for convenience , the meaning of certain terms and phrases employed in the specification , examples , and appended claims are provided below . as used herein , a “ colony stimulating factor ” or “ csf ” refers to a molecule that is capable of binding to a hematopoietic stem cell or a cell of the myelomonocytic lineage that is differentiated from a hematopoietic stem cell . examples of myelomonocytic cells differentiated from hematopoietic stem cells , include : colony - forming unit , granulocyte - erythrocyte - monocyte - megakaryocyte ( cfu - gemm ), cfu megakaryocyte ( cfu - meg ), cfu - eosinophil ( cfu - eo ), cfu - granulocyte / monocyte ( cfu - gm ), cfu - erythroid ( cfu - e ), monocytes and neutrophils . examples of csfs include : granulocyte colony - stimulating factor ( g - csf ), granulocyte - macrophage colony - stimulating factor ( gm - csf ), monocyte colony stimulating factor ( m - csf or csf - 1 ) and binding fragments thereof . for use in the invention , a csf may be : i ) purified or recombinant ; ii ) wildtype ( natural ) or a variant ( mutant ); iii ) fully , partially or non - glycosylated ; iv ) a full - length protein or binding fragment ; or v ) human or non - human . “ colony stimulating factor 1 ( csf - 1 , also known as m - csf ) is distinguished from other colony stimulating factors in its ability to stimulate the formation of predominantly macrophage colonies . a “ short ” form that encodes a monomeric protein of 224 amino acids preceded by a 32 amino acid signal sequence ( kawasaki et al ., ( 1985 ) science 230 : 292 - 296 ); and a “ long ” form encoding a monomeric protein of 522 amino acids , also preceded by the 32 amino acid signal sequence . the amino acid sequence of the short form is shown herein as seq . i . d . no . 1 and the amino acid sequence of the long form is shown herein as seq i . d . no . 2 . “ granulocyte colony stimulating factor ” or “ g - csf ” refers to a full length protein , polypeptide or peptide that substantially corresponds in sequence to a natural g - csf or a fragment thereof and that binds to a csf receptor . two naturally occurring forms of g - csf exist with 204 or 207 amino acids , of which the first 30 represent a signal . these two forms are a consequence of alternative splicing in the second intron . both forms have five cysteine residues ; four forming two disulfide bonds and one free . binding studies have shown that g - csf binds to g - csf receptors on cfu - gm and neutrophils . none or only slight binding is observed with erythroid , lymphoid , eosinophilic cell lines as well as macrophages . the amino acid sequence of natural human g - csf is presented herein as seq . id . no . 1 ( see also u . s . pat . nos . 4 , 810 , 643 ; 4 , 999 , 291 ; and 5 , 676 , 941 ). at least two kinds of rhg - csf are available on the world market : escherichia coli derived g - csf ( filgrastrim ), which has no sugar chain ; and chinese hamster ovary cell derived g - csf ( renograstrim ), which has a sugar chain at thr - 133 . the amino acid sequence of natural bovine g - csf is presented herein as seq . id . no . 2 . in addition to these natural proteins , functional variants , that are easier to isolate from recombinant culture , have been developed , based on the replacement of one or more cysteine residue ( e . g . at positions 17 , 36 , 42 , 64 and / or 74 ) by a serine residue . ( see e . g . u . s . pat . no . 5 , 580 , 755 ). additional variants of natural g - csf , which contain an alanine at position 1 , a threonine at position 3 , a tyrosine at position 4 , an arginine at position 5 , a serine at position 17 , an asparagine at position 145 or a serine at position 147 and that exhibit increased in vivo half - life have also been described ( see e . g . u . s . pat . nos . 5 , 218 , 092 and 5 , 214 , 132 ). g - csf has proven to be clinically effective in promoting recovery in patients with chemo - or radiotherapy - induced neutropenia . both radioimmunoassay and bioassays have been used to measure the pharmacokinetics of g - csf ( eguchi , k et al ., ( 1989 ) cancer res . 49 : 5221 - 24 ). peak serum concentrations have been reported to be proportional to dose , both for intravenous and subcutaneous routes . c sub max values are maintained for 30 - 60 min after short ( 20 - 30 min ) intravenous infusions before concentrations decline logarithmically with time . the estimated terminal half - life for g - csf after short intravenous infusions is 0 . 75 - 7 . 