Drug pre-targeting by means of bi-specific antibodies and hapten constructs comprising a carrier peptide and the active agent(s)

Abstract

The present invention relates to targetable constructs which may be bound by a bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds the targetable construct. The targetable construct comprises a carrier portion which comprises or bears at least one epitope recognizable by at least one arm of said bi-specific antibody or antibody fragment. The targetable construct further comprises one or more therapeutic or diagnostic agents or enzymes. The invention provides constructs and methods for producing the targetable constructs and bi-specific antibodies or antibody fragments, as well as methods for using them.

1 . A compound of the formula:  
     
       
         
               
               
             
                   
                   
               
                   
                 X-Phe-Lys(HSG)-D-Tyr-Lys(HSG)-Lys(Y)-NH 2 ; 
               
                   
                   
               
           
              
              
              
             
          
         
       
       wherein the compound includes a hard acid cation chelator at X or Y, and a soft acid cation chelator at remaining X or Y.  
     
   
   
       2 . The compound of  claim 1 , wherein the hard acid cation chelator includes a carboxylate or amine group.  
   
   
       3 . The compound of  claim 1 , wherein the hard acid cation chelator is selected from the group consisting of NOTA, DOTA, DTPA, and TETA.  
   
   
       4 . The compound of  claim 1 , wherein the soft acid cation chelator includes a thiol group.  
   
   
       5 . The compound of  claim 1 , wherein the soft acid cation chelator is selected from the group consisting of Tscg-Cys and Tsca-Cys.  
   
   
       6 . The compound of  claim 1 , further comprising at least one radionuclide, therapeutic agent or diagnostic agent.  
   
   
       7 . The compound of  claim 6 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  50 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr, and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       8 . The compound of  claim 1  comprising:  
     
       
         
               
               
             
                   
               
                 DOTA- 
                   
               
                 Phe-Lys(HSG)-D-Tyr-Lys(HSG)-Lys(Tscg-Cys)-NH 2 . 
               
                   
               
           
              
              
              
              
             
          
         
       
     
   
   
       9 . The compound of  claim 1  comprising:  
     
       
         
               
               
             
                   
               
                 Tscg- 
                   
               
                 Cys-Phe-Lys(HSG)-D-Tyr-Lys(HSG)-Lys(DOTA)-NH 2 . 
               
                   
               
           
              
              
              
              
             
          
         
       
     
   
   
       10 . The compound of  claim 1 , wherein the hard acid cation chelator includes a cation selected from the group consisting of Group IIa and Group IIIa metal cations.  
   
   
       11 . The compound of  claim 1 , wherein the soft acid cation chelator includes a cation selected from the group consisting of transition metals, Bi, lanthanides and actinides.  
   
   
       12 . The compound of  claim 1 , wherein the soft acid cation chelator includes a cation selected from the group consisting of Tc, Re, and Bi.  
   
   
       13 . A targetable construct comprising:  
     
       
         
               
               
             
                   
                   
               
                   
                 X-Phe-Lys(HSG)-D-Tyr-Lys(HSG)-Lys(Y)-NH-R; 
               
                   
                   
               
           
              
              
              
             
          
         
       
       wherein the targetable construct includes a hard acid cation chelator at X or Y; a soft acid cation chelator at remaining X or Y; and a therapeutic agent, diagnostic agent or enzyme at R.  
     
   
   
       14 . The targetable construct of  claim 13 , wherein R is covalently linked to the targetable construct.  
   
   
       15 . The targetable construct of  claim 13 , wherein R is linked to the targetable construct by a linker moiety.  
   
   
       16 . The targetable construct of  claim 15 , wherein the linker moiety includes at least one amino acid.  
   
   
       17 . The compound of  claim 13 , further comprising at least one radionuclide bound to at least one of the hard acid chelator and soft acid chelator.  
   
   
       18 . The compound of  claim 17 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       19 . The targetable construct of  claim 13 , wherein said therapeutic agent includes a radionuclide, drug, prodrug or toxin.  
   
   
       20 . The targetable construct of  claim 19 , wherein said prodrug is selected from the group consisting of epirubicin glucuronide, CPT-11, etoposide glucuronide, daunomicin glucuronide and doxorubicin glucuronide.  
   
