Radio-labelled antibody fragments for use in the prognosis, diagnosis of cancer as well as for the prediction of cancer therapy response

Abstract

The application provides polypeptides comprising or essentially consisting of at least one heavy chain variable domain of a heavy chain antibody (V HH ) or a functional fragment thereof, wherein said V HH or a functional fragment thereof specifically binds to a target protein that is present on and/or specific for a solid tumor, e.g. HER2. The application further provides nucleic acids encoding such polypeptides; methods for preparing such polypeptides; host cells expressing or capable of expressing such polypeptides; compositions, and in particular to pharmaceutical compositions, that comprise such polypeptides, nucleic acids and/or host cells. The application further provides such polypeptides, nucleic acids, host cells and/or compositions, for use in methods for detection, imaging, prognosis and diagnosis of cancer as well as for predicting patient response(s) to therapeutics.

1 . A radiolabelled heavy chain variable domain derived from a heavy chain antibody (V HH ) or a functional fragment thereof, which specifically binds to a target protein that is present on and/or specific for a solid tumor, for use in a method for the diagnosis and/or prognosis of cancer and/or prediction of response to cancer therapy in a subject, wherein said V HH  has a calculated mean effective dose of between 0.002 and 0.1 mSv/MBq in said subject. 
     
     
         2 . A composition comprising at least one radiolabelled heavy chain variable domain derived from a heavy chain antibody (V HH ) or a functional fragment thereof, which V HH  specifically binds to a target protein that is present on and/or specific for a solid tumor, for use in a method for the for the diagnosis and/or prognosis of cancer and/or prediction of response to cancer therapy in a subject, wherein said V HH  has a calculated mean effective dose of between 0.002 and 0.1 mSv/MBq in said subject. 
     
     
         3 . The radiolabelled VHH or a functional fragment thereof for use according to  claim 1 , wherein:
 said subject is a human subject;   said VHH or a functional fragment thereof specifically binds to HER2;   said VHH or a functional fragment thereof does not compete with the monoclonal antibody Herceptin® (Trastuzumab) for binding to HER2, as determined using a suitable competition assay;   said VHH or a functional fragment thereof specifically binds to said target protein that is present on and/or specific for a solid tumor with an affinity of less than 5 nM;   said V HH  or a functional fragment thereof is labelled with a radio-isotope chosen from the group consisting of 68Ga, 123I, 123I, 125I, 131I, 18F, 111In, 99mTc, 64Cu, 86Y, 76Br, 89Zr, 177Lu, 133Xe, 90Y, 201TI, 82Rb, 209At, 210At, 211At, 209At, 210At and 211At; or   said VHH or a functional fragment thereof is labelled with 68Ga.   
     
     
         4 . The composition for use according to  claim 2 , wherein:
 said subject is a human subject;   said V HH  or a functional fragment thereof specifically binds to HER2;   said VHH or a functional fragment thereof does not compete with the monoclonal antibody Herceptin® (Trastuzumab) for binding to HER2, as determined using a suitable competition assay;   said VHH or a functional fragment thereof specifically binds to said target protein that is present on and/or specific for a solid tumor with an affinity of less than 5 nM;   said V HH  or a functional fragment thereof is labelled with a radio-isotope chosen from the group consisting of 68Ga, 123I, 123I, 125I, 131I, 18F, 111In, 99mTc, 64Cu, 86Y, 76Br, 89Zr, 177Lu, 133Xe, 90Y, 201TI, 82Rb, 209At, 210At, 211At, 209At, 210At and 211At; or   said VHH or a functional fragment thereof is labelled with 68Ga.   
     
     
         5 - 8 . (canceled) 
     
     
         9 . The radiolabelled V HH  for use according to  claim 1 , wherein:
 the amino acid sequence of said V HH  comprises the combination of: a CDR1 region having SEQ ID NO: 1, a CDR2 region having SEQ ID NO: 2, and a CDR3 region having SEQ ID NO: 3;   said V HH  has at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4 or a functional fragment thereof;   said VHH has an amino acid sequence with SEQ ID NO: 4 or a functional fragment thereof;   said cancer is breast cancer;   said VHH or wherein said composition is administered intravenously or intraperitoneally; or   said V HH  is in a monovalent format.   
     
     
         10 . The composition for use according to  claim 2 , wherein:
 the amino acid sequence of said V HH  comprises the combination of: a CDR1 region having SEQ ID NO: 1, a CDR2 region having SEQ ID NO: 2, and a CDR3 region having SEQ ID NO: 3;   said V HH  has at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4 or a functional fragment thereof;   said VHH has an amino acid sequence with SEQ ID NO: 4 or a functional fragment thereof;   said cancer is breast cancer;   said VHH or wherein said composition is administered intravenously or intraperitoneally; or   said V HH  is in a monovalent format.   
     
     
         11 - 14 . (canceled) 
     
     
         15 . A radiolabelled heavy chain variable domain derived from a heavy chain antibody (V HH ) or a functional fragment thereof, which specifically binds to HER2, for use in a method for the diagnosis of HER-2 positive cancer lesions in human subjects initially diagnosed to be HER-2 negative in a standard assay for identifying HER-2 positive cancer lesions. 
     
