Maytansinoids in cancer therapy: advancements in antibody–drug conjugates and nanotechnology-enhanced drug delivery systems

Abstract

Cancer remains the second leading cause of death globally, driving the need for innovative therapies. Among natural compounds, maytansinoids have shown significant promise, contributing to nearly 25% of recently approved anticancer drugs. Despite their potential, early clinical trials faced challenges due to severe side effects, prompting advancements in delivery systems such as antibody-maytansinoid conjugates (AMCs). This review highlights the anticancer activity of maytansinoids, with a focus on AMCs designed to target cancer cells specifically. Preclinical and clinical studies show that AMCs, including FDA-approved drugs like Kadcyla and Elahere, effectively inhibit tumor growth while reducing systemic toxicity. Key developments include improved synthesis methods, linker chemistry and payload design. Ongoing research aims to enhance the safety and efficacy of AMCs, integrate nanotechnology for drug delivery, and identify novel therapeutic targets. These advancements hold potential to transform maytansinoid-based cancer treatments in the future.

Introduction

The global cancer burden continues to grow, with the Globocan 2022 report estimating nearly 20 million new cancer cases and 9.7 million deaths worldwide. Lung cancer remains the most frequently diagnosed cancer globally, accounting for 12.4% of all cancer cases (2.5 million cases), followed by breast cancer (11.6%), colorectal cancer (9.6%), prostate cancer (7.3%), and stomach cancer (4.9%). Lung cancer is also the leading cause of cancer-related deaths, contributing to 18.7% of global cancer mortality, followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach cancers (6.8%) [1]. The disparity in cancer incidence and mortality between regions remains significant. For example, cancer incidence rates are 4- to fivefold higher in regions like Australia/New Zealand compared to Western Africa. These data underscore the importance of continued efforts in cancer prevention, early diagnosis, and equitable access to care globally [1]. Cancer accounts for over 10 million deaths annually, underscoring its position as the second leading cause of mortality worldwide [2–4]. Its multifactorial and intricate nature represents a constant challenge to human health, necessitating relentless investigation of innovative therapeutic strategies [5–7]. Natural compounds, recognized for their high anticancer potential, have attracted significant scientific interest; over the past four decades, these compounds represent nearly 25% of newly approved anticancer drugs [2, 3, 5, 8]. Concerning this, maytansine stands out among natural compounds for its robust and promising anticancer properties [9]. Maytansine is a naturally occurring compound in the East African shrub Maytenus spp. [10]. It was first isolated from Maytenus serrata and Maytenus buchananii in the 1970s, and its anticancer properties were quickly identified [11, 12]. Maytansine and its derivatives, collectively known as maytansinoids (DMs), constitute a class of potent microtubule polymerization inhibitors [13]. These compounds effectively induce apoptosis in cancer cells by disrupting the microtubule network—a fundamental component of the cell cytoskeleton essential for cell division [14, 15]. Despite their efficacy, early clinical trials of maytansinoids were hindered by severe side effects, including neurotoxicity and hepatotoxicity [9, 15, 16]. Advancements in drug delivery technology have paved the way for the development of various DMs. Notably, antibody-maytansinoid conjugates (AMCs) combine the specificity of antibodies with the potent anticancer activity of maytansinoids [17]. AMCs address several limitations of conventional therapies by reducing systemic toxicity through targeted delivery and demonstrating potential in overcoming resistance mechanisms in cancer treatment. AMCs are designed to deliver maytansinoids directly to cancer cells while minimizing exposure to healthy cells [17]; this is achieved by conjugating the maytansinoid payload to a monoclonal antibody (mAb) via a stable linker [12]. The mAb then binds to a specific antigen on the cancer cell’s surface, leading to the internalization of the entire conjugate [18, 19]. Once inside the cancer cell, the linker cleaves, releasing the maytansinoid payload to exert its cytotoxic effects [18]. The review examines the evolution of maytansinoid-based therapies, from the challenges of direct maytansinoid use to the advancement of AMCs. It provides an analysis of the chemistry and mechanisms underlying the antitumor effects of maytansine and its derivatives, followed by an evaluation of recent preclinical and clinical studies on AMCs as promising therapeutic agents.

Review methodology

To compile relevant literature, we conducted a comprehensive search across major electronic databases—PubMed/MedLine, Scopus, ScienceDirect, Web of Science, and Google Scholar—covering studies published from January 1977 to March 2024. We used Medical Subject Headings (MeSH) terms combined with Boolean operators (“AND,” “OR”) to search for topics such as “maytansine,” “maytansinoid,” “antibody-maytansinoid conjugates,” “anticancer,” “drug delivery,” “clinical trials,” “animal models,” “toxicity,” “safety,” “side effects,” “mechanism of action,” “bioavailability,” and “pharmacokinetics.” We included original experimental and clinical studies on maytansinoids and AMCs, prioritizing studies on maytansinoid chemistry, novel delivery systems, biological pathways, and nanotechnology. To identify clinical trials specifically, we reviewed www.ClinicalTrials.gov, recording trial status, cancer type, participant numbers, and outcomes. Only peer-reviewed articles in English were included, excluding theses, abstracts, case reports, commentaries, editorials, unpublished data and non-English studies. Studies were initially screened by title and abstract for relevance, with a subsequent full-text review to confirm their suitability. After applying these criteria, we selected 107 articles for review.