   
       21 . The targetable construct of  claim 19 , wherein said toxin is selected from the group consisting of ricin, abrin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin,  Pseudomonas  exotoxin, and  Pseudomonas  endotoxin.  
   
   
       22 . The targetable construct of  claim 13 , wherein said therapeutic agent comprises doxorubicin, SN-38, etoposide, methotrexate, 6-mercaptopurine or etoposide phosphate.  
   
   
       23 . The targetable construct of  claim 13 , wherein the diagnostic agent includes one or more agents for photodynamic therapy.  
   
   
       24 . The targetable construct of  claim 23 , wherein said agent for photodynamic therapy is a photosensitizer.  
   
   
       25 . The targetable construct of  claim 24 , wherein said photosensitizer is selected from the group consisting of benzoporphyrin monoacid ring A (BPD-MA), tin etiopurpurin (SnET2), sulfonated aluminum phthalocyanine (AlSPc) and lutetium texaphyrin (Lutex).  
   
   
       26 . The targetable construct of  claim 13 , wherein said diagnostic agent comprises one or more image enhancing agents for use in magnetic resonance imaging (MRI).  
   
   
       27 . The targetable construct of  claim 26 , wherein said enhancing agents include Mn, Fe, La and Gd.  
   
   
       28 . The targetable construct of  claim 13 , wherein said diagnostic agent comprises one or more radiopaque or contrast agents for X-ray or computed tomography.  
   
   
       29 . The targetable construct of  claim 28 , wherein said radiopaque or contrast agents include barium diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosemetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, or thallous chloride.  
   
   
       30 . The targetable construct of  claim 13 , wherein said diagnostic agent comprises one or more ultrasound contrast agents.  
   
   
       31 . The targetable construct of  claim 30 , wherein said ultrasound contrast agent includes a liposome or dextran.  
   
   
       32 . The targetable construct of  claim 31 , wherein the liposome is gas-filled.  
   
   
       33 . The targetable construct of  claim 13 , wherein said enzyme includes an enzyme capable of converting drug intermediate to a toxic form to increase toxicity of said drug at a target site.  
   
   
       34 . A method of treating or diagnosing or treating and diagnosing a disease or a condition that may lead to a disease comprising: 
 (A) administering to said subject a bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds a targetable construct;    (B) optionally, administering to said subject a clearing composition, and allowing said composition to clear non-localized antibodies or antibody fragments from circulation; and    (C) administering to said subject a targetable construct comprising the compound of  claim 1  which further comprises at least one diagnostic or therapeutic cation, and/or one or more chelated or chemically bound therapeutic agent, diagnostic agent, or enzyme.    
   
   
       35 . The method of  claim 34 , wherein the bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds a targetable construct and the targetable construct are administered at substantially the same time.  
   
   
       36 . The method of  claim 34 , wherein the therapeutic cation emits particles and/or positrons having 20 to 10,000 keV.  
   
   
       37 . The method of  claim 34 , wherein said therapeutic cation is selected from the group consisting of  111 In,  177 Lu,  212 Bi,  213 Bi,  211 At,  62 Cu,  64 Cu,  67 Cu,  90 Y,  125 I,  131 I,  32 P,  33 P,  47 Sc,  111 Ag,  67 Ga,  142 Pr,  153 Sm,  161 Tb,  166 Dy,  166 Ho,  186 Re,  188 Re,  189 Re,  212 Pb,  223 Ra,  225 Ac,  59 Fe,  75 Se,  77 As,  89 Sr,  99 Mo,  105 Rh,  109 Pd,  143 Pr,  149 Pm,  169 Er,  194 Ir,  198 Au,  199 Au and  211 Pb.  
   
   
       38 . The method of claim of  claim 34 , wherein the diagnostic cation emits particles and/or positrons having 25-10,000 keV.  
   
   
       39 . The method of  claim 34 , wherein said diagnostic cation is selected from the group consisting of  110 In,  111 In,  177 Lu,  18 F,  52 Fe,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  86 Y,  90 Y,  89 Zr,  94m Tc,  94 Tc,  99m Tc,  120 I,  123 I,  124 I,  125 I,  131 I,  154-158 Gd,  32 P,  11 C,  13 N,  15 O,  186 Re,  188 Re,  51 Mn,  52m Mn,  55 Co,  72 As,  75 Br,  76 Br,  82m Rb and  83 Sr.  
   
