NaPi2B-TARGETED POLYMER ANTIBODY-DRUG CONJUGATES AND METHODS OF USE THEREOF

Abstract

Disclose herein are dosing regimens for targeted NaPi2b antibody-drug conjugates for treating cancer.

What is claimed is: 
     
         1 . A method of treating a NaPi2b expressing tumor in a subject in need thereof, the method comprising administering to the subject a NaPi2b-targeted antibody polymer-drug conjugate by infusion at a dose of about 20 mg/m 2  or about 30 mg/m 2  on the first day of treatment and every four weeks thereafter,
 wherein the conjugate comprises a NaPi2b antibody comprising: a CDRH1 comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5); a CDRH2 comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6); a CDRH3 comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7); a CDRL1 comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8); a CDRL2 comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9); and a CDRL3 comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10); and   a polymer-drug conjugate of Formula A:   
       
         
           
           
               
               
           
         
       
       wherein:
 the polymer comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from about 5 kDa to about 10 kDa; 
 m is an integer from 20 to 75, 
 m 1  is an integer from about 5 to about 35, 
 m 2  is an integer from about 3 to about 10, 
 m 3a  an integer from 0 to about 4, 
 m 3b  is an integer from 1 to about 5, 
 the sum of m, m 1 , m 2 , m 3a , and m 3b  ranges from about 40 to about 75, and 
 m 5  is an integer from about 2 to about 5. 
 
     
     
         2 . The method of  claim 1 , wherein the NaPi2b antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 4; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         3 . The method of  claim 1 , wherein the subject is human. 
     
     
         4 . The method of  claim 1 , wherein the dose is about 20 mg/m 2 . 
     
     
         5 . The method of  claim 1 , wherein the dose is about 30 mg/m 2 . 
     
     
         6 . The method of  claim 1 , wherein the tumor is selected from the group consisting ovarian cancer, non-small cell lung cancer (NSCLC), papillary thyroid cancer, endometrial cancer, papillary renal cell cancer, cholangiocarcinoma, salivary duct cancer, clear cell renal cancer, breast cancer, kidney cancer or cervical cancer. 
     
     
         7 . The method of  claim 6 , wherein the ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. 
     
     
         8 . The method of  claim 7 , wherein the epithelial ovarian cancer is subtyped as high-grade serous ovarian cancer, low-grade ovarian cancer or clear cell ovarian cancer. 
     
     
         9 . The method of  claim 8 , wherein the ovarian cancer is platinum resistant and the subject has received no more than 3 line of prior therapy. 
     
     
         10 . The method of  claim 4 , wherein the subject has ovarian cancer and has received no more than 3 line of prior therapy. 
     
     
         11 . The method of  claim 6 , wherein the NSCLC cancer is non-squamous and is sub-typed as adenocarcinoma. 
     
     
         12 . The method of  claim 6 , wherein the subject has NSCLC and has received prior treatment with a platinum-based regimen and a PD-1 or PD-L1monoclonal antibody. 
     
     
         13 . The method of  claim 12 , wherein the platinum-based regimen and PD-1 or PD-L1 monoclonal antibody are administered in combination. 
     
     
         14 . The method of  claim 12 , wherein the platinum-based regimen and PD-1 or PD-L1 monoclonal antibody are administered sequentially. 
     
     
         15 . The method of  claim 11 , wherein the subject has received no treatment with a cytotoxic agent or has received no immunotherapy treatment. 
     
     
         16 . The method of  claim 6 , wherein the papillary thyroid cancer is progressive, radioactive iodine-refractory, loco-regional recurrent or metastatic disease. 
     
     
         17 . The method of  claim 16 , wherein the subject has papillary thyroid cancer and is resistance or intolerance to kinase inhibitor therapy. 
     
     
         18 . The method of  claim 6 , wherein the endometrial cancer is epithelial endometrial cancer and is not a stromal tumor or a carcinosarcoma. 
     
     
         19 . The method of  claim 6 , wherein the papillary renal cell cancer has a predominantly papillary growth pattern. 
     
     
         20 . The method  claims 6 , wherein the cancer has a histologic diagnosis of salivary duct cancer has progressed after standard systemic therapy.