Anti-tigit antibodies

Abstract

The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.

1 . An antibody or antigen binding fragment thereof that binds to human TIGIT, wherein the antibody or antigen binding fragment is selected from the group consisting of:
 a. an antibody or antigen binding fragment comprising: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, 79, 80, 81, 82, 83 or 140, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, 65, 66, 67, 68, 69, 70, 71, 72, 73 or 41, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6, 74, 75, 76, 77, 78 or 142;   b. an antibody or antigen binding fragment comprising: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:57, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:58, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:59, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:60, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:61, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:62; and   c. an antibody or antigen binding fragment comprising: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:89, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 134, 135 or 147, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:90, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166 or 167, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:92, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 or 148, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:93.   
     
     
         2 . The antibody or antigen binding fragment of  claim 1 , wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6. 
     
     
         3 . The antibody or antigen binding fragment of  claim 1 , wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:89, 134 or 135, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:90, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:93. 
     
     
         4 . The antibody or antigen binding fragment of  claim 1 , wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 134, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:90, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:93. 
     
     
         5 . An antibody or antigen binding fragment thereof that binds to human TIGIT comprising a light chain immunoglobulin, a heavy chain immunoglobulin or both a light chain and a heavy chain immunoglobulin selected from the group consisting of:
 a. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:7 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:8;   b. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:63 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:64;   c. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:95;   d. an antibody or antigen binding fragment thereof comprising a variable heavy chain selected from the group consisting of SEQ ID NOs: 9-24, 37-47 and 63 and/or a variable light chain selected from the group consisting of any one of SEQ ID NOs: 25-30, 48-52 and 64;   e. an antibody or antigen binding fragment thereof comprising a variable heavy chain selected from the group consisting of SEQ ID NOs: 124-129 and/or a variable light chain selected from the group consisting of any one of SEQ ID NOs: 130-133;   f. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:128 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:132;   g. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:127 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:130; and   h. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:128 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:133;   i. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:143 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:145;   j. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:149 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:151;   k. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:144 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:146;   l. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:150 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:152;   m. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs: 7, 9-24, 37-47 and 63 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 8, 25-30, 48-52 and 64;   n. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs: 7, 9-24, 37-47 and 63 and/or a variable light chain comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 8, 25-30, 48-52 and 64, wherein any sequence variations occur in the framework regions of the antibody;   o. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs: 124-129 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 130-133; and   p. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs: 124-129 and/or a variable light chain comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 130-133, wherein any sequence variations occur in the framework regions of the antibody;   q. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 132;   r. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 132, wherein any sequence variations occur in the framework regions of the antibody;   s. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:127 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 130;   t. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:127 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 130, wherein any sequence variations occur in the framework regions of the antibody;   u. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 133;   v. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO:128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 133, wherein any sequence variations occur in the framework regions of the antibody.   
     
     
         6 . The antibody or antigen binding fragment of  claim 1 , wherein the antibody or antigen binding fragment thereof binds to human TIGIT with a KD value of about 1×10-9 M to about 1×10-12 M as determined by surface plasmon resonance (e.g., BIACORE) or a similar technique (e.g. KinExa or OCTET). 
     
     
         7 . An antibody or antigen binding fragment thereof that binds to the same epitope of human TIGIT as an antibody selected from the group consisting of:
 a. an antibody comprising the variable heavy chain of SEQ ID NO:7 and the variable light chain of SEQ ID NO:8,   b. an antibody comprising the variable heavy chain of SEQ ID NO:63 and the variable light chain of SEQ ID NO:64, and   c. an antibody comprising the variable heavy chain of SEQ ID NO:94 and the variable light chain of SEQ ID NO:95;   wherein the antibody or fragment thereof has at least one of the following characteristics:   i. binds to human TIGIT with a KD value of about 1×10-9 M to about 1×10-12 M as determined by surface plasmon resonance (e.g., BIACORE) or a similar technique (e.g. KinExa or OCTET);   ii. cross-reacts with cynomolgous and rhesus TIGIT;   iii. blocks binding of human TIGIT to human CD155 and human CD112;   iv. increases T cell activation;   v. stimulates antigen-specific T-cell production of IL-2 and IFNγ;   vi. blocks induction of T cell suppression of activation induced by TIGIT ligation with cognate ligands CD155 and CD112.   
     