Chemistry of maytansinoids

Maytansinoids are characterized by intricate chemical structures that form the basis of their potent anticancer activity. Understanding the structural features of maytansinoids is fundamental for optimizing their therapeutic potential and designing derivatives with enhanced properties. This section explores the structural diversity and relationships among maytansinoids and their derivatives, recognizing that their efficacy depends on their complex and distinctive chemical structure. Maytansinoids belong to the macrolide family and are closely related to the ansamycin group of antibiotic compounds. Their defining feature is a 19-member ansa macrolide structure, known as maytansine, which is covalently linked to a chlorinated benzene ring chromophore [11, 20]. Since maytansine’s initial discovery in 1972, several analogs have been isolated, most varying in the substituents of the C3 ester group [21] (Fig. 1). Key structural elements of maytansinoids include the macrocyclic lactam ring, a highly strained cyclohexane ring, and an extended polyketide side chain The macrocyclic lactam ring, a stable 19-member structure is essential for the rigidity and stability of maytansinoids, serving as the scaffold for cellular interactions. This ring is essential for their biological activity, as it serves as a scaffold for interactions with cellular targets [22]. The cyclohexane ring plays a fundamental role in cytotoxicity. This structural feature contributes to the compound’s ability to disrupt microtubule formation, a fundamental process in cell division [9, 16, 23]. The polyketide side chain, extending from the macrocyclic ring, plays a pivotal role in microtubule disruption. Its flexible structure allows it to interact more dynamically with tubulin subunits, destabilizing microtubule assembly. This enhanced interaction increases the efficacy of maytansinoids compared to other compounds targeting microtubules, such as taxanes, which primarily stabilize microtubules. By inducing microtubule depolymerization, the polyketide side chain amplifies the cytotoxic effects, leading to cell cycle arrest and apoptosis in cancer cells [9, 16, 23]. Therefore, this intricate interplay of structural motifs defines the unique biological activity of maytansinoids and underscores their potential as promising agents in oncology research.

Fig. 1.

Representative chemical structure of maytansinoids.The figure illustrates the chemical structure of maytansine, a potent anticancer compound, and its key derivatives (DM1, DM3, and DM4). The variations in the “R” group define the derivatives: DM1 (R = CH₂CH₂SH), DM3 (R = CH₂CH₂CH(CH₃)SH), and DM4 (R = CH₂CH₂C(CH₃)₂SH). These derivatives are characterized by enhanced cytotoxicity and modifiable features that make them suitable for antibody-maytansinoid conjugates in targeted cancer therapy

Anticancer mechanisms of action of maytansinoids

Maytansinoids exert their mechanism of action primarily by inhibiting the polymerization of microtubules (Fig. 2). Microtubules are dynamic cytoskeletal fibers of tubulin subunits that play essential roles in developing and maintaining cell signaling, cell division, and mitosis [23, 24]. Maytansinoids can be conjugated to specific targeting molecules to enhance their selectivity for cancer cells, minimizing off-target effects [25]. The destabilization of microtubules and inhibition of tubulin assembling leads to mitotic arrest and subsequent cell death [16]. Maytansine attaches to a specific area of microtubules called the vinca domain. This binding site is distinct from those targeted by other microtubule inhibitors, such as vinca alkaloids and taxanes. Vinca alkaloids bind to the β-subunit of tubulin and inhibit tubulin polymerization, while taxanes stabilize microtubules by binding to the taxane site. In contrast, maytansinoids uniquely induce microtubule depolymerization through their specific interaction with the vinca domain, disrupting microtubule assembly. This site comprises a sequence of amino acids at the interface of α and β subunits within the microtubule structure [26]. When specific molecules bind to this site, they cause the α and β subunits to come together, forming aggregates of the microtubules. At higher concentrations, these aggregates cause the tubulin assemblies to take on a curved shape. Due to their distinctive binding site, Maytansinoids can noncompetitively contend with vinca compounds in binding to and deactivating tubulin polymerization. Prota et al. utilized X-ray crystallography to identify a new binding site on the β-subunit of tubulin, capable of binding with maytansine and its derivatives. Maytansine and maytansinoids exhibit cytotoxic effects by impeding mitosis and halting the proliferation of cancer cells [27]. This inhibition occurs through binding at the maytansine site, which prevents the elongation of tubulin by blocking the addition of monomers. This process leads to the poisoning of the ends of growing tubulin chains or the sequestration of soluble tubulin in a form that cannot be polymerized [28].

Fig. 2.

Anticancer mechanisms of maytansinoids at the cellular level. Maytansinoids bind to tubulin within microtubules, leading to microtubule interference and cell cycle arrest in the mitotic phase. This disruption activates the mitotic checkpoint, halting chromosome segregation. Concurrently, maytansinoids initiate the apoptotic pathway by activating procaspase-8 and procaspase-10, which are cleaved into active forms. These initiator caspases then activate procaspase-3 and procaspase-7, producing the executioner caspases (caspase-3 and caspase-7) that dismantle cellular components and induce programmed cell death. Together, these processes lead to effective cancer cell elimination

Inhibition of microtubule dynamics

Transitioning to a broader perspective, the inhibition of microtubule dynamics emerges as a central theme in understanding the anticancer effects of maytansinoids. By targeting the maytansine site of microtubules, these compounds disrupt the delicate balance of microtubule assembly and disassembly, fundamental processes for cell division [29]. During cell division, the mitotic spindle—a dynamic array of microtubules—forms to separate chromosomes and orient the cleavage plane [30]. Maytansinoids bind specifically to the microtubule protein tubulin, preventing microtubules from properly polymerizing and depolymerizing. As microtubule-targeting agents, Maytansinoids have a mechanism of action distinct from other classes such as taxanes and vinca alkaloids. Taxanes stabilize microtubules to prevent depolymerization, and vinca alkaloids inhibit tubulin polymerization. In contrast, maytansinoids bind to the vinca domain and uniquely induce microtubule depolymerization. This action, combined with their integration into AMCs allows for targeted delivery, reduced systemic toxicity, and potential efficacy against drug-resistant cancers, providing significant therapeutic advantages over traditional agents. This interference with microtubule dynamics eventually leads to cell cycle arrest because chromosomes cannot bind the tubulin fibers during mitosis, particularly in the G2/M phase [16]. These structural insights have informed the development of AMCs which enable targeted delivery and reduce systemic toxicity. They also serve as a foundation for synthetic modifications designed to enhance efficacy and improve the therapeutic index. Thus, by disrupting microtubule dynamics, maytansinoids initiate a cascade of events that inhibit cancer cell division and promote therapeutic efficacy.

Activation of mitotic checkpoint

By blocking microtubule dynamics, maytansinoids activate the mitotic checkpoint, also known as the spindle assembly checkpoint [31]. This checkpoint ensures that all chromosomes are correctly attached to the spindle before cell division proceeds [32]. Activating this checkpoint delays mitosis, providing time for the cell to repair any errors or trigger apoptotic cell death in the case of extensive damage. In antibody-maytansinoid conjugates (AMCs), the stable linker plays a fundamental role by ensuring the conjugate remains intact during circulation. Once the AMC is internalized by the cancer cell, the linker selectively cleaves to release the cytotoxic maytansinoid payload, enhancing the precision of drug delivery and minimizing systemic toxicity [31, 32]. The activation of the mitotic checkpoint by maytansinoids disrupts cancer cell proliferation and serves as a fundamental step in their anticancer mechanism.

Induction of apoptosis

Prolonged maytansinoid exposure can induce apoptosis by disrupting microtubules, cell cycle arrest, and mitotic checkpoint activation [31]. In addition to mitotic checkpoint activation, maytansinoid-induced microtubule disruption triggers caspase activation and mitochondrial pathways. The destabilization of microtubules can lead to mitochondrial membrane permeabilization, releasing cytochrome c and activating caspase cascades, which are essential for programmed cell death. These multiple apoptotic pathways enhance the efficacy of maytansinoids against cancer cells. For example, Venghateri et al. studied the mechanism of action of ansamitocin P3, a structural analog of maytansine. The authors discovered that ansamitocin P3 treatment activated the spindle assembly checkpoint, blocking the cells in the mitotic phase and leading to apoptosis through the p53-mediated apoptotic pathway [31]. Through apoptosis induction, maytansinoids effectively eliminate cancer cells, reinforcing their role as potent anticancer agents.

These mechanisms underline the therapeutic potential of maytansinoids, particularly in antibody–drug conjugates, where targeted delivery enhances efficacy while minimizing off-target toxicity. This highlights their significant role in advancing cancer therapies.

Innovations in targeted delivery systems of maytansinoids

Overcoming biological barriers to enhance delivery

Addressing biological barriers is essential for improving the delivery and optimizing the therapeutic efficacy of maytansinoids in cancer treatment. Despite their potent cytotoxicity against cancer cells, clinical utilization of maytansinoids faces challenges related to poor solubility, rapid elimination, and non-specific effects. Innovative strategies have been devised to overcome these obstacles and improve the selective delivery of maytansinoids to tumor sites.

The strategies include:

• i)Developing molecular conjugates with antibodies to achieve specificity, prolong retention time, and reduce clearance rates [33].
• ii)Utilizing peptides [34, 35] and aptamers [36, 37] as binders, enabling localized and targeted therapy directed toward specific cell or tumor types. These alternative binders offer versatility and may provide advantages in specific contexts, such as ease of synthesis or increased tissue penetration [37].
• iii)Employing nanoparticles to shield drugs from degradation, improve solubility, and ensure targeted accumulation in tumor tissues through mechanisms such as enhanced permeability and retention effects [38]. Nanoparticles shield drugs from degradation (facilitating their delivery) and capitalize on their tendency to accumulate in tumor tissues due to permeable vasculature and impaired lymphatic drainage. [39]. Consequently, this accumulation mitigates systemic toxicity [40]. The design and formulation of delivery systems must meticulously consider the tumor microenvironment’s intricacies, encompassing factors such as pH, enzymatic activity and temperature [41]. By accounting for these parameters, delivery systems can achieve optimal release kinetics, improve therapeutic efficacy, and attenuate adverse effects [42]. Furthermore, advancements in nanotechnology have led to the development of stimuli-responsive nanoparticles, which can release drugs in response to specific triggers within the tumor microenvironment, further refining targeted drug delivery while minimizing off-target effects [43, 44].

Antibody-maytansinoid conjugates and synthesis

Many antibody–drug conjugates (ADCs) are designed to target specific receptors overexpressed on the surface of cancer cells. These receptors play a fundamental role in cancer cell proliferation and survival, making them attractive targets for therapeutic intervention. Several target receptors for maytansin conjugates have been identified, with one prominent example being the HER2 receptor tyrosine kinase (ErbB2), a member of the epidermal growth factor receptor family known as transmembrane receptors. Alongside HER4 and HER3, these receptors play pivotal roles in cancer development and are frequently overexpressed in breast, ovarian, and gastric cancers [45]. The extracellular portion of these receptors provides an accessible site for antibody binding, making them attractive targets for specific therapies. Notably, drugs such as trastuzumab (a humanized HER2 antibody) have been in clinical use since 1998 for the treatment of breast cancer, with improved outcomes observed when combined with cytotoxic compounds [46, 47].

Similarly, AMCs have been engineered to target various receptors implicated in cancer development and progression. These include the folate receptor (FR) in ovarian cancer [48], as well as the C19, C20, and C22 family of receptors, known as B-cell markers, which are commonly overexpressed in leukemia and lymphoma cells [49, 50]. AMCs have also been designed to target the insulin-like growth factor 1 receptor (IGF-IR) found in cancers affecting the lung, head and neck, breast, prostate, and osteosarcoma [51]. Therefore, by strategically selecting these pharmaceutical targets, AMCs can be tailored to specific receptor types, ensuring therapy selectivity for particular cancer types and tissues. This strategic approach enhances their efficacy and minimizes off-target effects [18, 52]. As previously reported, AMCs belong to a class of targeted cancer therapies that combine the specificity of mAbs with the cytotoxicity of maytansinoid payloads [53]. These derivatives often involve chemical modifications to the maytansinoid structure to improve solubility, stability, and targeting [54]. AMCs offer several advantages over traditional chemotherapy drugs. First, a mAb directed against a specific marker on the surface of tumor cells ensures high specificity, thus reducing the risk of side effects [55]. Second, AMCs exhibit remarkable effectiveness, enabling cancer cell eradication even at very low doses [53, 56, 57]. Third, AMCs have effectively treated cancer cells resistant to other chemotherapy agents [53]. The synthesis of AMCs involves several key steps, including the selection of the antibody, conjugation chemistry, and purification. Here is an overview of the process:

• i.Antibody selection: The first step in AMC synthesis is the selection of an appropriate mAb. Ideally, the chosen mAb should target a specific antigen overexpressed on cancer cell surfaces but not normal cells [53]. Commonly used mAbs in AMC development include trastuzumab (Herceptin), rituximab (Rituxan), and others, depending on the cancer type being targeted [17, 58].
• ii.Maytansinoid payload: Fig. 3 illustrates the chemical structures of several prominent maytansinoid derivatives found in natural extracts, known for their amplified cytotoxic activity. Additionally, the diagram depicts three primary semi-synthetic derivatives that have been extensively studied and exhibit a significantly enhanced potency, ranging from 100 to 1000 times higher than maytansine [59]. These derivatives are particularly noteworthy as they are amenable to modifications at the C-3 position, rendering them suitable as pharmacological warheads [60]. This strategic placement allows facile conjugation with selected antibodies, enhancing their therapeutic potential. Furthermore, their inherent structural features facilitate chemical synthesis. Notably, maytansinoids like DM1 (thiolated maytansine derivative, also named Mertansine) are highly potent cytotoxic agents [55, 61]. these maytansinoids require modification to create a linker-payload complex, enabling controlled payload release within the target cancer cell. Typically, the payload is modified with a linker that remains stable in circulation but can be readily cleaved inside the target cell [62].
• iii.Linker chemistry: The linker is a fundamental element of AMCs. According to studies conducted by Kupchan [63], the presence of an ester chain at the C-3 position is fundamental for maintaining the biological activity of maytansinoids. This ester chain provides steric protection, preventing the hydrophilic portion of the molecule from reacting and enhancing its permeability. Consequently, maytansinol (depicted in Fig. 3) has emerged as the primary precursor because its acylation product enables subsequent modifications to the ester chain. This pivotal role positions maytansinol as a versatile starting point for further derivatization. Regarding linkers for attaching antibodies, they connect the mAb and the drug payload while ensuring stability in circulation [64]. There are two main types of linkers used in the synthesis of AMCs: cleavable linkers and non-cleavable linkers (Fig. 4). Cleavable linkers are designed to be stable in circulation but can be selectively cleaved from the payload by cellular enzymes inside the endosomes and lysosomes. These cleavage mechanisms include acidic degradation, thiol-disulfide exchange reactions, and protease cleavage by cathepsin B [65, 66]. Common cleavable linkers include disulfide (SPDP, SPP, and SSNPP), hydrazone, and protease-cleavable linkers. On the other hand, non-cleavable linkers are more stable and typically undergo cleavage only after internalization of the AMC into the target cell [67]. This cleavage process releases the maytansinoid payload within the cells. Non-cleavable linkers are often used when efficient internalization of the AMC is desired [67]. Some examples are the maleimide, thioethers derivatives, and disulfide linkers (like SMCC).
• iv.Conjugation: The chemical conjugation of the antibody, linker, and maytansinoid payload is fundamental. Various conjugation chemistries can be used, including thiol-maleimide chemistry targeting cysteine residues on the antibody or lysine-specific chemistry. Careful selection of conjugation sites on the antibody ensures that binding specificity is not disrupted during this process [67].
• v.Purification: after conjugation, the AMC mixture typically contains unreacted components, including unconjugated antibody, linker, and payload. Purification methods are employed to ensure the final product’s purity and potency. Techniques like hydrophobic interaction chromatography or size-exclusion chromatography effectively remove impurities from the mixture [29, 68].
• vi.Characterization: the resulting AMC conjugate is then characterized to confirm its identity, purity, and effectiveness. Mass spectrometry, liquid chromatography, and gel electrophoresis are commonly used for this analysis [69].
• vii.Formulation: conjugates are carefully formulated to maintain stability during storage and administration. Stabilizers, buffer solutions, or other excipients may be added to preserve the integrity of the conjugate [70].
• viii.Preclinical and clinical testing: before AMCs can advance to clinical trials or become approved therapies, they undergo extensive preclinical and clinical testing to assess safety, efficacy, and pharmacokinetics. Therefore, developing these conjugates is a complex and highly specialized process combining chemistry, biology, and pharmacology expertise. Successful AMCs can offer a targeted approach to cancer therapy with reduced systemic toxicity compared to traditional chemotherapy [9, 17, 54]. In Fig. 5, the mechanism of action of antibody-maytansinoid conjugates (AMCs) is illustrated, showing targeted delivery, internalization, and apoptosis induction.

