The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required.

Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV.

Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV.

Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV.