Radiolabeled anti-pd-l1 antibodies for immuno-pet imaging

Abstract

Radiolabeled anti-PD-L1 antibodies and their use in immuno-PET imaging are provided herein. Included are methods of detecting the presence of PD-L1 proteins in a patient or sample.

What is claimed is: 
     
         1 .- 10 . (canceled) 
     
     
         11 . A method for treating a tumor comprising:
 (a) selecting a subject with a solid tumor;   (b) determining that the solid tumor is PD-L1-positive; and   (c) administering one or more doses of an inhibitor of the PD-1/PD-L1 signaling axis to the subject in need thereof.   
     
     
         12 . The method of  claim 11 , wherein step (b) comprises:
 (i) administering a radiolabeled antibody conjugate to the subject in need thereof, wherein the conjugate comprises:   an antibody or antigen-binding fragment thereof that binds PD-L1, wherein said antibody or antigen-binding fragment thereof is covalently bonded to one or more moieties of formula (A):
   -L-M z    (A)
 
   wherein L is a chelating moiety; M is a positron emitter; and z, independently at each occurrence, is 0 or 1; and wherein at least one of z is 1; and   (ii) imaging localization of the radiolabeled antibody conjugate in the tumor by positron emission tomography (PET) imaging, wherein presence of the radiolabeled antibody conjugate in the tumor indicates that the tumor is PD-L1-positive.   
     
     
         13 . The method of  claim 12 , wherein the subject is administered 0.1-10 mg/kg of the radiolabeled antibody conjugate. 
     
     
         14 . The method of  claim 12 , wherein the radiolabeled antibody conjugate is administered sub-cutaneously or intravenously to the subject. 
     
     
         15 . The method of  claim 12 , wherein PET imaging is done 2-7 days after administering the radiolabeled antibody conjugate. 
     
     
         16 . The method of  claim 12 , wherein step (b) is carried out before treating the subject with an inhibitor of the PD-1/PD-L1 signaling axis. 
     
     
         17 . The method of  claim 12  further comprising:
 (a) administering the radiolabeled antibody conjugate after treating the subject with at least one dose of an inhibitor of the PD-1/PD-L1 signaling axis; and 
 (b) imaging localization of the radiolabeled antibody conjugate in the tumor by PET imaging, wherein a decrease from the baseline in the area of localization of the radiolabeled antibody conjugate in the tumor indicates tumor regression. 
 
     
     
         18 . The method of  claim 17 , wherein the subject is administered the radiolabeled antibody conjugate 1-20 weeks after administration of the inhibitor of the PD-1/PD-L1 signaling axis. 
     
     
         19 . The method of  claim 11 , wherein the tumor is selected from the group consisting of blood cancer, brain cancer, renal cell cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, hepatic cell carcinoma, bone cancer, colon cancer, non-small-cell lung cancer, squamous cell carcinoma of head and neck, colorectal cancer, mesothelioma, B cell lymphoma, and melanoma. 
     
     
         20 . The method of  claim 11 , wherein the inhibitor of the PD-1/PD-L1 signaling axis is an anti-PD-1 antibody or antigen-binding fragment thereof. 
     
     
         21 . The method of  claim 20 , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab and REGN2810. 
     
     
         22 . The method of  claim 11 , wherein the inhibitor of the PD-1/PD-L1 signaling axis is an anti-PD-L1 antibody or antigen-binding fragment thereof. 
     
     
         23 . The method of  claim 22 , wherein the anti-PD-L1 antibody is atezolizumab. 
     
     
         24 . The method of  claim 22 , wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDRs) in a heavy chain variable region (HCVR) of SEQ ID NO: 82; and three light chain complementarity determining regions (LCDRs) in a light chain variable region (LCVR) of SEQ ID NO: 90. 
     
     
         25 . The method of  claim 22 , wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 84; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 88; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 94; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 96. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 12 , wherein the chelating moiety comprises desferrioxamine. 
     
     
         28 . The method of  claim 12 , wherein the positron emitter is  89 Zr. 
     
     
         29 . The method of  claim 12 , wherein -L-M is 
       
         
           
           
               
               
           
         
       
       wherein Zr is the positron emitter  89 Zr. 
     
     
         30 . The method of  claim 12 , wherein antibody or antigen-binding fragment thereof is covalently bonded to one, two, or three moieties of Formula (A). 
     
     
         31 . The method of  claim 12 , wherein the antibody has one or more properties selected from the group consisting of:
 (a) binds monomeric PD-L1 with a binding dissociation equilibrium constant (K D ) of less than about 310 pM as measured in a surface plasmon resonance assay at 37° C.;   (b) binds monomeric human PD-L1 with a K D  less than about 180 pM in a surface plasmon resonance assay at 25° C.;   (c) binds dimeric human PD-L1 with a K D  of less than about 15 pM as measured in a surface plasmon resonance assay at 37° C.; and   (d) binds dimeric human PD-L1 with a K D  less than about 8 pM in a surface plasmon resonance assay at 25°.   
     
     
         32 . The method of  claim 12 , wherein the antibody comprises three heavy chain complementarity determining regions (HCDRs) in a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 34, 50, 82, 98, 146, 162, 178, 186, 234, 250, 266, 290, 306, 314, and 330; and three light chain complementarity determining regions (LCDRs) in a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 42, 58, 90, 106, 154, 170, 194, 242, 258, and 274.