Anti-pd-l1 antibodies, compositions and articles of manufacture

Abstract

The present application relates to anti-PD-L1 antibodies, nucleic acid encoding the same, therapeutic compositions thereof, and their use enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, including infection (e.g., acute and chronic) and tumor immunity.

1 - 95 : (canceled) 
     
     
         96 : An isolated nucleic acid encoding a heavy chain variable region of an anti-PD-L 1 antibody, wherein the antibody comprises the heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19. 
   
     
     
         97 : The nucleic acid of  claim 96 , wherein the antibody further comprises variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4), wherein one or more of the framework sequences is the following:
 LC-FR1 comprises the amino acid sequence of SEQ ID NO: 11;   LC-FR2 comprises the amino acid sequence of SEQ ID NO: 12;   LC-FR3 comprises the amino acid sequence of SEQ ID NO: 13; or   LC-FR4 comprises the amino acid sequence of SEQ ID NO: 14.   
     
     
         98 : The nucleic acid of  claim 97 , wherein the antibody further comprises variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), wherein one or more of the framework sequences is the following:
 HC-FR1 comprises the amino acid sequence of SEQ ID NO: 4;   HC-FR2 comprises the amino acid sequence of SEQ ID NO: 5;   HC-FR3 comprises the amino acid sequence of SEQ ID NO: 6; or   HC-FR4 comprises the amino acid sequence of SEQ ID NO: 7.   
     
     
         99 : The nucleic acid of  claim 96 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 90% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 90% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         100 : The nucleic acid of  claim 96 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 95% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 95% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         101 : The nucleic acid of  claim 96 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 98% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 98% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         102 : The nucleic acid of  claim 101 , wherein the heavy chain variable region amino acid sequence has at least 99% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20. 
     
     
         103 : The nucleic acid of  claim 102 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:21. 
     
     
         104 : The nucleic acid of  claim 103 , wherein the antibody is a full-length antibody. 
     
     
         105 : The nucleic acid of  claim 104 , wherein the antibody comprises a human constant region. 
     
     
         106 : The nucleic acid of  claim 105 , wherein the constant region is IgG1. 
     
     
         107 : The nucleic acid of  claim 106 , wherein the antibody comprises an effector-less Fc mutation, wherein the effector-less Fc mutation is N297A based on the Kabat numbering system. 
     
     
         108 : The nucleic acid  claim 96 , wherein the nucleic acid encoding the heavy chain variable region is on a separate vector from a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         109 : The nucleic acid of  claim 103 , wherein the nucleic acid encoding the heavy chain variable region is on a separate vector from a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         110 : The nucleic acid of  claim 107 , wherein the nucleic acid encoding the heavy chain variable region is on a separate vector from a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         111 : The nucleic acid of  claim 96 , wherein the nucleic acid encoding the heavy chain variable region is on the same vector as a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         112 : The nucleic acid of  claim 103 , wherein the nucleic acid encoding the heavy chain variable region is on the same vector as a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         113 : The nucleic acid of  claim 107 , wherein the nucleic acid encoding the heavy chain variable region is on the same vector as a nucleic acid encoding the light chain variable region of the anti-PD-L1 antibody. 
     
     
         114 : The nucleic acid of  claim 96 , wherein the nucleic acid encoding the heavy chain variable region further encodes the light chain variable region of the anti-PD-L1 antibody. 
     
     
         115 : The nucleic acid of  claim 103 , wherein the nucleic acid encoding the heavy chain variable region further encodes the light chain variable region of the anti-PD-L1 antibody. 
     
     
         116 : The nucleic acid of  claim 107 , wherein the nucleic acid encoding the heavy chain variable region further encodes the light chain variable region of the anti-PD-L1 antibody. 
     
     
         117 : An isolated nucleic acid encoding a light chain variable region of an anti-PD-L1 antibody, wherein the antibody comprises a heavy chain variable region and the light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19. 
   
     
     
         118 : The nucleic acid of  claim 117 , wherein the antibody further comprises variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4), wherein one or more of the framework sequences is the following:
 LC-FR comprises the amino acid sequence of SEQ ID NO: 11;   LC-FR2 comprises the amino acid sequence of SEQ ID NO: 12;   LC-FR3 comprises the amino acid sequence of SEQ ID NO: 13; or   LC-FR4 comprises the amino acid sequence of SEQ ID NO: 14.   
     
     
         119 : The nucleic acid of  claim 118 , wherein the antibody further comprises variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), wherein one or more of the framework sequences is the following:
 HC-FR1 comprises the amino acid sequence of SEQ ID NO: 4;   HC-FR2 comprises the amino acid sequence of SEQ ID NO: 5;   HC-FR3 comprises the amino acid sequence of SEQ ID NO: 6; or   HC-FR4 comprises the amino acid sequence of SEQ ID NO: 7.   
     
     
         120 : The nucleic acid of  claim 117 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 90% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 90% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         121 : The nucleic acid of  claim 117 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 95% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 95% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         122 : The nucleic acid of  claim 117 , wherein:
 (a) the heavy chain variable region amino acid sequence has at least 98% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20, and   (b) the light chain variable region amino acid sequence has at least 98% sequence identity to the light chain variable region amino acid sequence of SEQ ID NO:21.   
     
