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Parasites & Vectors Dec 2022Vector control plays a key role in reducing the public health burden of mosquito-borne diseases. Today's vector control strategies largely rely on synthetic insecticides...
Vector control plays a key role in reducing the public health burden of mosquito-borne diseases. Today's vector control strategies largely rely on synthetic insecticides that can have a negative environmental impact when applied outdoors and often become inefficient because of the mosquitoes' ability to develop resistance. An alternative and promising approach to circumvent these challenges involves the implementation of insecticides derived from nature (biopesticides) for vector control. Biopesticides can constitute naturally occurring organisms or substances derived from them that have lifespan-shortening effects on disease vectors such as mosquitoes. Here we present the discovery and evaluation of natural product-based biological control agents that can potentially be developed into biopesticides for mosquito control. We screened a natural product collection comprising 390 compounds and initially identified 26 molecules with potential ability to kill the larval stages of the yellow fever mosquito Aedes aegypti, which is responsible for transmitting viruses such as dengue, Zika, chikungunya and yellow fever. Natural products identified as hits in the screen were further evaluated for their suitability for biopesticide development. We show that a selection of the natural product top hits, bactobolin, maytansine and ossamycin, also killed the larval stages of the malaria-transmitting mosquito Anopheles gambiae as well as the adult form of both species. We have further explored the usefulness of crude extracts and preparations from two of the best candidates' sources (organisms of origin) for mosquitocidal activity, that is extracts from the two bacteria Burkholderia thailandensis and Streptomyces hygroscopicus var. ossamyceticus.
Topics: Animals; Humans; Mosquito Vectors; Biological Products; Biological Control Agents; Yellow Fever; Plant Extracts; Mosquito Control; Insecticides; Culex; Zika Virus; Zika Virus Infection; Aedes; Larva
PubMed: 36539851
DOI: 10.1186/s13071-022-05594-z -
Cancer Journal (Sudbury, Mass.)Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past... (Review)
Review
Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past decade, there has been rapid development of ADCs aimed at different types of breast cancer. The success of the monoclonal antibody trastuzumab has led to the evolution of several ADCs targeting HER2-positive breast cancer. Trastuzumab-emtansine, the first approved ADC targeting HER2-positive breast cancer, has become standard of care for patients with high-risk early-stage HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. More recently, the observation of the bystander effect, in which ADCs target both antigen-positive cells and adjacent antigen-negative cells, has led to the reclassification of "HER2-low" breast cancer and the development of trastuzumab-deruxtecan to target this population. This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Immunoconjugates; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal
PubMed: 36383904
DOI: 10.1097/PPO.0000000000000634 -
Clinical Pharmacokinetics Jun 2018Antibody-drug conjugates are an emerging class of biopharmaceuticals changing the landscape of targeted chemotherapy. These conjugates combine the target specificity of... (Review)
Review
Antibody-drug conjugates are an emerging class of biopharmaceuticals changing the landscape of targeted chemotherapy. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics. Several antibody-drug conjugates have received approval for the treatment of various types of cancer including gemtuzumab ozogamicin (Mylotarg), brentuximab vedotin (Adcetris), trastuzumab emtansine (Kadcyla), and inotuzumab ozogamicin, which recently received approval (Besponsa). In addition to these approved therapies, there are many antibody-drug conjugates in the drug development pipeline and in clinical trials, although these fall outside the scope of this article. Understanding the pharmacokinetics and pharmacodynamics of antibody-drug conjugates and the development of pharmacokinetic/pharmacodynamic models is indispensable, albeit challenging as there are many parameters to incorporate including the disposition of the intact antibody-drug conjugate complex, the antibody, and the drug agents following their dissociation in the body. In this review, we discuss how antibody-drug conjugates progressed over time, the challenges in their development, and how our understanding of their pharmacokinetics/pharmacodynamics led to greater strides towards successful targeted therapy programs.