     
         16 . A composition comprising at least one radiolabelled heavy chain variable domain derived from a heavy chain antibody (V HH ) or a functional fragment thereof, which specifically binds to HER2, for use in a method for the diagnosis of HER-2 positive cancer lesions in human subjects initially diagnosed to be HER-2 negative in a standard assay for identifying HER-2 positive cancer lesions. 
     
     
         17 . The radiolabelled V HH  or a functional fragment thereof, for use according to  claim 15 ,
 wherein said V HH  does not compete with the monoclonal antibody Herceptin® (Trastuzumab) for binding to HER2, as determined using a suitable competition assay,   for use in a method for the diagnosis of HER-2 positive cancer lesions in human subjects initially diagnosed to be HER-2 negative in a FISH assay for Her2 gene amplification,   wherein said human subjects were initially diagnosed to be HER-2 negative in a FISH assay for Her2 gene amplification by yielding a score of less than about 2.0,   wherein said HER-2 positive cancer lesions are HER-2 positive metastatic cancer lesions,   wherein said V HH  or a functional fragment thereof has a calculated mean effective dose of between 0.002 and 0.1 mSv/MBq in said human subject,   wherein said VHH or a functional fragment thereof specifically binds to HER2 with an affinity of less than 5 nM.   
     
     
         18 . The composition for use according to  claim 16 ,
 wherein said V HH  does not compete with the monoclonal antibody Herceptin® (Trastuzumab) for binding to HER2, as determined using a suitable competition assay,   for use in a method for the diagnosis of HER-2 positive cancer lesions in human subjects initially diagnosed to be HER-2 negative in a FISH assay for Her2 gene amplification,   wherein said human subjects were initially diagnosed to be HER-2 negative in a FISH assay for Her2 gene amplification by yielding a score of less than about 2.0,   wherein said HER-2 positive cancer lesions are HER-2 positive metastatic cancer lesions,   wherein said V HH  or a functional fragment thereof has a calculated mean effective dose of between 0.002 and 0.1 mSv/MBq in said human subject,   wherein said VHH or a functional fragment thereof specifically binds to HER2 with an affinity of less than 5 nM.   
     
     
         19 - 22 . (canceled) 
     
     
         23 . The radiolabelled V HH  or a functional fragment thereof, for use according to  claim 15 , wherein:
 said V HH  is labelled with a radio-isotope chosen from the group consisting of 68Ga, 123I, 123I, 125I, 131I, 18F, 111In, 99mTc, 64Cu, 86Y, 76Br, 89Zr, 177Lu, 133Xe, 90Y, 201TI, 82Rb, 209At, 210At, 211At, 209At, 210At and 211At; or   said VHH or a functional fragment thereof is labelled with 68Ga.   
     
     
         24 . The composition for use according to  claim 16 , wherein:
 said V HH  is labelled with a radio-isotope chosen from the group consisting of 68Ga, 123I, 123I, 125I, 131I, 18F, 111In, 99mTc, 64Cu, 86Y, 76Br, 89Zr, 177Lu, 133Xe, 90Y, 201TI, 82Rb, 209At, 210At, 211At, 209At, 210At and 211At; or   said VHH or a functional fragment thereof is labelled with 68Ga.   
     
     
         25 . The radiolabelled V HH  for use according to  claim 15 , wherein:
 said V HH  comprises one or more of the combinations chosen from the group comprising: a CDR1 region having SEQ ID NO: 1, a CDR2 region having SEQ ID NO: 2, and a CDR3 region having SEQ ID NO: 3;   said V HH  has at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4 or a functional fragment thereof; or   said VHH has an amino acid sequence with SEQ ID NO: 4 or a functional fragment thereof.   
     
     
         26 . The composition for use according to  claim 16 , wherein:
 said V HH  comprises one or more of the combinations chosen from the group comprising: a CDR1 region having SEQ ID NO: 1, a CDR2 region having SEQ ID NO: 2, and a CDR3 region having SEQ ID NO: 3;   said V HH  has at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4 or a functional fragment thereof; or   said VHH has an amino acid sequence with SEQ ID NO: 4 or a functional fragment thereof.   
     
     
         27 . (canceled) 
     
     
         28 . The radiolabelled VHH or a functional fragment thereof, for use according to  claim 15 , wherein said cancer is breast cancer. 
     
     
         29 . The radiolabelled V HH  or a functional fragment thereof, for use according to  claim 15 , wherein said V HH  or wherein said composition is administered intravenously or intraperitoneally. 
     
     
         30 . The radiolabelled V HH  for use according to  claim 15 , wherein said V HH  is in a monovalent format. 
     
     
         31 . The composition for use according to  claim 16 , wherein said cancer is breast cancer. 
     
     
         32 . The composition for use according to  claim 16 , wherein said V HH  or wherein said composition is administered intravenously or intraperitoneally. 
     
     
         33 . The composition for use according to  claim 16 , wherein said V HH  is in a monovalent format.