     
         123 : The nucleic acid of  claim 122 , wherein the heavy chain variable region amino acid sequence has at least 99% sequence identity to the heavy chain variable region amino acid sequence of SEQ ID NO:20. 
     
     
         124 : The nucleic acid of  claim 123 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:21. 
     
     
         125 : The nucleic acid of  claim 124 , wherein the antibody is a full-length antibody. 
     
     
         126 : The nucleic acid of  claim 125 , wherein the antibody comprises a human constant region. 
     
     
         127 : The nucleic acid of  claim 126 , wherein the constant region is IgG. 
     
     
         128 : The method of  claim 127 , wherein the antibody comprises an effector-less Fc mutation, wherein the effector-less Fc mutation is N297A based on the Kabat numbering system. 
     
     
         129 : The nucleic acid of  claim 117 , wherein the nucleic acid encoding the light chain variable region is on a separate vector from a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         130 : The nucleic acid of  claim 124 , wherein the nucleic acid encoding the light chain variable region is on a separate vector from a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         131 : The nucleic acid of  claim 128 , wherein the nucleic acid encoding the light chain variable region is on a separate vector from a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         132 : The nucleic acid of  claim 117 , wherein the nucleic acid encoding the light chain variable region is on the same vector as a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         133 : The nucleic acid of  claim 124 , wherein the nucleic acid encoding the light chain variable region is on the same vector as a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         134 : The nucleic acid of  claim 128 , wherein the nucleic acid encoding the light chain variable region is on the same vector as a nucleic acid encoding the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         135 : The nucleic acid of  claim 117 , wherein the nucleic acid encoding the light chain variable region further encodes the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         136 : The nucleic acid of  claim 124 , wherein the nucleic acid encoding the light chain variable region further encodes the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         137 : The nucleic acid of  claim 128 , wherein the nucleic acid encoding the light chain variable region further encodes the heavy chain variable region of the anti-PD-L1 antibody. 
     
     
         138 : A vector comprising the nucleic acid of  claim 96 . 
     
     
         139 : A vector comprising the nucleic acid of  claim 103 . 
     
     
         140 : A vector comprising the nucleic acid of  claim 107 . 
     
     
         141 : A vector comprising the nucleic acid of  claim 117 . 
     
     
         142 : A vector comprising the nucleic acid of  claim 124 . 
     
     
         143 : A vector comprising the nucleic acid of  claim 128 . 
     
     
         144 : An isolated recombinant host cell transformed with the nucleic acid of  claim 96 . 
     
     
         145 : An isolated recombinant host cell transformed with the nucleic acid of  claim 103 . 
     
     
         146 : An isolated recombinant host cell transformed with the nucleic acid of  claim 107 . 
     
     
         147 : An isolated recombinant host cell transformed with the nucleic acid of  claim 117 . 
     
     
         148 : An isolated recombinant host cell transformed with the nucleic acid of  claim 124 . 
     
     
         149 : An isolated recombinant host cell transformed with the nucleic acid of  claim 128 . 
     
     
         150 : An isolated recombinant host cell transformed with the vector of  claim 138 . 
     
     
         151 : An isolated recombinant host cell transformed with the vector of  claim 139 . 
     
     
         152 : An isolated recombinant host cell transformed with the vector of  claim 140 . 
     
     
         153 : An isolated recombinant host cell transformed with the vector of  claim 141 . 
     
     
         154 : An isolated recombinant host cell transformed with the vector of  claim 142 . 
     
     
         155 : An isolated recombinant host cell transformed with the vector of  claim 143 . 
     
     
         156 : The isolated recombinant host cell of  claim 144 , which is eukaryotic. 
     
     
         157 : The isolated recombinant host cell of  claim 156 , which is mammalian. 
     
     
         158 : The isolated recombinant host cell of  claim 157 , which is a Chinese Hamster Ovary (CHO) cell. 
     
     
         159 : The isolated recombinant host cell of  claim 144 , which is prokaryotic. 
     
     
         160 : The isolated recombinant host cell of  claim 159 , which is  E. coli.    
     
     
         161 : A method of making an anti-PD-L1 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19, 
   said method comprising culturing a recombinant host cell transformed with a first nucleic acid encoding the heavy chain variable region and a second nucleic acid encoding the light chain variable region.   
     
     
         162 : A method of making an anti-PD-L1 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19, 
   said method comprising culturing a recombinant host cell transformed with a nucleic acid encoding the heavy chain variable region and the light chain variable region.   
     
     
         163 : A method of making an anti-PD-L1 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19, 
   said method comprising culturing a recombinant host cell transformed with a first vector comprising a nucleic acid encoding the heavy chain variable region and a second vector comprising the light chain variable region.   
     
     
         164 : A method of making an anti-PD-L1 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises an HVR-H1, HVR-H2 and HVR-H3, wherein further:
 (i) the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 15; 
 (ii) the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 16; and 
 (iii) the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 3; and 
   (b) the light chain variable region comprises an HVR-L1, HVR-L2 and HVR-L3, wherein further:
 (iv) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; 
 (v) the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 18; and 
 (vi) the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 19, 
   said method comprising culturing a recombinant host cell transformed with a vector comprising a nucleic acid encoding the heavy chain variable region and the light chain variable region.