Diffuse large B cell lymphoma (DLBCL) is a common and aggressive malignancy that accounts for 38-50% of lymphomas each year. There are two distinct subtypes of DLBCL: germinal center B cell-like (GCB) and activated B cell-like (ABC). Patients with ABC DLBCL have an inferior overall survival following multi-agent chemotherapy and respond differently to treatment compared to GCB DLBCL. In particular, the B cell receptor (BCR) signaling inhibitor, Ibrutinib, produced a response in 37% of DLBCL tumors with an ABC gene expression profile versus a 5% response in those tumors with a GBC gene expression profile. However, ABC cases with mutations in the BCR subunit, CD79B (along with a MYD88 mutation) produced an 80% response rate to ibrutinib. Using a protein-protein interaction-based proximity ligation assay, researchers at the National Cancer Institute (NCI), have discovered the molecular basis behind this difference in the ABC DLBCL tumor response rate: the presence of the My-T-BCR complex in double mutant cases contributes to ibrutinib disassembly, leading to an increase in drug resonsiveness.
This technology describes experimental methods to detect the My-T-BCR complex in patient biopsy samples and predict their responsiveness to ibrutinib and other inhibitors of BCR signaling.
The NCI seeks licensees and/or co-development partners to develop this technology toward commercialization.
- Diagnosis of DLBCL
- Classification of ABC DLBCL patients with mutations in the BCR subunit, CD79B (including a MYD88 mutation) who should have an increased response to ibrutinib
- The methods can be expanded to include multiple combinations of antibody pairs with different targets, in combination with other tumor-specific markers, or common pathology reagents to improve sensitivity or specificity of the predictions
- The My-T-BCR complex described in this invention may be important in other B-cell mediated disorders, in which case these methods may be applicable to additional diseases and disorders, such as leukemias and autoimmune diseases
- Proof-of-concept studies are complete and described (Phelan and Young et al. Nature, 2018)
- No other technology exists to detect protein-protein interactions in intact cells to predict response to BCR pathway inhibitors
- IND-enabling studies largely completed
Louis Staudt MD, Ph.D. (NCI), Ryan Young (NCI), James Phelan (NCI), Stefania Pittaluga (NCI), Sandrine Roulland (NCI)
Phelan JD, et. al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. [PMID 29925955]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/518,994 , Filed 13 Jun 2017
- PCT: PCT Application Number PCT/US2018/025377 , Filed 30 Mar 2018