Activatable anti-pdl1 antibodies, and methods of use thereof

Abstract

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

1 . (canceled) 
     
     
         2 . A method of treating, alleviating a symptom of, or delaying the progression of a cancer in a subject, comprising administering intravenously an activatable anti-PDL1 antibody to the subject, wherein the subject is a human and wherein the activatable antibody comprises:
 a. an antibody (AB) that specifically binds to human PDL1, wherein the AB comprises:   i. a heavy chain variable region comprising a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO:212, a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO:246, and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence or SEQ ID NO:235; and   ii. a light chain variable region comprising a light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence of SEQ ID NO:209, a light chain complementarity determining region 2, (CDRL2) comprising the amino acid sequence of SEQ ID NO:215, a light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO:228;   b. a cleavable moiety (CM) linked to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease, wherein the comprises the amino acid sequence of SEQ ID NO: 377; and   c. a masking moiety (MM) linked to the AB, wherein the MM comprises the amino acid sequence of SEQ ID NO: 63, wherein the MM inhibits the binding of the AB to human PDL1 when the activatable antibody is in an uncleaved state;   wherein the activatable anti-PDL1 antibody is administered at a dose selected from the group consisting of 6 mg/kg, 15 mg/kg, and 30 mg/kg.   
     
     
         3 . The method of  claim 2 , wherein the AB comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 46 and a light chain variable (VL) comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 137. 
     
     
         4 . The method of  claim 2 , wherein the activatable antibody 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. 
     
     
         5 . The method of  claim 2 , wherein the activatable antibody 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. 
     
     
         6 . The method of  claim 2 , wherein the activatable antibody is administered on a schedule of one dose every 7-30 days. 
     
     
         7 . The method  claim 6 , wherein the wherein the activatable antibody is administered on a schedule of one dose every 14 days. 
     
     
         8 . The method  claim 6 , wherein the wherein the activatable antibody is administered on a schedule of one dose every 21 days. 
     
     
         9 . The method of  claim 2 , wherein the activatable antibody is administrated as a monotherapy. 
     
     
         10 . The method of  claim 2 , wherein the activatable antibody is administrated as a component of a combination therapy. 
     
     
         11 . The method  claim 10 , wherein the combination therapy comprises administering a dose of an anti-CTLA-4 antibody or a B-RAF inhibitor 
     
     
         12 . The method of  claim 11 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         13 . The method of  claim 11 , wherein the anti-CTLA-4 antibody is administered intravenously. 
     
     
         14 . The method of  claim 11 , wherein the anti-CTLA-4 antibody is administered at a dose of 3 mg/kg, 6 mg/kg or 10 mg/kg. 
     
     
         15 . The method of  claim 11 , wherein the anti-CTLA-4 antibody is administered at a fixed dose 240 mg, 480 mg or 800 mg. 
     
     
         16 . The method of  claim 11 , wherein the B-RAF inhibitor is vemurafenib. 
     
     
         17 . The method of  claim 11 , wherein the B-RAF inhibitor is administered orally. 
     
     
         18 . The method of  claim 11 , wherein the B-RAF inhibitor is administered at a dose of 960 mg. 
     
     
         19 . The method of  claim 11 , wherein the B-RAF inhibitor is administered at a dose of 875 mg. 
     
     
         20 . The method of  claim 11 , wherein the administering step comprises administering the activatable antibody and the B-RAF inhibitor over a same period of time. 
     
     
         21 . The method of  claim 11 , wherein a dose of the B-RAF inhibitor is administered twice daily. 
     
     
         22 . The method of  claim 11 , wherein at least 4 doses each of the activatable antibody and the B-RAF inhibitor are administered. 
     
     
         23 . The method of  claim 11 , wherein the administering steps comprise administering multiple doses of the activatable antibody and the anti-CTLA-4 antibody over a first period of time, followed by administration of multiple doses of the activatable antibody as a monotherapy over a second period of time. 
     
     
         24 . The method  claim 11 , wherein a dose of the activatable antibody and a dose of the anti-CTLA-4 antibody are administered concomitantly as a combination therapy every 21 days for 4 doses, followed by administration of a dose of the activatable antibody as a monotherapy every 14 days. 
     
     
         25 . The method of  claim 11 , wherein the administering steps comprise administering multiple doses of the activatable antibody as a monotherapy over a first period of time, followed by concomitant administration of multiple doses of the activatable antibody and the anti-CTLA-4 antibody as a combination therapy over a second period of time. 
     
     
         26 . The method of  claim 11 , wherein the administering step comprises (i) administering multiple doses of the activatable antibody as a monotherapy over a first period of time, (ii) subsequently administering multiple doses of the activatable antibody and the anti-CTLA-4 antibody as a combination therapy over a second period of time, and (iii) subsequently administering multiple doses of the activatable antibody as a monotherapy over a third period of time. 
     
     
         27 . The method of  claim 11 , wherein the activatable antibody is administered as a monotherapy every 14 days for 4 doses, followed by administration of the activatable antibody and the anti-CTLA-4 antibody as a combination therapy every 21 days, for 4 doses, followed by administration of the activatable antibody as a monotherapy every 14 days. 
     
     
         28 . The method of  claim 2 , wherein the subject exhibits one or more of the following characteristics:
 a. PD-1/PDL1 inhibitor-naïve,   b. CTLA-4 inhibitor-naïve,   c. BRAF V600E  mutation positive,   d. BRAF inhibitor-naïve,   e. PDL1 positive,   f. PDL1 unknown, and   g. been previously treated with a PD1/PDL1 inhibitor.   
     
     
         29 . The method of  claim 2 , wherein the subject has no further standard of care available. 
     
     
         30 . The method of  claim 2 , wherein a PD1/PDL1 inhibitor therapy is not approved for the subject's cancer. 
     
     
         31 . The method of  claim 2 , wherein the subject has been previously treated with a PD-1/PDL1 inhibitor, wherein treatment with the PD-1/PDL1 inhibitor was discontinued for reasons other than toxicity, and wherein the subject is CTLA-4 inhibitor-naïve. 
     
     
         32 . The method of  claim 2 , wherein the subject is immunotherapy naïve. 
     
     
         33 . The method of  claim 2 , wherein the antibody is administered at a dose of 6 mg/kg. 
     
     
         34 . The method of  claim 2 , wherein the antibody is administered at a dose of 15 mg/kg. 
     
     
         35 . The method of  claim 2 , wherein the antibody is administered at a dose of 30 mg/kg. 
     
     
         36 . The method of  claim 2 , wherein the antibody is administered to the subject at least twice over a period. 
     
     
         37 . The method of  claim 36 , wherein the antibody is administered to the subject at a frequency of between a day to once every eight weeks. 
     
     
         38 . The method of  claim 36 , wherein the antibody is administered to the subject at a frequency of between a day to once every 28 days. 
     
     
         39 . The method of  claim 36 , wherein the antibody is administered to the subject at a frequency of between a day to once a month. 
     
     
         40 . The method of  claim 36 , wherein the antibody is administered to the subject at a frequency of between a week to once a month. 
     
     
         41 . The method of  claim 36 , wherein the antibody is administered to the subject at a frequency of between a week to once every two months. 
     
     
         42 . The method of  claim 36 , wherein the frequency of administration of the antibody during the duration is the same between different administrations. 
     
     
         43 . The method of  claim 36 , wherein the frequency of administration of the antibody during the duration is the different between different administrations.