Maytansine And Its Analogues

Maytansine And Its Analogues

Maytansine is benzoansamacrolide originally isolated from the shrub Maytenus ovatus. It is a highly effective microtubule-targeting compound and is being widely studied as a cytotoxic component of antibody-drug conjugates.

Biological activity

Similar to vinca alkaloids, maytansine binds tubulin at the vinblastine binding site, thereby depolymerizing tubulin and inducing mitotic arrest. Microtubules are dynamic cytoskeletal polymers that can switch randomly between growing and shortening states, which is called "dynamic instability". They have precise segregation of chromosomes in cell division, transportation of cellular cargo, and positioning and intracellular organelles. The inhibition of microtubule function leads to cell cycle arrest and cell death. Drugs targeting microtubules include vinca alkaloids, taxanes, and epothilones, which can inhibit the dynamic instability of microtubules, induce mitotic arrest, inhibit cell proliferation, and induce apoptosis.

Maytansine can effectively resist Lewis lung cancer and B16 murine melanoma solid tumors in vivo and has anti-leukemia activity against P388 murine lymphocytic leukemia. Screening of 60 human cancer cell types by the National Cancer Institute confirmed the anti-proliferative activity of maytansine on microtubule targeting. Although maytansine inhibits the assembly of microtubules and kills cancer cells, its clinical use is affected by severe side effects and poor efficacy. When evaluated as a single agent, maytansine failed to show any significant response in patients with different types of cancer.

structure of Maytansine, DM1 and DM4 Figure 1: structure of Maytansine, DM1 and DM4 (Manu Lopus, 2010).

Maytansine analogues

The anticancer properties of maytansinoids are attributed to their ability to disrupt microtubule function. The maytansine-like emtansine (DM1), for example, binds to the ends of microtubules and inhibits their dynamic instability.

Ravtansine (DM4) is a maytansinoid, which is a chemical derivative of maytansine, which has been studied as a cytotoxic payload for various antibody-drug conjugates (ADC).

  • Other maytansinoids include
    • Ansamitocin
    • Mertansine/emtansine (DM1)
    • Ravtansine/soravtansine (DM4)

ADCs drugs with Maytansine and its analogues

The first and only ADC based on maytansinoid, trastuzumab emtansine (Kadcyla) was approved for HER2-positive metastatic breast cancer in 2013.

ADC Target Clinical indication Linker Payloads Development status Developer
AbGn-107 | Ab1-18Hr1CD71Solid tumors - Colorectal cancer, Pancreatic cancer, Stomach / gastric cancers, Biliary cancerCleavable linkerDM4Phase I AbGenomics BV, Taiwan Branch
AMG 224BCMARelapsed or Refractory (r/r) Multiple MyelomaNoncleavable linker 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (MCC)DM1Phase IAmgen
AMG-595 EGFRviiiGlioma (GBM) / Brain cancerNon-cleavable linkerDM1Phase I, Development has been discontinuedAmgen
AMG172CD70 (CD27L)Renal Cell Carcinoma (RCC), Kidney CancerNon-cleavable linkerDM1Phase I (Completed) (Development Discontinued)Amgen
Anetumab Ravtansine | BAY 94-9343 MesothelinMalignant pleural mesotheliomaA reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]DM4Phase IIBayer HealthCare Pharmaceuticals and ImmunoGen
Anti-ADAM9 ADC (Anti-ADAM9-sulfoSPDB-DM4)ADAM9ADAM9-expressing tumors, Prostate Cancer; Renal Cell Carcinoma, Pancreatic CancerLysine-linked via a cleavable sulfo-SPDB linkerDM4PreclinicalMacrogenics and ImmunoGen
AVID100EGFRAdvanced epithelial carcinomas, Adult Triple-Negative Breast Cancer, Head and Neck Squamous Cell Carcinoma, Non-Small Cell Lung Cancer DM1Phase I/IIaFormation Biologics | Forbius
AVID300EGF receptor, EGFR, ErbB-1 and HER1 in humans. Non-cleavable linkerDM1(Early) Discovery | PreclinicalFormation Biologics
Bivatuzumab mertansine | Anti-CD44v6-DM1CD44v6Squamous cell carcinoma of the head and neck or esophagus DM1Phase I, this program is discontinued (2005)Boehringer Ingelheim | ImmunoGen
BT1718MT1-MMPTriple negative breast cancer, non-small cell lung cancer, Soft tissue sarcomaA hindered disulfide linkerDM1PreclinicalBicycle Therapeutics
Cantuzumab mertansineCanAgPancreatic cancer, biliary cancer, colorectal cancers, gastric cancers, uterine cancers, non-small cell lung cancers (NSCLC), and bladder cancerA stable thiopentanoate linker (or reducible SPP (N-succinimidyl 4-(2-pyridyldithio)) linker)DM1Phase I, Phase II. Discontinued - Phase-I GlaxoSmithKline (GSK) / ImmunoGen
Cantuzumab RavtansineCanAgGastric cancer (metastatic or locally advanced)A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]DM4Phase II. This program is discontinued ImmunoGen
F0002-ADC | CD30-MCC-DM1CD30Refractory or Recurrent CD30+ Hematologic MalignanciesStable SMCC linkerDM1Phase IFudan-Zhangjiang Bio-Pharmaceutica
IMGN 289EGFRviiiSolid Tumors DM1 ImmungoGen
IMGN-242CanAgGastric cancer (metastatic or locally advanced)A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]DM4Phase II. This program is discontinuedImmunoGen
IMGN-388α-V integrinSolid tumors/endothelial cells DM4This program is discontinued ImmunoGen
IMGN-633 (AVE9633)CD33, Siglec-3Acute myeloid leukemia (AML)A disulfide bondDM4This program has been discontinued (May 2009) ImmunoGen
Indatuximab RavtansineCD138Multiple myeloma (MM), Bladder cancer; Breast cancerA reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]DM4Phase II ImmunoGen | BioTest
Laprituximab emtansineEGFRHead and neck cancers, Non-small cell lung (NSCLC) EGFR positive Solid tumorsA noncleavable succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker.DM1Phase I. This program is discontinued ImmunoGen
Lorvotuzumab mertansineCD56Small-cell lung cancer (SCLC), Leukemia, multiple myeloma, etc.A thiopentanoate linker (or reducible SPP  (N-succinimidyl 4-(2-pyridyldithio)) linker)DM1This program has been discontinued (2013/2014). Independent Children's Oncology Group Clinical Phase II Trials in pediatric oncology continue. ImmunoGen
LY3076226FGFRAdvanced or metastatic cancer DM4Phase IEli Lilly and Company
MEN1309 | OBT076 Ly75/CD205Diffuse large B-cell lymphoma (DLBCL), Triple Negative Breast Cancer (TNBC)Cleavable linkerDM4 Menarini Ricerche and Oxford BioTherapeutics
Mirvetuximab SoravtansineFolate receptor 1Ovarian tumor, non-small cell lung cancer (NSCLC)N-Succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate linker (Sulfo-SPDB).DM4Phase III ImmunoGen
MLN-2704PSMAProstate CancerDisulfide linkerDM1Phase-I / II. Discontinued in Prostate (2006) Millennium/Takeda
Naratuximab emtansineCD37 (tetraspanin-26, TSPAN26)Chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Lymphoma, diffuse large B cell (DLBCL)A succinimidyl-4-(N-maleimidomethyl) cyclohexane- 1-carboxylate (SMCC) linkerDM1Phase IIImmunoGen
PEN-221SSTR2Neuroendocrine, Small cell lung cancersAn optimized cleavable linkerDM1Phase IIaTarveda Therapeutics
Praluzatamab RavtansineCD166CD166-postitive solid tumorsReducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]DM4Phase I/IICytomX Therapeutics, ImmunoGen (Originator)
REGN2878-DM1 (Anti-PRLR-ADC)PRLRBreast CancerNon-cleavable SMCC linkerDM1 Regeneron
SAR 566658Sialoglycotope CA6/huDS6 (Mucin 1)Ca6 positive tumors, Ovarian, Breast, and other Epithelial cancersSPDBDM4Phase II. DiscontinuedSanofi, ImmunoGen
SAR408701CEACAM5NSCLC; Solid Tumors, Stomach; AdenocarcinomaSPDBDm4Phase III - Non-small cell lung cancer (NSCLC)
Phase I/II - Solid tumors
Sanofi, ImmunoGen
SAR428926LAMP1Solid tumors, Advanced triple negative breast cancer (TNBC)A disulfide-containing cleavable linker N-succinimidyl-4-(2-pyridyldithio) butyrate (SPDB)Dm4Phase I ImmunoGen; Sanofi
Trastuzumab Emtansine | T-DM1 | Kadcyla®erbB-2, EGFR2, HER2, HER-2, p185c-erbB2, NEU, CD340HER2+ metastatic breast cancer (MBC)Noncleavable succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linkerDm1Approved 2013;
Approved 2019
Genentech Roche in collaboration with ImmunoGen
Zt/g4-DM1 | Anti-RON-ADCRON A thioether linkerDM1Preclinical developmentSchool of Pharmacy, Texas Tech University Health Science Center, Amarillo, TX and the Zhejiang University School of Medicine, Hangzhou, China

References

  1. Kumar, A., White, J., James Christie, R., Dimasi, N., & Gao, C. Antibody-Drug Conjugates. Platform Technologies in Drug Discovery and Validation. 2017; 50:441-480.
  2. Manu Lopus, Emin Oroudjev, et al. Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules. Mol Cancer Ther. 2010 Oct; 9(10):2689-2699.
  3. Victor S. Goldmacher, Charlene A. Audette, Yinghua Guan, et al. High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction. PLoS One. 2015; 10(2):e0117523.
  4. Victor S. Goldmacher, Thomas Chittenden, Ravi V. J. Chari, Yelena V. Kovtun, John M. Lambert. Chapter Twenty-Three - Antibody–Drug Conjugates for Targeted Cancer Therapy. Annual Reports in Medicinal Chemistry. 2012; 47:349-366.
  5. Manu Lopus. Antibody-DM1 Conjugates as Cancer Therapeutics. Cancer Lett. 2011 Aug 28; 307(2):113-118.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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