Diagnosis of macrophage mediated disease

a macrophage and disease technology, applied in immunology disorders, therapy, antibody medical ingredients, etc., can solve the problems of cartilage deterioration and bone erosion, degradation of pathogens, and consequent destruction of joint integrity, so as to reduce liver uptake, less inflamed, and less inflamed

Inactive Publication Date: 2007-10-04
LOW PHILIP S +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0060] The protocols described in Examples 2, 3, and 4 were followed, except that 0.25 mCi of EC20 was administered. In order to determine whether macrophages might be responsible for the uptake of EC20, resident macrophages were systemically eliminated from arthritic rats using a liposomal clodronate preparation (n=3 rats/group). By four days after clodronate treatment, evaluation of paw size revealed that clodronate-treated rats were significantly less inflamed than untreated rats (data not shown). To determine whether macrophage elimination would influence uptake of the folate-linked imaging agent, EC20 biodistribution analysis was then performed on the clodronate-treated rats and compared to the same analysis of both healthy rats and arthritic rats not treated with clodronate. A...

Problems solved by technology

Activated macrophages nonspecifically engulf and kill foreign pathogens within the macrophage by hydrolytic and oxidative attack resulting in degradation of the pathogen.
The synovial inflammation causes cartilage deterioration and bone erosion with consequent destruction of joint integrity.
The clinical manifestations of RA include pain, swelling, and tenderness in the joints resulting in limitation of motion, weakness, fatigue, and weight loss.
However, these agents have a minimal effect on the progression of the disease and are associated with toxic side effects.
Disease-modifyin...

Method used

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  • Diagnosis of macrophage mediated disease
  • Diagnosis of macrophage mediated disease
  • Diagnosis of macrophage mediated disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials

[0047] EC20 (a folate-linked chelator 99mTc), EC28 (the same 99mTc chelate complex without folate), and folate-fluorescein isothiocyanate (folate-FITC) were gifts from Endocyte, Inc. (West Lafayette, Ind.). Heat-killed Mycoplasma butericum was purchased from BD Biosciences (Sparks, Md.). Folic acid, light mineral oil, clodronate, collagenase-A, and streptavidin-R-phycoerythrin were obtained from Sigma Chemical Co. (St. Louis, Mo.), and Dubelco's Modified Eagle Medium (DMEM) was from Gibco-BRL (Gathersberg, Md.). 3H-folic acid was obtained from American Radiolabeled Chemicals, Inc. (St. Louis, Mo.) and Microcon®-30 membranes were purchased from Millipore Corp. (Bedford, Mass.). RK-4-biotin and ED2-R-phycoerythrin antibodies were acquired from Bachem Biosciences, Inc. (Philadelphia, Pa.) and Accurate Chemical and Scientific Corp. (Westbury, N.Y.), respectively.

example 2

Animal Model of Arthritis

[0048] Arthritis was induced in 150-200 g female Lewis rats (Charles River Laboratories, Inc., Wilmington, Mass.), n=4 / dose group. Briefly, 0.5 mg of heat-killed Mycoplasma butericum, suspended in mineral oil (5 mg / ml), was injected on day 0 into the left hind foot of rats following anesthesia with ketamine and xylazine. Disease was allowed to progress for 21 days, and animals were weighed on a daily basis to ensure the status of their health. All treated animals developed arthritis, as evidenced by dramatic swelling in the injected paw, progressive swelling in all noninjected limbs due to the systemic progression of arthritis, and radiographic analysis of affected limbs. All rats were maintained on a folate-deficient diet (DYETS, Inc., Bethlehem, Pa.) for 3 weeks prior to administration of folate-FITC in order to lower serum folate levels to physiologically relevant concentrations. Control rats were also maintained on a folate-deficient diet but not induce...

example 3

Elimination of Endogenous Macrophages

[0049] Evaluation of macrophage independent uptake of the folate-linked imaging agent was accomplished by killing endogenous macrophages with liposomal clodronate. Liposomes were formed by rehydrating a thin film of egg phosphatidylcholine (60 mole %) and cholesterol (40 mole %) in an isotonic clodronate solution (250 mg / ml). Small unilamellar vesicles were then generated by extrusion of the liposomes ten times through a 100 nm polycarbonate membrane using a 10 ml thermobarrel extruder (Lipex Biomembranes, Vancouver, Canada). Unencapsulated clodronate was removed by dialysis through a Spectrapor 300,000 Mr-cutoff cellulose acetate membrane (Spectrum Laboratories, Rancho Domingues, Calif.), and the clodronate concentration in the retained liposomes was determined as described in J Microencapsul. 3(2) 109-14 (1986). Seventeen days following induction of the arthritis and three days prior to administration of the imaging agent (EC20), rats destined...

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Abstract

The invention relates to a method of treating or monitoring/diagnosing a disease state mediated by activated macrophages. The method comprises the step of administering to a patient suffering from a macrophage mediated disease state an effective amount of a composition comprising a conjugate or complex of the general formula
Ab-X
where the group Ab comprises a ligand capable of binding to activated macrophages, and when the conjugate is being used for treatment of the disease state, the group X comprises an immunogen, a cytotoxin, or a compound capable of altering macrophage function, and when the conjugate is being used for monitoring/diagnosing the disease state, X comprises an imaging agent. The method is useful for treating a patient suffering from a disease selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammation, infections, osteomyelitis, atherosclerosis, organ transplant rejection, pulmonary fibrosis, sarcoidosis, and systemic sclerosis.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C § 119(e) to U.S. Provisional Application Ser. No. r 60 / 288,208, filed on May 2, 2001.FIELD OF THE INVENTION [0002] This invention relates to methods for treating and monitoring disease states mediated by activated macrophages. More particularly, ligands that bind to activated macrophages are complexed with an imaging agent, or an immunogen, a cytotoxin or an agent for altering macrophage function for administration to a diseased host for diagnosis and / or treatment of macrophage mediated disease. BACKGROUND AND SUMMARY OF THE INVENTION [0003] The mammalian immune system provides a means for the recognition and elimination of foreign pathogens. While the immune system normally provides a line of defense against foreign pathogens, there are many instances where the immune response itself is involved in the progression of disease. Exemplary of diseases caused or worsened by the host's own immu...

Claims

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Application Information

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IPC IPC(8): A61K51/00A61K49/00A61B5/055G01R33/28A61K9/127A61K39/00A61K39/385A61K39/395A61K45/00A61K47/48A61K51/10A61P1/04A61P9/10A61P11/00A61P17/00A61P19/02A61P25/00A61P29/00A61P31/04A61P37/06
CPCA61K9/127A61K47/4833A61K51/0482A61K51/1027A61K47/48561A61K47/646A61K47/6849A61P1/00A61P1/04A61P11/00A61P17/00A61P19/00A61P19/02A61P19/04A61P25/00A61P29/00A61P31/04A61P37/00A61P37/02A61P37/06A61P9/10A61K49/00
Inventor LOW, PHILIP S.TURK, MARY JO
Owner LOW PHILIP S
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