Mutations associated with resistance to inhibitors of Bruton's Tyrosine Kinase (BTK)
Inventors
Chang, Betty • Buggy, Joseph J. • Steggerda, Susanne M.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10954567-B2
Publication Date
2021-03-23
Expiration Date
Abstract
Described herein are mutations that confer resistance to treatment with a BTK inhibitor. Described herein are modified BTK polypeptides that exhibit decreased inhibition (i.e. are resistant) to a covalent and/or irreversible BTK inhibitor. Also described herein modifications of PLCy2 and CARD 11 polypeptides that confer resistance to treatment with a BTK inhibitor. Described herein are diagnostic methods for detecting the modified polypeptides and nucleic acids encoding the modified polypeptides and applications of the methods thereof. Described herein are compositions, combinations, and kits containing the modified polypeptides and methods of using the modified polypeptides. Also described herein are methods of using modified BTK polypeptides as screening agents for the identification and design of second-generation BTK inhibitors.
Core Innovation
The invention relates to treating a hematological cancer with ibrutinib by testing a sample from a subject for a modification at amino acid position 481 of a BTK polypeptide, where the amino acid sequence set forth in SEQ ID NO: 1 is used as the reference. The method determines whether the encoded BTK polypeptide has a modification at the specified position and includes detecting the absence of the modification in the sample from the subject before treatment.
The document further describes mutant BTK polypeptides and nucleic acids encoding the mutant BTK variants, including resistance driven by BTK Cys481 alterations such as C481S. It also expands resistance to downstream BCR pathway genes, including PLCγ2 R665W/S707F and CARD11 L232LL, together with nucleic acid/protein detection approaches, monitoring and optimization, and kit/system embodiments for detecting mutant BTK.
The partial content also describes screening methods to identify second-generation BTK inhibitors that are active against BTK C481 mutants, and characterizing resistance mechanisms. The described approach uses amino acid position 481 of BTK, including detection using nucleic acid encoding the BTK polypeptide, to assess BTK modification status as part of administering ibrutinib.
Claims Coverage
The provided independent claim covers a treatment method with ibrutinib guided by testing for a BTK amino acid position 481 modification; the claim includes two principal inventive features focused on BTK position 481 modification status and absence detection before dosing.
Treatment guided by absence of BTK position 481 modification before ibrutinib administration
Testing a sample containing a nucleic acid molecule encoding a BTK polypeptide from the subject to determine whether the encoded BTK polypeptide has a modification at amino acid position 481 of the amino acid sequence set forth in SEQ ID NO: 1; detecting the absence of the modification in the sample from the subject; and administering ibrutinib to the subject.
Ibrutinib dosing conditioned on absence of BTK position 481 modification
administering ibrutinib to the subject at a daily dosage of 420 mg/day or 560 mg/day
Across the identified claim, the inventive coverage is centered on determining whether a subject’s BTK polypeptide encoded by nucleic acid has a modification at amino acid position 481 (SEQ ID NO: 1), using detection of the absence of that modification as a basis for administering ibrutinib, and administering ibrutinib at daily dosage levels of 420 mg/day or 560 mg/day.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
Interested in licensing this patent?