Correction to “Shifting the Antibody–Drug Conjugate Paradigm: A Trastuzumab-Gold-Based Conjugate Demonstrates High Efficacy against Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Mouse Model”
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PROVIDER: S-EPMC10789141 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundAntibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2.MethodsTMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively.ResultsNuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM.ConclusionTMAB can serve as an effective targeting agent, and the TMAB-conjugated PAMAM can be exploited as a potential targeted chemotherapeutic drug delivery system for tumors that overexpress HER2.
| S-EPMC4370923 | biostudies-literature
Project description:BackgroundLong-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.MethodsRNA-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.ResultsHigh 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.ConclusionsThis study provides the rationale for the future development of a GPR56-targeted ADC approach to potentially treat a large fraction of MSS CRC patients.
| S-EPMC10070492 | biostudies-literature
Project description:PurposeThe phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE.MethodsHERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient.ResultsAt the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan-Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up.ConclusionThis is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015.
| S-EPMC8260531 | biostudies-literature
Project description:We assumed that the effect of adjuvant trastuzumab on survival is mediated by the treatment time and we conducted this trial-level meta-regression to determine the appropriate length of treatment. Twelve adjuvant trastuzumab trials (from January 2000 to June 2019, consisting of 20,271 patients) were included. We considered 12-month trastuzumab treatment as the standard. The primary study endpoint was disease-free survival (DFS). By quantifying the relationship between shortened treatment time (month) and altered recurrence risk (expressed as hazard ratio), we found the regression coefficient β was 0.05 (95% confidence interval: 0.02-0.08, P = 0.002), indicating the recurrence risk would increase 5.1% for each month that treatment was shortened. Accordingly, 3, 6, and 9-month reductions in treatment time resulted in 16%, 35%, and 57% increases in recurrence risk, respectively. We revealed a significant linear association between shortened treatment time of trastuzumab and recurrence risk. The clinical duration of adjuvant trastuzumab should be tailored.
| S-EPMC7406512 | biostudies-literature
Project description:Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.
| S-EPMC3563710 | biostudies-literature
Project description:Antibody-drug conjugates (ADCs) are biochemotherapeutics consisting of a cytotoxic chemical drug linked covalently to a monoclonal antibody. Two main classes of ADCs, namely cysteine and lysine conjugates, are currently available on the market or involved in clinical trials. The complex structure and heterogeneity of ADCs makes their biophysical characterization challenging. For cysteine conjugates, hydrophobic interaction chromatography is the gold standard technique for studying drug distribution, the naked antibody content, and the average drug to antibody ratio (DAR). For lysine ADC conjugates on the other hand, which are not amenable to hydrophobic interaction chromatography because of their higher heterogeneity, denaturing mass spectrometry (MS) and UV/Vis spectroscopy are the most powerful approaches. We report here the use of native MS and ion mobility (IM-MS) for the characterization of trastuzumab emtansine (T-DM1, Kadcyla(®)). This lysine conjugate is currently being considered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and combines the anti-HER2 antibody trastuzumab (Herceptin(®)), with the cytotoxic microtubule-inhibiting maytansine derivative, DM1. We show that native MS combined with high-resolution measurements and/or charge reduction is beneficial in terms of the accurate values it provides of the average DAR and the drug load profiles. The use of spectral deconvolution is discussed in detail. We report furthermore the use of native IM-MS to directly determine DAR distribution profiles and average DAR values, as well as a molecular modeling investigation of positional isomers in T-DM1.
| S-EPMC4534172 | biostudies-literature
Project description:Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) Ab-drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T-DXd-induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T-DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose-dependent and dose-frequency-dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T-DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T-DXd-related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T-DXd-induced ILD/pneumonitis in which target-independent uptake of T-DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T-DXd therapy.
| S-EPMC7734153 | biostudies-literature
Project description:Enthusiasm for the use of antibody-drug conjugates (ADCs) in cancer therapy has risen over the past few years. The success of this therapeutic approach relies on the identification of cell surface antigens that are widely and selectively expressed on tumor cells. Studies have shown that native ALK protein is expressed on the surface of most neuroblastoma cells, providing an opportunity for development of immune-targeting strategies. Clinically relevant antibodies for this target have not yet been developed. Here, we describe the development of an ALK-ADC, CDX-0125-TEI, which selectively targets both wild-type and mutated ALK-expressing neuroblastomas. CDX-0125-TEI exhibited efficient antigen binding and internalization, and cytotoxicity at picomolar concentrations in cells with different expression of ALK on the cell surface. In vivo studies showed that CDX-0125-TEI is effective against ALK wild-type and mutant patient-derived xenograft models. These data demonstrate that ALK is a bona fide immunotherapeutic target and provide a rationale for clinical development of an ALK-ADC approach for neuroblastomas and other ALK-expressing childhood cancers such as rhabdomyosarcomas.
| S-EPMC10023134 | biostudies-literature
Project description:BackgroundEpithelial ovarian cancer (EOC) is a lethal malignant tumor, for which new treatment options are urgently required. Lipolysis-stimulated lipoprotein receptor (LSR) is widely expressed in EOC, and it is associated with poor prognosis. In this study, we developed an antibody-drug conjugate (ADC) targeting LSR as a new therapeutic approach to EOC.MethodsWe, herein, developed novel anti-LSR monoclonal antibodies (mAbs) and an LSR-ADC by conjugating monomethyl auristatin E as a payload. We subsequently evaluated the in vitro and in vivo (on xenograft models) antitumor effect of the LSR-ADC.ResultsAn overexpression of LSR was observed not only in the primary EOC tumor but also in its lymph node and omental metastases. The EOC cell lines NOVC7-C and OVCAR3 strongly expressed LSR (as compared to ES2 cells). Both the anti-LSR mAb and the LSR-ADC were able to specifically bind to LSR-positive cells and were rapidly internalized and trafficked to the lysosomes. The LSR-ADC demonstrated a potent antitumor effect against NOVC-7C and OVCAR3, but little activity against ES2 cells. In vitro, the LSR-ADC exhibited a potent antitumor effect against NOVC-7C and OVCAR3. Moreover, in the OVCAR3 xenograft models as well as in the patient-derived xenograft models of LSR-positive EOC, the LSR-ADC significantly inhibited tumor growth. The LSR-ADC also suppressed the omental/bowel metastases in OVCAR3-Luc xenografts and improved the median survival.ConclusionThe developed LSR-ADC demonstrated a significant antitumor activity against LSR-positive EOC cell lines and tumors. Our preclinical data support the use of the LSR-ADC as a novel therapy for patients with LSR-positive ovarian cancer.
| S-EPMC9679668 | biostudies-literature
Project description:Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.
| S-EPMC11791482 | biostudies-literature