Preclinical efficacy studies of DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd.

Okajima, Daisuke; Yasuda, Satoru; Yokouchi, Yusuke; Fujitani, Tomomichi; Sakurai, Katsunobu; Yamaguchi, Junko; Kitamura, Michiko; Terauchi, Tomoko; Shibutani, Tomoko; Aida, Tetsuo; Nakada, Takashi; Tokuhiro, Shinya; Toki, Tadashi; Noguchi, Yutaka; Abe, Yuki; Agatsuma, Toshinori

doi:10.1200/jco.2018.36.15_suppl.e24206

Cited by 13 publications

(20 citation statements)

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“…DS-1062a is an ADC targeting Trop-2 and delivering DXd, a topoisomerase I inhibitor and derivative of exatecan 74. Inclusion criteria include the diagnosis of an unresectable advanced NSCLC not amenable to curative intent therapeutic approaches.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…This study is ongoing and currently actively recruiting; it has an estimated study completion date of June 20, 2021. Prior to this clinical trial, one group demonstrated that DS-1062 markedly reduced in vitro cancer cell growth with IC50 dosing in the nanomolar range in Trop-2+ cell lines (CFPAC1, BxPC-3); to contrast the group also demonstrated that in Trop-2-negative tumor cells (Calu-6), 100-fold greater dosing was needed to achieve IC50 74…”

Section: Clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

<p>Targeting Trop-2 in solid tumors: future prospects</p>

Zaman¹,

Jadid²,

Denson³

et al. 2019

OTT

121

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Trop-2 is a transmembrane glycoprotein that is upregulated in all cancer types independent of baseline levels of Trop-2 expression. Trop-2 is an ideal candidate for targeted therapeutics due to it being a transmembrane protein with an extracellular domain overexpressed on a wide variety of tumors as well as its upregulated expression relative to normal cells. As a result, several Trop-2-targeted therapeutics have recently been developed for clinical use, such as anti-Trop-2 antibodies and Trop-2-targeted antibody–drug conjugates (ADC). Subsequently, multiple early-phase clinical trials have demonstrated safety and clinical benefit of Trop-2-based ADCs across multiple tumor types. This includes clinical benefit and tolerability in tumor types with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and small-cell lung cancer. In this review, we elaborate on all clinical trials involving Trop-2.

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Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

<p>Targeting Trop-2 in solid tumors: future prospects</p>

Zaman¹,

Jadid²,

Denson³

et al. 2019

OTT

121

View full text Add to dashboard Cite

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“…The major difference between Kadcyla and Enhertu is the payload consisting of an agent with topoisomerase I inhibitor activity, mc-GGFG-Dxd, 37 based on exatecan (or Dxd). [38][39][40][41][42][43] Dxd is a derivative of DX-8951, a novel topoisomerase I inhibitor that has more potent efficacy than irinotecan against various tumor xenograft models, including irinotecan-resistant tumors, and it was developed up to phase III. 44,45 This payload encompasses a stable protease-sensitive cleavable linker that releases Dxd, having a primary hydroxyl group.…”

Section: Fda-approved Adcsmentioning

confidence: 99%

Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

2020

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“…The anti-TROP-2 ADC DS-1062a is composed of an enzymatically cleavable peptide linker conjugated to a topoisomerase-I inhibitor, DXd, 58 that is a derivative of the camptothecin Exatecan, which is said to be 10-fold more potent than SN-38. 59,60 This ADC showed dose-dependent tumor-growth inhibition in human cancer xenografts, as well as favorable PK profiles and safety in Cynomolgus monkeys.…”

Section: Ds-1062a (Daiichi-sankyo)mentioning

confidence: 99%

“…59,60 This ADC showed dose-dependent tumor-growth inhibition in human cancer xenografts, as well as favorable PK profiles and safety in Cynomolgus monkeys. 58 Preliminary data from a Phase 1 clinical trial in patients with relapsed NSCLC (NCT03401385) indicate that the agent has been safely tolerated at doses of up to 2 mg/kg, with 1 partial response in 18 tumor evaluable patients. 61 An update of the data presented at the 2019 ASCO meeting included 39 patients given doses as high as 8.0 mg/kg.…”

Section: Ds-1062a (Daiichi-sankyo)mentioning

confidence: 99%

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan

Goldenberg

Sharkey

2019

mAbs

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Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.

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Preclinical efficacy studies of DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd.

Cited by 13 publications

References 0 publications

<p>Targeting Trop-2 in solid tumors: future prospects</p>

<p>Targeting Trop-2 in solid tumors: future prospects</p>

Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan

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