Polyspecific immunoconjugates and antibody compositiesfor targeting the multidrug resistant phenotype

Abstract

Polyspecific immunoconjugates and antibody composites that bind a multidrug transporter protein and an antigen associated with a tumor or infectious agent are used to overcome the multidrug resistant phenotype. These immunoconjugates and composites also can be used diagnostically to determine whether the failure of traditional chemotherapy is due to the presence of multidrug resistant tumor cells, multidrug resistant HIV-infected cells or multidrug resistant infectious agents.

What is claimed is:  
     
         1 . A polyspecific immunoconjugate comprising: 
 (a) at least one antibody component that binds with a first epitope of a multidrug transporter protein;    (b) at least one antibody component that binds with a first epitope of an antigen, wherein said antigen is associated with a tumor or an infectious agent; and    (c) at least one diagnostic or therapeutic agent.    
     
     
         2 . The polyspecific immunoconjugate of  claim 1 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         3 . The polyspecific immunoconjugate of  claim 2 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         4 . The polyspecific immunoconjugate of  claim 3 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         5 . The polyspecific immunoconjugate of  claim 4 , wherein said diagnostic agent is selected from the group consisting of radioactive label, photoactive agent or dye, florescent label, enzyme label, bioluminescent label, chemiluminescent label, colloidal gold and paramagnetic ion.  
     
     
         6 . The polyspecific immunoconjugate of  claim 5 , wherein said radioactive label is selected from the group consisting of γ-emitters and positron-emitters.  
     
     
         7 . The polyspecific immunoconjugate of  claim 6 , wherein said γ-emitters have a gamma radiation emission peak in the range of 50-500 Kev.  
     
     
         8 . The polyspecific immunoconjugate of  claim 7 , wherein said γ-emitters with a gamma radiation emission peak in the range of 50-500 Kev are selected from the group consisting of  99m Tc,  67 Ga,  123 I,  125 I and  131 I.  
     
     
         9 . The polyspecific immunoconjugate of  claim 4 , wherein said therapeutic agent is selected from the group consisting of radioisotope, boron addend, immunomodulator, toxin, photoactive agent or dye, cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug, antiprotozoal drug and chemosensitizing agent.  
     
     
         10 . The polyspecific immunoconjugate of  claim 9 , wherein said radioisotope is selected from the group consisting of α-emitters, β-emitters, γ-emitters, Auger electron emitters, neutron capturing agents that emit a particles and radioisotopes that decay by electron capture.  
     
     
         11 . The polyspecific immunoconjugate of  claim 9 , wherein said radioisotope is selected from the group consisting of  198 Au,  32 P,  125 I,  131 I,  90 Y,  186 Re,  188 Re,  67 Cu and  211 At.  
     
     
         12 . The polyspecific immunoconjugate of  claim 4 , further comprising an antibody component that binds with a second epitope of said multidrug transporter protein.  
     
     
         13 . The polyspecific immunoconjugate of  claim 12 , further comprising an antibody component that binds with a second epitope of said tumor or infectious agent associated antigen, or with an epitope of a second antigen associated with said tumor or said infectious agent.  
     
     
         14 . The polyspecific immunoconjugate of any one of claims  4 ,  12  or  13 , further comprising an immunomodulator, wherein said immunomodulator is selected from the group consisting of cytokines, stem cell growth factors and hematopoietic factors.  
     
     
         15 . A method for treating a mammal having either a multidrug resistant tumor that expresses a tumor associated antigen or a multidrug resistant disease caused by an infectious agent, said method comprising the step of administering a polyspecific immunoconjugate to the mammal, wherein said polyspecific immunoconjugate comprises: 
 (a) at least one antibody component that binds with a first epitope of a multidrug transporter protein,    (b) at least one antibody component that binds with a first epitope of an antigen, wherein said antigen is associated with said tumor or said infectious agent, and    (c) at least one therapeutic agent.    
     
     
         16 . The method of  claim 15 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         17 . The method of  claim 16 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         18 . The method of  claim 15 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         19 . The method of  claim 18 , wherein said therapeutic agent is selected from the group consisting of radioisotope, boron addend, toxin, immunomodulator, photoactive agent or dye, cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug, antiprotozoal drug and a chemosensitizing agent.  
     
     
         20 . The method of  claim 19 , wherein said radioisotope is selected from the group consisting of α-emitters, β-emitters, γ-emitters, Auger electron emitters, neutron capturing agents that emit α-particles and radioisotopes that decay by electron capture.  
     
     
         21 . The method of  claim 19 , wherein said radioisotope is selected from the group consisting of  198 Au,  32 P,  125 I,  131 I,  90 Y,  186 Re,  188 Re,  67 Cu and  211 At.  
     
