reagent for the first and the second immunoassay performed together in a single tube.

3. A composition for determining glomerular filtration rate or effective renal blood flow, wherein the composition comprises at least one antibody that binds at least one xenobiotic selected from the group iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, inulin, para-aminohippuric acid, iodohippurate, and mercaptoacetyltriglycine-rhenium (MAG3-Re), wherein determining glomerular filtrations rate or effective renal blood flow is performing an immunoassay with the antibody, thereby determining a concentration of the xenobiotic in at least one post-administration sample from a subject.

4. The composition according to claim 3 wherein the antibody comprises an antibody fragment.

5. The composition according to claim 3 wherein the antibody is polyclonal.

6. The composition according to claim 3 wherein the antibody is monoclonal.

7. The composition according to claim 3 wherein the antibody is formulated to perform immunoassay.

8. The composition according to claim 3 wherein the antibody is an antiserum.

9. The composition according to claim 3 wherein the antibody is a solid.

10. The composition according to claim 3 wherein the antibody is in solution.

11. The composition according to claim 3 wherein the antibody is attached to a solid phase.

12. An immunizing composition comprising an antigen for producing antibodies to a xenobiotic selected from the group consisting of iohexol, iothalamate, ioversol, GdHP-D03A, chromium-EDTA, inulin, para-aminohippuric acid, iodohippurate, and mercaptoacetyltriglycine-rhenium (MAG3-Re).

13. A diagnostic kit for quantifying by functional immunoassay a physiological process selected from at least one of glomerular filtration rate, effective renal blood flow, filtration fraction, blood volume, intravascular space, and bile acid activity, the kit comprising a xenobiotic composition, an antibody for the xenobiotic, a detection probe, a container, and instructions for use.

14. A composition comprising a first xenobiotic selected from the group comprising iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, and inulin and a second xenobiotic selected from the group comprising para-aminohippuric acid, iodohippurate and mercaptoacetyltriglycine-rhenium (MAG3-Re).

15. The composition according to claim 14 wherein the composition is an immunoassay standard.

16. The composition according to claim 14 wherein the composition is a pharmaceutical.

17. A method for quantifying at least one physiological process, the method comprising: obtaining at least one physiological material from a subject, wherein the subject is further administered a composition comprising at least one xenobiotic, and obtaining between 1 minute and 5 days following administration of the xenobiotic at least one post-administration sample of the physiological material from the subject;determining a concentration of the xenobiotic in the at least one sample by at least one immunoassay technique; andcalculating a rate of change from a rate formula of the xenobiotic in the post-administration sample of the physiological material and expressing quantitatively the performance of the physiological process from the rate data.

18. The method according to claim 17 wherein the rate formula conforms to a one compartmental model.

19. The method according to claim 18, wherein the one compartmental model is mathematically expressed as C1(t)=C1(0)e−kt

20. The method according to claim 17 wherein the rate formula conforms to an at least one compartmental model.

21. The method according to claim 17 wherein the physiological material is at least one sample selected from the group comprising blood, urine, cerebrospinal fluid, lymph, tissue, and feces.

22. The method according to claim 17 wherein the xenobiotic is at least one xenobiotic selected from the group comprising iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, inulin, para-aminohippuric acid, iodohippurate, mercaptoacetyltriglycine-rhenium, colloids, dextran, dextran derivatives, bile acid derivatives and analogs, and albumin derivatives.

23. The method according to claim 22 wherein a diameter of a xenobiotic colloidal particle is in the range of 2 nanometers to 1000 nanometers.

24. The method according to claim 17 wherein the physiological process measures kidney function.

25. The method according to claim 24 wherein the kidney function is selected from the group of glomerular filtration rate, effective renal blood flow, filtration fraction, and glomerular sieving.

26. The method according to claim 17 wherein the xenobiotic is a glomerular filtration rate marker.

27. The method according to claim 26 wherein the glomerular filtration rate marker is selected from the group consisting of iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, and inulin.

28. The method according to claim 17 wherein the xenobiotic is excreted through the glomeruli of the kidney.

29. The method according to claim 17 wherein the xenobiotic is an effective renal blood flow marker.

30. The method according to claim 29 wherein the effective renal blood flow marker is selected from the group comprising para-aminohippuric acid, iodohippurate and mercaptoacetyltriglycine-rhenium.

31. The method according to claim 17 wherein the xenobiotic is excreted through the tubules of the kidney.

32. The method according to claim 17 comprising formulating the composition to contain a first xenobiotic for measuring the glomerular filtration rate of the kidney and a second xenobiotic for measuring the effective renal blood flow of the kidney.

33. The method according to claim 32 wherein the first xenobiotic is selected from the group of glomerular filtration rate markers consisting of iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, and inulin, and the second xenobiotic is selected from the group of effective renal blood flow markers consisting of para-aminohippuric acid, iodohippurate and mercaptoacetyltriglycine-rhenium.

34. The method according to claim 17 wherein the composition comprises at least one marker of glomerular filtration, wherein the marker of glomerular filtration is excreted through the glomeruli of the kidney, and comprises at least one marker of effective renal blood flow, wherein the marker of effective renal blood flow is excreted through the tubules of the kidney.

