maytansine has been researched along with Neoplasms* in 80 studies
30 review(s) available for maytansine and Neoplasms
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Syndecans in cancer: A review of function, expression, prognostic value, and therapeutic significance.
While our understanding of tumors and how to treat them has advanced significantly since the days of Aminopterin and the radical mastectomy, cancer remains among the leading causes of death worldwide. Despite innumerable advancements in medical technology the non-static and highly heterogeneous nature of a tumor can make characterization and treatment exceedingly difficult. Because of this complexity, the identification of new cellular constituents that can be used for diagnostic, prognostic, and therapeutic purposes is crucial in improving patient outcomes worldwide. Growing evidence has demonstrated that among the myriad of changes seen in cancer cells, the Syndecan family of proteins has been observed to undergo drastic alterations in expression. Syndecans are transmembrane heparan sulfate proteoglycans that are responsible for cell signaling, proliferation, and adhesion, and many studies have shed light on their unique involvement in both tumor progression and suppression. This review seeks to discuss Syndecan expression levels in various cancers, whether they make reliable biomarkers for detection and prognosis, and whether they may be viable targets for future cancer therapies. The conclusions drawn from the literature reviewed in this article indicate that changes in expression of Syndecan protein can have profound effects on tumor size, metastatic capability, and overall patient survival rate. Further, while data regarding the therapeutic targeting of Syndecan proteins is sparse, the available literature does demonstrate promise for their use in cancer treatment going forward. Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Disease Models, Animal; Humans; Immunoconjugates; Immunotherapy, Adoptive; Maytansine; Mice; Neoplasms; Prognosis; Progression-Free Survival; Receptors, Chimeric Antigen; Survival Rate; Syndecans; Xenograft Model Antitumor Assays | 2021 |
Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.
Covering: 2014-2019We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer efficacy of microtubule targeted agents identified from plants, microbes, and marine organisms is well documented. We highlight new microtubule targeted agents currently in clinical evaluations for the treatment of drug resistant cancers and the accumulating evidence that the anticancer efficacy of these agents is not solely due to their antimitotic effects. Indeed, the effects of microtubule targeted agents on interphase microtubules are leading to their potential for more mechanistically guided use in cancers as well as neurological disease. The discussion of these agents as more targeted drugs also prompts a reevaluation of our thinking about natural products that target other components of the cytoskeleton. For instance, actin active natural products are largely considered chemical probes and non-selective toxins. However, studies utilizing these probes have uncovered aspects of actin biology that can be more specifically targeted to potentially treat cancer, neurological disorders, and infectious disease. Compounds that target intermediate filaments and septins are understudied, but their continued discovery and mechanistic evaluations have implications for numerous therapeutic indications. Topics: Actins; Animals; Biological Products; Colchicine; Cytoskeleton; Drug Resistance, Neoplasm; Eukaryotic Cells; Genome; Humans; Maytansine; Microtubules; Neoplasms; Nervous System Diseases; Taxoids | 2020 |
Exploiting the folate receptor α in oncology.
Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody-drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices. Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Ovarian Epithelial; Endometrial Neoplasms; Female; Fluorescent Dyes; Folate Receptor 1; Folic Acid; Folic Acid Antagonists; Humans; Immunoconjugates; Immunologic Factors; Immunotherapy, Adoptive; Lung Neoplasms; Maytansine; Mesothelioma; Molecular Imaging; Molecular Targeted Therapy; Neoplasms; Optical Imaging; Ovarian Neoplasms; Radionuclide Imaging; Theranostic Nanomedicine; Tubulin Modulators | 2020 |
Antibody-Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned.
Topics: Ado-Trastuzumab Emtansine; Aminoglycosides; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Gemtuzumab; Humans; Immunoconjugates; Inotuzumab Ozogamicin; Maytansine; Models, Biological; Neoplasms; Trastuzumab | 2018 |
Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings.
Maytansinoids, the potent cytotoxic derivatives of the alkaloid maytansine are used as payloads in antibody maytansinoid conjugates. This article reviews clinical and preclinical hepatotoxicity observed with antibody maytansinoid conjugates used to treat cancer. Specific aspects of drug distribution, metabolism and excretion that may impact hepatotoxicity are reviewed vis-à-vis the kind of maytansinoid in the conjugate, cleavable or non-cleavable linkers, linker-payload combinations, drug to antibody ratio, metabolite formation, hepatic enzyme induction in relation to drug-drug interactions and species, age and gender differences. The article also sheds light on factors that may protect the liver from toxic insults. Topics: Animals; Antineoplastic Agents, Phytogenic; Chemical and Drug Induced Liver Injury; Humans; Immunoconjugates; Maytansine; Neoplasms | 2018 |
Antibody-Drug Conjugates for Cancer Treatment.
The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody-drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors. Topics: Ado-Trastuzumab Emtansine; Breast Neoplasms; Brentuximab Vedotin; Drug Development; Hodgkin Disease; Humans; Immunoconjugates; Lymphoma, Large-Cell, Anaplastic; Maytansine; Neoplasms; Trastuzumab | 2018 |
Are Microbial Endophytes the 'Actual' Producers of Bioactive Antitumor Agents?
For millenia, plants have been a major source of medications against human and animal diseases. In the case of anticancer agents, a significant number of current agents can trace their source back to nominally plant secondary metabolites, with examples being taxol, vinca alkaloids, camptothecin (CPT), and their modified derivatives. However, it is now becoming apparent that these and other plant-derived materials, plus similar agents from marine sources may well have a microbe in their background. In this short Opinion, evidence for such claims are presented for some of the agents currently in use or in preclinical and clinical trials against cancer. Topics: Animals; Antineoplastic Agents; Bacteria; Biological Products; Endophytes; Fungi; Humans; Maytansine; Neoplasms; Paclitaxel; Plants; Porifera; Rhizosphere; Urochordata | 2018 |
Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review.
Attaching a cytotoxic "payload" to an antibody to form an antibody-drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors-platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment. Topics: Ado-Trastuzumab Emtansine; Aminobenzoates; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Gemtuzumab; Humans; Immunoconjugates; Maytansine; Neoplasms; Oligopeptides; Sialic Acid Binding Ig-like Lectin 3; Trastuzumab | 2017 |
Status Quo in Antibody-Drug Conjugates - Can Glyco- Enzymes Solve the Current Challenges?
Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others are in clinical trials. However, unstable linkers, low drug potency and unwanted bystander-effects are only some of the drawbacks of ADCs. Enzymes used in combination with prodrugs happen to be a promising alternative. The glyco-enzyme horseradish peroxidase (HRP) has proven to activate the hormone indole-3-acetic acid (IAA) to a highly potent cytotoxic drug. This combination of IAA and HRP has been investigated for the use in strategies such as gene-directed enzyme prodrug therapy (GDEPT) and antibody-directed enzyme prodrug therapy (ADEPT). This article reviews the current state of research in ADC engineering and describes the potential major enhancements through use of glycoenzymes in combination with a prodrug. Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Brentuximab Vedotin; Clinical Trials as Topic; Drug Design; Glycoconjugates; Horseradish Peroxidase; Humans; Immunoconjugates; Indoleacetic Acids; Maytansine; Molecular Targeted Therapy; Neoplasms; Prodrugs; Trastuzumab; Tubulin Modulators | 2017 |
ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers.
