Monoclonal antibodies to activated erbb family members and methods of use

Abstract

Antibodies which bind to activated members of the erbB, TNF, and IgSF family of receptors and pharmaceutical compositions comprising the same are disclosed. Peptides and mimetics of erbB, TNF, and IgSF receptors and pharmaceutical compositions comprising the same are also described. Methods of using such antibodies, peptides, and mimetics in tumor therapeutic, prophylactic, imaging and diagnostic applications are disclosed.

1 .- 83 . (canceled) 
     
     
         84 . An isolated dual-specificity antibody having specificity for both an activated erbB2 receptor and an activated erbB3 receptor, wherein the antibody has an affinity for the activated erbB2 receptor that is at least about 10-fold greater than the affinity the antibody has for an erbB2 receptor that is not activated. 
     
     
         85 . The isolated antibody of  claim 84  wherein the antibody binds to an epitope shared by an erbB2-erbB3 heterodimer. 
     
     
         86 . The isolated antibody of  claim 84  wherein the antibody has an affinity for the activated erbB2 receptor that is at least about 100-fold greater than the affinity the antibody has for the erbB2 receptor that is not activated. 
     
     
         87 . The isolated antibody of  claim 84  wherein the antibody has specificity for one or more cystine knots on the activated erbB2 receptor and erbB3 receptor. 
     
     
         88 . The isolated antibody of  claim 87  wherein the antibody has a binding constant of at least 5×10 6  Ka for each activated erbB2 receptor and erbB3 receptor. 
     
     
         89 . The isolated antibody of  claim 88  wherein the antibody has a binding constant of at least 1×10 7  Ka for each activated erbB2 receptor and erbB3 receptor. 
     
     
         90 . The isolated antibody of  claim 89  wherein the antibody has a binding constant of at least 2×10 7  Ka for each activated erbB2 receptor and erbB3 receptor. 
     
     
         91 . The isolated antibody of  claim 90  wherein the antibody has a binding constant of at least 1×10 8  Ka for each activated erbB2 receptor and erbB3 receptor. 
     
     
         92 . The isolated antibody of  claim 84  wherein the antibody is selected from the group consisting of a monoclonal antibody, a humanized antibody, a camelized antibody, a chimeric antibody, a primatized antibody, a phage-displayed antibody, a single chain antibody, a FAb fragment thereof, or a F(Ab) 2  fragment thereof. 
     
     
         93 . The isolated antibody of  claim 84  wherein the antibody binds to an assembly domain of the receptor. 
     
     
         94 . The isolated antibody of  claim 94  wherein the assembly domain is cystine rich. 
     
     
         95 . The isolated antibody of  claim 87  wherein said isolated antibody binds to subdomain IV of said activated erbB3 receptor. 
     
     
         96 . The isolated antibody of  claim 84  wherein the antibody is conjugated to a radioactive agent, a chemotherapeutic agent or an imaging agent. 
     
     
         97 . The isolated antibody of  claim 96  wherein the radioactive agent is  47 Sc,  67 Cu,  90 Y,  86 Y,  109 Pd,  123 I,  125 I,  131 I,  186 Re,  199 Au,  211 At,  212 Pb,  18 F or  212 Bi. 
     
     
         98 . The isolated antibody of  claim 97  wherein the antibody is conjugated to a chemotherapeutic agent and wherein the chemotherapeutic agent is selected from the group consisting of methotrexate (amethopterin), doxorubicin (adrimycin), daunorubicin, cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, cyclophosphamide, cis-platin, vindesine, mitomycin, bleomycin, tamoxiphen, taxol, ricin, ricin A chain,  Pseudomonas exotoxin  (PE), diphtheria toxin (DT),  Clostridium perfringens  phospholipase C (PLC), bovine pancreatic ribonuclease (BPR), pokeweed antiviral protein (PAP), abrin, abrin A chain, cobra venom factor (CVF), gelonin (GEL), saporin (SAP), modeccin, viscumin and volkensin. 
     