   
       40 . The method of  claim 34 , wherein said diagnostic agent is used to perform positron-emission tomography (PET).  
   
   
       41 . The method of  claim 34 , wherein said diagnostic agent is used to perform SPECT imaging.  
   
   
       42 . The method of  claim 34 , wherein said diagnostic cation or agent includes one or more image enhancing agents for use in magnetic resonance imaging (MRI).  
   
   
       43 . The method of  claim 42 , wherein said enhancing agent is selected from the group consisting of Mn, Fe, La and Gd.  
   
   
       44 . The method of  claim 34 , wherein said diagnostic agent comprises one or more radiopaque or contrast agents for X-ray or computed tomography.  
   
   
       45 . The method of  claim 44 , wherein said radiopaque or contrast agents include barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosemetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, or thallous chloride.  
   
   
       46 . The method of  claim 34 , wherein said diagnostic agent comprises one or more ultrasound contrast agents.  
   
   
       47 . The method of  claim 46 , wherein said ultrasound contrast agent includes a liposome or dextran.  
   
   
       48 . The method of  claim 47 , wherein said liposome is gas-filled.  
   
   
       49 . The method of  claim 34 , wherein said diagnostic agents are selected from the group consisting of a fluorescent compound, a chemiluminescent compound, and a bioluminescent compound.  
   
   
       50 . The method of  claim 49 , wherein said fluorescent compound is selected from the group consisting of fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine.  
   
   
       51 . The method of  claim 49 , wherein said chemiluminescent compound is selected from the group consisting of luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester.  
   
   
       52 . The method of  claim 49 , wherein said bioluminescent compound is selected from the group consisting of luciferin, luciferase and aequorin.  
   
   
       53 . The method of  claim 34 , wherein said targeted tissue is a tumor.  
   
   
       54 . The method of  claim 53 , wherein said tumor produces or is associated with antigens selected from the group consisting of colon-specific antigen-p (CSAp), carcinoembryonic antigen (CEA), CD19, CD20, CD21, CD22, CD23, CD30, CD74, CD80, HLA-DR, Ia, MUC 1, MUC 2, MUC 3, MUC 4, EGFR, HER 2/neu, PAM-4, TAG-72, EGP-1, EGP-2, A3, KS-1, Le(y), S100, PSMA, PSA, tenascin, folate receptor, VEGFR, necrosis antigens, IL-2, T101, MAGE.  
   
   
       55 . The method of  claim 34 , wherein said at least one arm that specifically binds a targeted tissue is a monoclonal antibody or a fragment of a monoclonal antibody.  
   
   
       56 . The method of  claim 34 , wherein said at least one other arm that specifically binds a targetable construct is a monoclonal antibody or a fragment of a monoclonal antibody.  
   
   
       57 . The method of  claim 34 , wherein said at least one arm that specifically binds a targeted tissue is a human, chimeric or humanized antibody or a fragment of a human, chimeric or humanized antibody.  
   
   
       58 . The method of  claim 34 , wherein said at least one other arm that specifically binds a targetable construct is a human, chimeric or humanized antibody or a fragment of a human, chimeric or humanized antibody.  
   
   
       59 . The method of  claim 34 , wherein said bi-specific antibody or antibody fragment further comprises a therapeutic nuclide.  
   
   
       60 . The method of  claim 59 , wherein said therapeutic nuclide is selected from the group consisting of  111 In,  177 Lu,  212 Bi,  213 Bi,  211 At,  62 Cu,  64 Cu,  67 Cu,  90 Y,  125 I,  131 I,  131 I,  32 P,  33 P,  47 Sc,  111 Ag,  67 Ga,  142 Pr,  153 Sm,  161 Tb,  166 Dy,  166 Ho,  186 Re,  188 Re,  189 Re,  212 Pb,  223 Ra,  225 Ac,  59 Fe,  75 Se,  77 As,  89 Sr,  99 Mo,  105 Rh,  109 Pd,  143 Pr,  149 Pm,  169 Er,  194 Ir,  198 Au,  199 Au and  211 Pb.  
   
   
       61 . The method of  claim 34 , wherein the bi-specific antibody comprises the Fv of MAb Mu-9 and the Fv of MAb 679.  
   
