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

20:00 EDT 9 Jun 2019 | NIH

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.

IC: 
NCI
NIH Ref. No.: 
e-171-2017
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
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
Development Status: 

Pre-clinical (in vivo)

Updated On: 
Jun 10, 2019
Date Published: 
Monday, June 10, 2019
Provider Classifications: 
Publications: 
Patent Application: 
62/518,994
PCT/US2018/025377
Licensing Contacts: 
Lead Inventor: 
Inventor IC: 
NCI
NCI
NCI
NCI
NCI
Inventor Lab URL: 
https://ccr.cancer.gov/Lymphoid-Malignancies-Branch/louis-m-staudt
LPM FIrst Name: 
John
LPM Last Name: 
Hewes
Inv Is lead: 
LPM Phone: 
240-276-5515
LPM Suffix: 
Ph.D.
LPM Organization: 
NCI - National Cancer Institute
DTDT Classification: 
Diagnostics
DTDT Description: 
Diagnostics
Pat Filing Date: 
2017-06-13
2018-03-30
Publication Link: 
https://www.ncbi.nlm.nih.gov/pubmed/29925955
Publication Caption: 
PMID 29925955
Publication Title: 

Phelan JD, et. al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. 

Collaboration Sought: 
Yes
Institute or Center: 
Collaboration Opportunity: 

Licensing only

E Number Only: 
e-171-2017
Inventor First Name: 
Louis
Ryan
James
Stefania
Sandrine
Inventor Last Name: 
Staudt
Young
Phelan
Pittaluga
Roulland

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

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