A5004074955- Toxin Mechanisms and Immunotoxins
- Polyamine Metabolism and Applications
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Axon Guidance and Neuronal Signaling
- Vehicle emissions and performance
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Inorganic and Organometallic Chemistry
- Electron and X-Ray Spectroscopy Techniques
- Radiopharmaceutical Chemistry and Applications
- Engineering Applied Research
- Chemical Synthesis and Analysis
- Allergic Rhinitis and Sensitization
- Microfluidic and Capillary Electrophoresis Applications
- Asthma and respiratory diseases
- Biochemical and Structural Characterization
- Neuroscience and Neural Engineering
- Transgenic Plants and Applications
- Urinary and Genital Oncology Studies
Bicycle Therapeutics (United Kingdom)
2018-2024
Kymab (United Kingdom)
2022
Abstract The EphA2 receptor is found at high levels in tumors and low normal tissue expression biopsies a predictor of poor outcome patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, nanoparticle-based approaches (1–3). However, until now only EphA2-targeting antibody–drug conjugates (ADC) entered clinical development. For example, MEDI-547 an ADC that displayed encouraging antitumor activity preclinical models progressed...
Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery payloads into tumors. Herein we describe the discovery BT8009, Nectin-4 targeting BTC currently under clinical evaluation. is overexpressed in multiple tumor types and clinically validated target selective cytotoxic payloads. A bicyclic peptide was identified by phage display, which showed highly binding but suffered from low plasma stability poor physicochemical properties. Multiparameter chemical...
Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, receptor tyrosine kinase highly expressed number of solid tumors, identified Bicycle families with low nanomolar affinity. toxin conjugate (BTC) was generated by derivatization one these the potent cytotoxin DM1 via cleavable linker. This BTC demonstrated antitumor activity vivo but poorly tolerated, which hypothesized to be result...
Abstract 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 as a target toxin delivery this indication. Despite excellent data little are reported EV other expressing tumors therapy can produce significant toxicities many patients, frequently leading to discontinuation treatment. Thus, additional approaches with...
Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that difficult drug conventional small molecules due extended protein–protein interactions it forms both receptors. The hit series was shown bind TSLP hotspot, also by IL-7Rα. Guided first X-ray...
Abstract Small molecule toxin conjugates offer a novel approach to tumor antigen specific targeting, allowing reduced systemic exposures and efficient penetration of cytotoxic payloads, compared large antibody conjugates. BT8009 is Bicycle Toxin Conjugate (BTC®) in which Nectin-4 binding Bicycle® (bicyclic peptide) conjugated through an inert sarcosine spacer chain, cleavable linker, the antimitotic MMAE. Increased expression has been reported multiple types (including bladder, breast,...
Abstract We have identified a Nectin-4 targeting peptide for delivery of cytotoxic agents to expressing tumors. is cell adhesion molecule, that highly expressed in certain tumor types, including bladder, TNBC and NSCLC, but has restricted distribution normal tissue. Bicycles® are small (1.5kDa) fully synthetic, structurally constrained, drugs combine the affinity antibodies with pharmacokinetic properties molecules. The Bicycle phage display platform was utilised rapidly identify high (18...
Abstract Ephrin receptor A2 (EphA2) is a member of the family cell-cell junction proteins and both highly overexpressed in several solid tumors associated with poor prognosis patients. Bicycles® are novel therapeutic agents: bicyclic peptides constrained via chemical scaffold, which confer structural stability leading to high affinity selectivity usually antibodies. Bicycles can be elaborated carry payloads specific target their relatively small size (1.5-3 kDa) allows rapid tissue...
We have identified a Nectin-4 targeting peptide for delivery of cytotoxic agents to expressing tumors. is cell adhesion molecule, that highly expressed in certain tumor types, including bladder, TNBC and NSCLC, but has restricted distribution normal tissue. Bicycles® are small (1.5kDa) fully synthetic, structurally constrained, drugs combine the affinity antibodies with pharmacokinetic properties molecules. The Bicycle phage display platform was utilised rapidly identify high (18 nM)...
<p>Supplementary information detailing methods used to generate in vitro and vivo data presented paper</p>
Supplementary Figure from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
Supplementary Data from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
Supplementary Data from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
<p>Supplementary data are provided to further understand the pharmacokinetics and efficacy of BT5528 EphA2 expression in tumors. Figure S1: Plasma concentration-time curves MMAE following IV dosing 1 mouse, rat, cynomolgus Monkey at mg/kg (n=3 per species). Related vivo PK. S2: tumour growth inhibition CDX PDX xenograft models correlated. 3 qw has a range anti-tumour activities across different cell-line derived patient-derived (*p<0.05, **p<0.01, ***p<0.001 2way ANOVA from D0...
<p>Supplementary Chemical Structures provides an inventory and structural diagrams of all Bicycle conjugates used in paper</p>
<p>Supplementary information detailing methods used to generate in vitro and vivo data presented paper</p>
<div>Abstract<p>The EphA2 receptor is found at high levels in tumors and low normal tissue expression biopsies a predictor of poor outcome patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, nanoparticle-based approaches (<a href="#bib1 bib2 bib3" target="_blank">1–3</a>). However, until now only EphA2-targeting antibody–drug conjugates (ADC) entered clinical development. For example, MEDI-547 an ADC...
<div>Abstract<p>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 as a target toxin delivery this indication. Despite excellent data little are reported EV other expressing tumors therapy can produce significant toxicities many patients, frequently leading to discontinuation treatment. Thus,...
<div>Abstract<p>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 as a target toxin delivery this indication. Despite excellent data little are reported EV other expressing tumors therapy can produce significant toxicities many patients, frequently leading to discontinuation treatment. Thus,...
<div>Abstract<p>The EphA2 receptor is found at high levels in tumors and low normal tissue expression biopsies a predictor of poor outcome patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, nanoparticle-based approaches (<a href="#bib1 bib2 bib3" target="_blank">1–3</a>). However, until now only EphA2-targeting antibody–drug conjugates (ADC) entered clinical development. For example, MEDI-547 an ADC...
<p>Supplementary Chemical Structures provides an inventory and structural diagrams of all Bicycle conjugates used in paper</p>
Supplementary Data from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
Supplementary Data from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
Supplementary Figure from BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors
<p>Supplementary data are provided to further understand the pharmacokinetics and efficacy of BT5528 EphA2 expression in tumors. Figure S1: Plasma concentration-time curves MMAE following IV dosing 1 mouse, rat, cynomolgus Monkey at mg/kg (n=3 per species). Related vivo PK. S2: tumour growth inhibition CDX PDX xenograft models correlated. 3 qw has a range anti-tumour activities across different cell-line derived patient-derived (*p<0.05, **p<0.01, ***p<0.001 2way ANOVA from D0...