2 h for doses up to 60 mμ g / kg . after single subcutaneous injections , serum concentrations peak in 4 - 6 h , and by 24 h , serum concentrations are & lt ; 10 % c sub max . after doses of 5 - 10 mμ g / kg , serum concentrations of & gt ; 10 ng / ml are maintained for up to 16 h . “ granulocyte - macrophage colony stimulating factor ” or “ gm - csf ” is naturally produced by many cell types and has been found to promote growth of progenitors of several myeloid lines and , to a lesser extent , of the megakaryocyte line . its main effects are to increase neutrophil and monocyte production , and to prolong neutrophil survival . the 127 amino acid sequence of natural human gm - csf is presented herein as seq . id . no . 3 . the amino acid sequence of murine ( sparrow , l . et al ., ( 1985 ) proc . natl . acad . sci . usa 82 : 292 - 296 ) and gibbon gm - csf ( burgess , a . w ., et al ., ( 1986 ) biochem . j . 235 : 805 - 814 ) have also been described . the primary amino acid sequences of gm - csf strongly predict two α - helices close to the n - terminus ( positions 13 to 27 and 31 to 46 in the murine molecule ), which appear to be required for biological activity . truncation of either helix by introduction of a helix breaking glycine residue markedly reduced the activity of the molecule ( gough , n . m . ( 1987 ) eur . j . biochem . 169 : 353 - 358 ( 1987 ). functional variants or analogs of human gm - csf that comprise at least one substitution , deletion or insertion ( e . g . leu23 , asp27 , glu39 ), which inactivates an n - glycosylation site , thereby facilitating microbial expression are described in u . s . pat . nos . 5 , 032 , 676 and 5 , 229 , 496 . pharmacokinetic studies of gm - csf by enzyme - linked immunoabsorbent assay and bioassay show that for intravenous and subcutaneous routes , serum concentrations are related to dose , though this relation is not strictly linear ( cebon , j . et al ., ( 1988 ) blood 72 : 1340 - 47 ). after intravenous administration over 30 min there is a distribution half - life ( t sub ½ alpha ) of 5 - 15 min and an elimination phase ( t sub ½ beta ) of 1 - 9 h . after single subcutaneous bolus injections , peak serum concentrations are reached within 4 h and the elimination half - life is 2 . 9 h at doses of 10 mμ g / kg . at subcutaneous doses of 5 - 10 mμ g / kg serum concentrations & gt ;= 10 ng / ml are achieved for 8 - 24 h . enterobacteriaceae sp ., enterococcus sp ., haemophilus influenza , mycobacterium tuberculosis , neisseria gonorrhoeae , plasmodiumfalciparum , pseudomonas aeruginosa , shigella dysenteriae , staphylococcus aureus , streptococcus pneumoniae ), virus ( e . g . hiv , herpes , hepatitis ), fungi ( e . g . candida sp . ), or protozoa . “ inflammation ” refers to locations of tissue damage in an individual , regardless of the underlying cause or etiology . for example , the tissue damage can result from microbial invasion ( an infection ), autoimmune processes , tissue or organ allograft rejection , neoplasia , idiopathic diseases or such injurious external influences as heat , cold , radiant energy , electrical or chemical stimuli , or mechanical trauma . whatever the cause , the ensuing inflammatory response is quite similar consisting of a complicated set of functional and cellular adjustments involving changes in microcirculation , movement of fluids , and influx and activation of inflammatory cells ( e . g . leukocytes ). a “ label ” refers to molecule that is capable of generating a detectable image that can be detected either by the naked eye or using an appropriate instrument , e . g . positron emission tomography ( pet ), single photon emission tomography ( spect ) or magnetic resonance imaging ( mri ). certain preferred labels are radionuclides . particularly preferred radionuclides are selected from the group consisting of 123 i , 99m tc , 18 f , 68 ga , 62 cu , 111 in . additional labels are suitable for obtaining a magnetic resonance image ( mri ), including unpair spin atoms and free radicals ( e . g . iron , lanthides and gadolinium ) and contrast agents ( e . g . chelated dtpa manganese ). “ peptides ” refers to polymerized amino acids with a relatively small number of residues ( i . e . in the range of about 2 to about 50 ) and a defined sequence . a “ pharmaceutically acceptable carrier ” refers to a biocompatible solution , having due regard to sterility , ph , isotonicity , stability , and the like and can include any and all solvents , diluents ( including sterile saline , sodium chloride injection , ringer &# 39 ; s injection , dextrose injection , dextrose and sodium chloride injection , lactated ringer &# 39 ; s injection and other aqueous buffer solutions ), dispersion media , coatings , antibacterial and antifungal agents , isotonic agents , and the like . the pharmaceutically acceptable carrier may also contain stabilizers , preservatives , antioxidants , or other additives , which are well known to one of skill in the art , or other vehicle as known in the art . “ polypeptide ” refers to polymerized