Did you mean: duocarmycin
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Hepatology (Baltimore, Md.) Aug 2019Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel...
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican-3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3-specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody-drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA-damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3-specific ADCs: hYP7-DC and hYP7-PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3-positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7-DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7-DC in vitro and in vivo. Furthermore, single treatment of hYP7-PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Female; Glypicans; Humans; Immunoconjugates; Liver Neoplasms; Mice
PubMed: 30353932
DOI: 10.1002/hep.30326 -
The Lancet. Oncology Aug 2019Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical...
BACKGROUND
Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours.
METHODS
We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited.
FINDINGS
Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4-48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8-46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3-67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2-30·2) of 16 patients with gastric cancer, four (25%, 7·3-52·4) of 16 patients with urothelial cancer, and five (39%, 13·9-68·4) of 13 patients with endometrial cancer.
INTERPRETATION
Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation.
FUNDING
Synthon Biopharmaceuticals.
Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 31257177
DOI: 10.1016/S1470-2045(19)30328-6 -
The Journal of Antibiotics Jun 1985This report defines the transformations that antitumor antibiotic CC-1065 underwent under basic and acidic conditions. The isolation, purification, characterization, and...
This report defines the transformations that antitumor antibiotic CC-1065 underwent under basic and acidic conditions. The isolation, purification, characterization, and biological properties of a cyclopropapyrroloindole fragment, and an acidic fragment, PDE-I dimer, from a mild alkaline fragmentation and the phenolic product, AAP, resulting from alkylation of acetic acid by the cyclopropyl function are described.
Topics: Antibiotics, Antineoplastic; Circular Dichroism; Duocarmycins; Indoles; Leucomycins; Magnetic Resonance Spectroscopy
PubMed: 4019318
DOI: 10.7164/antibiotics.38.746 -
Proceedings of the National Academy of... Apr 1995Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065,... (Comparative Study)
Comparative Study Review
Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Base Sequence; Binding Sites; Consensus Sequence; DNA; Duocarmycins; Indoles; Leucomycins; Models, Molecular; Molecular Sequence Data; Molecular Structure; Nucleic Acid Conformation; Pyrroles; Structure-Activity Relationship
PubMed: 7731958
DOI: 10.1073/pnas.92.9.3642 -
Journal of Medicinal Chemistry Oct 2009
Review
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Duocarmycins; Indoles; Molecular Structure; Pyrroles; Structure-Activity Relationship
PubMed: 19639994
DOI: 10.1021/jm9006214 -
JACS Au Dec 2022Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency,... (Review)
Review
Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency, their unusual mechanism of bioactivity, and the beautiful modularity of their structure-activity relationship (SAR). This Perspective analyzes how the molecular designs of synthetic duocarmycins have evolved: from (1) early SAR studies, through to modern applications for directed cancer therapy as (2) prodrugs and (3) antibody-drug conjugates in late-stage clinical development. Analyzing 583 primary research articles and patents from 1978 to 2022, we distill out a searchable A0-format "Minard map" poster of ca. 200 key structure/function-tuning steps tracing chemical developments across these three key areas. This structure-based overview showcases the ingenious approaches to tune and target bioactivity, that continue to drive development of the elegant and powerful duocarmycin platform.
PubMed: 36590260
DOI: 10.1021/jacsau.2c00448 -
Cancers Feb 2022Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically... (Review)
Review
Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla, Enhertu, Trodelvy, and Abraxane). Most of these nanomedicines are antibody-drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla, Enhertu, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody-drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed.
PubMed: 35267507
DOI: 10.3390/cancers14051198 -
British Journal of Cancer Apr 2023Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential...
BACKGROUND
Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential for the development of new therapeutic approaches. GPR56, an adhesion GPCR, is highly expressed in CRC tumours and correlates with poor survival. Here, we describe the generation and preclinical evaluation of a novel ADC consisting of an anti-GPR56 antibody (10C7) conjugated with the DNA-damaging payload duocarmycin.
METHODS
RNA-seq dataset analysis was performed to determine GPR56 expression in CRC subtypes. The specificity of binding, epitope mapping, and internalisation of 10C7 was examined. 10C7 was conjugated to payload and ADC cytotoxicity was assessed against a panel of CRC cell lines and tumour organoids. Antitumour efficacy was evaluated in xenograft models of CRC cell lines and patient-derived tumours.
RESULTS
High GPR56 was shown to be associated with the microsatellite stable (MSS) subtype that accounts for 80-85% of CRC. GPR56 ADC selectively induced cytotoxicity in CRC cells and tumour organoids at low nanomolar potency in a GPR56-dependent manner and showed significant antitumour efficacy against GPR56-expressing xenograft models.
CONCLUSIONS
This study provides the rationale for the future development of a GPR56-targeted ADC approach to potentially treat a large fraction of MSS CRC patients.
Topics: Humans; Cell Line, Tumor; Colorectal Neoplasms; Immunoconjugates; Prognosis; Receptors, G-Protein-Coupled
PubMed: 36759728
DOI: 10.1038/s41416-023-02192-3 -
Journal For Immunotherapy of Cancer Sep 2023B7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Vobramitamab duocarmazine (also referred to as MGC018 and herein referred to as vobra...
INTRODUCTION
B7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Vobramitamab duocarmazine (also referred to as MGC018 and herein referred to as vobra duo) is an investigational duocarmycin-based antibody-drug conjugate (ADC) directed against the B7-H3 antigen. It is composed of an anti-B7-H3 humanized IgG1/kappa monoclonal antibody chemically conjugated through a cleavable valine-citrulline linker to a ocarmycin-hydroxyenzamide zaindole (vc-seco-DUBA). Vobra duo has shown preliminary clinical activity in B7-H3-expressing tumors.
METHODS
B7-H3 expression was evaluated by flow-cytometry in a panel of human NB cell lines. Cytotoxicity was evaluated in monolayer and in multicellular tumor spheroid (MCTS) models by the water-soluble tetrazolium salt,MTS, proliferation assay and Cell Titer Glo 3D cell viability assay, respectively. Apoptotic cell death was investigated by annexin V staining. Orthotopic, pseudometastatic, and resected mouse NB models were developed to mimic disease conditions related to primary tumor growth, metastases, and circulating tumor cells with minimal residual disease, respectively.
RESULTS
All human NB cell lines expressed cell surface B7-H3 in a unimodal fashion. Vobra duo was cytotoxic in a dose-dependent and time-dependent manner against all cell lines (IC50 range 5.1-53.9 ng/mL) and NB MCTS (IC50 range 17.8-364 ng/mL). Vobra duo was inactive against a murine NB cell line (NX-S2) that did not express human B7-H3; however, NX-S2 cells were killed in the presence of vobra duo when co-cultured with human B7-H3-expressing cells, demonstrating bystander activity. In orthotopic and pseudometastatic mouse models, weekly intravenous treatments with 1 mg/kg vobra duo for 3 weeks delayed tumor growth compared with animals treated with an irrelevant (anti-CD20) duocarmycin-ADC. Vobra duo treatment for 4 weeks further increased survival in both orthotopic and resected NB models. Vobra duo compared favorably to TOpotecan-TEMozolomide (TOTEM), the standard-of-care therapy for NB relapsed disease, with tumor relapse delayed or arrested by two or three repeated 4-week vobra duo treatments, respectively. Further increased survival was observed in mice treated with vobra duo in combination with TOTEM. Vobra duo treatment was not associated with body weight loss, hematological toxicity, or clinical chemistry abnormalities.
CONCLUSION
Vobra duo exerts relevant antitumor activity in preclinical B7-H3-expressing NB models and represents a potential candidate for clinical translation.
Topics: Child; Humans; Mice; Animals; Immunoconjugates; Duocarmycins; Neuroblastoma; Antineoplastic Agents; B7 Antigens; Antibodies, Monoclonal, Humanized
PubMed: 37775116
DOI: 10.1136/jitc-2023-007174 -
Molecular Cancer Therapeutics Jun 2023MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor, which is widely overexpressed in various solid cancer types, is an attractive target for...
MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor, which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. BYON3521 is a novel site-specifically conjugated duocarmycin-based antibody-drug conjugate (ADC), comprising a humanized cysteine-engineered IgG1 monoclonal antibody with low pmol/L binding affinity towards both human and cynomolgus MET. In vitro studies showed that BYON3521 internalizes efficiently upon MET binding and induces both target- and bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high MET-expressing cancer cell lines; in moderate and low MET-expressing cancer cell lines good potencies and partial efficacy were observed. In mouse xenograft models, BYON3521 showed significant antitumor activity upon single-dose administration in multiple non-MET-amplified tumor types with low, moderate, and high MET expression, including complete tumor remissions in models with moderate MET expression. In the repeat-dose Good Laboratory Practice (GLP) safety assessment in cynomolgus monkeys, BYON3521 was well tolerated and based on the observed toxicities and their reversibility, the highest non-severely toxic dose was set at 15 mg/kg. A human pharmacokinetics (PK) model was derived from the PK data from the cynomolgus safety assessments, and the minimal efficacious dose in humans is estimated to be in the range of 3 to 4 mg/kg. In all, our nonclinical data suggests that BYON3521 is a safe ADC with potential for clinical benefit in patients. A first-in-human dose-escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045).
Topics: Animals; Humans; Mice; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Immunoconjugates; Immunoglobulin G; Xenograft Model Antitumor Assays
PubMed: 37042205
DOI: 10.1158/1535-7163.MCT-22-0596