Fig. 3.

Chemical structure of maytansine natural and semi-synthetics derivates

Fig. 4.

Chemical structure of the most common linkers between maytansinoid derivates and mAb

Fig. 5.

Mechanism of action of Antibody-Maytansinoid Conjugates (AMCs) in targeted cancer therapy. The AMC consists of an antibody, a maytansinoid payload, and a linker. The antibody targets specific antigen receptors on the cancer cell surface, allowing for targeted drug delivery. Upon binding to the antigen receptor, the AMC is internalized into the cancer cell through endocytosis. Within the cell, the AMC is transported to the lysosome, where the linker is cleaved, releasing the cytotoxic maytansinoid drug. The released drug induces apoptosis, leading to the death of the cancer cell

Advances in antibody–drug conjugates for cancer therapy

Over the past few decades, drug discovery and design have undergone extraordinary advancements because proteomic approaches have facilitated the clinical use of diverse cancer detection and diagnosis assays. Furthermore, research on AMCs has intensified, leading to numerous in vitro and in vivo preclinical studies. These investigations provide compelling evidence regarding the anticancer efficacy of these so-called “biological missiles” [9, 15, 18, 31, 71, 72]. Seki et al. developed a novel chemical conjugation technology called AJICAP®. This method enables site-specific modification of antibodies using IgG Fc-affinity peptide-based reagents, resulting in a new AMC. To evaluate its effectiveness, they compared it with trastuzumab-emtansine (T-DM1, Kadcyla®), a well-known and FDA-approved AMC [73]. The comparison revealed that the AMC produced by the AJICAP® methodology enables therapeutic index expansion. Therefore, this conjugation technology has a solid potential to create a new generation of AMCs characterized by high homogeneity and robust in vivo stability [73]. In another study, Scribner et al. investigated the anticancer potential of IMGC936, a novel AMC targeted against ADAM metallopeptidase domain 9 (ADAM9), a transmembrane protein overexpressed in several types of cancer [43]. IMGC936 demonstrated cytotoxicity against ADAM9-positive human tumor cell lines and potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models. Moreover, IMGC936 exhibited an acceptable safety profile in cynomolgus monkeys and favorable pharmacokinetic properties. These auspicious preclinical outcomes prompted the first clinical study of IMGC936 in patients with advanced solid tumors, with expected results by 2024 [43]. Additionally, Li et al. evaluated the preclinical activity of STRO-001 in B-cell non-Hodgkin lymphoma (NHL) models, given that overexpression of CD74 has been observed [74]. STRO-001 is an anti-CD74 ADC comprised of an anti-CD74 aglycosylated human IgG1 antibody conjugated to a non-cleavable dibenzocyclooctyne (DBCO) linker maytansinoid warhead in a site-specific manner. This results in a predominantly single-species ADC with a drug-antibody ratio (DAR) of 2 [75]. The study assessed the cytotoxicity of STRO-001 in NHL cell lines and its antitumor efficacy and toxicity in xenograft NHL models. STRO-001 exhibited nanomolar and sub-nanomolar cytotoxicity in 88% of the cancer cell lines evaluated. Furthermore, potent cytotoxicity was targeted to proliferating B cells, while a diminished cytotoxicity was observed on naïve human B cells. In vivo diffuse large B-cell lymphoma (DLBCL) models SU-DHL-6 and U2932 exhibited a linear dose–response relationship. Moreover, tumor regression was observed at lower doses than 5 mg/kg, with maximal activity and complete cures induced at 10 mg/kg. Additionally, STRO-001 demonstrated significant efficacy in prolonging survival or inducing tumor regression in MCL Mino and Jeko-1 xenografts, respectively, at doses as low as 3 mg/kg. This resulted in tumor eradication in both models [74]. These findings provide support for the current clinical trials of STRO-001 in patients with B-cell NHL. Therefore, preclinical studies consistently highlight that AMCs represent advantageous systems for effectively delivering maytansinoids.These systems can inhibit tumor growth and simultaneously provide high specificity, stability, and tolerability (Table 1). The observed efficacy and safety profiles across in vitro and in vivo studies demonstrate the translational potential of AMCs. In vitro models highlight the direct cytotoxic effects of AMCs on cancer cells, whereas in vivo studies provide evidence of their pharmacokinetics, tolerability, and sustained antitumor activity in more complex biological environments. These complementary findings underscore the role of AMCs in bridging laboratory research and clinical applications, supporting their development as a fundamental approach for targeted cancer therapy.

Table 1.