amino acids comprised of a larger number of residues than a peptide ( i . e . greater than about 50 amino acids ) “ protein ” refers to a polypeptide that occurs naturally and has a definite three dimensional structure under physiological conditions . “ subject ” shall mean a human or animal ( e . g . a non - human mammal ( e . g . rat , mouse , cat , dog , horse , sheep , cow , monkey , avian , or amphibian ) a “ therapeutic agent ” refers to an agent that is capable of producing a biological effect in a subject . preferred therapeutic agents are capable of preventing the establishment of or treating a site of infection or inflammation . examples include antimicrobial agents including : aminoglycosides , amphenicols , β - lactams ( e . g . carbapenems , cephalosporins , cephamycins , monobactams , oxacephems and penicillins ), lincosamides , macrolides , polypeptides and peptides ( e . g . defensins , bacitracin , polymyxin , cecropins , magainin ii , indolicidin , ranalexin , protegrins , gallinacins , tritrpticin , lactoferricin , drosomycin , holotricin , thanatin , dermaseptin , iturins , syringomycins , nikkomycins , polyoxins , fr - 900403 , echinocandins , pneumocandins , aculeacins , mulundocandins , wf11899 , aureobasidins , schizotrin a , cepacidines , zeamatin , cyclopeptides and d4e1 ), tetracyclines , 2 , 4 - diaminopyrimidines , nitrofurans , quinolones and analogs , sulfones , sulfonamides ; antifungal agents including : polyenes , allyamines , imidazoles , triazoles ; antivirals including : purines / pyrimidinones ( e . g . acyclovir , dideoxy - cytidine , - adenosine , or - inosine , interferons , amantadine , ribavirin ); radionuclides ( e . g . 131 i , 186 re , 188 re , 90 y , 212 bi , 211 at , 89 sr , 166 ho , 153 sm , 67 cu and 64 cu ; and antiinflammatory agents including non - steroidal agents , such as aminoarylcarboxylic acid derivatives , arylacetic acid derivatives , arylbutyric acid derivatives , arylcarboxylic acids , arylpropionic acid derivatives , pyrazoles , pyrazolones , salicylic acid derivatives thiazinecarboxamides and others , as well as steroidal agents , such as glucocorticoids . for other antimicrobial and antiinflammatory agents , see e . g . the merck index . in addition to therapeutic agents that are currently in use , the instant invention contemplates agents that are in development or will be developed and that are useful for treating or preventing the progression of an infection or inflammatory response , e . g ., antisense therapies . the invention is based , at least in part , on the surprising finding that radiolabeled g - csf effectively localizes to sites of infection . this empirical result is surprising , since the expression level of csf receptors on cells has been found to be relatively low , compared to the expression level of other growth factor receptors on hematopoietic cells ( park et al ., “ hemopoietic growth - factor receptors ” p39 - 75 in ). based on the cross - reactivity between csfs and csf receptors ( walker , f ., and a . w . burgess ( 1987 ) j . cell . physiol . 130 : 255 - 261 ), it is expected that other csfs will also bind to sites of infection . based on the instant disclosed specificity of g - csf to localize at sites of infection and inflammation , the invention features novel agents that target sites of infection and inflammation in vivo and methods for using the agents to identify , prevent and / or treat sites of infection and inflammation . method for making agents that target sites of infection and inflammation in accordance with the invention , a csf is associated with ( brought into spatial proximity to ) a label or therapeutic agent . spatial proximity between the csf and label or therapeutic agent may be effected in any manner which preserves the binding specificity of the csf for a site of infection or inflammation . for example , spatial proximity may be effected by a covalent or non - covalent chemical bond . such a chemical bond may occur directly or through a chemical intermediary , e . g . a chelator whereby the chelator is conjugated to the csf prior to or after insertion of radiolabel in the chelator . for example , the label or therapeutic agent can be directly conjugated to a csf via : 1 ) any free amino group ( ε - amino groups at lysine residues or a free amine group at the n - terminus of a csf ) 2 ) a free sulfhydryl group ( e . g . on a cysteine residue that is already present or engineered into the csf ), or 3 ) a carbohydrate moiety . chelating agents , which are particularly useful for conjugating radioisotopes to csfs , include : diethylene triamine pentaacetic acid ( dtpa ) ( hnatowich , d . j ., ( 1982 ) int . j . appl . radiat . isot . 33 : 327 - 332 ) and ethylene diamine tetraacetic acid ( edta ). examples of other chelating groups include dioxime ligands , functionalized cyclams , n 2 s 2 ligands , n 3 , s ligands , an isonitrile , a hydrazine , a hynic ( hydrazinonicotinic acid ), a 2 - methylthiolnicotinic acid , or a carboxylate . in addition , a reactive thiol can be attached to a lysine residue via iminothiolane or thiol residues can be conjugated to a csf using an amino sequence containing one or more cysteine residues . alternatively , association between a label or therapeutic agent and a csf can be effected via an auxiliary molecule such as mannitol , gluconate , glucoheptonate , tartrate , and the like or by incorporating the label or therapeutic agent and the csf into a micelle , microsphere or liposome . preferably , the chelating structure , auxiliary molecule , or label is placed in spatial proximity to any position of the csf which does not interfere with the interaction of the csf with the target site of infection or inflammation . labels may be placed in spatial proximity to a csf using known procedures which are specific to the label . for example , when using 123 i , the csf may be labeled in accordance with the known radioiodination procedures such as direct radioiodination with chloramine t , iodogen , lactoperoxidase , or indirectly via radioiodination exchange for a halogen or an organometallic group of a pendant moiety subsequently attached to csf . when the radionuclide is 99m tc , the imaging agent may be labeled using any method suitable for attaching 99m tc to the csf . preferably , when the radionuclide is 99m tc , an auxiliary molecule such as mannitol , gluconate , glucoheptonate , or tartrate is included in the labeling reaction mixture , with or without a chelating structure . more preferably , 99m tc is placed in spatial proximity to the targeting molecule by reducing 99m tco 4 with tin in the presence of mannitol and the targeting molecule . other reducing agents , including tin tartrate or non - tin reductants such as sodium dithionite . disulfide reduction an technetium insertion according to the schwarz method may also be used . after the labeling reaction is complete , the reaction mixture may optionally be purified using one or more chromatography steps such as sep pack or high performance liquid chromatography ( hplc ). any suitable hplc system may be used if a purification step is performed , and the yield of agent obtained from the hplc step may be optimized by varying the parameters of the hplc system , as is known in the art . any hplc parameter may be varied to optimize the yield . for example , the ph may be varied , e . g ., raised to decrease the elution time of the peak corresponding to the targeting agent of the invention . agents comprising a csf and label or therapeutic agent can be tested for ability to bind a site of infection or inflammation as described in the following examples . alternatively , the agents can be tested for binding in in vitro assays in cells or cell lines of the myelomonocytic lineage . the invention as embodied in a kit for imaging or therapy comprises one or more of the compositions described above , in combination with a pharmaceutically acceptable carrier such as human serum albumin . human serum albumin for use in the kit of the invention may be made in any way , for example , through purification of the protein from human serum or though recombinant expression of a vector containing a gene encoding human serum albumin . other substances may also be used as carriers in accordance with this embodiment of the invention , for example , detergents , dilute alcohols , carbohydrates , auxiliary molecules , and the like . the kit of the invention may of course also contain such other items as may facilitate its use , such as syringes , instructions , buffers , reducing agents , buffers , reducing agents , reaction vials , and the like . in one embodiment , a kit according to the invention contains from about 1 to about 30 mci of the radionuclide - labeled imaging agent described above , in combination with a pharmaceutically acceptable carrier . the imaging agent and carrier may be provided in solution or in lyophilized form . when the imaging agent and carrier of the kit are in lyophilized form , the kit may optionally contain a sterile and physiologically acceptable reconstitution medium such as water , saline , buffered saline , and the like . in another embodiment , the kit of the invention may contain the targeting molecule which has been covalently or non - covalently combined with a chelating agent ; an auxiliary molecule such as mannitol , gluconate , glucoheptonate , tartrate , and the like ; and a reducing agent such as sncl 2 , na dithionite or tin tartrate . the targeting molecule / chelating agent and the auxiliary molecule may be present as separate components of the kit or they may be combined into one kit component . the unlabeled targeting molecule / chelating agent , the auxiliary molecule , and the reducing agent may be provided in solution or in lyophilized form , and these components of the kit of the invention may optionally contain stabilizers such as nacl , silicate , phosphate buffers , ascorbic acid , gentisic acid , and the like . additional stabilization of kit components may be provided in this embodiment , for example , by providing the reducing agent in an oxidation - resistant form . determination and optimization of such stabilizers and stabilization methods are well within the level of skill in the art . when the targeting molecule / chelating agent of this embodiment are in lyophilized form , the kit may optionally contain a sterile and physiologically acceptable reconstitution medium such as water , saline , buffered saline , and the like . the amounts of unlabeled targeting molecule / chelating agent , auxiliary molecule , and reducing agent in this embodiment are optimized in accordance with the methods for making the cardiovascular imaging agent set forth above . radionuclides , including , but not limited to , 99m tc obtained from a commercially available 99 mo / 99m tc generator or commercially available 123i , may be combined with the unlabeled targeting molecule / chelating agent and the reducing agent for a time and at a temperature sufficient to chelate the radionuclide to the targeting molecule / chelating agent , and the imaging agent thus formed is injected into the patient . for use in treating or preventing the development of an infection or inflammation , a therapeutically effective amount of therapeutic agent of the invention alone or in conjunction with a “ pharmaceutically acceptable carrier ” can be administered to a subject by any mode that allows the agent to be delivered to the infection or inflammation site . preferred routes of administration include administration via injection ( subcutaneous , intravenous , parenteral , intraperitoneal , intrathecal , etc .). the injection can be in a bolus or a continuous infusion . depending on the route of administration , the therapeutic agent can be coated with or disposed within a selected material ( e . g . positively or negatively charged liposomes ), to protect the agent from natural conditions , which may detrimentally effect its ability to perform its intended function , increase its in vivo availability or increase its localization at sites of infection and inflammation . a “ therapeutically effective amount ” of a therapeutic agent refers to that amount necessary or sufficient to eliminate , reduce or contain ( prevent the spread of ) an infection or inflammation . the “ therapeutically effective amount ” can vary depending on such factors as the infection or inflammation being treated , the particular therapeutic agent , the size of the subject , or the severity of the infection or inflammation . however , one of ordinary skill in the art can empirically determine the effective amount of a particular compound without performing undue experimentation . imaging agents of the invention may be used in accordance with the methods of the invention by one of skill in the art , e . g ., by specialists in nuclear medicine , to image sites of infection or inflammation in a subject . any site of infection or inflammation may be imaged using the imaging agents of the invention . images can be generated by virtue of differences in the spatial distribution of the imaging agents which accumulate at a site of infection or inflammation . the spatial distribution may be measured using any means suitable for the particular label , for example , a gamma camera , a pet apparatus , a spect apparatus , and the like . some lesions may be evident when a less intense spot appears within the image , indicating the presence of tissue in which a lower concentration of imaging agent accumulates relative to the concentration of imaging agent which accumulates in surrounding tissue . alternatively , a lesion may be detectable as a more intense spot within the image , indicating a region of enhanced concentration of the imaging agent at the site of the lesion relative to the concentration of agent which accumulates in surrounding tissue . accumulation of lower or higher amounts of the imaging agent at a lesion may readily be detected visually . alternatively , the extent of accumulation of the imaging agent may be quantified using known methods for quantifying radioactive emissions . a particularly useful imaging approach employs more than one imaging agent to perform simultaneous studies . preferably , a detectably effective amount of the imaging agent