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Imaging and therapeutic method using monocytesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, Attached To Antibody Or Antibody Fragment Or Immunoglobulin; DerivativeImaging and therapeutic method using monocytes description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070009434, Imaging and therapeutic method using monocytes. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. .sctn.119(e) to U.S. Provisional Application Ser. No. 60/696,740, filed on Jul. 5, 2005, and to U.S. Provisional Application Ser. No. 60/801,636, filed on May 18, 2006, each incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] This invention relates to methods for treating and diagnosing disease states mediated by monocytes. More particularly, ligands that bind to monocytes are complexed with an imaging agent for use in diagnosis or to an immunogen, a cytotoxin, or an agent for altering monocyte function for use in the treatment of monocyte-mediated disease. BACKGROUND [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 immune response are autoimmune diseases and other diseases in which the immune response contributes to pathogenesis. For example, macrophages are generally the first cells to encounter foreign pathogens, and accordingly, they play an important role in the immune response, but activated macrophages can also contribute to the pathophysiology of disease in some instances. [0004] The folate receptor is a 38 KD GPI-anchored protein that binds the vitamin folic acid with high affinity (<1 nM). Following receptor binding, rapid endocytosis delivers the vitamin into the cell, where it is unloaded in an endosomal compartment at low pH. Importantly, covalent conjugation of small molecules, proteins, and even liposomes to folic acid does not block the vitamin's ability to bind the folate receptor, and therefore, folate-drug conjugates can readily be delivered to and can enter cells by receptor-mediated endocytosis. [0005] Because most cells use an unrelated reduced folate carrier to acquire the necessary folic acid, expression of the folate receptor is restricted to a few cell types. With the exception of kidney, choroid plexus, and placenta, normal tissues express low or nondetectable levels of the folate receptor. However, many malignant tissues, including ovarian, breast, bronchial, and brain cancers express significantly elevated levels of the receptor. In fact, it is estimated that 95% of all ovarian carcinomas overexpress the folate receptor. It has been reported that the folate receptor .beta., the nonepithelial isoform of the folate receptor, is expressed on activated (but not resting) synovial macrophages. Thus, folate receptors are expressed on a subset of macrophages (i.e., activated macrophages). SUMMARY [0006] It is unknown, however, whether folate receptors are expressed on monocytes, the precursor cells for macrophages. Thus, Applicants have undertaken to determine whether folate receptors are expressed on monocytes and whether monocyte targeting, using a ligand such as folate, to deliver cytotoxic or other inhibitory compounds to monocytes, is useful therapeutically. Applicants have also undertaken to determine whether an imaging agent linked to a ligand capable of binding to monocytes may be useful for diagnosing inflammatory pathologies. [0007] A method is provided for treating and diagnosing disease states mediated by monocytes. In one embodiment, the monocytes are activated monocytes. In one embodiment, disease states mediated by monocytes are treated by delivering an immunogen to the monocytes, by linking the immunogen to a ligand that binds to monocytes, to redirect host immune responses to monocytes. In another embodiment, monocytes can be inactivated or killed by other methods such as by the delivery to monocytes of cytotoxins or other compounds capable of altering monocyte function. [0008] In the embodiment where an immunogen is delivered to monocytes to inactivate or kill monocytes, ligands that bind to monocytes are conjugated with an immunogen to redirect host immune responses to the monocytes, or the ligand is conjugated to a cytotoxin for killing of monocytes. Ligands that can be used in the conjugates of the present invention include those that bind to receptors expressed on monocytes (e.g., activated monocytes), such as the folate receptor, or ligands such as monoclonal antibodies directed to cell surface markers expressed on monocytes or other ligands that bind to activated monocytes. In another embodiment, ligands that bind to monocytes are conjugated to an imaging agent and the conjugate is used to diagnose diseases mediated by monocytes. [0009] In another embodiment, a method is provided for diagnosing a disease state mediated by monocytes. The method comprises the steps of isolating monocytes from a patient suffering from a monocyte-mediated disease state, contacting the monocytes with a composition comprising a conjugate or complex of the general formula A.sub.b-X [0010] where the group A.sub.b comprises a ligand that binds to monocytes and the group X comprises an imaging agent, and quantifying the percentage of monocytes that expresses a receptor for the ligand. In another embodiment, A.sub.b comprises a folate receptor binding ligand. In yet another embodiment, A.sub.b comprises a monocyte-binding antibody or antibody fragment or other ligands that bind to activated monocytes. In another embodiment, the imaging agent comprises a metal chelating moiety that binds an element that is a radionuclide. In still another embodiment, the imaging agent comprises a chromophore selected from the group consisting of fluorescein, Oregon Green, rhodamine, phycoerythrin, Texas Red, and AlexaFluor 488. [0011] In another embodiment, a method is provided for diagnosing a disease state mediated by monocytes. The method comprises the steps of administering parenterally to a patient a composition comprising a conjugate or complex of the general formula A.sub.b-X where the group A.sub.b comprises a ligand that binds to monocytes and the group X comprises an imaging agent, and quantifying the percentage of monocytes that expresses a receptor for the ligand. [0012] In another embodiment, a method is provided for treating a disease state mediated by monocytes. The method comprises the steps of administering to a patient suffering from a monocyte-mediated disease state an effective amount of a composition comprising a conjugate or complex of the general formula A.sub.b-X where the group A.sub.b comprises a ligand that binds to monocytes and the group X comprises an immunogen, a cytotoxin, or a compound capable of altering monocyte function, and eliminating the monocyte-mediated disease state. [0013] In yet another embodiment, a compound for diagnosing or treating a disease state mediated by monocytes is provided. The compound is selected from the following group of compounds: BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 shows folate-fluorescein binding to human monocytes isolated from peripheral blood and left untreated or preincubated with a 100-fold excess of unlabeled folic acid to compete with folate-fluorescein for binding. [0015] FIG. 2 shows folate-fluorescein (folate-FITC e.g. folate-fluorescein isothiocyanate) binding, quantified by flow cytometry, to CD11b.sup.+ human monocytes (panel A) and to CD11b.sup.+ human monocytes preincubated with an excess of unlabeled folic acid (panel B) to compete with folate-FITC for binding. [0016] FIG. 3 shows flow cytometry analysis, using CD11b (A), CD14 (B), CD16 (C), CD69 (D), and HLA-DR (E) antibodies, of CD markers that are co-expressed with the folate receptor on human monocytes. [0017] FIG. 4 shows binding of .sup.3H-folic acid to white blood cells from humans, dogs, rabbits, rats, mice, or to KB cells. The cells were either preincubated with a 100-fold excess of unlabeled folic acid (cross-hatched bars labeled with an "xs") or not preincubated with excess unlabeled folic acid (solid bars). [0018] FIG. 5 shows folate-FITC binding, analyzed by flow cytometry, to peripheral blood monocytes from dogs (panels A and C) and horses (panels B and D) and competition of binding by unlabeled folic acid. [0019] FIG. 6 shows folate-FITC (A-C) or folate-AlexaFluor 488 (D-F) binding, analyzed by flow cytometry, to peripheral blood monocytes from dogs and competition of binding by unlabeled folic acid. Continue reading about Imaging and therapeutic method using monocytes... 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