Compound, strategy, preclinical studies, and significant positive outcomes of included preclinical studies

Compound	Strategy	Preclinical studies	Positive outcomes	References
DM1	PUFAylation: conjugation with a polyunsaturated fatty acid	In vivo: tumor xenograft-bearing mouse model	Similar antitumor effects to free DM1 with less adverse effect	[76]
DM1	Conjugation to gold nanoparticles (GNs)	In vivo: mouse models of hepatocellular carcinoma	Improved potency and tolerability of the GN-DM1 when compared to the DM1 analogs	[77]
DM1	AJICAP®: a novel chemical conjugation for modification of antibodies in a site-specific manner by IgG Fc-affinity peptide-based reagents	In vivo: rat safety study	Therapeutic index expansion compared to the currently FDA-approved trastuzumab-emtansine (T-DM1, Kadcyla®)	[73]
DM21-C	Antibody-maytansinoid conjugates (AMC) targeted against ADAM metallopeptidase domain 9	In vitro: cytotoxic potency; Bystander Activity In vivo: tumor xenograft studies on Female CD-1 Nude mice; Toxicology study conducted using cynomolgus monkeys (Macaca fascicular’s)	Cytotoxicity toward ADAM9-positive human tumor cell lines; potent antitumor activity; and acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties	[43]
Non-cleavable dibenzocyclooctyne (DBCO) maytansinoid linker	Anti-CD74 aglycosylated human IgG1 antibody (SP7219) conjugated to a non-cleavable dibenzocyclooctyne (DBCO)-maytansinoid linker-warkead	In vitro: nanomolar and sub-nanomolar cytotoxicity in non-Hodgkin lymphomas cell lines In vivo: Linear dose–response in DLBCL models; prolonged survival or induced tumor regression in MCL Mino and Jeko-1 xenografts	Nanomolar cellular potency; potent cytotoxicity on proliferating B cells and diminished cytotoxicity on naïve human B cells; significant anti-tumor in DLBCL and MCL xenografts	[74]

Role of nanotechnology in maytansinoids’ delivery

The therapeutic potential of maytansinoids in cancer treatment is hindered by their poor water solubility and associated toxic side effects. Nanotechnology has emerged as a transformative approach to address these limitations and optimize the delivery of maytansinoids specifically to tumor sites.

Nanocarriers and nanoparticles: a paradigm shift

In 2014, the National Research Council defined nanotechnology as a novel technological paradigm, offering a revolutionary change in resolving technological problems and generating innovative processes and products [78]. Nanosystems (nanoparticles, nano-devices, and nanofibers) are commonly referred to as engineered materials from 1 to 100 nm; however, in specific contexts, such as the pharmaceutical industry, the upper limit extends to approximately 1000 nm [79]. These products have demonstrated remarkable accomplishments across diverse fields, such as waste management, computational science, biomedical engineering, and drug delivery. The entrapment of molecules within nanostructures, serving as controlled delivery systems, has significantly improved the transport of small, insoluble, and thermally sensitive drugs [80–82]. This advancement has dramatically enhanced the medical potential of such compounds. In the context of cancer, nanoparticles have emerged as a strategic solution to overcome the limitations associated with conventional treatments. For example, evidence suggests that nanotechnology can enhance the membrane transport properties of anticancer drugs. Nanoscale carriers allow these drugs to cross biological barriers and efficiently reach tissue or organ targets. Furthermore, encapsulating biomolecules within nanosystems could increase their bioavailability and improve their bodily distribution. Consequently, therapeutic anticancer effects would be amplified while minimizing drug-associated side effects and degradation. Additionally, the half-life of drugs can be extended through this approach [83]. In this context, recent studies have investigated the encapsulation of maytansinoids within diverse nanocarriers, revealing promising enhancements in their anticancer properties and reduced toxicity. These studies underscore the potential of nanotechnology to revolutionize drug delivery and improve patient outcomes in cancer therapy.

Nanotechnology approaches for enhancing maytansinoid delivery

As previously discussed, the clinical utility of maytansinoids as free drugs is hampered by systemic toxicity and non-selectivity, posing challenges for preclinical and clinical investigations [76]. In response, recent years have witnessed the application of nanotechnology-based solutions to address these complexities, enabling efficient loading of maytansinoids and their derivatives. Notably, DM1 has been encapsulated within different nanostructures, yielding promising results in chemotherapy.

