Therapeutic agents and uses thereof

Abstract

The present application provides an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein (for example, PSA or hK2) for use in the treatment of prostate cancer, and a method for the treatment of prostate cancer in a patient, the method comprising the step of administering a therapeutically effective amount of an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein to the patient.

1 . An agent comprising or consisting of a binding moiety with specificity for a kallikrein protein for use in the treatment of prostate cancer. 
     
     
         2 . Use of an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein in the manufacture of a medicament for the treatment of prostate cancer. 
     
     
         3 . A method for the treatment of prostate cancer in a patient, the method comprising the step of administering a therapeutically effective amount of an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein. 
     
     
         4 . The agent of  claim 1 , the use of  claim 2 , or the method of  claim 3 , wherein the binding moiety is an antibody or antigen-binding fragment thereof. 
     
     
         5 . The agent, use, or method of any preceding claim, wherein the binding moiety has specificity for a human kallikrein protein. 
     
     
         6 . The agent, use, or method of any preceding claim, wherein the binding moiety has specificity for a kallikrein selected from the group consisting of prostate-specific antigen (PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2). 
     
     
         7 . The agent, use, or method of any preceding claim, wherein the binding moiety has specificity for PSA. 
     
     
         8 . The agent, use, or method of  claim 7  wherein the binding moiety has specificity for the free (that is, non-complexed) isoform of PSA. 
     
     
         9 . The agent, use, or method of  claim 8  wherein the binding moiety has specificity for an epitope that is exposed on the free isoform of PSA, but is unexposed on the complexed isoform of PSA. 
     
     
         10 . The agent, use, or method of  claim 9  wherein the epitope that is exposed on the free isoform of PSA, but is unexposed on the complexed isoform of PSA, is a conformational (that is, non-linear) epitope. 
     
     
         11 . The agent, use, or method of  claim 10  wherein the conformational epitope is formed from amino acid residues that are part of the kallikrein-loop surrounding the catalytic cleft of PSA, and may include the active site triad of His41, Asn96, and Ser189). 
     
     
         12 . The agent, use, or method of any preceding claim, wherein the binding moiety competes for binding to PSA with an antibody selected from the group consisting of PSA30, 4D4, 5C3, and 5A10, and an antigen-binding fragment thereof. 
     
     
         13 . The agent, use, or method of any preceding claim, wherein the binding moiety comprises one or more complementarity determining regions (CDRs) of an antibody selected from the group consisting of PSA30, 4D4, 5C3, and 5A10. 
     
     
         14 . The agent, use, or method of any preceding claim, wherein the binding moiety comprises or consists of an antibody selected from the group consisting of PSA30, 4D4, 5C3, and 5A10, and antigen-binding fragments thereof. 
     
     
         15 . The agent, use, or method of any of  claims 1 - 6 , wherein the binding moiety has specificity for human glandular kallikrein (hK2). 
     
     
         16 . The agent, use, or method of  claim 15 , wherein the binding moiety competes for binding to hK2 with an antibody selected from the group consisting of 11B6, and 7G1. 
     
     
         17 . The agent, use, or method of  claim 15  or  16  wherein the binding moiety comprises one or more complementarity determining regions (CDRs) of an antibody selected from the group consisting of 11B6, and 7G1. 
     
     
         18 . The agent, use, or method of any of  claim 15 - 17 , wherein the binding moiety comprises or consists of an antibody selected from the group consisting of 11B6, and 7G1, and antigen-binding fragments thereof. 
     
     
         19 . The agent, use, or method of any preceding claim wherein the agent further comprises a therapeutic moiety, such as a cytotoxic moiety. 
     
     
         20 . The agent, use, or method of  claim 19  wherein the agent comprises the binding moiety linked directly, or indirectly, to the therapeutic moiety. 
     
     
         21 . The agent, use, or method of  claim 19  or  20  wherein the agent displays tumour uptake characteristics substantially equivalent to the tumour uptake characteristics of binding moiety alone. 
     
     
         22 . The agent, use, or method of any of  claims 19 - 21 , wherein the therapeutic moiety is a cytotoxic moiety that comprises or consists of one or more radioisotopes. 
     
     
         23 . The agent, use, or method of  claim 22  wherein the one or more radioisotopes is or are each independently selected from the group consisting of beta-emitters, Auger-emitters, conversion electron-emitters, alpha-emitters, and low photon energy-emitters. 
     
     
         24 . The agent, use, or method of  claim 22  or  23  wherein one or more radioisotopes each independently has or have an emission pattern of locally absorbed energy that creates a high dose absorbance in the vicinity of the agent. 
     
     
         25 . The agent, use, or method of any of  claims 22  to  24  wherein one or more radioisotopes is or are each independently selected from the group consisting of long-range beta-emitters, such as  90 Y,  32 P,  186 Re;  166 Ho,  76 As/ 77 As,  89 Sr,  153 Sm; medium range beta-emitters, such as  131 I,  177 Lu,  67 Cu,  161 Tb,  105 Rh; low-energy beta-emitters, such as  45 Ca or  35 S; conversion or Auger-emitters, such as  51 Cr,  67 Ga,  99 Tc m ,  111 In,  114m In,  123 I,  125 I,  201 Tl; and alpha-emitters, such as  212 Bi,  213 Bi,  223 Ac,  225 Ac,  212 Pb,  255 Fm,  223 Ra,  149 Tb and  221 At. 
     
     
         26 . The agent, use, or method of any of  claims 19 - 21 , wherein the therapeutic moiety is a cytotoxic moiety that comprises or consists of one or more cytotoxic drugs. 
     
