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Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer
Gemma E Mudd1, Heather Scott1, Liuhong Chen1
1BicycleTx Limited, B900 Babraham Research Campus, Cambridge CB22 3AT, U.K.
Abstract:
Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a Nectin-4 targeting BTC currently under clinical evaluation. Nectin-4 is overexpressed in multiple tumor types and is a clinically validated target for selective delivery of cytotoxic payloads. A Nectin-4 targeting bicyclic peptide was identified by phage display, which showed highly selective binding for Nectin-4 but suffered from low plasma stability and poor physicochemical properties. Multiparameter chemical optimization involving introduction of non-natural amino acids resulted in a lead Bicycle that demonstrated high affinity for Nectin-4, good stability in biological matrices, and a much-improved physicochemical profile. The optimized Bicycle was conjugated to the cytotoxin Monomethyl auristatin E via a cleavable linker to give the targeted drug conjugate BT8009, which demonstrates potent anticancer activity in in vivo rodent models.
Insights
Researchers developed BT8009, a novel Nectin-4 targeting bicycle toxin conjugate (BTC), for cancer therapy. This optimized molecule shows potent anticancer activity by delivering cytotoxic payloads directly to tumors.
Area of Science:
- Oncology
- Drug Discovery
- Molecular Biology
Background:
- Bicycle toxin conjugates (BTCs) offer targeted delivery of cytotoxic payloads to tumors.
- Nectin-4 is a clinically validated target overexpressed in various cancer types.
Purpose of the Study:
- To describe the discovery and preclinical evaluation of BT8009, a Nectin-4 targeting BTC.
- To optimize a bicyclic peptide for improved stability and physicochemical properties for targeted cancer therapy.
Main Methods:
- Phage display was used to identify a Nectin-4 targeting bicyclic peptide.
- Chemical optimization using non-natural amino acids improved the lead compound's properties.
- The optimized bicycle was conjugated to Monomethyl auristatin E to create BT8009.
Main Results:
- The lead bicyclic peptide demonstrated high Nectin-4 affinity but poor stability.
- Optimization yielded a bicycle with enhanced affinity, stability, and physicochemical profile.
- BT8009 exhibited potent anticancer activity in preclinical in vivo rodent models.
Conclusions:
- BT8009 represents a promising Nectin-4 targeting bicycle toxin conjugate for cancer treatment.
- The optimized molecule demonstrates effective targeted delivery and potent antitumor efficacy.
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