Release date:2023/4/23 9:47:08

In recent years, antibody-drug conjugates (ADCs) for tumor-targeted therapies have received great attention; among them, ADCs with maytansine derivatives as cytotoxic agents have been highly favored by researchers and a series of breakthroughs have been achieved.

ADC: Composition and Mechanism of Action

More than 100 years ago, researchers proposed the concept of "magic bullets" for antibody-targeted cancer treatment. As antibody technology continues to mature, there has been a global boom in the development of ADCs, which are composed of three major components: antibodies, linkers and toxin warheads.


Figure 1. Rational design of ADCs components. Source: Reference [1]

ADCs specifically recognize tumor antigens and form ADC-antigen complexes to enter target cells through receptor-mediated cytocytosis, further releasing highly active warhead molecules to complete the selective killing of tumor cells.

Maytansinoids as Payloads of ADCs

Maytansine and its derivatives (generally named maytansinoids), a 19-member ansa macrolide structure attached to a chlorinated benzene ring, were originally isolated from the shrub Maytenus ovatus. It is a potent microtubule-targeting compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. It showed potent anticancer activity in human nasopharynx carcinoma KB cells (EC-8 PM), murine lymphocytic leuke- mia P-388 cells (EC 50-0.6 PM), and murine leukemia L1210 cells (EC 50-2 PM).

However, due to the narrow therapeutic window and high systemic toxicity of maytansine, maytansine not an oncological chemotherapeutic agent when used alone and has been clinically banned from direct use in human therapy. ADCs as targeted therapy might be a promising approach to address the limitations of single-agent therapy. 

Based on the mechanism of action of ADC, its payload is usually a highly cytotoxic small molecule. Maytansinoids have an in vitro inhibitory activity of up to 1000 times higher than conventional chemotherapeutic agents (e.g. doxorubicin) against a wide range of tumor cells, with half maximal inhibitory concentration (IC50) reaching sub-nanomolar levels. Maytansinoids are more potent in killing actively dividing cells than quiescent cells. Maytansinoids have good stability and solubility in water, allowing them to couple with antibodies without breaking down or causing aggregation. However, Maytansinoids does not possess a suitable functional group to derivatize and enable its coupling to antibodies.

A series of maytansine analogs with disulfide or thiol substituents have been recently synthesized for covalent attachment to mAbs. Among them, DM1 and DM4 are currently being studied clinically as ADC payloads.


Figure 2. Structures of maytansine and the maytansine thiomethyl analogs S-methyl DM1 and S-methyl DM4. Source: reference [2]

Antibody-maytansinoid Conjugates

Now, there are two ADCs with maytansinoid-based payloads approved by the FDA, Kadcyla and Elahere.


Kadcyla (Trastuzumab Emtansine, T-DM1), developed by Roche, is a HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane1-carboxylate).

It was approved by the FDA in 2013 to treat metastatic breast cancer, which was previously treated with ado-trastuzumab and a taxane.


Figure 3. Structure of Kadcyla


Elahere (mirvetuximab soravtansine-gynx) is a first-in-class ADC consisting of a folate receptor alpha (FRα)-conjugated antibody, a cleavable linker, and the maytansinoid payload DM4.

On November 14, 2022, the FDA granted accelerated approval of Elahere for use in adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens.


Figure 4. Structure of Elahere, Source:

In addition to the two approved drugs mentioned above, several Antibody-maytansinoid Conjugates have now entered clinical phase II/III, with warheads still focused on DM1/DM4, while targets have further expanded to FOLR1, CD37, CD56, CD19, CD138, Mesothelin, CA6, etc.

ADC Developer Target antigen Linker Cytotoxin Indication(s) Phase
Naratuximab emtansine ImmunoGen CD37 Noncleavable (SMCC) DM1 Diffuse large B cell lymphoma and follicular lymphoma II
Lorvotuzumab mertansine ImmunoGen CD56 Cleavable disulfide DM1 Leukemia II
Coltuximab ravtansine ImmunoGen CD19 Cleavable disulfide DM4 Diffuse large B cell lymphoma, acute lymphocytic leukaemia II
Indatuximab ravtansine Biotest CD138 Cleavable disulfide DM4 Multiple myeloma II
Anetumab ravtansine Bayer Health Care Mesothelin Cleavable disulfide DM4 Mesothelioma and other solid tumors II
SAR566658 Sanofi CA6 Cleavable disulfide DM4 Triple-negative breast cancer II

Table. Antibody-maytansinoid Conjugates in phase III and phase II development. Source: Reference [1]

The above is the brief research and development process of maytansine from being undruggable with strong activity, narrow safety window, and obvious toxicity to being successfully applied to clinical treatment as an ADC warhead. In fact, in addition to maytansine, there are many strong cytotoxic substances used in clinical development, such as dolastatins, auristatins, calicheamicins, duocarmycins, and camptothecin derivatives, etc.

And as more and more undruggables have become possible in recent years, many areas that have been studied for years or even suspended have the potential to become blue ocean markets. Then, both for the industry and for industry investors, the breakthrough and rapid development of technology requires extra attention and in-depth research.

Biopharma PEG is a professional PEG supplier. We can provide high-purity PEG linkers from milligram to kilogram scale in GMP and Non-GMP grade for your antibody-maytansinoid conjugates development.  The use of PEGs as a linker between the antibody and payload molecules allows for higher ADC loading. PEGs create a protective shield that wraps the ADC payload from its microenvironment, improving solubility and stability. Other benefits include reduced aggregation and thus lower immunogenicity, improved pharmacokinetics, increased circulation time and reduced toxicity. 

[1] Zhao P, Zhang Y, Li W, Jeanty C, Xiang G, Dong Y. Recent advances of antibody-drug conjugates for clinical applications. Acta Pharm Sin B. 2020;10(9):1589-1600. doi:10.1016/j.apsb.2020.04.012
[2] Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, Jordan MA. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010 Oct;9(10):2689-99. doi: 10.1158/1535-7163.MCT-10-0644. PMID: 20937594; PMCID: PMC2954514.
[3] Wang, Jeffrey & Shen, wei-chiang & Zaro, Jennica. (2015). Antibody-Drug Conjugates: The 21st Century Magic Bullets for Cancer. 10.1007/978-3-319-13081-1.

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