Topics: Ado-Trastuzumab Emtansine; Aminoglycosides; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Gemtuzumab; Humans; Immunoconjugates; Inotuzumab Ozogamicin; Maytansine; Models, Biological; Neoplasms; Trastuzumab
PubMed: 29188435
DOI: 10.1007/s40262-017-0619-0 -
Breast Cancer Research and Treatment Aug 2020Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature... (Review)
Review
PURPOSE
Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients.
METHODS
We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles.
RESULTS
The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1-2 events, 0.5% grade 3-4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing drug-induced ILD.
CONCLUSIONS
ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Camptothecin; Disease Management; Drug Monitoring; Everolimus; Female; Humans; Immunoconjugates; Incidence; Lapatinib; Lung Diseases, Interstitial; Neoplasm Metastasis; Paclitaxel; Pneumonia; Receptor, ErbB-2; Trastuzumab
PubMed: 32591987
DOI: 10.1007/s10549-020-05754-8 -
Cancer Research May 2024Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer....
UNLABELLED
Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance.
SIGNIFICANCE
Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.
Topics: Humans; Female; Breast Neoplasms; Immunogenic Cell Death; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Animals; Mice; Microtubule-Associated Proteins; Xenograft Model Antitumor Assays; Cell Line, Tumor; Antineoplastic Agents, Immunological; Drug Resistance, Neoplasm; Antigens, Neoplasm; Trastuzumab; CD8-Positive T-Lymphocytes
PubMed: 38319231
DOI: 10.1158/0008-5472.CAN-23-2812 -
Pharmacology Research & Perspectives Aug 2020The development of targeted therapies has drastically improved the outcome of patients with different types of cancer. T-DM1 (trastuzumab-emtansine) is an antibody-drug...
The development of targeted therapies has drastically improved the outcome of patients with different types of cancer. T-DM1 (trastuzumab-emtansine) is an antibody-drug conjugate used for the treatment of HER2-positive breast cancer combining the FDA approved mAb (monoclonal antibody) trastuzumab and the microtubule cytotoxic agent DM1 (emtansine). Despite clinical successes achieved by targeted therapies, a large number of patients develop resistance during treatment. To explore mechanisms of resistance to T-DM1, the MDA-MB-361 HER2-positive breast cancer cell line was exposed in vitro to T-DM1 in the absence or presence of ciclosporin A. Previously reported mechanisms of resistance such as trastuzumab-binding alterations, MDR1 upregulation, and SLC46A3 downregulation were not observed in these models. Despite a decrease in HER2 expression at the cell surface, both resistant cell lines remained sensitive to HER2 targeted therapies such as mAbs and tyrosine kinase inhibitors. In addition, sensitivity to DNA damaging agents and topoisomerase inhibitors were unchanged. Conversely resistance to anti-tubulin agents increased. Resistant cells displayed a decreased content of polymerized tubulin and a decreased content of βIII tubulin although the downregulation of βIII tubulin by siRNA in the parental cell line did not modified the sensitivity to T-DM1. Both cell lines resistant to T-DM1 also presented giant aneuploid cells. Several SLC (solute carrier) transporters were found to be differentially expressed in the resistant cells in comparison to parental cells. These results suggest that some characteristics such as increased baseline aneuploidy and altered intracellular drug trafficking might be involved in resistance to T-DM1.
Topics: Ado-Trastuzumab Emtansine; Aneuploidy; Antineoplastic Agents; Antineoplastic Agents, Immunological; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Receptor, ErbB-2; Solute Carrier Proteins; Tubulin
PubMed: 32583565
DOI: 10.1002/prp2.617 -
Antimicrobial Agents and Chemotherapy Nov 1974A quantitative microbiological assay and a bioautography system with Penicillium avellaneum UC-4376 was developed for the antitumor drugs maytansine, and its homologues,...
A quantitative microbiological assay and a bioautography system with Penicillium avellaneum UC-4376 was developed for the antitumor drugs maytansine, and its homologues, maytanprine and maytanbutine. The susceptibility of the assay is 1.5 mug/ml.
