A5059576323- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Endometrial and Cervical Cancer Treatments
- Uterine Myomas and Treatments
- Sarcoma Diagnosis and Treatment
- Cancer therapeutics and mechanisms
- Radiopharmaceutical Chemistry and Applications
- CAR-T cell therapy research
- Advanced Biosensing Techniques and Applications
- Extracellular vesicles in disease
- Radiomics and Machine Learning in Medical Imaging
- Cancer Treatment and Pharmacology
- Synthesis and Biological Evaluation
- Venous Thromboembolism Diagnosis and Management
- Toxin Mechanisms and Immunotoxins
- Bioactive Compounds and Antitumor Agents
- Cancer Immunotherapy and Biomarkers
- Peptidase Inhibition and Analysis
- Nanofabrication and Lithography Techniques
- Synthesis and biological activity
- Medical Imaging Techniques and Applications
- Cardiac tumors and thrombi
- Multiple Myeloma Research and Treatments
- MicroRNA in disease regulation
- Colorectal Cancer Treatments and Studies
Weill Cornell Medicine
2020-2025
Cornell University
2020-2025
Children's Cancer and Blood Foundation
2020-2025
Daiichi-Sankyo (Japan)
2015-2023
An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as new antitumor drug candidate, and its preclinical pharmacologic profile assessed.In vitro in vivo activities of DS-8201a were evaluated compared T-DM1 several HER2-positive cell lines patient-derived xenograft (PDX) models. The mechanism action for the efficacy also evaluated. Pharmacokinetics cynomolgus monkeys safety profiles rats assessed.DS-8201a exhibited HER2 expression-dependent...
Antibody–drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue have significant antitumor efficacy with a wide therapeutic window. DS ‐8201a is human epidermal growth factor receptor 2 ( HER 2)‐targeting antibody–drug conjugate prepared using novel linker‐payload system potent topoisomerase I inhibitor, exatecan derivative DX ‐8951 derivative, d). It was effective against trastuzumab emtansine (T‐ DM 1)‐insensitive patient‐derived xenograft models both high...
Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. significantly suppressed tumor growth an immunocompetent model human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured mice rejected not only rechallenged...
Anti‐HER2 therapies are beneficial for patients with HER2‐positive breast or gastric cancer. T‐DM1 is a HER2‐targeting antibody–drug conjugate (ADC) comprising the antibody trastuzumab, linker, and tubulin inhibitor DM1. Although effective in treating advanced cancer, all eventually develop resistance. DS‐8201a new ADC incorporating an anti‐HER2 antibody, newly developed, enzymatically cleavable peptide novel, potent, exatecan‐derivative topoisomerase I (DXd). has drug‐to‐antibody‐ratio...
Abstract Purpose: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody–drug conjugate with topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential antitumor activity in preclinical models. Experimental Design: In vitro pharmacologic activities the mechanisms of action U3-1402 were assessed several human cell lines....
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7-8 with the topoisomerase I inhibitor DXd. In this study, we investigated pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration T-DXd, PK total Ab (the sum conjugated unconjugated Ab) were almost similar, indicating that linker stable during...
Abstract Purpose: We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody–drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism. Experimental Design: used two mouse xenograft models administered at concentration 4 mg/kg: (i) heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, (ii) homogeneous both types transplanted...
Abstract Purpose: Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is rare and aggressive cancer with poor prognosis. High clinical efficacy trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported phase II trial (STATICE trial). We performed co-clinical study T-DXd using patient-derived xenograft (PDX) models participants the STATICE trial. Experimental Design: Tumor specimens were resected during primary surgery or biopsied at recurrence from patients...
Abstract Background HER3 (human epidermal growth factor receptor 3) is a member of HER family, and overexpressed in breast cancer, NSCLC, melanoma, gastric cancer pancreatic patients` tissues. U3-1402a an antibody-drug conjugate (ADC) comprised fully human anti-HER3 monoclonal immunoglobulin G1 (IgG1) antibody (U3-1287) covalently conjugated via cleavable peptide linker to exatecan derivative (DXd). The DXd released after internalization leads apoptosis the target tumor cells by inhibition...
1031 Background: DS-8201a, a HER2-targeting antibody–drug conjugate (ADC), with topoisomerase I inhibitor, exatecan drivative (DX-8951 derivative, DXd) has been shown to have antitumor effects in preclinical xenograft models and clinical trials, but the involvement of immune system efficacy DS-8201a not elucidated yet. Methods: The individually combination an anti-PD-1 antibody was determined syngeneic mouse model human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Mice whose tumors had...
Abstract Antibody-drug conjugates (ADCs) represent a promising drug class which expresses wider therapeutic window than conventional chemotherapeutic agents by effecting efficient and specific delivery to antigen-expressing tumor cells. DS-8201a is HER2-targeting ADC structurally composed of humanized anti-HER2 antibody, enzymatically cleavable peptide-linker, novel topoisomerase I inhibitor (DXd), cell-membrane permeable more potent SN-38 the active metabolite irinotecan. This achieves high...
<div>Abstract<p>Background: Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is rare and aggressive cancer with poor prognosis. High clinical efficacy trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported phase 2 trial (STATICE trial). We performed co-clinical study T-DXd using patient-derived xenograft (PDX) models participants the STATICE trial. Patients methods: Tumor specimens were resected during primary surgery or biopsied at...
<p>Growth curve</p>
<p>ER and p53 immunohistochemistry of original patient-derived xenograft (PDX) tumors</p>
<p>Growth curve</p>
<p>ER and p53 immunohistochemistry of original patient-derived xenograft (PDX) tumors</p>
Abstract Background Anti-HER2 therapies are beneficial for patients with HER2-positive breast and gastric cancer. T-DM1 is an HER2-targeting antibody-drug conjugate (ADC), which structurally composed of the anti-HER2 antibody trastuzumab tubulin inhibitor DM1. has shown efficacy in advanced cancer, but all eventually develop resistance to T-DM1. DS-8201a a novel ADC potent topoisomerase I DX-8951 derivative. achieved high drug-to-antibody-ratio (DAR: 7-8) homogeneous drug conjugation. The...
<p>Cell line and patient-derived xenograft studies</p>
<p>Histopathological findings in the intestines, bone marrow and lung repeated dose study monkeys</p>