The recent approval of trastuzumab emtansine (Kadcyla®) and brentuximab vedotin (Adcetris ®) has spurred tremendous investment in new approaches for the targeted delivery of pharmaceutical agents. Targeted delivery approaches, such as Antibody Drug Conjugates (ADCs), typically rely on an endogenous or exogenous "trigger" that results in the release of the pharmacologically active agent at the intended site of action. Lysosomal and intracellular triggers include proteolytic cleavage, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, and reductive cleavage. Recent work has also illustrated that exogenous triggers and extracellular enzymes can be harnessed to result in linker cleavage at the site of action. As these linker technologies have grown, so also has our understanding of the biophysical parameters that drive exposure and stability. The growth in targeted delivery approaches has also driven advancement in bioanalytical strategies for assessing the distribution, processing, and metabolism of these agents. This review provides a systematic overview of each of these areas, particularly focusing on recent advancements in the field that has the potential to expand the scope of therapeutic areas that ADCs and other targeted delivery approaches can be designed to address. Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Biopharmaceutics; Brentuximab Vedotin; Cross-Linking Reagents; Drug Delivery Systems; Drug Design; Humans; Immunoconjugates; Maytansine; Neoplasms; Trastuzumab | 2017 |
Strategies and challenges for the next generation of antibody-drug conjugates.
Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Antineoplastic Agents; Brentuximab Vedotin; Drug Design; Drug Stability; Humans; Immunoconjugates; Maytansine; Neoplasms; Trastuzumab | 2017 |
Antibody-Drug Conjugates: A Clinical Pharmacy Perspective on an Emerging Cancer Therapy.
Antibody-drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado-trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology. Topics: Ado-Trastuzumab Emtansine; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Brentuximab Vedotin; Female; Gemtuzumab; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Lymphoma; Maytansine; Neoplasms; Trastuzumab | 2016 |
New developments for antibody-drug conjugate-based therapeutic approaches.
The clinical success of Adcetris(®) (brentuximab vedotin) and Kadcyla(®) (ado-trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Brentuximab Vedotin; Clinical Protocols; Drug-Related Side Effects and Adverse Reactions; Humans; Immunoconjugates; Immunotherapy; Immunotoxins; Maytansine; Neoplasms; Risk Assessment; Trastuzumab | 2016 |
Mesothelin Immunotherapy for Cancer: Ready for Prime Time?
Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer. Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; GPI-Linked Proteins; Humans; Immunoconjugates; Immunotherapy; Maytansine; Mesothelin; Neoplasms | 2016 |
Reinvention of chemotherapy: drug conjugates and nanoparticles.
Recent advances in nanotechnology have addressed some of the issues related to lack of selectivity and nonspecific toxicities associated with conventional chemotherapy. Nanoparticles are therapeutic carriers that can be fine tuned for specific application and for passive or active tumor targeting.. Although the nanoparticle field is rapidly expanding, there are to date only six nanoparticle-based drug delivery platforms and two antibody-drug conjugates that are clinically approved for cancer therapy. Here, we review the clinical data of liposomal anthracyclines, nanoparticle formulations of paclitaxel and trastuzumab emtansine. We then briefly comment on efficacy and safety issues of nanoparticles, as well as on the next-generation nanoparticles for cancer therapy.. The emerging development of cancer nanotechnology offers the opportunity of reinvestigating the potential of cytotoxic agents, improving tumor targeting and drug delivery, leading to better safety profile and antitumor activity. Adding specificity to nanoparticles may allow personalization of cancer therapy using chemotherapy. Topics: Ado-Trastuzumab Emtansine; Albumin-Bound Paclitaxel; Albumins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Drug Carriers; Humans; Maytansine; Nanoparticles; Nanotechnology; Neoplasms; Paclitaxel; Trastuzumab | 2015 |
Renal toxicity of anticancer agents targeting HER2 and EGFR.
EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents. Topics: Acute Kidney Injury; Ado-Trastuzumab Emtansine; Afatinib; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lapatinib; Maytansine; Neoplasms; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Renal Dialysis; Renal Insufficiency, Chronic; Trastuzumab | 2015 |
Antibody-drug conjugates: an emerging modality for the treatment of cancer.
Antibody-drug conjugates (ADCs) offer promise as a therapeutic modality that can potentially reduce the toxicities and poor therapeutic indices caused by the lack of specificity of conventional anticancer therapies. ADCs combine the potency of cytotoxic agents with the target selectivity of antibodies by chemically linking a cytotoxic payload to an antibody, potentially creating a synthetic molecule that will deliver targeted antitumor therapy that is both safe and efficacious. The ADC repertoire contains a range of payload molecules, antibodies, and linkers. Two ADC molecules, Kadcyla® and Adcetris®, have been approved by the FDA, and many more are currently in clinical development. Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brentuximab Vedotin; Drug Approval; Drug Design; Humans; Immunoconjugates; Maytansine; Molecular Targeted Therapy; Neoplasms; Trastuzumab; United States; United States Food and Drug Administration | 2014 |
[The growing field of immunoconjugates in oncology. A successful link(er) between antibodies and small cytotoxic molecules].
As evidenced by the recent FDA approvals of brentuximab vedotin (Adcetris(®)) and trastuzumab emtansine (Kadcyla(®)), antibody-drug conjugates (ADC) are becoming an important class of biotherapeutics in oncology. In addition, the strong pipeline of ADC in clinical development, bearing 38 ADC for the treatment of both solid and hematological malignancies, emphasizes the interest and confidence of clinicians and pharmaceutical industry in the area. Although the ADC concept looks pretty simple, it took decades before it turned out to be a successful therapeutic solution. Improving the understanding of ADC mechanism of action allowed identifying the most critical factors influencing ADC efficacy and toxicity. This led to still ongoing research efforts in antibody and alternative scaffold engineering, in linker and conjugation chemistry, as well as in the screening and selection of optimal target antigens and cytotoxics. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brentuximab Vedotin; Drug Discovery; Humans; Immunoconjugates; Maytansine; Medical Oncology; Neoplasms; Trastuzumab | 2014 |
[Design of next generation antibody drug conjugates].
Chemotherapy remains one of the major tools, along with surgery, radiotherapy, and more recently targeted therapy, in the war against cancer. There have appeared a plethora of highly potent cytotoxic drugs but the poor discriminability between cancerous and healthy cells of these agents limits their broader application in clinical settings. Therapeutic antibodies have emerged as an important class of biological anticancer agents, thanks to their ability in specific binding to tumor-associated antigens. While this important class of biologics can be used as single agents for the treatment of cancer through antibody-dependent cell cytotoxicity (ADCC), their therapeutical efficacy is often limited. Antitumor antibody drug conjugates (ADCs) combine the target-specificity of monoclonal antibody (mAb) and the highly active cell-killing drugs, taking advantages of the best characteristics out of both components. Thus, insufficiency of most naked mAbs in cancer therapy has been circumvented by arming the immunoglobulin with cytotoxic drugs. Here mAbs are used as vehicles to transport potent payloads to tumor cells. ADCs contain three main components: antibody, linker and cytotoxics (also frequently referred as payload). Antibodies can recognize and specifically bind to the tumor-specific antigens, leading to an antibody-assisted internalization, and payload release. While ADC has demonstrated tremendous success, a number of practical challenges limit the broader applications of this new class of anticancer therapy, including inefficient cellular uptake, low cytotoxicity, and off-target effects. This review article aims to cover recent advances in optimizing linkers with increased stability in circulation while allowing efficient payload release within tumor cells. We also attempt to provide some practical strategies in resolving the current challenges in this attractive research area, particularly to those new to the field. Topics: Aminobenzoates; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Survival; Cytotoxins; Drug Design; Humans; Immunoconjugates; Maytansine; Neoplasms; Oligopeptides | 2013 |
Antibody-drug conjugates: the chemistry behind empowering antibodies to fight cancer.