     
         22 . The method of  claim 19 , further comprising the step of administering a chemosensitizing agent to said mammal.  
     
     
         23 . The method of  claim 19 , wherein said therapeutic agent is a chemosensitizing agent.  
     
     
         24 . The method of  claim 23 , further comprising the step of administering a chemotherapeutic agent selected from the group consisting of cancer chemotherapeutic drug, antibacterial drug, antiviral drug, antifungal drug and antiprotozoal drug.  
     
     
         25 . The method of  claim 19 , further comprising the step of administering an immunomodulator, wherein said immunomodulator is selected from the group consisting of cytokine, stem cell growth factor and hematopoietic factor.  
     
     
         26 . The method of  claim 25 , wherein said cytokine is granulocyte-colony stimulating factor.  
     
     
         27 . The method of  claim 25 , wherein said hematopoietic factor is thrombopoietin.  
     
     
         28 . The method of  claim 25 , wherein said immunomodulator is administered prior to or simultaneously with said administration of said polyspecific immunoconjugate.  
     
     
         29 . The method of  claim 25 , wherein said immunomodulator is administered subsequent to said administration of said polyspecific immunoconjugate.  
     
     
         30 . A method for detecting the location of multidrug resistant (MDR) tumor cells, MDR HIV-infected cells or MDR infectious agents in a mammal having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the mammal with an antibody composite comprising (1) at least one antibody component that binds a first epitope of a multidrug transporter protein, and (2) at least one antibody component that binds a first epitope of an antigen that is associated with the tumor or the infectious agent, wherein said antibody composite is conjugated with a biotin-binding-molecule or with biotin;    (b) parenterally injecting a clearing composition comprised of: 
 (i) biotin, when said antibody composite is conjugated with a biotin-binding molecule, or  
 (ii) a biotin-binding molecule, when said antibody composite is conjugated with biotin,  
 and allowing said clearing composition to substantially clear said antibody composite from sites that do not contain MDR tumor cells, MDR HIV-infected cells or MDR infectious agents; and  
   (c) parenterally injecting a diagnostic composition comprised of: 
 (i) biotin, when said antibody composite is conjugated with a biotin-binding molecule, or  
 (ii) a biotin-binding molecule, when said antibody composite is conjugated with biotin,  
 and a diagnostic agent which is conjugated with said biotin or said biotin-binding molecule.  
   
     
     
         31 . The method of  claim 30 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         32 . The method of  claim 31 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         33 . The method of  claim 32 , wherein said multidrug X transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         34 . The method of  claim 33 , wherein said diagnostic agent is selected from the group consisting of radioactive label, photoactive agent or dye, fluorescent label and paramagnetic ion.  
     
     
         35 . The method of  claim 34 , wherein said radioactive label is selected from the group consisting of γ-emitters and positron-emitters.  
     
     
         36 . The method of  claim 35 , wherein said γ-emitters have a gamma radiation emission peak in the range of 50-500 Kev.  
     
     
         37 . The method of  claim 36 , wherein said γ-emitters with a gamma radiation emission peak in the range of 50-500 Kev are selected from the group consisting of  99m Tc,  67 Ga,  123 I,  125 I and  131 I.  
     
     
         38 . The method of  claim 37 , wherein said biotin-binding molecule is avidin or streptavidin.  
     
     
         39 . A method for treating a mammal having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the mammal with an antibody composite comprising (1) at least one antibody component that binds a first epitope of a multidrug transporter protein, and (2) at least one antibody component that binds a first epitope of an antigen that is associated with the tumor or the infectious agent, wherein said antibody composite is conjugated with a biotin-binding molecule or with biotin;    (b) parenterally injecting a clearing composition comprised of: 
 (i) biotin, when said antibody composite is conjugated with a biotin-binding molecule, or  
 (ii) a biotin-binding molecule, when said antibody composite is conjugated with biotin,  
 and allowing said clearing composition to substantially clear said antibody composite from sites that do not contain multidrug resistant (MDR) cells or MDR infectious agents; and  
   (c) parenterally injecting, a therapeutic composition comprised of: 
 (i) biotin, when said antibody composite is conjugated with a biotin-binding molecule, or  
 (ii) a biotin-binding molecule, when said antibody composite is conjugated with biotin,  
 and a therapeutic agent which is conjugated with said biotin or said biotin-binding molecule.  
   
     
     
         40 . The method of  claim 39 , wherein said biotin-binding molecule is avidin or streptavidin.  
     
