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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
EV20/Omomyc: A novel dual MYC/HER3 targeting immunoconjugate
Sandra Bibbò1, Emily Capone1, Giulio Lovato1
1Department of Innovative Technologies in Medicine & Dentistry, University "G. D'Annunzio" of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), University "G. D'Annunzio" of Chieti-Pescara, Chieti, Italy.
Abstract:
MYC is one of the most important therapeutic targets in human cancer. Many attempts have been made to develop small molecules that could be used to curb its activity in patients, but most failed to identify a suitable direct inhibitor. After years of preclinical characterization, a tissue-penetrating peptide MYC inhibitor, called Omomyc, has been recently successfully used in a Phase I dose escalation study in late-stage, all-comers solid tumour patients. The study showed drug safety and positive signs of clinical activity, prompting the beginning of a new Phase Ib combination study currently ongoing in metastatic pancreatic adenocarcinoma patients. In this manuscript, we have explored the possibility to improve Omomyc targeting to specific cancer subtypes by linking it to a therapeutic antibody. The new immunoconjugate, called EV20/Omomyc, was developed by linking a humanised anti-HER3 antibody, named EV20, to Omomyc using a bifunctional linker. EV20/Omomyc shows antigen-dependent penetrating activity and therapeutic efficacy in a metastatic model of neuroblastoma. This study suggests that directing Omomyc into specific cell types using antibodies recognising tumour antigens could improve its therapeutic activity in specific indications, like in the paediatric setting.
Insights
A novel peptide MYC inhibitor, Omomyc, shows promise in cancer therapy. Linking Omomyc to an anti-HER3 antibody (EV20/Omomyc) enhances its targeting and efficacy in preclinical models, suggesting improved cancer subtype treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- MYC is a critical therapeutic target in human cancers, but direct inhibitors have been challenging to develop.
- Omomyc, a tissue-penetrating peptide MYC inhibitor, has shown safety and preliminary clinical activity in Phase I trials for solid tumors.
- Improving targeted delivery of MYC inhibitors could enhance their therapeutic potential in specific cancer subtypes.
Purpose of the Study:
- To investigate the potential of enhancing Omomyc's cancer targeting by conjugating it to a therapeutic antibody.
- To develop and evaluate an immunoconjugate, EV20/Omomyc, for targeted delivery of Omomyc to cancer cells.
Main Methods:
- Development of EV20/Omomyc by linking a humanized anti-HER3 antibody (EV20) to the Omomyc peptide via a bifunctional linker.
- Assessment of antigen-dependent penetration and therapeutic efficacy of EV20/Omomyc in preclinical models, specifically a metastatic neuroblastoma model.
Main Results:
- EV20/Omomyc demonstrated antigen-dependent penetration, indicating targeted delivery.
- The immunoconjugate exhibited therapeutic efficacy in a metastatic neuroblastoma model.
- This approach suggests potential for improved therapeutic activity in specific cancer indications.
Conclusions:
- Targeting Omomyc to specific cancer cells using antibody conjugates, such as EV20/Omomyc, can improve its therapeutic efficacy.
- This strategy holds promise for treating specific cancer subtypes, including pediatric cancers.
- Further development of antibody-drug conjugates for MYC inhibition warrants investigation.
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