For more than a century, the concept of a "magic bullet" to deliver cytotoxic therapy to the site of disease has been envisioned but only recently have technological advances enabled antibody-drug conjugates to fulfill that dream. The recent approvals of brentuximab vedotin and ado-trastuzumab emtansine and emerging data for many molecules in clinical trials highlight the potential for antibody-drug conjugates to offer new therapeutic options for patients. This chapter reviews the evolution, state of the art, and potential future improvements that are enabling rapid development of this important class of cancer therapeutics. Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Brentuximab Vedotin; Humans; Immunoconjugates; Maytansine; Neoplasms; Trastuzumab | 2013 |
Drug conjugates such as Antibody Drug Conjugates (ADCs), immunotoxins and immunoliposomes challenge daily clinical practice.
Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brentuximab Vedotin; Humans; Immunoconjugates; Immunotoxins; Liposomes; Maytansine; Neoplasms; Trastuzumab | 2012 |
ADME of antibody-maytansinoid conjugates.
The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radio-labeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack cross-reactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Drug Evaluation, Preclinical; Humans; Maytansine; Mice; Neoplasms; Tissue Distribution; Trastuzumab; Tubulin Modulators; Xenograft Model Antitumor Assays | 2012 |
Antibody-DM1 conjugates as cancer therapeutics.
Synthetic derivatives of the microtubule-targeted agent maytansine, commonly known as drug maytansinoids or DMs, are emerging as potential cancer therapeutics. DM1 is an antibody-conjugatable maytansinoid that was developed to overcome systemic toxicity associated with maytansine and to enhance tumor-specific delivery. Antibody-DM1 conjugates showed promising results in preclinical and clinical evaluations. However, the molecular mechanism of the drug component DM1 was largely unknown. Recently, researchers have examined the mechanism of DM1 at molecular and cellular levels. According to their findings, DM1 binds at the tips of microtubules and suppresses the dynamicity of microtubules. The antibody-DM1 conjugate cleaves inside cells and releases the active drug in a time-dependent manner. The suppression of microtubule dynamics by DM1 induces mitotic arrest and cell death. Topics: Antibodies; Antineoplastic Agents; Cell Line, Tumor; Humans; Immunoconjugates; Maytansine; Microtubules; Neoplasms | 2011 |
Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer.
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase 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 recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited. Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunoconjugates; Maytansine; Neoplasms; Receptor, ErbB-2; Trastuzumab | 2011 |
[Antibody-drug conjugate--a new age for personalized cancer treatment].
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brentuximab Vedotin; Clinical Trials as Topic; Humans; Immunoconjugates; Maytansine; Neoplasms; Precision Medicine; Trastuzumab; Treatment Outcome | 2011 |
[Immunoconjugates, drug-armed antibodies to fight against cancer].
Monoclonal antibodies constitute a growing class of therapeutic agents. They are classically used in combination with chemotherapeutic drugs for cancer treatment. The concept of coupling a cytotoxic agent to an antibody can be viewed as a means to confer a selectivity for tumoral cells to highly cytotoxic drugs which cannot be used in human, or a higher power to antibodies which have a low anti-tumoral activity on their own. Gemtuzumab ozogamicin is the only drug-armed antibody available on the market, for the treatment of acute myeloid leukaemia. Other immunoconjugates are currently under clinical development. The most used cytotoxic agents derive from calicheamicin, maytansin and auristatin, compounds which are 100 to 1 000 fold more toxic than the classical chemotherapeutic drugs. Today, we know that the efficacy of an immunoconjugate depends not only on the coupled cytotoxic agent, but also on the selected target, the coupling method and the linker. Topics: Aminobenzoates; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Gemtuzumab; Humans; Immunoconjugates; Immunotoxins; Maytansine; Neoplasms; Oligopeptides; Structure-Activity Relationship | 2009 |
Targeted cancer therapy: conferring specificity to cytotoxic drugs.
The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody-drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody-drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody-maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumo Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Survival; Drug Design; Humans; Immunotoxins; Maytansine; Molecular Structure; Neoplasms; Xenograft Model Antitumor Assays | 2008 |
[Targeting of antitumor drugs with monoclonal antibodies].
About forty years ago, immuno-targeting of antitumor drugs has been addressed as a way to improve their selectivity towards tumor cells. Despite the wide display of researches to solve inherent problems within this approach, rare were the immuno-conjugates which reached the clinical level. In any case, none of them was introduced in chemotherapy. However, there was a renewal of activity for the last ten years, due, in part, to the access to very highly cytotoxic-containing immuno-conjugates such as those elaborated from maytansinoides, enediynes or intercalating agents CC1065. It was also due to the design of the Adept concept. This antibody-directed enzyme prodrug therapy is based upon the use of monoclonal antibody to target an enzyme at the tumor cell surface which ultimately is expected to selectively deliver an antitumor drug from a suitable inactive prodrug. In both cases, clinical trials are in progress and one can expect that, at least, some immuno-conjugates will be soon introduced in cancer chemotherapy. Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Humans; Immunotoxins; Maytansine; Neoplasms; Nucleic Acid Synthesis Inhibitors; Prodrugs; Recombinant Proteins | 2000 |
Maytansine.
Topics: Animals; Chemical Phenomena; Chemistry; Digestive System; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Leukemia, Experimental; Leukemia, Lymphoid; Lymphoma; Maytansine; Mice; Mitosis; Neoplasms; Nervous System; Oxazines; Pregnancy; Teratogens | 1978 |
Pharmacology of antitumor agents from higher plants.
Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity. Topics: Animals; Antineoplastic Agents, Phytogenic; Aporphines; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Etoposide; Humans; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Maytansine; Melanoma; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Structure-Activity Relationship; Teniposide; Vinblastine; Vincristine | 1976 |
13 trial(s) available for maytansine and Neoplasms
Article | Year |
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Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial.
Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors.. Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D).. Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies.. CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types. Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Immunoconjugates; Maytansine; Neoplasms; Tumor Microenvironment | 2022 |
Covariate analysis of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate, based on first-in-human study.
Tusamitamab ravtansine is an anti-CEACAM5 antibody-drug conjugate indicated in patients with solid tumors. Based on a previous developed semimechanistic model describing simultaneously pharmacokinetic (PK) of SAR408701, two of its active metabolites: DM4 and methyl-DM4 and naked antibody, with integration of drug-to-antibody data, the main objective of the present analysis was to evaluate covariate's impact in patients from phase I/II study (n = 254). Demographic and pathophysiologic baseline covariates were explored to explain interindividual variability on each entity PK parameter. Model parameters were estimated with good precision. Five covariates were included in the final PK model: body surface area (BSA), tumor burden, albumin, circulating target, and gender. Comparison of BSA-adjusted dosing and flat dosing supported the current BSA-based dosing regimen, to limit under and over exposure in patients with extreme BSA. Overall, this model characterized accurately the PKs of all entities and highlighted sources of PK variability. By integrating mechanistic considerations, this model aimed to improve understanding of the SAR408701 complex disposition while supporting key steps of clinical development. Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunoconjugates; Maytansine; Neoplasms | 2022 |
A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody-drug conjugate, in patients with advanced or metastatic cancer.
Background We report a Phase 1 study of LY3076226, an antibody-drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2-5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2-7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov. Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Immunoconjugates; Male; Maximum Tolerated Dose; Maytansine; Metabolic Clearance Rate; Middle Aged; Neoplasms; Receptor, Fibroblast Growth Factor, Type 3; Urologic Neoplasms | 2021 |
First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors.
This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.. This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.. Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.. Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies. Topics: Adult; Aged; Antineoplastic Agents, Immunological; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Male; Maximum Tolerated Dose; Maytansine; Mesothelin; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Progression-Free Survival | 2020 |
Highlights of the NCCN Oncology Research Program.
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Child; Deoxycytidine; Female; Folate Receptor 1; Gemcitabine; Humans; Immunoconjugates; Male; Maytansine; Neoplasm Recurrence, Local; Neoplasms; Progression-Free Survival; Young Adult | 2019 |
Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.
Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors.. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity.. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response.. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Ovarian Epithelial; Carcinoma, Renal Cell; Diarrhea; Disease Progression; Dose-Response Relationship, Drug; Endometrial Neoplasms; Fatigue; Female; Humans; Hypophosphatemia; Immunoconjugates; Keratitis; Kidney Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Neoplasms; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Vision Disorders | 2017 |
Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.
Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ≥60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers. Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; CD56 Antigen; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Neoplasms; Treatment Outcome; Young Adult | 2016 |
Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study.
Cantuzumab mertansine (SB-408075; huC242-DM1) is a conjugate of the maytansinoid drug DM1 to the antibody huC242, which targets CanAg antigen. In previous studies, cantuzumab mertansine was considered safe and tolerable, but transaminitis precluded tolerance of higher doses. Based on those studies, it was suggested that treatment at intervals of the half-life of the intact immunoconjugate may allow a higher dose density. This provided the rationale for the three-times weekly treatment explored in this protocol.. Patients with advanced solid tumors and documented CanAg expression were treated with escalating doses of cantuzumab mertansine IV administered three-times a week in a 3 out of 4 weeks schedule. Plasma samples were assayed to determine pharmacokinetic parameters.. Twenty patients (pts) with colon (11/20), rectal carcinomas (2/20), or other malignancies (7/20) were treated with doses ranging from 30 to 60 mg/m2 per day of cantuzumab mertansine IV three-times a week. The maximum tolerated dose (MTD) was 45 mg/m2, and the dose-limiting toxicity was grade 3 transaminitis. Hepatic, hematologic, and neurosensory effects occurred, but were rarely severe with repetitive treatment at doses of 45 mg/m2.. Treatment with cantuzumab mertansine at 45 mg/m2 per day three-times weekly x 3-every-4-week schedule proved that a dose-intense treatment with an immunoconjugate can be safely administered. The pharmacokinetic profile of the intact immunoconjugate indicates that the linker is cleaved with a half-life of about 2 days, resulting in faster clearance of the maytansinoid relative to the antibody. Therefore, with the development of second-generation immunoconjugates, there is a need for improvement of the immunoconjugate linker to take full advantage of the slow clearance of full-length antibody molecules. Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Enzyme-Linked Immunosorbent Assay; Female; Half-Life; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Neoplasms | 2008 |
A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors.
The purpose is to determine the maximum-tolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption.. Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m(2). The maximum-tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated.. Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m(2)/week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life ( approximately 40 h).. This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents. Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunohistochemistry; Liver; Male; Maximum Tolerated Dose; Maytansine; Microtubules; Middle Aged; Neoplasms; Prodrugs; Time Factors; Transaminases | 2004 |
Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.
To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.. Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.. Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.. The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors. Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Immunoconjugates; Infusions, Intravenous; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Mucin-1; Neoplasms | 2003 |
Phase I study of maytansine using a 3-day schedule.
Maytansine, a new ansa macrolide antitumor antibiotic, was administered to 60 patients as part of a phase I study. The doses given ranged from 0.01 (starting level) to 0.9 mg/m2 for 3 days. The toxic effects encountered consisted principally of nausea, vomiting, diarrhea, and occasionally, stomatitis and alopecia. Superficial phlebitis was also encountered and occurred when the drug was diluted in a volume of less than 250 ml. Myelosuppression occurred infrequently; it was almost regularly associated with abnormal liver function tests. Antitumor activity was detected in one patient each with melanoma, breast carcinoma; and head and neck clear cell carcinoma. Further studies are indicated with this compound since it has shown evidence of activity with little or no myelosuppression. Topics: Blood Cell Count; Bone Marrow Diseases; Clinical Trials as Topic; Drug Evaluation; Humans; Liver Function Tests; Maytansine; Neoplasms; Oxazines | 1978 |
Initial clinical trials of maytansine, an antitumor plant alkaloid.
We have conducted a phase I clinical trial of maytansine, a plant alkaloid with potent tubulin-binding activity. For evaluation of toxicity, the schedule of drug administration consisted of a single iv infusion given every 3 weeks. Dose-limiting toxicity was observed at 2 mg/m2, and was manifested as profound weakness, diarrhea, nausea, and vomiting. Symptoms persisted for 3--14 days after drug administration. No consistent myelosuppression occurred at any dose level. Responses were observed in two patients (one each with non-Hodgkin's lymphoma and ovarian cancer) who were treated on the every-3-week schedule, as well as in two patients with acute lymphocytic leukemia treated with single weekly doses. Three of the four responding patients had received extensive prior treatment with vincristine, and two were clearly resistant to vincristine. Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Humans; Maytansine; Middle Aged; Neoplasms; Oxazines | 1978 |
Maytansine: a phase I study of an ansa macrolide with antitumor activity.
Maytansine has significant antitumor activity in animal model systems. The initial clinical trial of maytansine was carried out in 38 adult solid tumor patients. Five daily bolus injections were repeated at 21-day intervals. A total of 78 courses were administered over a dose range of 0.1--0.8 mg/m2/day X 5 days. Gastrointestinal toxicity was dose-related and dose-limiting at doses of greater than or equal to 0.5 mg/m2. Dose-related neurotoxicity was also observed. No drug-related myelosuppression or change in serum creatinine level was seen. Hepatic toxicity was subclinical and reversible. Of 16 patients evaluable for response, two with breast cancer had therapeutic benefit. Phase II studies of maytansine are recommended at a starting dose of 2.0--2.5 mg/m2/course repeated at 21-day intervals. Topics: Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Maytansine; Middle Aged; Neoplasms; Oxazines | 1978 |
37 other study(ies) available for maytansine and Neoplasms
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Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates.
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anticancer antibody-drug conjugates (ADC). In this work, we present an "inverse targeting" strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50 values between 10 and 60 nmol/L. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 value of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4-induced weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9% ± 3% and 3.8% ± 1.3% (P < 0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (P = 0.49) or at 10 mg/kg (P = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity before the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anticancer ADC therapy. Topics: Animals; Cell Line, Tumor; Immunoconjugates; Maytansine; Mice; Neoplasms; Therapeutic Index; Weight Loss | 2023 |
Maytansinol Derivatives: Side Reactions as a Chance for New Tubulin Binders.
Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders. Topics: Humans; Maytansine; Microtubules; Neoplasms; Tubulin; Tubulin Modulators | 2022 |
Mirvetuximab soravtansine (Elahere) for ovarian, fallopian tube, and primary peritoneal cancer.
Topics: Antibodies, Monoclonal, Humanized; Fallopian Tubes; Female; Humans; Maytansine; Neoplasms; Ovarian Neoplasms | 2022 |
Tubulin Maytansine Site Binding Ligands and their Applications as MTAs and ADCs for Cancer Therapy.
Microtubule Targeting Agents (MTAs) represent the most successful anticancer drugs for cancer chemotherapy. Through interfering with the tubulin polymerization and depolymerization dynamics, MTAs influence intracellular transport and cell signal pathways, inhibit cell mitosis and cell proliferation, and induce cell apoptosis and death. The tubulin maytansine site binding agents are natural or nature-derived products that represent one type of the MTAs that inhibit tubulin polymerization and exhibit potent antitumor activity both in vitro and in vivo. They are used as Antibody-Drug Conjugates (ADCs) in cancer chemotherapy.. Using SciFinder® as a tool, the publications about maytansine, its derivatives, maytansine binding site, maytansine site binding agents and their applications as MTAs for cancer therapy were surveyed with an exclusion on those published as patents. The latest progresses in clinical trials were obtained from the clinical trial web.. This article presents an introduction about MTAs, maytansine, maytansine binding site and its ligands, the applications of these ligands as MTAs and ADCs in cancer therapy.. The maytansine site binding agents are powerful MTAs for cancer chemotherapy. The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy. Topics: Antineoplastic Agents; Humans; Immunoconjugates; Ligands; Maytansine; Microtubules; Neoplasms; Trastuzumab; Tubulin | 2020 |
Endoplasmic reticulum-targeted glutathione and pH dual responsive vitamin lipid nanovesicles for tocopheryl DM1 delivery and cancer therapy.
The major drawbacks of the cytotoxin like DM1 are the off-target effects. Here, the targeting nanovesicles were developed by synthesizing tocopherol-SS-DM1 and conjugating a pH low insertion peptide (pHLIP) to PEGylated phospholipids, in which tocopherol-SS-DM1 improves the drug loading and is glutathione responsive in the cytoplasm, meanwhile, the pH insertion peptide targets the acidic microenvironment of cancer cells. Besides, these nanovesicles can accumulate at the endoplasmic reticulum and show increased cancer therapeutic effects both in vitro and in vivo. These targeting nanovesicles provide a novel formulation for subcellular organelle targeting, a platform for precisely delivery of cytotoxic DM1 to cancer cells, and an alternative strategy for antibody-drug conjugates (ADCs). Topics: A549 Cells; Animals; Antineoplastic Agents, Phytogenic; Drug Carriers; Drug Compounding; Drug Liberation; Endoplasmic Reticulum; Glutathione; Humans; Hydrogen-Ion Concentration; Lipids; Maytansine; MCF-7 Cells; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Prodrugs; Tocopherols; Tumor Microenvironment; Xenograft Model Antitumor Assays | 2020 |
Favorable therapeutic response after anti-Mesothelin antibody-drug conjugate treatment requires high expression of Mesothelin in tumor cells.
The cell surface glycoprotein Mesothelin is overexpressed in ovarian, fallopian tube, endometrial, cervical and primary peritoneal cancer and, therefore, might become a particular interesting tumor target in gynecologic oncology. However, even in malignant tumors of the same entity the level of Mesothelin expression varies between individuals, hence it can be expected that the response to Mesothelin-targeting therapies will be variable as well. In this study we explored the therapeutic potency of a novel anti-Mesothelin antibody-drug conjugate (Anetumab ravtansine) as a function of Mesothelin expression in the targeted tumor cells.. Anti-tumor activity studies were performed in human uterine xenograft tumor models that express Mesothelin at high, moderate or low levels. The antibody-drug conjugate (ADC) was applied in varying doses ranging from 2 to 15 mg/kg at variable intervals in tumor bearing SCID/beige mice and the impact on tumor growth was monitored.. The therapeutic response to the anti-Mesothelin ADC correlated closely with the level of Mesothelin expression in tumor cells. Within the applied dose levels complete tumor regression was achieved only in tumors which expressed Mesothelin at particularly high levels (Hela cell tumors). The application of high anti-Mesothelin ADC doses less frequently was more efficious than giving lower doses at a higher frequency.. The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology. Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Line, Tumor; Female; GPI-Linked Proteins; HeLa Cells; Humans; Immunoconjugates; Maytansine; Mesothelin; Mice; Mice, SCID; Neoplasms | 2020 |
Antibody drug conjugates of cleavable amino-benzoyl-maytansinoids.
ADCs based on the natural product maytansine have been successfully employed clinically. In a previous report, ADCs based on hydrophilic non-cell permeable maytansinoids was presented. The authors in this report further explore the maytansine scaffold to develop tubulin inhibitors capable of cell permeation. The research resulted in amino-benzoyl-maytansinoid payloads that were further elaborated with linkers for conjugating to antibodies. This approach was applied to MUC16 tumor targeting antibodies for ovarian cancers. A positive control ADC was evaluated alongside the amino-benzoyl-maytansinoid ADC and the efficacy observed was equivalent while the isotype control ADCs had no effect. Topics: Animals; Cell Line; Cell Line, Tumor; Cell Survival; Female; Humans; Immunoconjugates; Maytansine; Mice, SCID; Neoplasms; Structure-Activity Relationship; Transplantation, Heterologous; Tubulin Modulators | 2020 |
Macrophage entrapped silica coated superparamagnetic iron oxide particles for controlled drug release in a 3D cancer model.
Targeted delivery of drugs is a major challenge in treatment of diverse diseases. Systemically administered drugs demand high doses and are accompanied by poor selectivity and side effects on non-target cells. Here, we introduce a new principle for targeted drug delivery. It is based on macrophages as transporters for nanoparticle-coupled drugs as well as controlled release of drugs by hyperthermia mediated disruption of the cargo cells and simultaneous deliberation of nanoparticle-linked drugs. Hyperthermia is induced by an alternating electromagnetic field (AMF) that induces heat from silica-coated superparamagnetic iron oxide nanoparticles (SPIONs). We show proof-of-principle of controlled release by the simultaneous disruption of the cargo cells and the controlled, AMF induced release of a toxin, which was covalently linked to silica-coated SPIONs via a thermo-sensitive linker. Cells that had not been loaded with SPIONs remain unaffected. Moreover, in a 3D co-culture model we demonstrate specific killing of associated tumour cells when employing a ratio as low as 1:40 (SPION-loaded macrophage: tumour cells). Overall, our results demonstrate that AMF induced drug release from macrophage-entrapped nanoparticles is tightly controlled and may be an attractive novel strategy for targeted drug release. Topics: Animals; Cell Line; Coculture Techniques; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Ferric Compounds; Humans; Hyperthermia, Induced; Macrophages; Magnetic Phenomena; Maytansine; Mice; Models, Biological; Nanoparticles; Neoplasms; Silicon Dioxide | 2019 |
Bioinspired lipoproteins-mediated photothermia remodels tumor stroma to improve cancer cell accessibility of second nanoparticles.
The tumor stromal microenvironments (TSM) including stromal cells and extracellular matrix (ECM) form an abominable barrier hampering nanoparticles accessibility to cancer cells, significantly compromising their antitumor effects. Herein, we report a bioinspired lipoprotein (bLP) that can induce efficient photothermia to remodel TSM and improve second bLP accessibility to cancer cells for antitumor therapy. The multiple stromal cells and ECM components in TSM are remarkably disrupted by bLP-mediated photothermal effects, which cause a 4.27-fold enhancement of second bLP accumulation in tumor, deep penetration in whole tumor mass and 27.0-fold increase of accessibility to cancer cells. Of note, this bLP-mediated TSM-remodeling to enhance cancer cell accessibility (TECA) strategy produces an eminent suppression of tumor growth and results in a 97.4% inhibition of lung metastasis, which is superior to the counterpart liposomes. The bLP-mediated TECA strategy provides deeper insights into enhancing nanoparticle accessibility to cancer cells for antitumor therapy. Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Extracellular Matrix; Female; Humans; Infrared Rays; Lipoproteins; Maytansine; Mice; Mice, Nude; Nanoparticles; Neoplasms; Stromal Cells; Tumor Microenvironment | 2019 |
Cancer-derived exosomes from HER2-positive cancer cells carry trastuzumab-emtansine into cancer cells leading to growth inhibition and caspase activation.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1.. Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay.. T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7.. T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer. Topics: Ado-Trastuzumab Emtansine; Caspases; Cell Fractionation; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Enzyme Activation; Exosomes; Humans; Maytansine; MCF-7 Cells; Neoplasms; Protein Binding; Receptor, ErbB-2; Trastuzumab | 2018 |
Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Female; Humans; Maytansine; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Receptor, ErbB-2; Recombinant Fusion Proteins | 2018 |
cRGD-installed docetaxel-loaded mertansine prodrug micelles: redox-triggered ratiometric dual drug release and targeted synergistic treatment of B16F10 melanoma.
Topics: Cell Line, Tumor; Delayed-Action Preparations; Drug Synergism; Humans; Maytansine; Micelles; Neoplasms; Peptides, Cyclic; Prodrugs | 2017 |
Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo.
Conjugates based on nanostructured, superparamagnetic particles, a thermolabile linker and a cytotoxic maytansinoid were developed to serve as a model for tumour-selective drug delivery and release. It combines chemo- with thermal therapy. The linker-modified toxin was prepared by a combination of biotechnology and semisynthesis. Drug release was achieved by hyperthermia through an external oscillating electromagnetic field that induces heat inside the particles. Efficacy of this release concept was demonstrated both for cancer cell proliferation in vitro, and for tumour growth in vivo, in a xenograft mouse model. Biocompatibility studies for these magnetic-nanoparticle/ansamitocin conjugates complement this work. Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cycloaddition Reaction; Drug Carriers; Drug Liberation; Humans; Hyperthermia, Induced; Ki-67 Antigen; Magnetic Resonance Spectroscopy; Magnetite Nanoparticles; Maytansine; Mice; Mice, Nude; Neoplasms; Transplantation, Heterologous | 2017 |
Highly Potent, Anthracycline-based Antibody-Drug Conjugates Generated by Enzymatic, Site-specific Conjugation.
Antibody-drug conjugates (ADC) are highly potent and specific antitumor drugs, combining the specific targeting of mAbs with the potency of small-molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety, and efficacy profiles. To address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with predetermined drug-to-antibody ratios. Here, we used sortase-mediated antibody conjugation (SMAC) technology to generate homogeneous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a noncleavable peptide linker, using the anti-HER2 antibody trastuzumab (part of Kadcyla) and the anti-CD30 antibody cAC10 (part of Adcetris). Characterization of the resulting ADCs Topics: Ado-Trastuzumab Emtansine; Aminoacyltransferases; Animals; Anthracyclines; Antibodies, Monoclonal; Bacterial Proteins; Brentuximab Vedotin; Cell Line, Tumor; Cysteine Endopeptidases; Doxorubicin; Humans; Immunoconjugates; Ki-1 Antigen; Maytansine; Mice; Neoplasms; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays | 2017 |
Microscale screening of antibody libraries as maytansinoid antibody-drug conjugates.
Antibody-drug conjugates (ADCs) are of great interest as targeted cancer therapeutics. Preparation of ADCs for early stage screening is constrained by purification and biochemical analysis techniques that necessitate burdensome quantities of antibody. Here we describe a method, developed for the maytansinoid class of ADCs, enabling parallel conjugation of antibodies in 96-well format. The method utilizes ∼ 100 µg of antibody per well and requires <5 µg of ADC for characterization. We demonstrate the capabilities of this system using model antibodies. We also provide multiple examples applying this method to early-stage screening of maytansinoid ADCs. The method can greatly increase the throughput with which candidate ADCs can be screened in cell-based assays, and may be more generally applicable to high-throughput preparation and screening of different types of protein conjugates. Topics: Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Immunoconjugates; Maytansine; Neoplasms | 2016 |
Quantitative analysis of maytansinoid (DM1) in human serum by on-line solid phase extraction coupled with liquid chromatography tandem mass spectrometry - Method validation and its application to clinical samples.
A sensitive and specific method was developed and validated for the quantitation of maytansinoid (DM1) in human serum using on-line solid phase extraction (SPE)-liquid chromatography-tandem mass spectrometry (LC-MS/MS). Because DM1 contains a free thiol moiety, likely to readily dimerize or react with other thiol-containing molecules in serum, samples were pre-treated with a reducing agent [tris (2-carboxyethyl) phosphine] (TCEP) and further blocked with N-ethylmaleimide (NEM). The resulting samples were diluted with acetonitrile prior to the on-line solid phase extraction (SPE) on a C18 cartridge. A C18 (150×4.6mm ID 3μm particle size) column was used for chromatographic separation with a 10.0min HPLC gradient and DM1-NEM was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. DM1 concentrations were back-calculated from DM1-NEM amount found in the human serum samples. The quantitation range of the method was 0.200-200ng/mL when using 0.25mL serum. Within-run day precisions (n=6) were 0.9-4.4% and between-run day (3 days runs; n=18) precisions 2.5-5.6%. Method biases were between 3.5-14.5% across the whole calibration range. DM1-NEM exhibited sufficiently stability under all relevant analytical conditions and no DM1 losses from the ADC were observed. Finally, the assay was used for DM1 determination in human serum concentration after the intravenous administration of an investigational antibody drug conjugate (ADC) containing DM1 as payload. Topics: Chromatography, Liquid; Humans; Infusions, Intravenous; Maytansine; Neoplasms; Reproducibility of Results; Solid Phase Extraction; Tandem Mass Spectrometry | 2016 |
Third-generation antibody drug conjugates for cancer therapy--a balancing act.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Brentuximab Vedotin; Enzymes; Female; Half-Life; Humans; Immunoconjugates; Immunotherapy; Lymphoma, Large-Cell, Anaplastic; Maytansine; Neoplasms; Pharmaceutical Preparations; Trastuzumab | 2016 |
Analysis of small molecule antibody-drug conjugate catabolites in rat liver and tumor tissue by liquid extraction surface analysis micro-capillary liquid chromatography/tandem mass spectrometry.
Antibody-drug conjugates (ADCs) are some of the most promising antibody-related therapeutics. The fate of the cytotoxic moiety of ADCs in vivo after proteolytic degradation of the antibody needs to be well understood in order to mitigate toxicity risks and design proper first in patient studies.. The feasibility of liquid extraction surface analysis micro-capillary liquid chromatography/tandem mass spectrometry (LESA-μLC/MS/MS) was tested for direct surface sampling of two possible ADC catabolites composed of synthetically modified maytansinoid (DM1) and 4-[N-maleimidomethyl]cyclohexane-1-carbonyl (MCC) from rat liver and tumor tissue. Moreover, the iMatrixSpray was incorporated to prepare calibration standards (Cs) and quality control (QC) samples by spraying analyte solution at different concentrations directly on blank tissue.. Lys-MCC-DM1 sprayed on blank liver tissue was homogeneously distributed (12.3% variability). The assay was selective (inference ≤20%) and linear from 50.0 to 1000 ng/mL without any carry-over. Inter-run accuracy and precision were ≤2.3% and ≤25.9% meeting acceptance. Lys-MCC-DM1 was the only catabolite detected in liver and tumor tissue and was most likely responsible for the total radioactivity signal in liver tissue 72 h post-dose measured by quantitative whole body autoradiography (QWBA).. Both analytical assays (LESA-μLC/MS/MS and QWBA) are complementary to each other and provide useful quantitative and qualitative information in spatial tissue distribution of ADCs and their related catabolites. Copyright © 2016 John Wiley & Sons, Ltd. Topics: Animals; Antineoplastic Agents; Chromatography, Liquid; Immunoconjugates; Linear Models; Liquid-Liquid Extraction; Liver; Maleimides; Maytansine; Models, Biological; Molecular Imaging; Neoplasms; Rats; Reproducibility of Results; Tandem Mass Spectrometry | 2016 |
Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).
