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RSPO2-based peptibodies conjugated with pyrrolobenzodiazepine dimer or camptothecin analogs demonstrate potent
Abstract:
LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptors 4, 5, and 6) are three homologous receptors that are co-expressed or alternately expressed at high levels in tumor cells of colorectal cancer and high-risk neuroblastoma. Simultaneous targeting of all three receptors may provide increased efficacy or overcome drug resistance due to tumor heterogeneity and cancer cell plasticity. LGR4/5/6 all bind to R-spondins (RSPOs) with high affinity and potentiate Wnt/β-catenin signaling in response. Previously, we showed that a peptibody based on a mutant RSPO4 furin domain that bound to LGR4/5/6 without potentiating Wnt/β-catenin signaling was able to deliver cytotoxins into cancer cells that express any of the three receptors. We have now generated a mutant RSPO2 furin domain that retains high affinity binding to LGR4/5/6 without signaling activity. Peptibodies based on this RSPO2 furin mutant were conjugated with either pyrrolobenzodiazepine dimer or camptothecin derivative, and the resulting peptibodydrug conjugates (PDCs) showed potent and specific cytotoxic activity in neuroblastoma and colorectal cancer cell lines expressing any of LGR4/5/6 in vitro and robust anti-tumor activity in vivo. The results support the potential of RSPO2-based PDCs for the treatment of colorectal cancer, high-risk neuroblastoma, and other cancers that express LGR4/5/6.
Insights
Targeting LGR4/5/6 receptors with novel peptibody-drug conjugates (PDCs) shows potent anti-cancer activity. These RSPO2-based PDCs demonstrate efficacy against colorectal cancer and neuroblastoma, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Leucine-rich repeat containing, G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) are highly expressed in colorectal cancer and neuroblastoma.
- These receptors bind R-spondins (RSPOs) and potentiate Wnt/β-catenin signaling, crucial pathways in cancer.
- Targeting LGR4/5/6 simultaneously may overcome drug resistance and enhance treatment efficacy.
Purpose of the Study:
- To develop and evaluate novel peptibody-drug conjugates (PDCs) targeting LGR4/5/6 receptors.
- To assess the efficacy of RSPO2-based PDCs in preclinical models of colorectal cancer and neuroblastoma.
Main Methods:
- Generation of a mutant RSPO2 furin domain peptibody with high affinity for LGR4/5/6 but lacking signaling activity.
- Conjugation of the RSPO2 peptibody with cytotoxic agents (pyrrolobenzodiazepine dimer or camptothecin derivative).
- In vitro and in vivo evaluation of the resulting PDCs' cytotoxic and anti-tumor activity in cancer cell lines and models.
Main Results:
- RSPO2-based PDCs exhibited potent and specific cytotoxic activity against LGR4/5/6-expressing neuroblastoma and colorectal cancer cell lines in vitro.
- These PDCs demonstrated robust anti-tumor activity in vivo.
- The developed PDCs effectively delivered cytotoxic payloads into cancer cells expressing LGR4/5/6.
Conclusions:
- RSPO2-based peptibody-drug conjugates are a promising therapeutic strategy for colorectal cancer and high-risk neuroblastoma.
- Targeting LGR4/5/6 receptors with these PDCs offers a potential approach to overcome drug resistance in various cancers.
- Further development of RSPO2-based PDCs warrants investigation for clinical application.