For example, Xie et al. covalently coupled the DM1 agent to polyethylene glycol (PEG)-block-polylactide (PLA) with varying molecular weights. Through a maleimide-thiol reaction, they obtained two prodrug constructs: PGE_2K-PLA_2K-DM1 and PEG_2K-PLA_4K-DM1. These constructs were rigorously evaluated in vitro and in vivo, directly compared with DM1 physically encapsulated in nanosystems based on the same polymers and free-DM1. Notably, the polymeric prodrugs significantly mitigated DM1 toxicity, resulting in a 14–16% body weight loss in tested mice, as opposed to the approximately 30% weight loss and subsequent mortality observed in animals treated with the free form. Furthermore, the prodrugs exhibited remarkably higher antitumor potency than the free drug form in a tumor xenograft-bearing mouse model. In 2020, researchers employed a nanosystem based on polylactic co-glycolic acid-block-PEG to encapsulate nitrosylated DM1 (DM1-NO). The synergic effect of DM1-NO caused the inhibition of microtubule polymerization and the formation of highly toxic radicals, ultimately leading to tumor suppression [84]. The nanoparticles (DM1-NO-NPs), obtained through nanoprecipitation, exhibited an entrapment efficiency of 43% and a hydrodynamic diameter of 78 nm. In vivo evaluations conducted with H1299 tumor-bearing nude mice revealed that combining DM1-NO-NPs with radiotherapy led to significantly higher tumor inhibition. Specifically, the tumor suppression rate was enhanced by a remarkable 9.64-fold compared to radiotherapy treatment alone. Similarly, the administration of DM1-NO-NPs demonstrated higher tumor inhibition than DM1-NO or DM1-NPs alone, all in conjunction with radiotherapy. Zein has also been utilized as a carrier to encapsulate DM1, allowing evaluation of its tumor efficacy in A549 tumor-bearing mice. Comparisons were made with the free form of DM1, revealing inhibition rates of 97.3% and 92.7%, respectively [44]. On the other hand, Huang et al. introduced a novel strategy known as PUFAylation to modify the maytansinoid compound DM1 by attaching a polyunsaturated fatty acid (PUFA) [76]. They conducted a preclinical study on two types of nano self-assembled (NAs) PUFAylated prodrugs (i.e., dSS-DM1 and dMT-DM1) in a BALB/c nude mouse model bearing cell-derived xenografts. Advancements in DM1 delivery, such as DM1-NO-NPs and PUFAylated DM1, have shown reduced systemic toxicity and enhanced antitumor effects in preclinical models. DM1-NO-NPs, which achieved significant tumor suppression in xenografted mice, represent a potential candidate for early-phase clinical trials to assess pharmacokinetics and tolerability in humans. PUFAylated DM1, with demonstrated ability to address drug resistance, provides a basis for developing therapies targeting resistant cancers in clinical settings. These delivery systems mark progress toward translating preclinical findings into clinical applications. Remarkably, dMT-DM1 NAs exhibited antitumor effects comparable to free DM1 (p > 0.05), minimizing adverse effects such as weight loss. Notably, dMT-DM1 NAs demonstrated superior therapeutic efficacy against drug-resistant cervical cancer, offering a potential alternative for treating paclitaxel-resistant cervical cancer [76]. Porter et al. explored the attachment of gold nanoparticles (GN) to DM1, assessing its impact on tumor growth inhibition in mouse models of hepatocellular carcinoma [77]. By enhancing the stability of the drug-gold linkage, they improved the potency and tolerability of GN-DM1 compared to DM1 analogs. The authors suggested that the cytotoxic formulations could find applications beyond oncology, including antibody conjugation systems. These studies represent a significant advancement in the field, offering potential solutions to enhance the therapeutic efficacy of maytansinoids while minimizing adverse effects. The utilization of nanotechnology holds promise for revolutionizing drug delivery and improving patient outcomes in cancer treatment. In this regard, utilizing nanosystems for cancer treatment represents a pivotal objective in developing this emerging technology. However, safety concerns appear as researchers face translational challenges and seek regulatory approval for human use [82, 85, 86]. Although nanostructures designed to deliver cytotoxic agents are planned to target tumor cells selectively, they can inadvertently impact healthy cells. Ideally, anticancer nanoparticles should accumulate within the tumor microenvironment, releasing their cytotoxic molecules. However, recent reports indicate that entrapped molecules are not confined solely to the core of nanoparticles; they also reside on the surface of these systems. This dual localization raises concerns about the unintentional release of cytotoxic agents in healthy tissues. Moreover, nanoparticles can potentially influence the pharmacokinetics of coadministered drugs, leading to drug interactions and the emergence of microtoxic effects. To address these complexities, rigorous preclinical models are essential for evaluating the efficacy and safety of anticancer nanosystems, providing insights that accurately reflect potential human side effects. In addition to current nanotechnology-based delivery systems, emerging technologies hold promise for enhancing the targeted delivery of maytansinoids. CRISPR-based delivery systems could allow for precise genetic modifications to improve therapeutic targeting, while extracellular vesicles, such as exosomes, may serve as natural carriers to enhance drug stability and reduce immunogenicity [87]. These innovative approaches represent exciting future directions for improving the efficacy and safety of maytansinoid therapies. Nanotechnology-based drug delivery systems face several challenges despite their potential [88]. Achieving precise targeted release remains complex, as unintended interactions with healthy tissues and premature drug release can reduce therapeutic effectiveness [89]. Manufacturing scalable and reproducible nanoparticle systems poses technical and cost-related difficulties, further complicating clinical translation [89]. Regulatory approval is another significant hurdle, requiring extensive testing to establish safety, efficacy and quality standards. These challenges highlight the need for continued research and innovation to refine nanocarrier design and streamline the path to clinical application.

