Bicycle Therapeutics (United Kingdom)

Modern manufacturing organizations face unparalleled intricacy in the identification of optimal locations of production in light of converging pressures from protective tariffs, sustainability regulations, and geopolitical sourcing constraints that fundamentally reshape strategic decision frameworks. Traditional cost-optimization models fall short in their multidimensional nature of location choices, creating analytical gaps that expose organizations to regulatory vulnerabilities and competitive disadvantages. Product Lifecycle Management systems have evolved beyond engineering documentation platforms to function as comprehensive strategic intelligence frameworks, capable of integrating material specifications, supplier characteristics, environmental attributes, and regulatory requirements within unified data architectures. It is by synthesizing heterogeneous variables across financial, operational, and sustainability domains that PLM enables sophisticated scenario modeling, quantifying trade-offs between domestic and international manufacturing alternatives under dynamic market conditions. The article looks at how PLM's relational data structures facilitate the simultaneous consideration of tariff exposure, carbon intensity, supply chain resilience, and regulatory compliance requirements. Through integrating with enterprise resource planning and supply chain management platforms, PLM transforms fragmented information into actionable intelligence that supports strategic decisions about manufacturing location. Advanced implementations incorporating predictive analytics and machine learning capabilities enable organizations to forecast the impact of regulatory changes, sustainability mandates, and market volatility on long-term manufacturing economics, thereby elevating location decisions from tactical procurement choices to strategic imperatives aligned with corporate goals across financial performance, environmental stewardship, and operational resilience dimensions.

TPS4619 Background: BT8009 is a Bicycle toxin conjugate (BTC), comprising a highly selective bicyclic peptide targeting nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a cleavable linker. Nectin-4 is an adhesion molecule commonly expressed in many tumor types, including urothelial cancer (UC), and is a validated therapeutic target (Hoffman-Censits 2021). BT8009 has a low molecular weight and short plasma half-life, with potential to rapidly penetrate solid tumors and reduce toxicity by minimizing exposure to normal tissue (Rigby 2022). Results from the ongoing phase 1/2 clinical trial of BT8009 (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile in patients (pts) with advanced malignancies including UC (Baldini 2023). This global, open label, phase 2/3 multicenter adaptive study aims to evaluate the safety and efficacy of BT8009 as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with locally advanced or metastatic UC (la/mUC) (NCT06225596/BT8009-230; Duravelo-2). Methods: The trial will enroll up to 956 adult pts in 2 cohorts. Cohort 1 will include n≤641 previously untreated pts eligible for platinum-based chemotherapy. Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy. Pts must have la/mUC of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. Cohort 1 will be randomized 1:1:1 to receive: 1) BT8009 5 mg/m2 on days (D)1, 8, and 15 + pembro 200 mg on D1; 2) BT8009 6 mg/m2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance). Cohort 2 will be randomized 1:1 to receive: 1) BT8009 5 mg/m2 on D1, 8, and 15 or 2) BT8009 6 mg/m2 on D1 and 8. Cycle lengths will be 21D (28D for avelumab). After 30 pts in each dose arm have 9 weeks follow-up, an interim analysis will determine the optimal dose of BT8009 + pembro (Cohort 1) or BT8009 monotherapy (Cohort 2) to be used for the rest of the study. An additional Cohort 2 arm, optimal dose of BT8009 + pembro, will open after completion of the interim analysis. Discontinuation criteria include planned completion of therapy, progressive disease, and intolerable toxicity. Primary endpoints are progression-free survival (PFS; Cohort 1) and objective response rate (ORR; Cohort 2) assessed by blinded independent central review. Secondary endpoints are ORR (Cohort 1), PFS (Cohort 2), and overall survival, duration of response, disease control rate, safety/tolerability, and health-related quality of life (Cohorts 1 and 2). Pharmacokinetics, incidence/titers of antidrug antibodies, and tumor/peripheral biomarkers are exploratory endpoints. Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting. Clinical trial information: NCT06225596 .

