Development of a Lc–Ms/Ms Method for the Quantification of Toxic Payload Dm1 Cleaved from Bt1718 in a Phase I Study

Gowland, Catherine; Berry, Philip; Errington, Julie; Jeffrey, Philip D.; Bennett, Gavin; Godfrey, Lisa; Pittman, Marc; Niewiarowski, Andrew; Symeonides, Stefan N.; Veal, Gareth J.

doi:10.4155/bio-2020-0256

Cited by 15 publications

(8 citation statements)

References 17 publications

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“…In 2021, Bicycle Therapeutics (Nasdaq: BCYC) announced three investigational BTC (bicyclic peptide‒toxin coupled) drugs: BT1718, BT5528, and BT8009 36 , 37 , 38 . All in phase I/II clinical development.…”

Section: General Consideration Factor Of Pdc and Clinical Trials Of Pdcsmentioning

confidence: 99%

“… Name TTP Payload Linker Indication Development phase Clinical trials registry Ref. ANG1005 Angiopep-2 Paclitaxel Succinic acid Leptomeningeal metastases Phase III NCT03613181 (2021) 135 , 136 Glioma Glioblastoma brain tumor, recurrent Phase II NCT00539344 (2014) 137 Breast cancer brain metastases Phase II NCT02755987 (2016) 138 NCT01967810 (2020) Advanced solid tumors with and without bain metastases Phase I NCT02048059 (2020) 139 NCT00539383 (2016) GRN1005 Angiopep-2 Paclitaxel Succinic acid Breast cancer brain metastases; non-small cell lung cancer (nsclc) with brain metastases Phase II NCT01480583 (2016) 89 , 140 NCT01497665 (2019) NCT01679743 (2019) BT1718 MT1-MMP binder DM1 Disulfide Advanced solid tumours non-small cell lung cancer non-small cell lung sarcoma oesophageal cancer Phase I/II NCT03486730 (2020) 38 BT5528 EphA2 binder MMAE Amide Solid tumours EphA2-positive NSCLC Phase I NCT04180371 (2021) 36 , 39 , 141 BT8009 Nectin-4 binder MMAE Amide Solid tumors Phase I NCT04561362 (2021) …”

Section: General Consideration Factor Of Pdc and Clinical Trials Of Pdcsmentioning

confidence: 99%

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Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Miao

et al. 2023

Acta Pharmaceutica Sinica B

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Section: General Consideration Factor Of Pdc and Clinical Trials Of Pdcsmentioning

confidence: 99%

Section: General Consideration Factor Of Pdc and Clinical Trials Of Pdcsmentioning

confidence: 99%

Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Miao

et al. 2023

Acta Pharmaceutica Sinica B

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“…Another bicyclic peptide was utilized in the study of Gowland et al for the targeted delivery of mertansine to membrane type I matrix metalloproteinase (MT1-MMP) in an ongoing Phase I/IIa human clinical trial for the treatment of advanced solid tumors ( Figure 17 ). The first phase of this trial demonstrated the superior pharmacokinetic profile of the hybrid ( 54 ), while more data are expected upon completion of the clinical trial [ 136 ].…”

Section: Peptide Hybrids With Natural Productsmentioning

confidence: 99%

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

et al. 2022

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Cancer is one of the top leading causes of death worldwide. It is a heterogenous disease characterized by unregulated cell proliferation and invasiveness of abnormal cells. For the treatment of cancer, natural products have been widely used as a source of therapeutic ingredients since ancient times. Although natural compounds and their derivatives have demonstrated strong antitumor activity in many types of cancer, their poor pharmacokinetic properties, low cell selectivity, limited bioavailability and restricted efficacy against drug-resistant cancer cells hinder their wide clinical application. Conjugation of natural products with other bioactive molecules has given rise to a new field in drug discovery resulting to the development of novel, bifunctional and more potent drugs for cancer therapy to overcome the current drawbacks. This review discusses multiple categories of such bifunctional conjugates and highlights recent trends and advances in the development of natural product hybrids. Among them, ADCs, PDCs, ApDCs, PROTACs and AUTOTACs represent emerging therapeutic agents against cancer.

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“…Due to its low molecular weight and good distribution compared with antibody-drug conjugates, BT1718 may quickly penetrate and 'kill' tumor cells, showing a therapeutic effect on advanced solid tumors. The bicyclic peptide also has other inherent characteristics to minimize drug toxicity, such as short systemic half-life, rapid penetration into tumors, low systemic exposure, and rapid renal clearance [24].…”

Section: Targeting Integrinsmentioning

confidence: 99%

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Zhu

Tang

2021

Trends in Pharmacological Sciences

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Drug delivery systems are generally believed to comprise drugs and excipients. A peptide-drug conjugate is a single molecule that can simultaneously play multiple roles in a drug delivery system, such as in vivo drug distribution, targeted release, and bioactivity functions. This molecule can be regarded as an integrated drug delivery system, so it is called a molecular drug delivery system. In the context of cancer therapy, a peptide-drug conjugate comprises a tumor-targeting peptide, a payload, and a linker. Tumor-targeting peptides specifically identify membrane receptors on tumor cells, improve drug-targeted therapeutic effects, and reduce toxic and side effects. Payloads with bioactive functions connect to tumor-targeting peptides through linkers. In this review, we explored ongoing clinical work on peptide-drug conjugates targeting various receptors. We discuss the binding mechanisms of tumor-targeting peptides and related receptors, as well as the limiting factors for peptide-drug conjugate-based molecular drug delivery systems. Towards enhanced targeting on tumorsDespite the rapid development of anticancer drugs in the past few decades, cancer is one of the leading causes of death in the world [1]. Due to the lack of an effective means to distinguish tumor cells from normal cells [2], the accumulation efficiency of anticancer drugs in tumor cells is low and the toxic side effects on normal tissues are high. In the treatment process, drug resistance problems are caused by tumor heterogeneity [3], drug inactivation, transport, and metabolism, changes in drug targets, and tumor microenvironment dysfunction [4]. Although advanced drug delivery methods can partially solve problems of targeting, toxicity, and drug resistance [5], difficult industrialization, complicated process control, and huge costs remain insurmountable obstacles.Peptide-drug conjugates are emerging molecular drug delivery system (see Glossary) that achieve precise drug delivery and tumor-targeted release at the molecular level [6]. Current drug delivery systems, such as nano-drug delivery systems, use various complex excipients to assemble nanoscale particles that encapsulate drugs to be passively or actively delivered to target organs. The anticancer efficacy of nano-drug delivery systems is improved by an enhanced permeability retention effect to increase drug accumulation in tumors and the toxicity of nanodrug delivery systems is reduced by the long systemic circulation to decrease drug accumulation in normal organs [7]. However, a reappraisal of nano-drug delivery system design is suggested to improve their clinical efficacy and safety in cancer patients [8].By contrast, molecular drug delivery systems use a single peptide-drug conjugate molecule to achieve in vivo drug delivery, targeted drug release, and bioactivity, which can maximize the targeting effect and reduce drug resistance. Peptide-drug conjugates, which were first reported in 1972 by Freer et al.[9] (Box 1), are similar to the tethering of ligand-targeted drugs [10],

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Development of a Lc–Ms/Ms Method for the Quantification of Toxic Payload Dm1 Cleaved from Bt1718 in a Phase I Study

Cited by 15 publications

References 17 publications

Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

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