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Publication Number
US-12435379-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Provided herein are mutations in Bruton's Tyrosine Kinase (BTK) that confer resistance to treatment with a BTK inhibitors, such as Ibrutinib, and compositions and methods for the treatment, diagnosis, and characterization of BTK-inhibitor-resistant cancers.
Core Innovation
The disclosure relates to BTK-inhibitor resistance in chronic lymphocytic leukemia associated with a structurally novel BTK mutation T316A in the SH2 domain. It describes a CLL patient with relapse after ibrutinib and Richter transformation, where longitudinal sequencing detects the BTK mutation T316A in the SH2 domain and contrasts it with known kinase-domain resistance mutations C481S, T474A, and L528W.
The disclosure states that T316A does not directly disrupt ibrutinib binding yet confers comparable cellular/molecular resistance. Resistance is associated with reduced inhibition of BTK and downstream BCR signaling, including p-PLCγ2, p-AKT, and p-ERK, and the invention is framed around a threonine to alanine modification at a position corresponding to 316 of SEQ ID NO: 1 in BTK.
The disclosure further includes cDNA-encoding aspects for a mutant BTK polypeptide comprising the threonine to alanine modification at the position corresponding to 316, and for a BTK polypeptide without the threonine to alanine modification at that position. It additionally describes a method of generating a cDNA molecule encoding the mutant BTK polypeptide from a subject previously administered ibrutinib for treatment of malignant tumors, and the cDNA molecules comprise exon-exon junctions.
Claims Coverage
The independent claims identified in the provided partial content include two inventive areas: a composition containing mutant and non-mutant BTK-encoding exon-exon junction cDNA molecules, and a method of generating a mutant BTK-encoding cDNA molecule from an ibrutinib-treated subject. The independent claim set includes 2 independent claims (clm-00001 and clm-00003).
Mutant and non-mutant exon-exon junction BTK cDNA composition
A composition comprising a cDNA molecule encoding a mutant BTK polypeptide with a threonine to alanine modification at a position corresponding to position 316 of SEQ ID NO: 1, and a cDNA molecule encoding a BTK polypeptide without the threonine to alanine modification at that position, wherein the cDNA molecules comprise exon-exon junctions.
Generating SH2-domain T316A BTK cDNA from an ibrutinib-treated subject
A method comprising generating a cDNA molecule encoding a mutant BTK polypeptide with a threonine to alanine modification at a position corresponding to position 316 of SEQ ID NO: 1 from a subject that has previously been administered ibrutinib for treatment of malignant tumors.
Together, the claims cover exon-exon junction cDNA molecules that encode a BTK polypeptide bearing the threonine to alanine modification at position corresponding to 316 (T316A) and methods that generate such mutant BTK cDNA from an ibrutinib-treated subject, as part of addressing BTK-inhibitor resistance.
Stated Advantages
Confers comparable cellular/molecular resistance despite not directly disrupting ibrutinib binding.
Reduces inhibition of BTK and downstream BCR signaling, including p-PLCγ2, p-AKT, and p-ERK.
Documented Applications
Detection/characterization and longitudinal sequencing of BTK resistance associated with a structurally novel BTK mutation T316A in SH2 domain in a CLL patient relapsing after ibrutinib with Richter transformation.
Nucleic acid and protein biomarker detection and quantification of BTK biomarker modifications at a position corresponding to 316, including using sequencing, PCR/probe methods, and immunoassays, to identify relevant BTK biomarker modifications.
Guiding therapy decisions, including discontinuing first-generation BTK inhibitor and selecting second-generation BTK inhibitor or non-BTK therapeutics.
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