Erythropoietin-producing hepatocellular receptor A2 (EphA2), is a receptor tyrosine kinase involved in cell-cell interactions. It is known to be overexpressed in various tumors and is associated with poor prognosis. EphA2 has been proposed as a target for theranostic applications. Low molecular weight peptide-based scaffolds with low nanomolar affinities have been shown to be ideal in such applications. Bicyclic peptides have emerged as an alternative to traditional peptides for this purpose, offering affinities comparable to antibodies due to their constrained nature, along with high tissue penetration, and improved stability compared to linear counterparts. This study presents the development and comprehensive in vitro and in vivo preclinical evaluation of BCY18469, a novel EphA2-targeting bicyclic peptide-based radiotheranostic agent. Methods: The EphA2-targeting Bicycle® peptide BCY18469 was identified through phage-display and chemically optimized. BCY18469 was radiolabeled with 68Ga, 177Lu and 111In. The physicochemical properties, binding affinity and internalization as well as specificity of the peptide were evaluated in vitro. In vivo PET/MR and SPECT/CT imaging studies were performed using [68Ga]Ga-BCY18469 and [111In]In-BCY18469, respectively, along with biodistribution of [177Lu]Lu-BCY18469 up to 24 h post injection in HT1080- and PC-3-tumor bearing BALB/c nu/nu EphA2-overexpressing xenograft mouse models. Results: The EphA2-targeting bicyclic peptide BCY18469 showed high binding affinity toward human and mouse EphA2 (1.9 and 3.8 nM, respectively). BCY18469 specifically bound and internalized into EphA2-expressing HT1080 cells. Imaging studies showed high tumor enrichment at early time-points (SUV of 1.7 g/mL at 1 h p.i. and 1.2 g/mL at 2 h p.i. in PET/MRI, HT1080 xenograft) with tumor contrast as early as 5 min p.i. and kidney-mediated clearance. Biodistribution studies revealed high early tumor uptake (19.5 ± 3.5 %ID/g at 1 h p.i., HT1080 xenograft) with SPECT/CT imaging further confirming these findings (5.7 ± 1.5 %ID/g at 1 h p.i., PC-3 xenograft). Conclusion: BCY18469 demonstrated high affinity, specific targeting of EphA2, a favorable biodistribution profile, and clearance through renal pathways. These findings underscore the potentially important role of bicyclic peptides in advancing radiotheranostic approaches and encourage additional translational research.

A key component in the mountain bike industry is the telescopic front suspension, which offers the advantage of improved performance when traversing obstacles and rough terrain and during high impact landings. Over the last three decades these suspensions have become more widely adopted and more complex in design. Despite their popularity, there has been limited reported literature focused on the behavior of the telescopic front suspension as a dynamic subsystem in models commonly used in both the motorcycle and automotive industries, e.g., half moto and quarter car models. This paper presents a system identification and modeling approach that promises a deeper understanding of the dynamic behavior of vehicles with telescopic front suspensions.

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 are 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” (BTC) consisting of a Nectin-4–binding bicyclic peptide, a cleavable linker system and the cell penetrant toxin mono-methylauristatin E (MMAE). BT8009 shows significant antitumor activity in preclinical tumor models, across a variety of cancer indications and is well tolerated in preclinical safety studies. In several models, it shows superior or equivalent antitumor 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 hours 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 US, Canada, and Europe, enrolling patients with advanced solid tumors associated with Nectin-4 expression.

Bicycles are constrained bicyclic peptides formed through reaction of three cysteine residues within a linear sequence with a trivalent, symmetrical small molecule scaffold. Bicycles with high binding affinities to therapeutically important targets can be discovered using screening technologies such as phage display. Increasing the chemical diversity of Bicycles should improve the probability of finding hits to new targets and can be achieved by expanding the toolbox of Bicycle forming chemistries. Gold(III) S-arylation has recently been described as a method for the efficient bioconjugation of cysteine residues under conditions compatible with phage display. Herein, we explore the scope and generality of this methodology for Bicycle construction through the synthesis and evaluation of four novel tris-Gold complexes. These new scaffolds were systematically reacted with a variety of peptide sequences, varying in amino acid loop lengths. All four scaffolds proved to be capable and selective reactive partners for each peptide sequence and afforded the desired Bicycle products in 13-48% isolated yield. This work exemplifies Gold-mediated arylation as a general approach for construction of novel, highly constrained Bicycles.

BackgroundCD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™).MethodsNectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action.ResultsTranscriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists.ConclusionBT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.

Integral membrane proteins (IMPs) are central to many physiological processes and represent ∼60% of current drug targets. An intricate interplay with the lipid molecules in the cell membrane is known to influence the stability, structure and function of IMPs. Detergents are commonly used to solubilize and extract IMPs from cell membranes. However, due to the loss of the lipid environment, IMPs usually tend to be unstable and lose function in the continuous presence of detergent. To overcome this problem, various technologies have been developed, including protein engineering by mutagenesis to improve IMP stability, as well as methods to reconstitute IMPs into detergent-free entities, such as nanodiscs based on apolipoprotein A or its membrane scaffold protein (MSP) derivatives, amphipols, and styrene-maleic acid copolymer-lipid particles (SMALPs). Although significant progress has been made in this field, working with inherently unstable human IMP targets (e.g., GPCRs, ion channels and transporters) remains a challenging task. Here, we present a novel methodology, termed DirectMX (for direct membrane extraction), taking advantage of the saposin-lipoprotein (Salipro) nanoparticle technology to reconstitute fragile IMPs directly from human crude cell membranes. We demonstrate the applicability of the DirectMX methodology by the reconstitution of a human solute carrier transporter and a wild-type GPCR belonging to the human chemokine receptor (CKR) family. We envision that DirectMX bears the potential to enable studies of IMPs that so far remained inaccessible to other solubilization, stabilization or reconstitution methods.

Abstract Ephrin receptor A2 (EphA2) is a member of the Ephrin receptor family of cell-cell junction proteins and is both highly overexpressed in several solid tumors and associated with poor prognosis in patients. EphA2 is considered a high-value target for cancer therapeutics, but development of an antibody drug conjugate targeting EphA2 (MEDI-547) was stopped in early clinical development after severe adverse events, including bleeding toxicity were seen (Annunziata et al, 2013). We have developed a series of Bicycle Toxin Conjugates comprising a constrained bicyclic peptide (Bicycle®) that binds with high affinity and specificity to EphA2, which is covalently linked to a toxin payload via a cleavable linker. The small size of BTCs offers a significant advantage over other targeted cytotoxic approaches such as antibody-drug conjugates due to rapid extravasation, renal clearance and improved tumor penetration. BT5528 was selected from a panel of >75 Bicycle Toxin Conjugates (BTCs) with variations in Bicycle binder, molecular spacer, cleavable linker and toxin payload, based on in vivo efficacy and tolerability. BT5528 is effective in EphA2-expressing xenograft models, with efficacy seen from 1mg/kg qw and complete tumor regression at 3mg/kg qw. Rapid, complete regression of tumors is seen across a range of EphA2-expressing cell lines, including HT1080 fibrosarcoma line, MDA-MB-231 triple negative breast cancer line and NCI-H1975 lung cancer line and NSCLC PDX models. In order to test the benefit of the enhanced tumor penetration of BTCs, NSCLC PDX tumors were grown to >1000mm3 before commencing treatment. Complete regression of tumor was seen following 3 weeks of dosing. The bleeding events reported in early clinical trials of MEDI-547 (EphA2 ADC) were consistent with effects on the coagulation system in preclinical models. Dose-limiting toxicology in non-human primate (NHP) was reportedly Disseminated Intravascular Coagulation (DIC) and changes were seen in APTT and D-Dimer, with associated elevations in liver enzymes. Toxicology studies of BT5528 in rat and NHP showed no laboratory or clinical evidence of DIC, with normal levels of platelets, D-Dimer, APTT, and other coagulation-related parameters. Bicycle Toxin Conjugates (BTC) targeting EphA2 show potent antitumor activity in a range of solid tumor xenograft models. The BTCs show profound efficacy, without the limiting toxicity observed with previous Antibody Drug Conjugate approaches. IND-enabling studies for BT5528 are currently underway. Citation Format: Gavin Bennett, Philip Huxley, Amy Brown, Gemma Mudd, Peter U. Park, Nicholas Keen. BT5528, a Bicycle Toxin Conjugate targeting EphA2 has potent anti-tumor activity without bleeding or coagulation abnormalities in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5854.