     
         41 . The method of  claim 40 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         42 . The-method of  claim 41 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         43 . The method of  claim 42 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         44 . The method of  claim 43 , wherein said therapeutic agent is selected from the group consisting of radioisotope, boron addend, toxin, immunomodulator, photoactive agent or dye, cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug, antiprotozoal drug and a chemosensitizing agent.  
     
     
         45 . The method of  claim 44 , wherein said radioisotope is selected from the group consisting of α-emitters, β-emitters, γ-emitters, Auger electron emitters, neutron capturing agents that emit α-particles and radioisotopes that decay by electron capture.  
     
     
         46 . The method of  claim 44 , wherein said radioisotope is selected from the group consisting of  198 Au,  32 P,  125 I,  131 I,  90 Y,  186 Re,  188 Re,  67 Cu and  211 At.  
     
     
         47 . A method for detecting the presence of multidrug resistant (MDR) tumor cells, MDR HIV-infected cells or MDR infectious agents in a mammal, said method comprising: 
 (a) removing from the mammal a biological sample that is suspected of containing MDR tumor cells, MDR HIV-infected cells or MDR infectious agents;    (b) contacting said biological sample with an antibody composite which comprises (1) at least one antibody component that binds with a first epitope of a multidrug transporter protein, and (2) at least one antibody component that binds with a first epitope of an antigen that is associated with said tumor or said infectious agent, wherein said contacting is performed under conditions which allow the binding of said antibody composite to said biological sample; and    (c) detecting any of said bound antibody composite.    
     
     
         48 . The method of  claim 47 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         49 . The method of  claim 48 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         50 . The method of  claim 49 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         51 . The method of  claim 50 , wherein said antibody composite further comprises a diagnostic agent selected from the group consisting of radioisotope, fluorescent label, chemiluminescent label, enzyme label, bioluminescent label and colloidal gold.  
     
     
         52 . The method of  claim 50 , wherein said antibody composite further comprises biotin or a biotin-binding molecule.  
     
     
         53 . A method for detecting the location of multidrug resistant (MDR) tumor cells, MDR HIV-infected cells or MDR infectious agents in a mammal having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the mammal with a polyspecific immunoconjugate that comprises (1) at least one antibody component that binds with a first epitope of a multidrug transporter protein, (2) at least one antibody component that binds with a first epitope of an antigen that is associated with the tumor or infectious agent, and (3) a diagnostic agent;    (b) parenterally injecting said mammal with an antibody or antibody fragment that binds with said polyspecific immunoconjugate in an amount that is sufficient to decrease the level of circulating polyspecific immunoconjugate by about 10-85% within 2 to 72 hours;    (c) scanning said mammal with a detector to locate the site or sites of uptake of said polyspecific immunoconjugate.    
     
     
         54 . The method of  claim 53 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         55 . The method of  claim 54 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         56 . The method of  claim 55 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         57 . The method of  claim 56 , wherein said diagnostic agent is selected from the group consisting of radioactive label, photoactive agent or dye, fluorescent label and paramagnetic ion.  
     
     
         58 . The method of  claim 57 , wherein said radioactive label is selected from the group consisting of γ-emitters and positron-emitters.  
     
     
         59 . The method of  claim 58 , wherein said γ-emitters have a gamma radiation emission peak in the range of 50-500 Kev.  
     
     
         60 . The method of  claim 59 , wherein said γ-emitters with a gamma radiation emission peak in the range of 50-500 Kev are selected from the group consisting of  99m Tc,  67 Ga,  123 I,  125 I and  131 I.  
     
     
         61 . A method for treating a mammal having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the mammal with a polyspecific immunoconjugate comprising (1) at least one antibody component that binds with a first epitope of a multidrug transporter protein, (2) at least one antibody component that binds with a first epitope of an antigen that is associated with the tumor or infectious agent, and (3) a therapeutic agent; and    (b) parenterally injecting said mammal with an antibody or antibody fragment that binds with said polyspecific immunoconjugate in an amount that is sufficient to decrease the level of circulating polyspecific immunoconjugate by about 10-85% within 2 to 72 hours.    
     
     
         62 . The method of  claim 61 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         63 . The method of  claim 62 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         64 . The method of  claim 63 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         65 . The method of  claim 64 , wherein said therapeutic agent is selected from the group consisting of radioisotope, boron addend, toxin, immunomodulator, photoactive agent or dye, cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug, antiprotozoal drug and a chemosensitizing agent.  
     
     
         66 . The method of  claim 65 , wherein said radioisotope is selected from the group consisting of α-emitters, β-emitters, γ-emitters, Auger electron emitters, neutron capturing agents that emit α-particles and radioisotopes that decay by electron capture.  
     
