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.
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.
Figure 1: structure of Maytansine, DM1 and DM4 (Manu Lopus, 2010).
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).
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 | Ab1-18Hr1||CD71||Solid tumors - Colorectal cancer, Pancreatic cancer, Stomach / gastric cancers, Biliary cancer||Cleavable linker||DM4||Phase I||AbGenomics BV, Taiwan Branch|
|AMG 224||BCMA||Relapsed or Refractory (r/r) Multiple Myeloma||Noncleavable linker 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (MCC)||DM1||Phase I||Amgen|
|AMG-595||EGFRviii||Glioma (GBM) / Brain cancer||Non-cleavable linker||DM1||Phase I, Development has been discontinued||Amgen|
|AMG172||CD70 (CD27L)||Renal Cell Carcinoma (RCC), Kidney Cancer||Non-cleavable linker||DM1||Phase I (Completed) (Development Discontinued)||Amgen|
|Anetumab Ravtansine | BAY 94-9343||Mesothelin||Malignant pleural mesothelioma||A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]||DM4||Phase II||Bayer HealthCare Pharmaceuticals and ImmunoGen|
|Anti-ADAM9 ADC (Anti-ADAM9-sulfoSPDB-DM4)||ADAM9||ADAM9-expressing tumors, Prostate Cancer; Renal Cell Carcinoma, Pancreatic Cancer||Lysine-linked via a cleavable sulfo-SPDB linker||DM4||Preclinical||Macrogenics and ImmunoGen|
|AVID100||EGFR||Advanced epithelial carcinomas, Adult Triple-Negative Breast Cancer, Head and Neck Squamous Cell Carcinoma, Non-Small Cell Lung Cancer||DM1||Phase I/IIa||Formation Biologics | Forbius|
|AVID300||EGF receptor, EGFR, ErbB-1 and HER1 in humans.||Non-cleavable linker||DM1||(Early) Discovery | Preclinical||Formation Biologics|
|Bivatuzumab mertansine | Anti-CD44v6-DM1||CD44v6||Squamous cell carcinoma of the head and neck or esophagus||DM1||Phase I, this program is discontinued (2005)||Boehringer Ingelheim | ImmunoGen|
|BT1718||MT1-MMP||Triple negative breast cancer, non-small cell lung cancer, Soft tissue sarcoma||A hindered disulfide linker||DM1||Preclinical||Bicycle Therapeutics|
|Cantuzumab mertansine||CanAg||Pancreatic cancer, biliary cancer, colorectal cancers, gastric cancers, uterine cancers, non-small cell lung cancers (NSCLC), and bladder cancer||A stable thiopentanoate linker (or reducible SPP (N-succinimidyl 4-(2-pyridyldithio)) linker)||DM1||Phase I, Phase II. Discontinued - Phase-I||GlaxoSmithKline (GSK) / ImmunoGen|
|Cantuzumab Ravtansine||CanAg||Gastric cancer (metastatic or locally advanced)||A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]||DM4||Phase II. This program is discontinued||ImmunoGen|
|F0002-ADC | CD30-MCC-DM1||CD30||Refractory or Recurrent CD30+ Hematologic Malignancies||Stable SMCC linker||DM1||Phase I||Fudan-Zhangjiang Bio-Pharmaceutica|
|IMGN 289||EGFRviii||Solid Tumors||DM1||ImmungoGen|
|IMGN-242||CanAg||Gastric cancer (metastatic or locally advanced)||A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]||DM4||Phase II. This program is discontinued||ImmunoGen|
|IMGN-388||α-V integrin||Solid tumors/endothelial cells||DM4||This program is discontinued||ImmunoGen|
|IMGN-633 (AVE9633)||CD33, Siglec-3||Acute myeloid leukemia (AML)||A disulfide bond||DM4||This program has been discontinued (May 2009)||ImmunoGen|
|Indatuximab Ravtansine||CD138||Multiple myeloma (MM), Bladder cancer; Breast cancer||A reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]||DM4||Phase II||ImmunoGen | BioTest|
|Laprituximab emtansine||EGFR||Head and neck cancers, Non-small cell lung (NSCLC) EGFR positive Solid tumors||A noncleavable succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker.||DM1||Phase I. This program is discontinued||ImmunoGen|
|Lorvotuzumab mertansine||CD56||Small-cell lung cancer (SCLC), Leukemia, multiple myeloma, etc.||A thiopentanoate linker (or reducible SPP (N-succinimidyl 4-(2-pyridyldithio)) linker)||DM1||This program has been discontinued (2013/2014). Independent Children's Oncology Group Clinical Phase II Trials in pediatric oncology continue.||ImmunoGen|
|LY3076226||FGFR||Advanced or metastatic cancer||DM4||Phase I||Eli Lilly and Company|
|MEN1309 | OBT076||Ly75/CD205||Diffuse large B-cell lymphoma (DLBCL), Triple Negative Breast Cancer (TNBC)||Cleavable linker||DM4||Menarini Ricerche and Oxford BioTherapeutics|
|Mirvetuximab Soravtansine||Folate receptor 1||Ovarian tumor, non-small cell lung cancer (NSCLC)||N-Succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate linker (Sulfo-SPDB).||DM4||Phase III||ImmunoGen|
|MLN-2704||PSMA||Prostate Cancer||Disulfide linker||DM1||Phase-I / II. Discontinued in Prostate (2006)||Millennium/Takeda|
|Naratuximab emtansine||CD37 (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) linker||DM1||Phase II||ImmunoGen|
|PEN-221||SSTR2||Neuroendocrine, Small cell lung cancers||An optimized cleavable linker||DM1||Phase IIa||Tarveda Therapeutics|
|Praluzatamab Ravtansine||CD166||CD166-postitive solid tumors||Reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio) butanoate]||DM4||Phase I/II||CytomX Therapeutics, ImmunoGen (Originator)|
|REGN2878-DM1 (Anti-PRLR-ADC)||PRLR||Breast Cancer||Non-cleavable SMCC linker||DM1||Regeneron|
|SAR 566658||Sialoglycotope CA6/huDS6 (Mucin 1)||Ca6 positive tumors, Ovarian, Breast, and other Epithelial cancers||SPDB||DM4||Phase II. Discontinued||Sanofi, ImmunoGen|
|SAR408701||CEACAM5||NSCLC; Solid Tumors, Stomach; Adenocarcinoma||SPDB||Dm4||Phase III - Non-small cell lung cancer (NSCLC) |
Phase I/II - Solid tumors
|SAR428926||LAMP1||Solid tumors, Advanced triple negative breast cancer (TNBC)||A disulfide-containing cleavable linker N-succinimidyl-4-(2-pyridyldithio) butyrate (SPDB)||Dm4||Phase I||ImmunoGen; Sanofi|
|Trastuzumab Emtansine | T-DM1 | Kadcyla®||erbB-2, EGFR2, HER2, HER-2, p185c-erbB2, NEU, CD340||HER2+ metastatic breast cancer (MBC)||Noncleavable succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker||Dm1||Approved 2013; |
|Genentech Roche in collaboration with ImmunoGen|
|Zt/g4-DM1 | Anti-RON-ADC||RON||A thioether linker||DM1||Preclinical development||School of Pharmacy, Texas Tech University Health Science Center, Amarillo, TX and the Zhejiang University School of Medicine, Hangzhou, China|