     
         8 . The antibody or antigen binding fragment of  claim 7 , wherein the antibody binds to an epitope comprising the following regions of human TIGIT (SEQ ID NO:31): residues 54-57, 68-70 and 76-81. 
     
     
         9 . The antibody or antigen binding fragment of  claim 7 , wherein the antibody binds to an epitope comprising the following regions of human TIGIT (SEQ ID NO:31): residues 53-57, 60-65, 68-70, 72-81, 94-95, and 109-119. 
     
     
         10 . The antibody or antigen binding fragment of  claim 1 , which is a humanized antibody comprising two heavy chains and two light chains. 
     
     
         11 . The antibody or antigen binding fragment of  claim 1 , which is a humanized antibody, wherein the antibody comprises a human IgG1 constant domain and a human kappa constant domain. 
     
     
         12 . (canceled) 
     
     
         13 . An isolated polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 7-30, 37-52, 63-64, 94-95 or 124-133, 136-139, 143-146, 149-151. 
     
     
         14 . An isolated nucleic acid encoding: any one of the antibodies or antigen binding fragments of  claim 1 . 
     
     
         15 . An expression vector comprising the isolated nucleic acid of  claim 14 . 
     
     
         16 . A host cell comprising the expression vector of  claim 15 . 
     
     
         17 . (canceled) 
     
     
         18 . A composition comprising the antibody or antigen binding fragment of  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         19 . The composition of  claim 18 , further comprising an agent selected from the group consisting of:
 a. an anti-PD1 antibody or an antigen binding fragment thereof;   b. an anti-LAG3 antibody or an antigen binding fragment thereof;   c. an anti-VISTA antibody or an antigen binding fragment thereof;   d. an anti-BTLA antibody or an antigen binding fragment thereof;   e. an anti-TIM3 antibody or an antigen binding fragment thereof;   f. an anti-CTLA4 antibody or an antigen binding fragment thereof;   g. an anti-HVEM antibody or an antigen binding fragment thereof;   h. an anti-CD27 antibody or an antigen binding fragment thereof;   i. an anti-CD137 antibody or an antigen binding fragment thereof;   j. an anti-OX40 antibody or an antigen binding fragment thereof;   k. an anti-CD28 antibody or an antigen binding fragment thereof;   l. an anti-PDL1 antibody or an antigen binding fragment thereof;   m. an anti-PDL2 antibody or an antigen binding fragment thereof;   n. an anti-GITR antibody or an antigen binding fragment thereof;   o. an anti-ICOS antibody or an antigen binding fragment thereof;   p. an anti-SIRPα antibody or an antigen binding fragment thereof;   q. an anti-ILT2 antibody or an antigen binding fragment thereof;   r. an anti-ILT3 antibody or an antigen binding fragment thereof;   s. an anti-ILT4 antibody or an antigen binding fragment thereof; and   t. an anti-ILT5 antibody or an antigen binding fragment thereof.   
     
     
         20 . The composition of  claim 19 , wherein the anti-PD1 antibody or an antigen binding fragment thereof is selected from the group consisting of: pembrolizumab or an antigen binding fragment thereof and nivolumab or an antigen binding fragment thereof. 
     
     
         21 . (canceled) 
     
     
         22 . A method of treating cancer in a human subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment of  claim 1 , optionally in association with a further therapeutic agent or therapeutic procedure. 
     
     
         23 . A method of treating an infection or infectious disease in a human subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment of  claim 1 , optionally in association with a further therapeutic agent or therapeutic procedure. 
     
     
         24 . A vaccine comprising the antibody or antigen binding fragment of  claim 1  and an antigen. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled)