NaPi2b-targeted polymer antibody-drug conjugates and methods of use thereof
Inventors
HAILMAN, Eric P. • JARLENSKI, Donna M. • Bergstrom, Donald A.
Assignees
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Publication Number
US-11407825-B2
Publication Date
2022-08-09
Expiration Date
Abstract
Disclose herein are dosing regimens for targeted NaPi2b antibody-drug conjugates for treating cancer.
Core Innovation
The invention relates to treating a NaPi2b expressing tumor in a human subject by administering a NaPi2b-targeted antibody polymer-drug conjugate by infusion. The administered conjugate is defined as an NaPi2b antibody together with a polymer-drug conjugate of Formula A, and the method specifies a dosing schedule of a first-day dose followed by dosing every four weeks thereafter. The tumor treated is selected from ovarian cancer, endometrial cancer, and non-small cell lung cancer (NSCLC).
The NaPi2b-targeted antibody is defined by specific CDR amino acid sequences, including a CDRH1 comprising GYTFTGYNIH (SEQ ID NO: 5), a CDRH2 comprising AIYPGNGDTSYKQKFRG (SEQ ID NO: 6), a CDRH3 comprising GETARATFAY (SEQ ID NO: 7), a CDRL1 comprising SASQDIGNFLN (SEQ ID NO: 8), a CDRL2 comprising YTSSLYS (SEQ ID NO: 9), and a CDRL3 comprising QQYSKLPLT (SEQ ID NO: 10). The polymer-drug conjugate includes poly(l-hydroxymethylethylene hydroxymethyl-formal) (PHF) with defined molecular weight and integer parameter ranges.
The disclosed context further includes treatment selection and eligibility concepts grounded in tumor type and subtype, including epithelial endometrial cancer that is not a stromal tumor or a carcinosarcoma, and NSCLC limited to non-squamous and adenocarcinoma. Additional treatment-context refinements include subject limitations related to prior therapy and limitations on exposure to cytotoxic and/or immunotherapy, together with combination and sequence considerations involving PD-1/PD-L1 monoclonal antibodies and platinum-based regimens in combination with the NaPi2b-targeted conjugate.
Claims Coverage
The provided set identifies one independent claim. Across the independent claim, the inventive coverage is characterized by treating a NaPi2b expressing tumor in a human subject, administering a NaPi2b-targeted antibody polymer-drug conjugate by infusion on a first day and every four weeks thereafter, using an NaPi2b antibody with specified CDRH/CDRL sequences, and using a PHF-based polymer-drug conjugate of Formula A defined by molecular weight and integer parameter ranges, with tumor selection limited to specified cancer types.
NaPi2b-targeted antibody polymer-drug conjugate infusion dosing for NaPi2b expressing tumors
Administering to the subject a NaPi2b-targeted antibody polymer-drug conjugate by infusion at a dose of about 36 mg/m2 or about 43 mg/m2 on the first day of treatment and every four weeks thereafter for treating a NaPi2b expressing tumor in a human subject.
NaPi2b antibody defined by specific CDRH1/CDRH2/CDRH3/CDRL1/CDRL2/CDRL3 sequences
Using a NaPi2b antibody comprising a CDRH1 comprising GYTFTGYNIH (SEQ ID NO: 5), a CDRH2 comprising AIYPGNGDTSYKQKFRG (SEQ ID NO: 6), a CDRH3 comprising GETARATFAY (SEQ ID NO: 7), a CDRL1 comprising SASQDIGNFLN (SEQ ID NO: 8), a CDRL2 comprising YTSSLYS (SEQ ID NO: 9), and a CDRL3 comprising QQYSKLPLT (SEQ ID NO: 10).
PHF polymer-drug conjugate of Formula A with defined molecular weight and integer parameter ranges
Using a polymer-drug conjugate of Formula A wherein the polymer comprises poly(l-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from about 5 kDa to about 10 kDa, and wherein m is an integer from 20 to 75, m1 is an integer from about 5 to about 35, m2 is an integer from about 3 to about 10, m3a is an integer from 0 to about 4, m3b is an integer from 1 to about 5, the sum of m, m1, m2, m3a, and m3b ranges from about 40 to about 75, and m5 is an integer from about 2 to about 5.
Tumor selection limited to ovarian cancer, endometrial cancer, and NSCLC
Selecting the tumor to be treated from the group consisting of ovarian cancer, endometrial cancer, and non-small cell lung cancer (NSCLC).
Across the identified independent claim, the coverage centers on treating a NaPi2b expressing tumor with a NaPi2b-targeted antibody polymer-drug conjugate administered by infusion on day 1 and every four weeks, where the antibody is defined by specific CDR sequences and the conjugate includes a PHF-based polymer-drug of Formula A with defined molecular weight and integer parameter constraints, for ovarian cancer, endometrial cancer, or NSCLC.
Stated Advantages
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