Summary: An ansa macrolide isolated from the MAYTENUS genus of East African shrubs.
- Liu Z, Floss H, Cassady J, Chan K. Metabolism studies of the anti-tumor agent maytansine and its analog ansamitocin P-3 using liquid chromatography/tandem mass spectrometry. J Mass Spectrom. 2005;40:389-99 pubmedb>Maytansine, a potent clinically evaluated plant-derived anti-tumor drug, and its microbial counterpart, ansamitocin P-3, showed a substantially higher cytoxicity than many other anti-tumor drugs...
- Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res. 2011;13:R46 pubmed publisher..T-DM1 was found effective even on breast cancer cell lines with moderate HER2 expression levels and cross-resistance to trastuzumab and lapatinib (MDA-453 and JIMT-1). ..
- Mathew J, Perez E. Trastuzumab emtansine in human epidermal growth factor receptor 2-positive breast cancer: a review. Curr Opin Oncol. 2011;23:594-600 pubmed publisher..T-DM1 will likely play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. ..
- Hurvitz S, Dirix L, Kocsis J, Bianchi G, Lu J, Vinholes J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013;31:1157-63 pubmed publisher..In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT. ..
- Blanc V, Bousseau A, Caron A, Carrez C, Lutz R, Lambert J. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res. 2011;17:6448-58 pubmed publisherSAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies...
- LoRusso P, Weiss D, Guardino E, Girish S, Sliwkowski M. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17:6437-47 pubmed publisher..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...
- Beck A, Senter P, Chari R. World Antibody Drug Conjugate Summit Europe: February 21-23, 2011; Frankfurt, Germany. MAbs. 2011;3:331-7 pubmed..In addition, presentations on duocarmycin based-ADCs, alpha emitting immunoconjugates and antibody-conjugated nanoparticles were given by representatives from Syntarga, Algeta and the University of Stuttgart, respectively. ..
- Burris H, Rugo H, Vukelja S, Vogel C, Borson R, Limentani S, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398-405 pubmed publisher..9%), thrombocytopenia (8.0%), and fatigue (4.5%). T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose. ..
- Rodon J, Garrison M, Hammond L, de Bono J, Smith L, Forero L, et al. Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study. Cancer Chemother Pharmacol. 2008;62:911-9 pubmed publisher..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. ..
- Fishkin N, Maloney E, Chari R, Singh R. A novel pathway for maytansinoid release from thioether linked antibody-drug conjugates (ADCs) under oxidative conditions. Chem Commun (Camb). 2011;47:10752-4 pubmed publisher..5-7.5, 37 °C). Oxidized thioether-linked AMCs exhibit high, target-specific cytotoxicity toward cancer cells. ..
- Lapusan S, Vidriales M, Thomas X, De Botton S, Vekhoff A, Tang R, et al. Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Invest New Drugs. 2012;30:1121-31 pubmed publisher..AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc...
- Girish S, Gupta M, Wang B, Lu D, KROP I, Vogel C, et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol. 2012;69:1229-40 pubmed publisher..6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events. ..
- Lu D, Burris H, Wang B, Dees E, Cortes J, Joshi A, et al. Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer. Curr Drug Metab. 2012;13:911-22 pubmed..T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC)...
- Bender B, Schaedeli Stark F, Koch R, Joshi A, Chu Y, Rugo H, et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2012;70:591-601 pubmed..6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP. ..
- Chudasama V, Schaedeli Stark F, Harrold J, Tibbitts J, Girish S, Gupta M, et al. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer. Clin Pharmacol Ther. 2012;92:520-7 pubmed publisher..The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems. ..
- Verma S, Miles D, Gianni L, KROP I, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-91 pubmed publisher..Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.). ..
- Polson A, Calemine Fenaux J, Chan P, Chang W, Christensen E, Clark S, et al. Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Cancer Res. 2009;69:2358-64 pubmed publisher..Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans. ..
- KROP I, Kim S, Gonzalez Martin A, LoRusso P, Ferrero J, Smitt M, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:689-99 pubmed publisher..We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients...
- Younes A, Kim S, Romaguera J, Copeland A, Farial S, Kwak L, et al. Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;30:2776-82 pubmed publisher..SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab. ..
- KROP I, LoRusso P, Miller K, Modi S, Yardley D, Rodriguez G, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30:3234-41 pubmed publisher..T-DM1 may be an effective new treatment for this patient population. ..
- Shen B, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30:184-9 pubmed publisher..Thus, the chemical and structural dynamics of the conjugation site can influence antibody conjugate performance by modulating the stability of the antibody-linker interface. ..
- Erickson H, Lewis Phillips G, Leipold D, Provenzano C, Mai E, Johnson H, et al. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 2012;11:1133-42 pubmed publisher..These results indicate that, although the ADC linker can have clear impact on the PK and the chemical nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor. ..
- Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H, et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther. 2010;9:2700-13 pubmed publisherb>Maytansine and its analogues (maytansinoids) are potent microtubule-targeted compounds that inhibit proliferation of cells at mitosis...
- Junttila T, Li G, Parsons K, Phillips G, Sliwkowski M. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-56 pubmed publisher..is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials...
- Niculescu Duvaz I. Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer. Curr Opin Mol Ther. 2010;12:350-60 pubmed..been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc's cytotoxic and antimitotic maytansine derivative DM1...
- KROP I, Beeram M, Modi S, Jones S, Holden S, Yu W, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698-704 pubmed publisher..6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way. ..
- Kovtun Y, Audette C, Mayo M, Jones G, Doherty H, Maloney E, et al. Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res. 2010;70:2528-37 pubmed publisher..This study points the way to the development of ADCs that bypass multidrug resistance. ..
- Tassone P, Gozzini A, Goldmacher V, Shammas M, Whiteman K, Carrasco D, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res. 2004;64:4629-36 pubmed..HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing ..
- Riechelmann H, Sauter A, Golze W, Hanft G, Schroen C, Hoermann K, et al. Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral Oncol. 2008;44:823-9 pubmed publisher..Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study. ..
- Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9:2689-99 pubmed publisherb>Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack of tumor specificity have prevented successful clinical use...
- Cassady J, Chan K, Floss H, Leistner E. Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo). 2004;52:1-26 pubmedb>Maytansine and its congeners have been isolated from higher plants, mosses and from an Actinomycete, Actinosynnema pretiosum...
- Ikeda H, Hideshima T, Fulciniti M, Lutz R, Yasui H, Okawa Y, et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028-37 pubmed publisher..These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM. ..
- KROP I, Kim S, Martín A, LoRusso P, Ferrero J, Badovinac Črnjević T, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18:743-754 pubmed publisher..F Hoffman-La Roche/Genentech. ..
- Carvajal Hausdorf D, Schalper K, Bai Y, Black J, Santin A, Rimm D. Objective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance. Gynecol Oncol. 2017;145:154-158 pubmed publisher..g. lapatinib or afatinib) alone or in combination with extracellular domain-directed drugs (e.g. trastuzumab, pertuzumab, T-DM1). ..
- Gebhart G, Lamberts L, Wimana Z, Garcia C, Emonts P, Ameye L, et al. Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol. 2016;27:619-24 pubmed publisher..nct01565200. ..
- Krop I, Winer E. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Clin Cancer Res. 2014;20:15-20 pubmed publisher..Results from additional randomized studies in metastatic breast cancer are pending, and trials in the (neo)adjuvant setting are being initiated. ..
- Xie H, Audette C, Hoffee M, Lambert J, Blättler W. Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther. 2004;308:1073-82 pubmed..Tissue distribution studies with (125)I-labeled conjugate and antibody showed antibody-like behavior for the conjugate; the antibody of the conjugate did not distribute or bind significantly to any solid tissue. ..
- Spiteller P, Bai L, Shang G, Carroll B, Yu T, Floss H. The post-polyketide synthase modification steps in the biosynthesis of the antitumor agent ansamitocin by Actinosynnema pretiosum. J Am Chem Soc. 2003;125:14236-7 pubmed..Several of the enzymes have relaxed substrate specificities, resulting in multiple parallel pathways in a metabolic grid, albeit with a preferred sequence of reactions as listed above. ..
- Poon K, Flagella K, Beyer J, Tibbitts J, Kaur S, Saad O, et al. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol Appl Pharmacol. 2013;273:298-313 pubmed publisher..These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. ..
- Kang Q, Shen Y, Bai L. Biosynthesis of 3,5-AHBA-derived natural products. Nat Prod Rep. 2012;29:243-63 pubmed publisher..This review covers the biosynthesis of AHBA-derived natural products from a molecular genetics, chemical, and biochemical perspectives, and 174 references are cited. ..
- Wang H, Wang W, Xu Y, Yang Y, Chen X, Quan H, et al. Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells. Cancer Sci. 2017;108:1458-1468 pubmed publisher..Accordingly, we propose that V-ATPase activity in lysosomes is a novel biomarker for predicting T-DM1 resistance. ..
- Carol H, Szymanska B, Evans K, Boehm I, Houghton P, Smith M, et al. The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia. Clin Cancer Res. 2013;19:1795-805 pubmed publisher..These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19(+) ALL. ..
- Sapra P, Betts A, Boni J. Preclinical and clinical pharmacokinetic/pharmacodynamic considerations for antibody-drug conjugates. Expert Rev Clin Pharmacol. 2013;6:541-55 pubmed publisher..These models could be used to predict clinical efficacious doses of ADCs. ..
- Ma J, Zhao P, Shen Y. New amide N-glycosides of ansamitocins identified from Actinosynnema pretiosum. Arch Pharm Res. 2007;30:670-3 pubmed..The 1H-NMR and 13C-NMR assignments were made for 1 and 2 while the 13C-NMR assignment for 1 was revised. Bioassay results showed that 1 had antineoplastic activity. ..
- Giordano S, Temin S, Kirshner J, Chandarlapaty S, Crews J, Davidson N, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2078-99 pubmed publisher..To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer...
- Yan H, Endo Y, Shen Y, Rotstein D, Dokmanovic M, Mohan N, et al. Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity. Mol Cancer Ther. 2016;15:480-90 pubmed publisher..Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. ..
- Lu C, Bai L, Shen Y. A novel amide N-glycoside of ansamitocins from Actinosynnema pretiosum. J Antibiot (Tokyo). 2004;57:348-50 pubmed
- Werbovetz K, Brendle J, Sackett D. Purification, characterization, and drug susceptibility of tubulin from Leishmania. Mol Biochem Parasitol. 1999;98:53-65 pubmed..The vinca site agents vinblastine, maytansine, and rhizoxin bind to leishmanial tubulin as assessed by the quenching of intrinsic tubulin fluorescence and the ..