   
       62 . The method of  claim 61 , wherein Mu-9 and/or 679 are chimerized or humanized.  
   
   
       63 . The method of  claim 61 , wherein Mu-9 and/or 679 are human Mu-9 and 679.  
   
   
       64 . The method of  claim 61 , wherein the bi-specific antibody comprises one or more of the CDRs of Mu-9.  
   
   
       65 . The method of  claim 61 , wherein the bi-specific antibody comprises one or more of the CDRs of 679.  
   
   
       66 . The method of  claim 61 , wherein the bi-specific antibody is a fusion protein.  
   
   
       67 . The method of  claim 34 , wherein the bi-specific antibody comprises the Fv of MAb MN-14 and the Fv of MAb 679.  
   
   
       68 . The method of  claim 67 , wherein MN-14, and/or 679 are chimerized or humanized.  
   
   
       69 . The method of  claim 67 , wherein MN-14, and/or 679 are human MN-14 and 679.  
   
   
       70 . The method of  claim 67 , wherein the bi-specific antibody comprises one or more of the CDRs of MN-14.  
   
   
       71 . The method of  claim 67 , wherein the bi-specific antibody comprises one or more of the CDRs of 679.  
   
   
       72 . The method of  claim 67 , wherein the bi-specific antibody is a fusion protein.  
   
   
       73 . The method of  claim 34 , wherein the fusion protein is trivalent, and incorporates the Fv of an antibody reactive with CSAp.  
   
   
       74 . The method of  claim 34 , wherein the bi-specific antibody incorporates a Class-III anti-CEA antibody and the Fv of 679.  
   
   
       75 . The method of  claim 34 , wherein said targetable construct comprises one or more radioactive isotopes useful for killing diseased tissue.  
   
   
       76 . The method of  claim 34 , wherein said targetable construct comprises  10 B atoms, and said method further comprises the step of irradiating said boron atoms localized at said diseased tissue, thereby effecting BNCT of said diseased tissue.  
   
   
       77 . The method of  claim 34 , when said targetable construct comprises an enzyme, further administering to said subject a drug which said enzyme is capable of converting to a toxic form, and, therefore, increasing the toxicity of said drug at the target site.  
   
   
       78 . A method for detecting or treating target cells, tissues or pathogens in a mammal, comprising: 
 administering an effective amount of a bi-specific antibody or antibody fragment comprising at least one arm that specifically binds a target and at least one other arm that specifically binds a targetable construct; and    administering a targetable construct comprising the compound of  claim 1;     wherein said target includes a target cell, tissue, pathogen or a molecule produced by or associated therewith and at least one arm that specifically binds said target is capable of binding to a complementary binding moiety on the target    
   
   
       79 . The method of  claim 78 , wherein said pathogen is a fungus, virus, parasite, bacterium, protozoan, or mycoplasm.  
   
   
       80 . The method of  claim 79 , wherein said fungus is selected from the group consisting of  Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Candida albicans.    
   
   
       81 . The method of  claim 79 , wherein said virus is selected from the group consisting of human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, hepatitis B virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus, wart virus and blue tongue virus.  
   
   
       82 . The method of  claim 79 , wherein said  bacterium  is selected from the group consisting of  Anthrax bacillus, Streptococcus agalactiae, Legionella pneumophilia, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus, Hemophilis influenzae  B,  Treponema pallidum , Lyme disease spirochetes,  Pseudomonas aeruginosa, Mycobacterium leprae, Brucella abortus, Mycobacterium tuberculosis  and Tetanus toxin.  
   
   
       83 . The method of  claim 79 , wherein said parasite is a helminth or a malarial parasite.  
   
   
       84 . The method of  claim 79 , wherein said protozoan is selected from the group consisting of  Plasmodium falciparum, Plasmodium vivax, Toxoplasma gondii, Trypanosoma rangeli, Trypanosoma cruzi, Trypanosoma rhodesiensei, Trypanosoma brucei, Schistosoma mansoni, Schistosoma japanicum, Babesia bovis, Elmeria tenella, Onchocerca volvulus, Leishmania tropica, Trichinella spiralis, Onchocerca volvulus, Theileria parva, Taenia hydatigena, Taenia ovis, Taenia saginata, Echinococcus granulosus  and  Mesocestoides corti.    
   