of the invention is administered to a subject . in accordance with the invention , “ a detectably effective amount ” of the imaging agent of the invention is defined as an amount sufficient to yield an acceptable image using equipment which is available for clinical use . a detectably effective amount of the imaging agent of the invention may be administered in more than one injection . the detectably effective amount of the imaging agent of the invention can vary according to factors such as the degree of susceptibility of the individual , the age , sex , and weight of the individual , idiosyncratic responses of the individual , the dosimetry . detectably effective amounts of the imaging agent of the invention can also vary according to instrument and film - related factors . optimization of such factors is well within the level of skill in the art . the amount of imaging agent used for diagnostic purposes and the duration of the imaging study will depend upon the radionuclide used to label the agent , the body mass of the patient , the nature and severity of the condition being treated , the nature of therapeutic treatments which the patient has undergone , and on the idiosyncratic responses of the patient . ultimately , the attending physician will decide the amount of imaging agent to administer to each individual patient and the duration of the imaging study . the present invention is further illustrated by the following examples which should not be construed as limiting in any way . the contents of all cited references ( including literature references , issued patents , published patent applications ) as cited throughout this application are hereby expressly incorporated by reference . the practice of the present invention will employ , unless otherwise indicated , conventional techniques , which are within the skill of the art . such techniques are explained fully in the literature . in order to label g - csf with radioindium ( 111 in ), g - csf was conjugated with diethylenetriaminepentacetic acid ( dtpa ) via the active ester . dtpa conjugated g - csf was labeled with in - 111 and injected into rabbits bearing intramuscular bacterial infections . two new zealand white rabbits weighing approximately 2 - 3 kg were injected in their left posterior thigh with a 0 . 5 ml suspension of ˜ 10 9 e . coli for infection imaging and biodistribution studies . animals were injected with in - 111 - dtpa - g - csf at 24 hr after bacterial injection , when the animals were judged to have moderate infections by palpation . at 4 and 18 hours following injection of the in - 111 - dtpa - g - csf , the animals were anesthetized with ketamine / xylazine ( 15 . 0 and 1 . 5 mg / kg ) and scintigrams were acquired using a large field of view gamma camera equipped with a parallel hole medium energy collimator . regions - of - interest ( roi &# 39 ; s ) were drawn over the area of infection and the contralateral normal muscle and target - to - background ( t / b ) ratios were calculated . after acquiring the final images , the animals were sacrificed with an over dose of sodium pentobarbital and biodistribution was determined . for comparison with the imaging results , infected to normal muscle and pus to normal muscle ratios were calculated from biodistribution data . from roi analysis , the average target : background ( t / b ) ratios were 3 . 567 : 1 and 11 . 87 : 1 at 4 and 18 hours post injection , respectively . tc - 99m - labeled - bio - 100 was injected into rabbits bearing intramuscular bacterial infections . new zealand white rabbits weighing approximately 2 . 5 kg were injected in their left posterior thigh with a 0 . 5 ml suspension of ˜ 109 e . coli for infection imaging and biodistribution studies . animals were injected with tc - 99m - bio - 100 at 24 hr after bacterial injection , when the animals were judged to have moderate infections by palpation . at 18 hours following injection of the tc - 99m - bio - 100 , the animals were anesthetized with ketamine / xylazine ( 15 . 0 and 1 . 5 mg / kg ) and scintigrams were acquired using a large field of view gamma camera equipped with a parallel hole medium energy collimator . after acquiring the final images , the animals were sacrificed with an over dose of sodium pentobarbital and biodistribution was determined . for the comparison with the imaging results , infected to normal muscle and pus to normal muscle ratios were calculated from the biodistribution data . from roi analysis , the average target : background ( t / b ) ratios were 1 . 999 : 1 and 7 . 024 : 1 at 3 and 18 hours post injection , respectively .
the present invention provides novel agents for specifically targeting and detecting or treating focal sites of infection or inflammation in a subject .