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Cancer Treatment Reviews Dec 1978
Review
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
PubMed: 367597
DOI: 10.1016/s0305-7372(78)80014-0 -
Advanced Materials (Deerfield Beach,... Nov 2022DNA materials have emerged as potential nanocarriers for targeted cancer therapy to precisely deliver cargos with specific purposes. The short half-life and low...
DNA materials have emerged as potential nanocarriers for targeted cancer therapy to precisely deliver cargos with specific purposes. The short half-life and low bioavailability of DNA materials due to their interception by the reticuloendothelial system and blood clearance further limit their clinical translation. This study employs an HER2-targeted DNA-aptamer-modified DNA tetrahedron (HApt-tFNA) as a drug delivery system, and combines maytansine (DM1) to develop the HApt-DNA tetrahedron/DM1 conjugate (HApt-tFNA@DM1, HTD, HApDC) for targeted therapy of HER2-positive cancer. To optimize the pharmacokinetics and tumor-aggregation of HTD, a biomimetic camouflage is applied to embed HTD. The biomimetic camouflage is constructed by merging the erythrocyte membrane with pH-responsive functionalized synthetic liposomes, thus with excellent performance of drug delivery and tumor-stimulated drug release. The hybrid erythrosome-based nanoparticles show better inhibition of HER2-positive cancer than other drug formulations and exhibit superior biosafety. With the strengths of precise delivery, increased drug loading, sensitive tumor probing, and prolonged circulation time, the HApDC represents a promising nanomedicine to treat HER2-positive tumors. Notably, this study developsa dual-targeting nanoparticle by combining pH-sensitive camouflage and HApDC, initiating an important step toward the development and application of DNA-based medicine and biomimetic cell membrane materials in cancer treatment and other potential biological applications.
Topics: Humans; Female; Maytansine; Breast Neoplasms; Biomimetics; Cell Line, Tumor; DNA; Hydrogen-Ion Concentration; Receptor, ErbB-2
PubMed: 35064993
DOI: 10.1002/adma.202109609 -
Biomedicine & Pharmacotherapy =... Sep 2023Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological... (Review)
Review
Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents.
Topics: Maytansine; Microtubules; Antineoplastic Agents; Tubulin
PubMed: 37364476
DOI: 10.1016/j.biopha.2023.115039 -
The New England Journal of Medicine Feb 2019Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
METHODS
We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).
RESULTS
At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.
CONCLUSIONS
Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).
Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Maytansine; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Neoplasm, Residual; Peripheral Nervous System Diseases; Radiotherapy; Receptor, ErbB-2; Trastuzumab; Treatment Outcome; Young Adult
PubMed: 30516102
DOI: 10.1056/NEJMoa1814017 -
Lancet (London, England) Jun 2017Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the... (Review)
Review
Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Event-free survival after the confirmatory adjuvant trial completed recruitment was numerically better with pertuzumab plus trastuzumab than with trastuzumab alone. With survival rates of almost 5 years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a pathological complete response, new treatments in the past decade have clearly improved the prognosis of HER2-positive breast cancer. Despite these achievements, however, the persisting high toll of deaths resulting from HER2-positive breast cancer calls for continued, intensive clinical research of newer therapies and combinations.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; ErbB Receptors; Female; Humans; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab
PubMed: 27939064
DOI: 10.1016/S0140-6736(16)32417-5 -
Nature Reviews. Drug Discovery May 2017Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin... (Review)
Review
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
PubMed: 28303026
DOI: 10.1038/nrd.2016.268 -
International Journal of Molecular... Mar 2019Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed... (Review)
Review
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Maytansine; Protein Kinase Inhibitors; Receptor, ErbB-2; Trastuzumab
PubMed: 30841523
DOI: 10.3390/ijms20051115 -
Annals of Oncology : Official Journal... Jun 2021Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC).
PATIENTS AND METHODS
Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population.
RESULTS
A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy.
CONCLUSIONS
In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Drug Resistance, Neoplasm; Female; Humans; Immunoconjugates; Maytansine; Ovarian Neoplasms
PubMed: 33667670
DOI: 10.1016/j.annonc.2021.02.017 -
MAbs 2014Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective... (Review)
Review
Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors--target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0-8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antibody Specificity; Brentuximab Vedotin; Drug Delivery Systems; Humans; Immunoconjugates; Maytansine; Neoplasms; Trastuzumab; United States; United States Food and Drug Administration
PubMed: 24423619
DOI: 10.4161/mabs.27022 -
Cancer Cell Jan 2016Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an...
Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.
Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Immunotoxins; Maytansine; Mice; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 26766593
DOI: 10.1016/j.ccell.2015.12.008