Topics: Antineoplastic Agents, Phytogenic; Chromatography; Dose-Response Relationship, Drug; Maytansine; Penicillium
PubMed: 15825322
DOI: 10.1128/AAC.6.5.651 -
Current Oncology (Toronto, Ont.) Aug 2022Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally... (Review)
Review
Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.
Topics: Ado-Trastuzumab Emtansine; Breast Neoplasms; Female; Humans; Neoadjuvant Therapy; Prognosis; Trastuzumab
PubMed: 36005196
DOI: 10.3390/curroncol29080458 -
Cancer Management and Research 2013Non-Hodgkin lymphoma symbolizes a heterogeneous group of diseases resulting from malignant transformation of lymphocytes with differing patterns of behavior and... (Review)
Review
Non-Hodgkin lymphoma symbolizes a heterogeneous group of diseases resulting from malignant transformation of lymphocytes with differing patterns of behavior and responses to treatment. The potential curability of non-Hodgkin lymphoma differs among the various histologic subtypes and is associated in part with the stage at presentation. CD19 antigen is a type I transmembrane glycoprotein belonging to the immunoglobulin Ig superfamily. CD19 is specifically expressed in normal and neoplastic B-cells. Recent study showed that in a mouse model, CD19 and c-Myc synergize functionally to accelerate B-cell lymphomagenesis, which is associated with increased disease severity. Specificity is the most important challenge in cancer therapeutics. Antibody-drug conjugates have the prospect of enhancing the therapeutic efficacy over unconjugated monoclonal antibodies through the selective delivery of cytotoxic agents to cancer cells. The ubiquitous expression of CD19 in these tumors, especially at an earlier stage and the property of efficient internalization, makes CD19 an attractive and affective target for antibody-drug conjugate therapy as compared to CD20. SAR3419 (huB4-DM4) is a novel antibody-drug conjugate that is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached to the potent cytotoxic drug, a maytansine derivative (DM4), through a cleavable disulfide cross-linking agent N-Succinimidyl-4-2-pyridyldithio butanoic acid (SPDB). The preclinical efficacy of maytansine derivative-anti-CD19 conjugate was demonstrated in our laboratory, and SAR3419 was found to be more effective than CHOP in a xenograft model. Phase I trials have also been conducted on the basis of preclinical studies that demonstrated promising antitumor activity with acceptable safety results in human B-cell lymphoma models. Additional trials are ongoing and will provide additional insight into the full potential of this novel drug.
PubMed: 24023523
DOI: 10.2147/CMAR.S45957 -
Cancer Letters Feb 2023Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved in 2013 to treat HER2+ breast cancer. Despite its efficacy in the clinic, some...
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved in 2013 to treat HER2+ breast cancer. Despite its efficacy in the clinic, some patients exhibit intrinsic or acquired resistance to such ADC. To characterize mechanisms of resistance to T-DM1, we isolated several HER2+ resistant clones derived from the HCC1954 HER2+ cell line. The isolated clones were different as per their transcriptomic profiles. However, all the T-DM1-resistant clones showed decreased HER2 levels. Yet, the clones were still oncogenically dependent on HER2, as indicated by knock down experiments. The decrease in HER2 expression caused acquired resistance to T-DM1 and to other anti-HER2 therapies. Antibody array analyses showed that the epidermal growth factor receptor (EGFR) was expressed in these T-DM1-resistant HCC1954 clones. Indeed, therapies targeting EGFR, particularly cetuximab-DM1, demonstrated a strong anti-proliferative action on cells with acquired resistance to T-DM1 and HER2 loss. The expression of EGFR in cells resistant to T-DM1 offers the possibility of using therapies directed to this receptor to combat resistance to anti-HER2 drugs and loss of HER2 overexpression.
Topics: Humans; Female; Trastuzumab; Receptor, ErbB-2; Drug Resistance, Neoplasm; Ado-Trastuzumab Emtansine; Breast Neoplasms; Antibodies; Immunoconjugates
PubMed: 36455759
DOI: 10.1016/j.canlet.2022.216024