A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell. Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Humans; Immunoconjugates; Maytansine; Models, Biological; Neoplasms; Receptor, ErbB-2; Trastuzumab | 2016 |
Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.
Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Bystander Effect; Camptothecin; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Female; Humans; Immunoconjugates; Maytansine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Receptor, ErbB-2; Stomach Neoplasms; Topoisomerase I Inhibitors; Trastuzumab | 2016 |
A New Triglycyl Peptide Linker for Antibody-Drug Conjugates (ADCs) with Improved Targeted Killing of Cancer Cells.
A triglycyl peptide linker (CX) was designed for use in antibody -: drug conjugates (ADC), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-EGFR antibodies with maytansinoid payloads were prepared using CX or a noncleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were similar for several cancer cell lines; however, the CX ADC was more active (5-100-fold lower IC50) than the SMCC ADC in other cell lines, including a multidrug-resistant line. Both CX and SMCC ADCs showed comparable MTDs and pharmacokinetics in CD-1 mice. In Calu-3 tumor xenografts, antitumor efficacy was observed with the anti-EpCAM CX ADC at a 5-fold lower dose than the corresponding SMCC ADC in vivo Similarly, the anti-EGFR CX ADC showed improved antitumor activity over the respective SMCC conjugate in HSC-2 and H1975 tumor models; however, both exhibited similar activity against FaDu xenografts. Mechanistically, in contrast with the charged lysine-linked catabolite of SMCC ADC, a significant fraction of the carboxylic acid catabolite of CX ADC could be uncharged in the acidic lysosomes, and thus diffuse out readily into the cytosol. Upon release from tumor cells, CX catabolites are charged at extracellular pH and do not penetrate and kill neighboring cells, similar to the SMCC catabolite. Overall, these data suggest that CX represents a promising linker option for the development of ADCs with improved therapeutic properties. Mol Cancer Ther; 15(6); 1311-20. ©2016 AACR. Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Epithelial Cell Adhesion Molecule; ErbB Receptors; Humans; Immunoconjugates; Maximum Tolerated Dose; Maytansine; Mice; Mice, SCID; Neoplasms; Peptides; Xenograft Model Antitumor Assays | 2016 |
Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.
Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery. Topics: Ado-Trastuzumab Emtansine; Aminobenzoates; Animals; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Maytansine; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Oligopeptides; Radiation-Sensitizing Agents; Radiation, Ionizing; Signal Transduction; Trastuzumab; Tubulin Modulators | 2016 |
IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.
A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody-drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models. The level of expression of FRα on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors. Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bystander Effect; Cell Line, Tumor; Cytotoxicity, Immunologic; Female; Folate Receptor 1; Humans; Immunoconjugates; Maytansine; Mice, Nude; Mice, SCID; Molecular Targeted Therapy; Neoplasms; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays | 2015 |
What Can We Learn about Antibody-Drug Conjugates from the T-DM1 Experience?
Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation. Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates, and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40 antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for patients with cancer. Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Immunoconjugates; Maytansine; Neoplasms; Receptor, ErbB-2; Trastuzumab | 2015 |
Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing.
Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each of the AaMCs, except the AaMC bearing a d-Ala-d-Ala peptide linker, displayed more bystander killing in vitro than maytansinoid ADCs that utilize disulfide linkers. In mouse models, the anti-CanAg AaMC bearing a d-Ala-l-Ala dipeptide in the linker was shown to be more efficacious against heterogeneous HT-29 xenografts than maytansinoid ADCs that utilize disulfide linkers, while both types of the conjugates displayed similar tolerabilities. Topics: Aniline Compounds; Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Cell Survival; Humans; Immunoconjugates; Maytansine; Mice; Neoplasms | 2015 |
HER2 aberrations in cancer: implications for therapy.
Although anti-HER2 (human epidermal growth factor receptor 2) therapy is currently approved for breast, gastric, and gastroesophageal cancers overexpressing the HER2 protein or amplified for the HER2 gene, HER2 aberrations (gene amplification, gene mutations, and protein overexpression) are reported in other diverse malignancies. Indeed, about 1-37% of tumors of the following types harbor HER2 aberrations: bladder, cervix, colon, endometrium, germ cell, glioblastoma, head and neck, liver, lung, ovarian, pancreas, and salivary duct. Four HER2-targeted therapies have been approved for HER2-positive breast cancer: two antibodies (trastuzumab and pertuzumab), an antibody-drug conjugate (ado-trastuzumab emtansine), and a small molecule kinase inhibitor (lapatinib). In addition, afatinib, a small molecule kinase inhibitor that causes irreversible inhibition of EGFR (epidermal growth factor receptor) and HER2, was recently approved for EGFR-mutated non-small cell lung cancer. A large number of novel HER2-targeted agents are also in clinical trials. Herein we discuss the state of the art in understanding and targeting HER2 across anatomic tumor types. Topics: Ado-Trastuzumab Emtansine; Adult; Afatinib; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Male; Maytansine; Molecular Targeted Therapy; Mutation; Neoplasms; Peritoneal Neoplasms; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab; Up-Regulation; Uterine Cervical Neoplasms | 2014 |
Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect.
Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC(50) of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors. Topics: Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Bystander Effect; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins; Humans; Immunoconjugates; Maytansine; Mesothelin; Molecular Targeted Therapy; Neoplasms; Xenograft Model Antitumor Assays | 2014 |
Mechanistic pharmacokinetic/pharmacodynamic modeling of in vivo tumor uptake, catabolism, and tumor response of trastuzumab maytansinoid conjugates.
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) comprised of trastuzumab linked to the antimitotic agent DM1, has shown promising results in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Investigations of the mechanisms of the action of ADCs, including T-DM1, have been primarily descriptive or semiquantitative. However, quantitative pharmacokinetic/pharmacodynamic (PK/PD) analysis may provide insights into their complex behavior. The analyses described herein applied PK/PD modeling to nonclinical studies of maytansinoid conjugates.. The maytansinoid conjugates T-DM1 and T-SPP-DM1, with thioether and disulfide linkers, respectively, were tested in mouse efficacy, PK, and tumor uptake studies. (3)[H]DM1-bearing ADCs were used to facilitate the quantitation of the ADCs in plasma, as well as ADC and ADC catabolites in tumors. Three mechanistic PK/PD models were used to characterize plasma ADC, tumor ADC, and tumor catabolite concentrations. Tumor catabolite concentrations were used to fit tumor response. Model parameters were estimated using R software and nonlinear least squares regression.. Plasma ADC-associated DM1 concentrations of T-DM1 decreased more slowly than those of T-SPP-DM1, likely due to slower DM1 release. A comparison of the mechanistic models found that the best model allowed catabolism and catabolite exit rates to differ between ADCs, that T-DM1 exhibited both faster tumor catabolism and catabolite exit rate from tumors than T-SPP-DM1; findings inconsistent with expected behavior based on the physicochemical nature of the respective catabolites. Tumor catabolite concentrations adequately described tumor response with both ADCs showing similar potency.. Mechanistic PK/PD studies described herein provided results that confirmed and challenged current hypotheses, and suggested new areas of investigation. Topics: Ado-Trastuzumab Emtansine; Algorithms; Animals; Antibodies, Monoclonal, Humanized; Area Under Curve; Cell Line, Tumor; Female; Humans; Maytansine; Mice, Nude; Models, Biological; Neoplasms; Trastuzumab; Treatment Outcome; Tritium | 2014 |
The interplay between mutasynthesis and semisynthesis: generation and evaluation of an ansamitocin library.
