Gene Signatures for Determining ICOS Expression

Abstract

Gene expression signatures correlating to ICOS expression levels are provided. Methods of treatment comprising determining ICOS expression levels using gene signatures in patients and administering anti-ICOS antibodies are also provided.

1 . A method of determining the level of ICOS expression in a sample comprising detecting the levels of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from the mRNAs in Table 6. 
     
     
         2 . A method of predicting whether a cancer will respond to anti-ICOS antibody therapy, comprising detecting the levels of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from the mRNAs in Table 6 in a sample from a subject with cancer. 
     
     
         3 - 7 . (canceled) 
     
     
         8 . A method of treating cancer in a subject, comprising
 a) detecting the levels of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from the mRNAs in Table 6 in a sample from a subject; and   b) if the level of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the mRNAs is above a threshold level, then treating the subject with an effective amount of anti-ICOS antibody.   
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 2 , wherein the method comprises detecting the levels of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mRNAs selected from CCR5, CD2, CD96, CTLA4, CXCR6, FOXP3, ICOS, ITK, P2RY10, SIRPG, and TIGIT. 
     
     
         12 - 23 . (canceled) 
     
     
         24 . The method of  claim 2 , wherein the anti-ICOS antibody comprises:
 a) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 13; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 14; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 15; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 17; or   b) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 43; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 44; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 45; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 46; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 47; or   c) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 62; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 63; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 64; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 65; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 66; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; or   d) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 22, 62, 72, 82, 92, 102, and 112; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 23, 63, 73, 83, 93, 103, and 113; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 24, 64, 74, 84, 94, 104, and 114; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 25, 65, 75, 85, 95, 105, and 115; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 26, 66, 76, 86, 96, 106, and 116; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 27, 67, 77, 87, 97, 107, and 117; or   e) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 32, 162, 172, and 182; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 33, 163, 173, and 183; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 34, 164, 174, and 184; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 35, 165, 175, and 185; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 36, 166, 176, and 186; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 37, 167, 177, and 187; or   f) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 52, 122, 132, 142, and 152; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 53, 123, 133, 143, and 153; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 54, 124, 134, 144, and 154; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 55, 125, 135, 145, and 155; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 56, 126, 136, 146, and 156; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 57, 127, 137, 147, and 157; or   g) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 24; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 25; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; or   h) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 32; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 34; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 35; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 36; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 37; or   i) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 52; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 53; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 54; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 55; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 56; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 57; or   j) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 72; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 73; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 74; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 75; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 76; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 77; or   k) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 82; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 83; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 84; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 85; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 86; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 87; or   l) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 92; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 93; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 94; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 95; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 96; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 97; or   m) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 102; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 103; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 104; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 105; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 106; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 107; or   n) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 112; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 113; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 114; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 115; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 116; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 117; or   o) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 125; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 126; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 127; or   p) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 132; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 133; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 134; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 135; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 136; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 137; or (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 142; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 143; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 144; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 145; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 146; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 147; or   q) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 152; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 153; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 154; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 155; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 156; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 157; or   r) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 162; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 163; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 164; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 165; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 166; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 167; or   s) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 172; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 173; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 174; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 175; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 176; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 177; or   t) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 182; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 183; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 184; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 185; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 186; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 187.   
     
     
         25 - 58 . (canceled) 
     
     
         59 . A method of selecting a patient for treatment with a therapeutic agonist anti-ICOS antibody, comprising contacting T cells from the patient with a test agonist anti-ICOS antibody and determining whether NKp46 ligand (NKp46-L) is induced on the T cells. 
     
     
         60 - 67 . (canceled) 
     
     
         68 . The method of  claim 59 , wherein the therapeutic agonist anti-ICOS antibody and/or the test anti-ICOS antibody are independently selected from anti-ICOS antibodies comprising:
 a) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 13; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 14; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 15; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 17; or   b) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 43; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 44; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 45; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 46; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 47; or   c) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 62; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 63; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 64; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 65; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 66; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; or   d) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 22, 62, 72, 82, 92, 102, and 112; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 23, 63, 73, 83, 93, 103, and 113; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 24, 64, 74, 84, 94, 104, and 114; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 25, 65, 75, 85, 95, 105, and 115; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 26, 66, 76, 86, 96, 106, and 116; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 27, 67, 77, 87, 97, 107, and 117; or   e) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 32, 162, 172, and 182; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 33, 163, 173, and 183; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 34, 164, 174, and 184; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 35, 165, 175, and 185; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 36, 166, 176, and 186; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 37, 167, 177, and 187; or   f) (a) HCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 52, 122, 132, 142, and 152; (b) HCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 53, 123, 133, 143, and 153; (c) HCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 54, 124, 134, 144, and 154; (d) LCDR1 comprising an amino acid sequence selected from SEQ ID NOs: 55, 125, 135, 145, and 155; (e) LCDR2 comprising an amino acid sequence selected from SEQ ID NOs: 56, 126, 136, 146, and 156; and (f) LCDR3 comprising an amino acid sequence selected from SEQ ID NOs: 57, 127, 137, 147, and 157; or   g) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 24; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 25; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; or   h) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 32; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 34; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 35; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 36; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 37; or   i) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 52; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 53; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 54; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 55; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 56; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 57; or   j) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 72; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 73; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 74; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 75; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 76; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 77; or   k) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 82; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 83; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 84; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 85; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 86; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 87; or   l) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 92; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 93; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 94; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 95; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 96; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 97; or   m) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 102; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 103; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 104; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 105; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 106; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 107; or   n) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 112; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 113; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 114; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 115; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 116; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 117; or   o) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 125; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 126; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 127; or   p) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 132; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 133; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 134; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 135; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 136; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 137; or (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 142; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 143; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 144; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 145; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 146; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 147; or   q) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 152; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 153; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 154; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 155; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 156; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 157; or   r) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 162; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 163; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 164; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 165; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 166; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 167; or   s) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 172; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 173; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 174; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 175; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 176; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 177; or   t) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 182; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 183; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 184; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 185; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 186; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 187.   
     
     
         69 - 84 . (canceled)