Description:
R-spondins (RSPOs) are secreted proteins with critical roles in cancer development through binding to LGR4/5/6 and RNF43/ZNRF3 and potentiating Wnt signaling. UTHealth pioneering scientist engineered and fused an immunoglobin Fc domain to the mutated RSPOs (RSPO peptibodies). RSPO peptibodies can binds to LGR4/5/6 with high affinity but exhibit reduced Wnt signaling, suggesting a promising candidate for cancer treatment.
Background
R-spondins (RSPOs) and LGR4/5/6 form a ligand-receptor system with critical roles in normal development as well as in tumor initiation and progression. Aberrant expression of RSPO2 and RSPO3 through gain-of-expression of gene fusions was identified in subsets of colon and other solid tumors as a driving mechanism of oncogenesis. Overexpression of RSPO3 in lung adenocarcinomas due to transcriptional activation promotes tumor aggressiveness and anti-RSPO3 antibodies are being tested in clinical trials for cancer treatment.
Discovery
LGR4/5/6 are highly upregulated in multiple types of solid tumors. Researchers at UTHealth have engineered mutated RSPOs that can bind LGR4/5/6 with high affinity but exhibit reduced Wnt signaling. The engineered RSPO domain is fused to immunoglobin Fc domain (i.e. peptibodies). Drug conjugates of the RSPO peptibodies (PDCs) significantly suppressed the growth of cancer cells expressing LGR4/5/6 in vitro and in vivo without major adverse effect.
Benefits/Technology Advantages
•RSPO4 mutant-based peptibodies bind to all three LGRs with high affinity but no longer potentiates Wnt signaling.
•Drug conjugates of the peptibody displayed specific binding and cytotoxicity to cancer cells expressing LGR4/5/6 in vitro and antitumor effect in vivo.
•Both peptibodies and PDCs were rapidly internalized, following binding to LGR4/LGR5 with little nonspecific binding.
Potential Applications
The peptibodies as well as the PDCs are potential drug candidates that may provide diagnosis and treatment for a wide range of cancers, since LGRs are expressed broadly and highly in solid tumors, particularly in cancers of the digestive system, such as colon, stomach, and liver cancer. RSPO peptibodies can be conjugated to various drug payloads and developed into distinctive cancer therapeutics for different cancers.
Intellectual Property Status
U.S. Patent Application 17/586,258
Available for licensing
Associated Publications
“Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment.”
J Med Chem. 2021 Sep 9;64(17): 12572-12581
About the Lead Creator/Inventor
Dr. Qingyun (Jim) Liu, Ph.D.
Professor and Director, Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine;
Leads a research team primarily focused on the identification and characterization of targeted drug candidates in the area of cancer and immunology.
UTHealth Ref. No.: 2019-0016