Topics: Actinomycetales; Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Humans; Lactams, Macrocyclic; Maytansine; Mutation; Neoplasms; Streptomyces; Tubulin Modulators | 2012 |
Can cancer clinical trials be fixed?
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Biotechnology; Breast Neoplasms; Clinical Trials as Topic; Drug Approval; Drug Industry; Female; Humans; Maytansine; Neoplasms; Patient Advocacy; Survival Rate; Time Factors; Trastuzumab; Treatment Outcome; United States; United States Food and Drug Administration | 2011 |
Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells.
Combination therapy, in which two or more agents are applied, is more effective than single therapies for combating cancer. For this reason, combinations of chemotherapy with radiation are being explored in clinical trials, albeit with an empirical approach. We developed a screen to identify, from the onset, molecules that act in vivo in conjunction with radiation, using Drosophila as a model. Screens through two small molecule libraries from the NCI Developmental Therapeutics Program yielded microtubule poisons; this class of agents is known to enhance the effect of radiation in mammalian cancer models. Here we report an analysis of one microtubule depolymerizing agent, maytansinol isobutyrate (NSC292222; maytansinol), in Drosophila and in human cancer cells. We find that the effect of maytansinol is p53 dependent in Drosophila cells and human cancer cells, that maytansinol enhances the effect of radiation in both systems, and that the combinatorial effect of drug and radiation is additive. We also uncover a differential sensitivity to maytansinol between Drosophila cells and Drosophila larvae, which illustrates the value of studying cell behavior in the context of a whole organism. On the basis of these results, we propose that Drosophila might be a useful model for unbiased screens through new molecule libraries to find cancer drugs for combination therapy. Topics: Animals; Cell Death; Combined Modality Therapy; Drosophila melanogaster; HCT116 Cells; Humans; Larva; Maytansine; Mitosis; Mutation; Neoplasms; Radiation, Ionizing; Spindle Apparatus; Survival Analysis; Tumor Suppressor Protein p53 | 2011 |
Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates.
Antibody-drug conjugates (ADCs) are designed to eradicate cancer cells that express the target antigen on their cell surface. A key component of an ADC is the linker that covalently connects the cytotoxic agent to the antibody. Several antibody-maytansinoid conjugates prepared with disulfide-based linkers such as those targeting the CanAg antigen have been shown to display more activity in preclinical mouse xenograft models than corresponding conjugates prepared with uncleavable thioether-based linkers. To investigate how the linker influences delivery and activation of antibody-maytansinoid conjugates, we isolated and characterized the [(3)H]maytansinoids from CanAg-positive tumor tissues following a single intravenous administration of 300 microg/kg (based on maytansinoid dose) of anti-CanAg antibody (huC242)-(3)H-maytansinoid conjugates prepared with cleavable disulfide linkers and an uncleavable thioether linker. We identified three target-dependent tumor metabolites of the disulfide-linked huC242-SPDB-DM4, namely, lysine-N(epsilon)-SPDB-DM4, DM4, and S-methyl-DM4. We found similar metabolites for the less hindered disulfide-linked huC242-SPP-DM1 conjugate with the exception that no S-methyl-DM1 was detected. The sole metabolite of the uncleavable thioether-linked huC242-SMCC-DM1 was lysine-N(epsilon)-SMCC-DM1. The AUC for the metabolites of huC242-SMCC-DM1 at the tumor over 7 d was about 2-fold greater than the corresponding AUC for the metabolites of the disulfide-linked conjugates. The lipophilic metabolites of the disulfide-linked conjugates were found to be nearly 1000 times more cytotoxic than the more hydrophilic lysine-N(epsilon)-linker-maytansinoids in cell-based viability assays when added extracellularly. The cell killing properties associated with the lipophilic metabolites of the disulfide-linked conjugates (DM4 and S-methyl-DM4, and DM1) provide an explanation for the superior in vivo efficacy that is often observed with antibody-maytansinoid conjugates prepared with disulfide-based linkers in xenograft mouse models. Topics: Animals; Antibodies; Cell Line, Tumor; Cell Proliferation; Disulfides; Humans; Immunoconjugates; Maytansine; Mice; Mice, SCID; Neoplasms; Sulfides; Xenograft Model Antitumor Assays | 2010 |
Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice.
Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis. Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunotoxins; Maytansine; Mice; Mice, Nude; Models, Biological; Neoplasms; Time Factors; Trastuzumab; Xenograft Model Antitumor Assays | 2010 |
Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts.
Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-alpha, a cell surface protease of activated tumor fibroblasts.. A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-alpha, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers.. Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures.. We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm. Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Biomarkers, Tumor; Endopeptidases; Fibroblasts; Gelatinases; Humans; Immunoconjugates; Immunohistochemistry; Immunotherapy; Macaca fascicularis; Maytansine; Membrane Proteins; Mice; Neoplasms; Serine Endopeptidases; Surface Plasmon Resonance | 2008 |
Phase II evaluation of maytansine (NSC 153858) in advanced cancer. A Southeastern Cancer Study Group trial.
Maytansine given in a 3-day course q3 weeks produced only five responses (3%) in 163 evaluable adults with advanced cancer. The dose schedule employed is not recommended for further study. Topics: Adult; Aged; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Maytansine; Middle Aged; Neoplasms; Oxazines | 1985 |
Early clinical study of an intermittent schedule for maytansine (NSC-153858): brief communication.
Maytansine, an ansa macrolide, was evaluated in an early clinical trial in 40 adult patients with various solid tumors. Severe nausea and vomiting, sometimes associated with watery diarrhea and abdominal cramps, and liver function abnormalities, mainly elevation of serum glutamic--oxaloacetic transaminase levels, together constituted what we considered dose-limiting toxicity. Mild hematologic toxicity (mainly thrombocytopenia), neurotoxicity, and possibly cardiac toxicity were also noted. No antitumor effect was seen. An iv dose of 0.750 mg/m2 on days 1, 3, and 5 (total dose, 2.25 mg/m2) repeated every 4 weeks is recommended for Phase II trials. Topics: Adult; Aged; Atrial Fibrillation; Child, Preschool; Diarrhea; Drug Administration Schedule; Drug Evaluation; Female; Humans; Liver; Male; Maytansine; Middle Aged; Nausea; Neoplasms; Nervous System; Oxazines; Thrombocytopenia; Vomiting | 1978 |
A therapeutic trial of maytansine.
A phase II clinical trial of maytansine, a stathmokinetic ansa macrolide, was undertaken in 70 patients. The maximally tolerated dose was 2.0 mg/m2 repeated at 21-day intervals. Gastrointestinal and central neurologic toxicity were dose limiting. No myelosuppression was noted. Two patients demonstrated transient responses. Therapeutic results from four other clinical trials were reviewed. Although additional clinical trials may be warranted in patients with bladder and small cell carcinoma, at the dose schedule reported, maytansine does not appear to possess a broad spectrum of antitumor activity. Additional clinical trials should be limited. Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Digestive System; Drug Evaluation; Female; Humans; Liver; Male; Maytansine; Middle Aged; Neoplasms; Nervous System; Oxazines; Remission, Spontaneous | 1978 |