     
         99 . The isolated antibody of  claim 98  wherein the antibody is conjugated to an imaging agent and wherein the imaging agent is  43 K,  52 Fe  57 Co,  67 Cu,  67 Ga,  68 Ga,  77 Br,  81 Rb,  81M Kr,  87M Sr,  86 Y,  90 Y,  99M Tc,  111 In,  113M In,  123 I,  125 I,  127 Cs,  131 I,  132 I,  197 Hg,  203 Pb,  206 Bi,  18 F, a heavy metal, or a positron emitter of oxygen, nitrogen, iron, carbon, or gallium. 
     
     
         100 . The isolated antibody of  claim 99  wherein the heavy metal is selected from the group consisting of a chelate of iron, gadolinium and manganese. 
     
     
         101 . A composition comprising the isolated antibody of  claim 84  and a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         102 . The composition of  claim 101  wherein the composition is an injectable composition. 
     
     
         103 . The composition of  claim 101  further comprising a chemotherapeutic agent or an imaging agent. 
     
     
         104 . The composition of  claim 102  further comprising a therapeutically effective amount of methotrexate (amethopterin), doxorubicin (adriamycin), daunorubicin, cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, cyclophosphamide, cis-platin, vindesine, mitomycin, bleomycin, tamoxiphen, or taxol. 
     
     
         105 . A method of treating an individual who has an erbB2/erbB3 tumor which comprises administering to said individual a pharmaceutical composition comprising the antibody according to  claim 84  and a pharmaceutically acceptable excipient. 
     
     
         106 . The method of  claim 105  further comprising exposing said individual to radiation. 
     
     
         107 . The method of  claim 105  further comprising exposing said individual to a chemotherapeutic agent. 
     
     
         108 . A method of imaging an erbB2/erbB3 tumor in a patient suffering from an erbB2/erbB3 tumor which comprises administering to said patient a pharmaceutical composition comprising (i) the antibody according to  claim 96 , said antibody being conjugated to an imaging agent, and (ii) a pharmaceutically acceptable excipient, and detecting binding of the antibody to the erbB2/erbB3 tumor. 
     
     
         109 . A method of inhibiting progression of transformation or tumorigenesis of a cell that expresses erbB2 and erbB3 in an individual who has a predisposition for developing erbB2/erbB3 tumor, who has had an erbB2/erbB3 tumor removed or who has had an erbB2/erbB3 cancer enter remission, which comprises administering to said individual a pharmaceutical composition comprising the antibody according to  claim 84  and a pharmaceutically acceptable excipient. 
     
     
         110 . The method of  claim 109  which comprises inhibiting said cell from becoming a transformed tumor cell. 
     
     
         111 . A method of treating a patient suffering from an erbB tumor which comprises administering to the patient the antibody according to  claim 84  and a chemotherapeutic agent. 
     
     
         112 . The method of  claim 111  wherein said antibody is administered prior to administration of said chemotherapeutic agent. 
     
     
         113 . The method of  claim 111  wherein said chemotherapeutic agent is administered prior to administration of said antibody. 
     
     
         114 . The method of  claim 111  wherein said antibody and said chemotherapeutic agent are administered concurrently. 
     
     
         115 . A method of treating a patient suffering from an erbB tumor which comprises administering to the patient the antibody according to  claim 84  and radiation. 
     
     
         116 . The method of  claim 115  wherein said antibody is administered prior to administration of radiation. 
     
     
         117 . The method of  claim 115  wherein radiation is administered prior to administration of said antibody. 
     
     
         118 . The method of  claim 115  wherein said antibody and radiation are administered concurrently. 
     
     
         119 . The isolated antibody of  claim 84 , wherein the antibody specifically binds to at least one activation epitope in the extracellular region of the activated erbB2 receptor. 
     
     
         120 . The isolated antibody of  claim 84  wherein the antibody has an affinity for the activated erbB2 receptor that is at least about 5-fold greater than the affinity the antibody has for the erbB2 receptor that is not activated.