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Using a Proximity Ligation Assay to Diagnose Lymphoma Subsets and Predict Patient Responses to Targeted Therapies

Summary
Researchers at the National Cancer Institute (NCI) have developed a method to diagnose the Diffuse Large B cell lymphoma (DLBCL) subsets and predict their response to B cell receptor (BCR) signaling inhibitors, such as ibrutinib. The NCI seeks licensees and/or co-development partners to commercialize this technology.
NIH Reference Number
e-171-2017
Product Type
Keywords
  • Proximity Ligation Assay, PLA, Diffuse Large B Cell Lymphoma, DLBCL, Ibrutinib, Staudt
Collaboration Opportunity
This invention is available for licensing.
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Description of Technology

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.

Potential Commercial Applications
  • 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
Competitive Advantages
  • 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
Inventor(s)

Louis Staudt MD, Ph.D. (NCI), Ryan Young (NCI), James Phelan (NCI), Stefania Pittaluga (NCI), Sandrine Roulland (NCI)

Development Stage
Publications

Phelan JD, et. al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma.  [PMID 29925955]

Patent Status
  • 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
Therapeutic Area
Updated
Monday, June 10, 2019