Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer

Mudd, Gemma; Scott, Heather S.; Chen, Liuhong; Rietschoten, Katerine Van; Ivanova-Berndt, Gabriela; Dzionek, Katarzyna; Brown, Amy; Watcham, Sophie M.; White, Lewi; Park, Peter U.; Jeffrey, Phil; Rigby, Michael; Beswick, Paul J.

doi:10.1021/acs.jmedchem.2c00065

Cited by 40 publications

(34 citation statements)

References 26 publications

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“…Bicyclic Nectin-4 binders were identified using proprietary phage display technology ( 24 ) providing a preliminary binding sequence with low nmol/L affinity but having poor in vitro plasma stability and solubility. These initial phage display leads were subsequently chemically optimized as described previously in another article ( 25 ). The resultant binding peptide, BCY8126, showed good solubility and high affinity for human, NHP, rat and mouse Nectin-4.…”

Section: Resultsmentioning

confidence: 99%

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors

Rigby¹,

Bennett²,

Chen³

et al. 2022

Molecular Cancer Therapeutics

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Multiple tumor types overexpress Nectin-4 and the Antibody Drug Conjugate (ADC), enfortumab vedotin (EV) shows striking efficacy in clinical trials for metastatic urothelial cancer, which expresses high levels of Nectin-4, validating Nectin-4 as a clinical target for toxin delivery in this indication. Despite excellent data in urothelial cancer, little efficacy data is reported for EV in other Nectin-4 expressing tumors and EV therapy can produce significant toxicities in many patients, frequently leading to discontinuation of treatment. Thus, additional approaches to this target with the potential to extend utility and reduce toxicity are warranted. We describe the preclinical development of BT8009, a “Bicycle Toxin Conjugate” (BTCTM) consisting of a Nectin-4 binding bicyclic peptide, a cleavable linker system and the cell penetrant toxin mono-methylauristatin E (MMAE). BT8009 shows significant anti-tumor activity in pre-clinical tumor models, across a variety of cancer indications and is well tolerated in preclinical safety studies. In several models it shows superior or equivalent anti-tumor activity to an EV analog. As a small hydrophilic peptide-based drug BT8009 rapidly diffuses from the systemic circulation, through tissues to penetrate the tumor and target tumor cells. It is renally eliminated from the circulation, with a half-life of 1-2 h in rat and non-human primate. These physical and PK characteristics differentiate BT8009 from ADCs and may provide benefit in terms of tumor penetration and reduced systemic exposure. BT8009 is currently in a Phase 1/2 multicenter clinical trial across the USA, Canada and Europe, enrolling patients with advanced solid tumors associated with Nectin-4 expression.

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Section: Resultsmentioning

confidence: 99%

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors

Rigby¹,

Bennett²,

Chen³

et al. 2022

Molecular Cancer Therapeutics

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“…Several of these peptides were used to generate bicyclic peptide-drug conjugates (BDCs) that are being evaluated in clinical trials. [60] Another powerful display technology for generating cyclic peptide ligands is mRNA display. [6] In mRNA display, peptides are covalently linked to their encoding mRNA during ribosomal translation.…”

Section: Biological Screening: Phage and Mrna Displaymentioning

confidence: 99%

“…Bicyclic peptides that bind with nanomolar or even picomolar affinity were developed to a wide range of targets, including tumor markers. Several of these peptides were used to generate bicyclic peptide‐drug conjugates (BDCs) that are being evaluated in clinical trials [60] …”

Section: Cyclic Peptide Ligand Generationmentioning

confidence: 99%

Cyclic Peptides for Drug Development

Ji,

Nielsen,

Heinis

2023

Angew Chem Int Ed

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Cyclic peptides are fascinating molecules abundantly found in nature and exploited as molecular format for drug development as well as other applications, ranging from research tools to food additives. Advances in peptide technologies made over many years through improved methods for synthesis and drug development have resulted in a steady stream of new drugs, with an average of around one cyclic peptide drug approved per year. Powerful technologies for screening random peptide libraries, and de novo generating ligands, have enabled the development of cyclic peptide drugs independent of naturally derived molecules and now offer virtually unlimited development opportunities. In this review, we feature therapeutically relevant cyclic peptides derived from nature and discuss the unique properties of cyclic peptides, the enormous technological advances in peptide ligand development in recent years, and current challenges and opportunities for developing cyclic peptides that address unmet medical needs.

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“…In addition, Mudd et al developed a binding protein-4-targeted bicyclic toxin adduct to synthesize the conjugate BT8009 for the treatment of solid tumors. The bicyclic peptide obtained by phage display can specifically binds to Nectin-4 of tumor cells [ 108 ].…”

Section: Modified Phage For Tumor Therapymentioning

confidence: 99%

Modified Bacteriophage for Tumor Detection and Targeted Therapy

Shen

Wang

et al. 2023

Nanomaterials

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Malignant tumor is one of the leading causes of death in human beings. In recent years, bacteriophages (phages), a natural bacterial virus, have been genetically engineered for use as a probe for the detection of antigens that are highly expressed in tumor cells and as an anti-tumor reagent. Furthermore, phages can also be chemically modified and assembled with a variety of nanoparticles to form a new organic/inorganic composite, thus extending the application of phages in biological detection and tumor therapeutic. This review summarizes the studies on genetically engineered and chemically modified phages in the diagnosis and targeting therapy of tumors in recent years. We discuss the advantages and limitations of modified phages in practical applications and propose suitable application scenarios based on these modified phages.

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Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer

Cited by 40 publications

References 26 publications

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors

Cyclic Peptides for Drug Development

Modified Bacteriophage for Tumor Detection and Targeted Therapy

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