   
       85 . The method of  claim 79 , wherein said  mycoplasma  is selected from the group consisting of  Mycoplasma arthritidis, Mycoplasma hyorhinis, Mycoplasma orale, Mycoplasma arginini, Acholeplasma laidlawii, Mycoplasma salivarum, and Mycoplasma pneumoniae.    
   
   
       86 . The method of  claim 78 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       87 . The method of  claim 86 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F, 52Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 Ho,  121 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re 105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       88 . The method of  claim 86 , wherein the diagnostic agent includes an imaging agent.  
   
   
       89 . A method of treating or identifying diseased tissues in a subject, comprising: 
 administering to said subject a bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds a targetable construct;    optionally, administering to said subject a clearing composition, and allowing said composition to clear non-localized antibodies or antibody fragments from circulation; and    administering to said subject a targetable construct comprising the compound of  claim 1 .    
   
   
       90 . The method of  claim 89 , wherein said subject is mammalian.  
   
   
       91 . The method of  claim 90 , wherein said mammalian subject is selected from the group consisting of humans, primates, equines, canines and felines.  
   
   
       92 . The method of  claim 89 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       93 . The method of  claim 92 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       94 . The method of  claim 92 , wherein the diagnostic agent includes an imaging agent.  
   
   
       95 . The method of  claim 92 , wherein the therapeutic agent includes drugs, toxins, cytokines, hormones, or growth factors.  
   
   
       96 . A kit useful for treating or identifying diseased tissues in a subject comprising: 
 (A) a targetable construct comprising the compound of  claim 1;     (B) a bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds the targetable construct;    wherein the targetable construct includes a carrier portion which comprises or bears at least one epitope recognizable by said at least one other arm of said bi-specific antibody or antibody fragment, and one or more conjugated therapeutic or diagnostic agents, or enzymes; and    (C) optionally, a clearing composition useful for clearing non-localized antibodies and antibody fragments.    
   
   
       97 . The kit of  claim 96 , wherein said diagnostic agent selected from the group consisting of  110 In,  111 In,  177 Lu,  18 F,  52 Fe,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  86 Y,  90 Y,  89 Zr,  94m Tc,  94 Tc,  99m Tc,  120 I,  123 I,  124 I,  125 I,  131 I,  154-158 Gd,  32 P,  11 C,  13 N,  15 O,  186 Re,  188 Re,  51 Mn,  52m Mn,  55 Co,  72 As,  75 Br,  76 Br,  82m Rb and  83 Sr.  
   
   
       98 . The kit of  claim 96 , wherein said therapeutic agent is selected from the group consisting of  111 In,  177 Lu,  212 Bi,  213 Bi,  211 At,  62 Cu,  64 Cu,  67 Cu,  90 Y,  125 I,  131 I,  32 P,  33 P,  47 Sc,  111 Ag,  67 Ga,  142 Pr,  153 Sm,  161 Tb,  166 Dy,  166 Ho,  186 Re,  188 Re,  189 Re,  212 Pb,  223 Ra,  225 Ac,  59 Fe,  75 Se,  77 As,  89 Sr,  99 Mo,  105 Rh,  109 Pd,  143 Pr,  149 Pm,  169 Er,  194 Ir,  198 Au,  199 Au and  211 Pb.  
   
   
       99 . The method of  claim 96 , when said targetable construct comprises an enzyme, optionally, the kit further comprising a drug which enzyme is capable of converting to a toxic form to increase the toxicity of said drug at the target site.  
   
   
       100 . A targetable construct comprising the compound of  claim 1 .  
   
   
       101 . A method for imaging normal tissue in a mammal comprising: 
 administering an effective amount of a bi-specific antibody or antibody fragment; and    administering a targetable construct comprising the compound of  claim 1;     wherein the bi-specific antibody or antibody fragment comprises at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds the targetable construct; and wherein said at least one arm is capable of binding to a complementary binding moiety on the normal tissue or target cells produced by or associated therewith.    
   
   
       102 . The method of  claim 101 , wherein said normal tissue is tissue from the ovary, thymus, parathyroid, endometrium, bone marrow, or spleen.  
   
   
       103 . The method of  claim 101 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       104 . The method of  claim 103 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co, 62Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr, and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       105 . The method of  claim 103 , wherein the diagnostic agent includes a contrast agent.  
   