     
         27 . The agent, use, or method of  claim 26 , wherein the one or more therapeutic moieties is, or are each independently, selected from the group consisting of a cytostatic drug; an anti-androgen drug; cortisone and derivatives thereof; a phosphonate; a testosterone-5-α-reductase inhibitor; a boron addend; a cytokine; thapsigargin and its metabolites; a toxin (such as saporin or calicheamicin); a chemotherapeutic agent (such as an antimetabolite); or any other cytotoxic drug useful in the treatment of prostatic carcinoma. 
     
     
         28 . The agent, use, or method of any of  claims 19 - 21 , wherein the therapeutic moiety comprises or consists of one or more moieties suitable for use in activation therapy, such as photon activation therapy, neutron activation therapy, neutron induced Auger electron therapy, synchrotron irradiation therapy, or low energy X-ray photon activation therapy. 
     
     
         29 . The agent, use, or method of any preceding claim, wherein the agent further comprises a detectable moiety. 
     
     
         30 . The agent, use, or method of  claim 29  wherein the detectable moiety comprises or consists of a radioisotope. 
     
     
         31 . The agent, use, or method of  claim 30  wherein the detectable moiety comprises or consists of a radioisotope selected from the group consisting of: technetium-99m; indium-111; gallium-67; gallium-68; arsenic-72; zirconium-89; iodine-125, thallium-201. 
     
     
         32 . The agent, use, or method of  claim 30  or  31  wherein the agent comprises a pair of detectable and cytotoxic radionuclides, such as  86 Y/ 90 Y or  124 I/ 211 At. 
     
     
         33 . The agent, use, or method of  claim 30  wherein the radioisotope is capable of simultaneously acting in a multi-modal manner as a detectable moiety and also as a cytotoxic moiety. 
     
     
         34 . The agent, use, or method of  claim 29  wherein the detectable moiety comprises or consists of a paramagnetic isotope. 
     
     
         35 . The agent, use, or method of  claim 34  wherein the paramagnetic isotope is selected from the group consisting of: gadolinium-157; manganese-55, dysprosium-162, chromium-52; iron-56. 
     
     
         36 . The agent, use, or method of any of  claims 30  to  35  wherein the detectable moiety is detectable by an imaging technique such as SPECT, PET, MRI, Optical or ultrasound imaging. 
     
     
         37 . The agent, use, or method of any of any preceding claim wherein the agent further comprising a moiety for increasing the in vivo half-life of the agent. 
     
     
         38 . The agent, use, or method of  claim 37  wherein the moiety for increasing the in vivo half-life is selected from the group consisting of polyethylene glycol (PEG), human serum albumin, glycosylation groups, fatty acids and dextran. 
     
     
         39 . The agent, use, or method of any preceding claim wherein the prostate cancer to be treated is non-localised (i.e., disseminated) prostate cancer. 
     
     
         40 . The agent, use, or method of any preceding claim wherein the prostate cancer to be treated is metastatic prostate cancer, optionally micrometastatic prostate cancer. 
     
     
         41 . The agent, use, or method of  claim 40  wherein the metastatic prostate cancer to be treated is metastases of the lymph system; metastases of the bone (including spine, vertebrae, pelvis, ribs); metastasis within pelvis, rectum, bladder, urethra. 
     
     
         42 . The agent, use, or method of any preceding claim wherein the patient has prostate cancer and is less than 70, 65, 60, 55, 50, 45, 40 or less years old at the time of diagnosis of prostate cancer and/or at the time of treatment. 
     
     
         43 . The agent, use, or method of any preceding claim wherein the patient is characterised in that a family member, such as a father or brother, has been previously been diagnosed with prostate cancer. 
     
     
         44 . The agent, use, or method of any preceding claim wherein the prostate cancer to be treated is castration-resistant prostate cancer (CRPC). 
     
     
         45 . A therapeutic agent comprising a binding moiety with specificity for a kallikrein protein and a therapeutic moiety, as defined in any preceding claim, that is suitable for the treatment of prostate cancer. 
     
     
         46 . A pharmaceutical composition comprising a therapeutically effective amount of an agent as defined in any one of the preceding claims and a pharmaceutically-acceptable diluent, carrier or excipient. 
     
     
         47 . A pharmaceutical composition according to  claim 46  adapted for parenteral, intravenous, subcutaneous, intramuscular delivery or delivery by injection. 
     
     
         48 . A kit comprising an agent as defined in any one of  claims 1  to  45  or a pharmaceutical composition as defined in  claim 46  or  47 . 
     
     
         49 . An agent comprising or consisting of a binding moiety with specificity for a kallikrein protein (for example, as defined above by any of  claims 1 - 18 ) and a detectable moiety (for example as described above by any of  claims 29 - 36 ) for use in medicine by administration to a patient with prostate cancer before, or during, surgery, such as RadioGuided Surgery. 
     
     
         50 . Use of an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein (for example, as defined above by any of  claims 1 - 18 ) and a detectable moiety (for example as described above by any of  claims 29 - 36 ) in the manufacture of a medicament for administration to a patient with prostate cancer before or during the surgery, such as RadioGuided Surgery. 
     
     
         51 . A method surgery, such as RadioGuided Surgery, performed on a patient with prostate cancer, the method comprising the step of administering an effective amount of an agent comprising or consisting of a binding moiety with specificity for a kallikrein protein (for example, as defined above by any of  claims 1 - 18 ) and a detectable moiety (for example as described above by any of  claims 29 - 36 ) to the patient before or during the surgery. 
     
     
         52 . An agent for use in medicine substantially as described herein with reference to the description. 
     
     
         53 . A pharmaceutical composition substantially as described herein with reference to the description. 
     
     
         54 . Use of an agent substantially as described herein with reference to the description. 
     
     
         55 . A method of treatment as substantially described herein with reference to the description. 
     
     
         56 . A kit substantially as defined herein with reference to the description.