Provasopressin antagonists and uses thereof

Abstract

Provided herein are pro-VP antagonists, such as antibodies and antigen-binding portions thereof specific for pro-VP, for identifying and targeting expressing cancer cells. Applicants additionally provide methods of using said compositions, for example to image cancer cells in vivo and in biological samples. The compositions may also be used for treating patients suffering from a provasopressin-expressing cancer. Provasopressin-expressing cancers include neuroendocrine cancer, pancreatic cancer, and prostate cancer.

1 . A method of treating a provasopressin-expressing (pro-VP-expressing) cancer, comprising administering a therapeutically effective amount of a provasopressin-binding agent to a patient in need thereof, wherein the cancer is not small cell lung cancer (SCLC) or breast cancer. 
     
     
         2 . A method of treating a provasopressin-expressing (pro-VP-expressing) cancer, comprising administering, to a patient in need thereof, a therapeutically effective amount of a provasopressin-binding agent, and a therapeutically effective amount of a pharmaceutical composition comprising a chemotherapeutic agent. 
     
     
         3 . The method of  claim 1 , wherein the cancer is a neuroendocrine cancer. 
     
     
         4 . The method of  claim 1 , wherein the cancer is a prostate cancer. 
     
     
         5 . The method of  claim 1 , wherein the cancer is a pancreatic cancer. 
     
     
         6 . The method of  claim 2 , wherein the cancer is SCLC or breast cancer. 
     
     
         7 . The method of  claim 3 , wherein the neuroendocrine cancer is a brain, gastroenteric, ovarian, endomedrial, testicular, adrenal, or skin cancer. 
     
     
         8 . The method of  claim 1 , wherein the provasopressin-binding antibody is MAG-1, or a human antibody thereof, or a humanized antibody thereof, or a chimeric antibody thereof. 
     
     
         9 . The method of  claim 1 , wherein the provasopressin-binding antibody binds to the VAG region of the pro-VP protein. 
     
     
         10 . The method of  claim 1 , wherein the provasopressin-binding antibody is a mouse antibody, a human antibody, a mouse-human chimeric antibody, a humanized antibody. 
     
     
         11 . The method of  claim 1 , wherein the antigen-binding portion thereof is scFv, Fab, F(ab′) 2 , Fd, Fv, or dAb. 
     
     
         12 . The method of  claim 1 , further comprising administering an effective amount of a pharmaceutical composition comprising a chemotherapeutic agent. 
     
     
         13 . The method of  claim 2 , wherein the pharmaceutical composition comprising a chemotherapeutic agent further comprises epinephrine. 
     
     
         14 . The method of  claim 2 , wherein the pharmaceutical compositions are administered concomitantly. 
     
     
         15 . The method of  claim 2 , wherein the pharmaceutical compositions are administered in a single formulation. 
     
     
         16 . The method of  claim 2 , wherein the pharmaceutical compositions are administered as separate formulations. 
     
     
         17 . The method of  claim 1 , further comprising administering an effective amount of a pharmaceutical composition comprising at least one of dexamethasone, IBMX, 8-bromoadenosine 3′,5′-cyclic monophosphate (8br-cAMP), cyclophosphamide, cisplatin, etoposide VP-16, and forskolin. 
     
     
         18 . The method of  claim 1 , further comprising performing surgical removal of at least one tumor from the patient. 
     
     
         19 . The method of  claim 1 , further comprising performing radiation therapy. 
     
     
         20 . The method of  claim 1 , further comprising administering a somatostatin or an analogue thereof. 
     
     
         21 . The method of  claim 1 , further comprising administering at least one of imatinib, sunitinib, temozolide, thalidomide, sorafenib, and panitumumab. 
     
     
         22 . The method of  claim 1 , wherein the antibody or antibody-binding portion thereof comprises a label. 
     
     
         23 . The method of  claim 22 , wherein the label is selected from the group consisting of a fluorescent label, a radiolabel, a toxin, a metal compound, and biotin. 
     
     
         24 . The method of  claim 23 , wherein the fluorescent label is selected from the group consisting of Texas Red, phycoerythrin (PE), cytochrome c, and fluorescent isothiocyanate (FITC). 
     
     
         25 . The method of  claim 23 , wherein the radiolabel is selected from the group consisting of  32 P,  33 P,  43 K,  47 Sc,  52 Fe,  57 Co,  64 CU,  67 Ga,  67 Cu,  68 Ga,  71 Ge,  75 Br,  76 Br,  77 Br,  77 As,  77 Br,  81 Rb/ 81M Kr,  87M Sr,  90 Y,  97 Ru,  99 Tc,  100 Pd,  101 Rh,  103 Pb,  105 Rh,  109 Pd,  111 Ag,  111 In,  113 In,  119 Sb  121 Sn,  123 I,  125 I,  127 Cs,  128 Ba,  129 Cs,  131 I,  131 Cs,  143 Pr,  153 Sm,  161 Tb,  166 Ho,  169 Eu,  177 Lu,  186 Re,  188 Re,  189 Re,  191 Os,  193 Pt,  194 Ir,  197 Hg,  199 Au,  203 Pb,  211 At,  212 Pb,  212 Bi and  213 Bi. 
     
     
         26 . The method of  claim 23 , wherein the toxin is selected from the group consisting of ricin, ricin A chain (ricin toxin),  Pseudomonas  exotoxin (PE), diphtheria toxin (DT),  Clostridium perfringens  phospholipase C (PLC), bovine pancreatic ribonuclease (BPR), pokeweed antiviral protein (PAP), abrin, abrin A chain (abrin toxin), cobra venom factor (CVF), gelonin (GEL), saporin (SAP), modeccin, viscumin and volkensin. 
     
     
         27 . A method of killing or inhibiting the growth of a provasopressin-expressing cancer cell, comprising contacting the provasopressin-expressing cancer cell with a provasopressin-binding agent, wherein the provasopressin-expressing cancer cell is not a SCLC cell and not a breast cancer cell. 
     
     
         28 . A method of killing or inhibiting the growth of a provasopressin-expressing cancer cell, comprising contacting the provasopressin-expressing cancer cell with a provasopressin-binding agent, and a chemotherapeutic agent. 
     
     
         29 - 33 . (canceled) 
     
     
         34 . A method of phenotyping biological samples from patients having a provasopressin-expressing cancer other than small cell lung cancer or breast cancer, the method comprising:
 a) obtaining a biological sample from a patient;   b) rendering the biological sample amenable to immunoassay;   c) contacting the rendered sample with the a provasopressin-binding antibody or antigen-binding portion thereof under conditions that allow for binding of the antibody or antigen-binding portion to provasopressin; and   d) determining if the cells of the rendered sample inappropriately express provasopressin compared to a control tissue;   wherein if the test tissue inappropriately expresses provasopressin, the biological sample is identified as likely having cancerous cells.   
     
     
         35 - 41 . (canceled) 
     
     
         42 . A method of detecting a tumor in a patient having a provasopressin-expressing cancer other than small cell lung cancer and breast cancer, the method comprising:
 a) administering a pharmaceutical composition comprising a provasopressin-binding antibody or antigen-binding portion thereof to the patient;   b) detecting the label; and,   c) determining if the patient has cells that inappropriately express provasopressin compared to a control;   wherein the patient is identified as having a tumor or having an enhanced risk of having a tumor if the patient has cells that inappropriately express provasopressin.   
     
     
         43 - 52 . (canceled)