35. The method according to claim 17 wherein the physiological process is the glomerular filtration rate.

36. The method according to claim 35 wherein the glomerular filtration rate is expressed in ml/minutes and is calculated from the formula glomerular filtration rate=UV/P

37. The method according to claim 35 further comprising quantifying the glomerular filtration rate from the concentration of the xenobiotic in at least one blood, serum or plasma sample that was obtained at one or more measured time points.

38. The method according to claim 35 further comprising quantifying the glomerular filtration rate from the concentration of the xenobiotic in at least one blood, serum or plasma sample and at least one urine sample obtained at one or more measured time points.

39. The method according to claim 35 further comprising quantifying the glomerular filtration rate from the concentration of the xenobiotic in at least one urine sample obtained at one or more measured time points.

40. The method according to claim 17 wherein the at least one physiological process is effective renal blood flow.

41. The method according to claim 40 wherein the effective renal blood flow is expressed in ml/minutes and is calculated from the formula effective renal blood flow=UV/P

42. The method according to claim 41 wherein quantifying the effective renal blood flow value is assaying the concentration of the xenobiotic in at least one blood, serum or plasma sample that was obtained at one or more measured time points.

43. The method according to claim 41 wherein quantifying the effective renal blood flow is assaying the concentration of the xenobiotic in at least one blood, serum or plasma sample and at least one urine sample that was obtained at one or more measured time points.

44. The method according to claim 41 wherein quantifying the effective renal blood flow assaying the concentration of the xenobiotic in at least one urine sample that was obtained at one or more measured time points.

45. The method according to claim 17, wherein the performance in the subject of the physiological process is abnormal.

46. The method according to claim 17, wherein the performance in the subject of the physiological process is normal.

47. The method according to claim 17 wherein the at least one physiological process measures a circulatory system function.

48. The method according to claim 47 wherein the physiological process of the circulatory system is selected from blood volume, plasma volume, and intravascular volume.

49. The method according to claim 17 wherein the xenobiotic is selected from the group of dextran, dextran derivatives, and derivatized albumin.

50. The method according to claim 17 wherein the administered composition comprises a first xenobiotic for measuring plasma volume of the circulatory system and a second xenobiotic for measuring intravascular volume of the circulatory system.

51. The method according to claim 50 wherein the first xenobiotic is selected from the group of plasma volume markers comprising dextran, reduced dextran, albumin; and the second xenobiotic is selected from the group of intravascular volume markers comprising colloids.

52. The method according to claim 17 wherein the physiological process comprises at least one liver function.

53. The method according to claim 52 wherein the liver function is selected from asialoglycoprotein receptor activity, reticuloendothelial system activity, bile acid absorption, and bile acid elimination.

54. The method according to claim 17 wherein the subject is a mammal.

55. The method according to claim 54 wherein the mammal is a human.

56. The method according to claim 17 wherein the subject is an isolated organ system.

57. The method according to claim 17 wherein administering the xenobiotic is administering a plurality of doses for determining sequential performance of at least one physiological process.

58. The method according to claim 17 wherein the immunoassay technique comprises using at least one reagent selected from the group of an antibody, a binding protein, and a peptide.

59. The method according to claim 17 wherein the immunoassay technique comprises at least one antibody that binds at least one xenobiotic selected from the group comprising anti-iohexol, anti-iothalamate, anti-ioversol, anti-gadolinium-DTPA, anti-gadolinium-DOTA, anti-GdHP-D03A, anti-chromium-EDTA, anti-inulin, anti-para-aminohippuric acid, anti-iodohippurate, anti-mercaptoacetyltriglycine-rhenium, anti-colloids, anti-dextran, anti-dextran derivatives, and anti-albumin derivatives.

60. The method according to claim 59 wherein the antibody comprises an antibody fragment.

61. The method according to claim 59 wherein the antibody is polyclonal.

62. The method according to claim 59 wherein the antibody is monoclonal.

63. The method according to claim 17 wherein the immunoassay technique comprises at least one binding protein or peptide that binds the xenobiotic, wherein the xenobiotic is selected from the group comprising: iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, inulin, para-aminohippuric acid, iodohippurate, mercaptoacetyltriglycine-rhenium, colloids, dextran, dextran derivatives, and albumin derivatives.

64. The method according to claim 17 wherein the immunoassay technique comprises a first antibody that binds a first xenobiotic selected from the group comprising iohexol, iothalamate, ioversol, gadolinium-DTPA, gadolinium-DOTA, GdHP-D03A, chromium-EDTA, and inulin; and comprises a second antibody that binds a second xenobiotic selected from the group comprising para-aminohippuric acid, iodohippurate and -mercaptoacetyltriglycine-rhenium.

65. The method according to claim 17 wherein the immunoassay technique comprises a radio immunoassay, an enzyme immunoassay, an enzyme-linked immunosorbent assay, a fluorescence immunoassay, an automated immunoassay, a luminescent immunoassay and the like.

66. The method according to claim 17 wherein the xenobiotic is approved for human use.

67. The method according to claim 17 wherein the xenobiotic is approved for veterinary use.

68. A method for quantifying at least one physiological process in a subject, the method comprising: administering to the subject at least one xenobiotic, and obtaining between 1 minute and 5 days following administration of the xenobiotic at least one post-administration sample of at least one physiological material from the subject; determining a concentration of the xenobiotic in the sample by at least one immunoassay technique; andcalculating a rate of change from a rate formula of the xenobiotic in the post-administration sample of the physiological material and expressing quantitatively the performance of the physiological process from the rate data.