   
       106 . The method of  claim 103 , wherein the diagnostic agent includes an imaging agent  
   
   
       107 . The method of  claim 106 , wherein said imaging agent is an agent used for PET.  
   
   
       108 . The method of  claim 106 , wherein the imaging agent is an agent used for SPECT.  
   
   
       109 . The method of  claim 103 , wherein the therapeutic agent includes drugs, toxins, cytokines, hormones, or growth factors.  
   
   
       110 . A method of intraoperatively identifying diseased tissues, in a subject, comprising: 
 administering an effective amount of a bi-specific antibody or antibody fragment; and    administering a targetable construct comprising the compound of  claim 1;     wherein the bi-specific antibody or antibody fragment comprises at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds the targetable construct; and wherein said at least one arm is capable of binding to a complementary binding moiety on the target cells, tissues or pathogen or on a molecule produced by or associated therewith.    
   
   
       111 . The method of  claim 110 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       112 . The method of  claim 111 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  102 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       113 . The method of  claim 111 , wherein the diagnostic agent includes a contrast agent.  
   
   
       114 . The method of  claim 111 , wherein the diagnostic agent includes an imaging agent.  
   
   
       115 . The method of  claim 111 , wherein the therapeutic agent includes drugs, toxins, cytokines, hormones, or growth factors.  
   
   
       116 . A method for the endoscopic identification of diseased tissues, in a subject, comprising: 
 administering an effective amount of a bi-specific antibody or antibody fragment; and    administering a targetable construct comprising the compound of  claim 1;     wherein the bi-specific antibody or antibody fragment comprises at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds the targetable construct; and wherein said at least one arm is capable of binding to a complementary binding moiety on the target cells, tissues or pathogen or on a molecule produced by or associated therewith.    
   
   
       117 . The method of  claim 116 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       118 . The method of  claim 117 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  89 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       119 . The method of  claim 117 , wherein the diagnostic agent includes a contrast agent.  
   
   
       120 . The method of  claim 117 , wherein the diagnostic agent includes an imaging agent.  
   
   
       121 . The method of  claim 117 , wherein the therapeutic agent includes drugs, toxins, cytokines, hormones, or growth factors.  
   
   
       122 . A method for the intravascular identification of diseased tissues, in a subject, comprising: 
 administering an effective amount of a bi-specific antibody or antibody fragment comprising at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds a targetable construct;    wherein said at least one arm is capable of binding to a complementary binding moiety on the target cells, tissues or pathogen or on a molecule produced by or associated therewith, and    administering a targetable construct comprising the compound of  claim 1 .    
   
   
       123 . The method of  claim 122 , wherein said targetable construct further comprises at least one radionuclide, therapeutic agent, diagnostic agent or enzyme.  
   
   
       124 . The method of  claim 123 , wherein the radionuclide is selected from the group consisting of  225 Ac,  111 Ag,  72 As,  77 As,  211 At,  198 Au,  199 Au,  212 Bi,  213 Bi,  75 Br,  76 Br,  11 C,  55 Co,  62 Cu,  64 Cu,  67 Cu,  166 Dy,  169 Er,  18 F,  52 Fe,  59 Fe,  67 Ga,  68 Ga,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  166 Ho,  120 I,  123 I,  124 I,  125 I,  131 I,  110 In,  111 In,  194 Ir,  177 Lu,  51 Mn,  52m Mn,  99 Mo,  13 N,  15 O,  32 P,  33 P,  211 Pb,  212 Pb,  109 Pd,  149 Pm,  142 Pr,  143 Pr,  223 Ra,  82m Rb,  186 Re,  188 Re,  189 Re,  105 Rh,  47 Sc,  153 Sm,  75 Se,  83 Sr,  89 Sr,  161 Tb,  94m Tc,  94 Tc,  99m Tc,  86 Y,  90 Y,  90 Y, and  89 Zr; and, when the targetable construct includes more than one radionuclide, the radionuclides may be different radionuclides.  
   
   
       125 . The method of  claim 123 , wherein the diagnostic agent includes a contrast agent.  
   
   
       126 . The method of  claim 123 , wherein the diagnostic agent includes an imaging agent.  
   
   
       127 . The method of  claim 123 , wherein the therapeutic agent includes drugs, toxins, cytokines, hormones, or growth factors.