     
         67 . The method of  claim 65 , wherein said radioisotope is selected from the group consisting of  198 Au,  32 P,  125 I,  131 I,  90 Y,  186 Re,  188 Re,  67 Cu and  211 At.  
     
     
         68 . A method for detecting the location of multidrug resistant (MDR) tumor cells, MDR HIV-infected cells or MDR infectious agents in a subject having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the subject with a polyspecific immunoconjugate comprising (1) at least one antibody component that binds with a first epitope of a multidrug transporter protein, (2) at least one antibody component that binds with a first epitope of an antigen that is associated with a tumor or infectious agent, and (3) a diagnostic agent;    (b) surgically exposing or endoscopically accessing the interior of the body cavity of said subject; and    (c) scanning said interior body cavity with a detection probe to detect the sites of accretion of said polyspecific immunoconjugate.    
     
     
         69 . The method of  claim 68 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         70 . The method of  claim 69 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         71 . The method of  claim 70 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         72 . The method of  claim 71 , wherein said diagnostic agent is a radioisotope.  
     
     
         73 . The method of  claim 72 , wherein said radioisotope is a γ-emitter or a positron-emitter.  
     
     
         74 . The method of  claim 72 , wherein said diagnostic agent is a photoactive agent or dye.  
     
     
         75 . The method of  claim 74 , wherein said photoactive agent or dye is detected by laser-induced fluorescence.  
     
     
         76 . An antibody composite comprising: 
 (a) at least one antibody component that binds with a first epitope of a multidrug transporter protein; and    (b) at least one antibody component that binds with a first epitope of an antigen, wherein said antigen is associated with a tumor or an infectious agent.    
     
     
         77 . The antibody composite of  claim 76 , wherein said antibody components are selected from the, group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         78 . The antibody composite of  claim 77 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         79 . The antibody composite of  claim 78 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         80 . The antibody composite of  claim 79 , further comprising an antibody component that binds with a second epitope of said multidrug transporter protein.  
     
     
         81 . The antibody composite of  claim 80 , further comprising an antibody component that binds with a second epitope of said tumor or infectious agent associated antigen, or with an epitope of a second antigen associated with said tumor or said infectious agent.  
     
     
         82 . A method for treating a mammal having either a multidrug resistant tumor that expresses a tumor associated antigen or a multidrug resistant disease caused by an infectious agent, said method comprising the step of administering an antibody composite to the mammal, wherein said antibody composite comprises: 
 (a) at least one antibody component that binds with a first epitope of a multidrug transporter protein, and    (b) at least one antibody component that binds with a first epitope of an antigen, wherein said antigen is associated with said tumor or said infectious agent.    
     
     
         83 . The method of  claim 82 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         84 . The method of  claim 83 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         85 . The method of  claim 84 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.  
     
     
         86 . The method of  claim 85 , further comprising the step of administering a therapeutic agent to said mammal, wherein said therapeutic agent is selected from the group consisting of cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug and antiprotozoal drug.  
     
     
         87 . The method of  claim 86 , further comprising the step of administering an immunomodulator, wherein said immunomodulator is selected from the group consisting of cytokine, stem cell growth factor and hematopoietic factor.  
     
     
         88 . The method of  claim 87 , wherein said cytokine is granulocyte-colony stimulating factor.  
     
     
         89 . The method of  claim 87 , wherein said hematopoietic factor is thrombopoietin.  
     
     
         90 . The method of  claim 87 , wherein said immunomodulator is administered prior to or simultaneously with said administration of said antibody composite.  
     
     
         91 . The method of  claim 87 , wherein said immunomodulator is administered subsequent to said administration of said antibody composite.  
     
     
         92 . A method for treating a subject having a multidrug resistant disease caused by a tumor or infectious agent, said method comprising the steps of: 
 (a) parenterally injecting the subject with a polyspecific immunoconjugate comprising (1) at least one antibody component that binds with a first epitope of a multidrug transporter protein, (2) at least one antibody component that binds with a first epitope of an antigen that is associated with a tumor or infectious agent, and (3) a photoactive agent or dye;    (b) surgically exposing or endoscopically accessing the interior of the body cavity of said subject;, and    (c) treating sites of accretion of said polyspecific immunoconjugate to light, wherein said treatment activates said photoactive agent or dye.    
     
     
         93 . The method of claim  92 , wherein said antibody components are selected from the group consisting of: 
 (a) a murine monoclonal antibody;    (b) a humanized antibody derived from (a);    (c) a human monoclonal antibody;    (d) a subhuman primate antibody; and    (e) an antibody fragment derived from (a), (b), (c) or (d).    
     
     
         94 . The method of claim  93 , wherein said antibody fragment is selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv and minimal recognition unit.  
     
     
         95 . The method of claim  94 , wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.