Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof

Abstract

The invention relates generally to antibodies that bind programmed death ligand 1 (PDL1), activatable antibodies that specifically bind to PDL1 and methods of making and using these anti-PDL1 antibodies and anti-PDL1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

1 - 84 . (canceled) 
     
     
         85 . A composition comprising: an antibody or antigen binding fragment thereof (AB) and an activatable antibody,
 wherein the activatable antibody comprises the AB, and wherein the AB specifically binds mammalian PDL1;   wherein each of the AB and the activatable antibody comprises:   (a) a heavy chain variable region (VH) comprising:
 i. a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SEQ ID NO: 212; 
 ii. a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of SEQ ID NO: 246; 
 iii. a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of SEQ ID NO: 235; and 
   (b) a light chain variable region (VL) comprising:
 i. a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of SEQ ID NO: 209; 
 ii. a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence of SEQ ID NOs: 215 or 227; and 
 iii. a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of SEQ ID NO: 228; and 
   wherein the activatable antibody further comprises a masking moiety (MM) and a cleavable moiety (CM).   
     
     
         86 . The composition of  claim 85 , wherein the VL CDR2 of the antibody, the activatable antibody, or both comprises the amino acid sequence of SEQ ID NO: 215. 
     
     
         87 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
         88 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 58. 
     
     
         89 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a light chain comprising the amino acid sequence of SEQ ID NO: 137 and a VH comprising the amino acid sequence of SEQ ID NO: 46. 
     
     
         90 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a light chain comprising the amino acid sequence of SEQ ID NO: 985 and a VH comprising the amino acid sequence of SEQ ID NO: 46. 
     
     
         91 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a light chain comprising the amino acid sequence of SEQ ID NO: 428 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432. 
     
     
         92 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1008 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 432. 
     
     
         93 . The composition of  claim 85 , wherein the antibody, the activatable antibody, or both is conjugated to an agent. 
     
     
         94 . The composition of  claim 93 , wherein the agent has one or more of the following characteristics selected from the group consisting of:
 (i) the agent is a toxin or fragment thereof;   (ii) the agent is a microtubule inhibitor;   (iii) the agent is a nucleic acid damaging agent;   (iv) the agent is a dolastatin or a derivative thereof;   (v) the agent is an auristatin or a derivative thereof;   (vi) the agent is a maytansinoid or a derivative thereof;   (vii) the agent is a duocarmycin or a derivative thereof;   (viii) the agent is a calicheamicin or a derivative thereof;   (ix) the agent is auristatin E or a derivative thereof;   (x) the agent is monomethyl auristatin E (MMAE);   (xi) the agent is monomethyl auristatin D (MMAD);   (xii) the agent is DM1;   (xiii) the agent is DM4;   (xiv) the agent is a detectable moiety;   (xv) the agent is a diagnostic agent;   (xvi) the agent is conjugated to the antibody via a linker;   (xvii) the agent is conjugated to the antibody via a cleavable linker; and   (xviii) the agent is conjugated to the antibody via a non-cleavable linker.   
     
     
         95 . The composition of  claim 85 , wherein the AB of the activatable antibody is linked to the CM. 
     
     
         96 . The composition of  claim 95 , wherein the AB of the activatable antibody is directly linked to the CM. 
     
     
         97 . The composition of  claim 95 , wherein the AB of the activatable antibody is linked to the CM via a linking peptide. 
     
     
         98 . The composition of  claim 95 , wherein the MM is linked to the CM such that the activatable antibody in an uncleaved state comprises the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. 
     
     
         99 . The composition of  claim 95 , wherein the activatable antibody comprises a linking peptide between the MM and the CM, a linking peptide between the CM and the AB, or both a linking peptide between the MM and the CM and a linking peptide between the CM and the AB. 
     
     
         100 . The composition of  claim 95 , wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. 
     
     
         101 . The composition of  claim 100 , wherein the two linking peptides are not identical to each other. 
     
     
         102 . The composition of  claim 100 , wherein each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length. 
     
     
         103 . A pharmaceutical composition comprising the composition of  claim 85  and a carrier. 
     
     
         104 . The pharmaceutical composition of  claim 103  comprising an additional agent. 
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the additional agent is a therapeutic agent. 
     
     
         106 . A pharmaceutical composition comprising the composition of  claim 86  and a carrier. 
     
     
         107 . The pharmaceutical composition of  claim 106  comprising an additional agent. 
     
     
         108 . The pharmaceutical composition of  claim 107 , wherein the additional agent is a therapeutic agent. 
     
     
         109 . A pharmaceutical composition comprising the composition of  claim 93  and a carrier. 
     
     
         110 . The pharmaceutical composition of  claim 109  comprising an additional agent. 
     
     
         111 . The pharmaceutical composition of  claim 110 , wherein the additional agent is a therapeutic agent.