Nano-strategies to overcome drug resistance in cancer

Cancer cells possess the ability to develop resistance to traditional therapies, which represents a challenge to create new treatments and strategies to overcome it. Usually, cancer resistance is classifiied into two types: intrinsic resistance (also named primary resistance) and acquired resistance [90, 91]. Intrinsic resistance arises from endogenous factors within tumor cells before treatment, enabling them to adapt to initial therapeutic stress and enhance their survival capabilities. On the other hand, the acquired resistance results from adaptive changes in response to a given therapy, ultimately leading to treatment failure. Although these resistance types are distinct, many tumors exhibit resistance due to overlapping mechanisms. Various mechanisms contribute to cancer resistance, whether intrinsic or acquired. Among the most common are increased drug efflux pumps, reduced drug uptake, drug inactivation, evasion of apoptosis and immune surveillance, alterations in drug targets, phenotypic switches, and modifications in signaling pathways [90, 92, 93]. Concerning ADCs, resistance mechanisms are classified based on changes in antigen expression, processing of the ADC, and alterations in chemotherapy payload. T-DM1 resistance has been extensively studied in the case of maytansinoids since its clinical approval. Investigations have highlighted that the most frequently reported resistance mechanisms are associated with dysfunctional intracellular metabolism of T-DM1 and DM1-mediated cell death [94, 95]. Addressing drug resistance in cancer remains challenging due to tumor heterogeneity and the dynamic nature of their evolution. One widely explored approach involves combinational therapy, wherein two or more drugs simultaneously target multiple driver genes. This strategy aims to impede the emergence of new mutations resistant to multidrug treatments; in the case of ADCs, combining therapies is also recommended, and novel drug design strategies focus on modifying the payload, linker chemistry, or predictive biomarkers [91, 96]. In addition to existing approaches, researchers have dedicated substantial time and effort to explore novel solutions and strategies to improve drug efficacy. Among these, nanomedicine has emerged as a promising treatment platform, offering the potential to overcome drug resistance and opening new horizons in cancer therapy. Nanosystems possess several inherent advantages that can be harnessed to prevent resistance mechanisms. For example, one notable advantage lies in using nanoparticles as delivery agents for anticancer drugs. Using nanocarriers that predominantly enter cells via endocytosis minimizes drug expulsion by efflux pumps. These nanoparticles release the drug within the cell, away from cell membranes and efflux pumps, thereby enhancing drug retention [97, 98]. Nanocarriers such as polymer-based carriers and gold nanoparticles improve drug absorption and controlled release through specific mechanisms [99]. For instance, PEGylation (the attachment of polyethylene glycol, or PEG) enhances drug stability by protecting maytansinoids from enzymatic degradation and extending their circulation time in the body [100]. Polymer-based carriers, like polylactic-co-glycolic acid (PLGA), can improve the solubility of maytansinoids and provide sustained drug release through gradual degradation in the tumor microenvironment [101]. Gold nanoparticles act as effective carriers by improving drug delivery to tumors, enhancing cellular absorption, and increasing anticancer effectiveness, all without increasing systemic toxicity [102]. These mechanisms collectively enhance the bioavailability and therapeutic index of maytansinoids, representing a significant advancement in their delivery systems. Recent advancements have introduced innovative nanoparticle systems designed to combat drug resistance more effectively. For example, nanoparticles carrying two drugs simultaneously can target multiple pathways, addressing both intrinsic and acquired resistance mechanisms. These dual-drug systems enhance the therapeutic effect by overcoming efflux pumps and activating pro-apoptotic pathways within cancer cells. Nanoparticles designed to recognize specific tumor markers enable precise drug delivery to resistant cancer cells, minimizing off-target effects and improving treatment outcomes. On the other hand, another fundamental resistance mechanism involves cancer cells evading apoptosis. Nanoparticles can combat this by entrapping specific anti-apoptotic suppressors and activating pro-apoptotic pathways. For instance, Bcl-2-targeted siRNA or NF-κB inhibitors encapsulated within nanostructures have shown promising results in overcoming resistance. Furthermore, nanoparticles can simultaneously inhibit efflux pumps and promote apoptosis [103–105]. A dual mechanism can be achieved by encapsulating chemotherapeutic agents alongside molecules that inhibit efflux transporter expression, leading to multidrug nanoparticle approaches. Additionally, pH-responsive nanosystems offer a fascinating avenue for overcoming resistance. Since tumors often exhibit acidic microenvironments compared to blood and healthy tissues, nanoparticles based on pH-responsive materials (primarily polymers) can enhance tumor cell uptake. This approach improves treatment efficiency, facilitates targeted delivery, and reduces adverse drug reactions [106–108]. Furthermore, these pH-responsive nanocarriers can be employed as standalone therapy or in synergy with chemotherapy or immunotherapy. Finally, although the results are promising, early disease detection combined with vigilant therapeutic monitoring remains a fundamental strategy in combating drug resistance.

From lab to clinic: translational research in maytansinoid chemotherapy

In maytansinoid chemotherapy, translational research is pivotal in translating promising findings from preclinical investigations into effective treatments for cancer patients. This process faces fundamental challenges, including maytansinoid resistance, toxicity concerns, and patient interindividual variability. Translational research employs rigorous scientific investigation and experimentation to surpass these obstacles, aiming to enhance the therapeutic potential of maytansinoids for managing malignancies. By bridging the gap between fundamental scientific knowledge and practical clinical application, translational research contributes significantly to developing novel antineoplastic agents, ultimately improving outcomes for individuals affected by cancer [109].

Bridging the gap: the transition from preclinical to clinical research

Within the broader scope of medical research, AMCs have undergone extensive translational investigation aimed at optimizing their efficacy and exploring their potential as innovative therapeutic options for diverse types of cancer [110–113]. Specifically, the translational research involving AMCs encompasses several distinct stages:

1. First, the identification of candidate compounds and preclinical evaluation, where researchers begin by identifying AMCs with promising properties. These compounds undergo a rigorous preclinical assessment to evaluate safety, efficacy, and potential mechanisms of action. Preclinical studies on AMCs have identified key safety concerns, including neurotoxicity, hepatotoxicity and hematologic toxicities. These findings underscore the importance of balancing therapeutic efficacy and systemic toxicity. For example, dose-limiting toxicities observed in animal studies provide guidance for safe starting doses in human trials, with adaptive trial designs used to refine these regimens further.

2. Second, progression towarransitionind clinical trial phases for drug development, where successful candidates move from preclinical evaluation to clinical trials. These trials involve human subjects and assess the safety, tolerability, and effectiveness of AMCs. Transitioning from laboratory studies to clinical investigations is fundamental in bridging the gap between theory and practical application. Another challenge lies in addressing variations between animal models and human systems. For instance, organ-specific toxicities like liver damage seen in animal models may manifest differently in clinical settings. Close monitoring of organ function in trials is essential to address this variability. Additionally, the stability of linkers plays a pivotal role in AMC development. Instability may cause premature payload release and toxicity, while excessive stability can limit tumor targeting, underscoring the need for careful linker design.

3. Third, complementary studies are fundamental beyond clinical trials. Researchers focus on identifying biomarkers that can predict patient responses to AMC treatments. Additionally, they explore combination therapy approaches and investigate the underlying mechanisms of resistance [109]. Bon et al. [113] evaluated the effectiveness of T-DM1 as a second-line treatment for HER2-positive advanced breast cancer patients who had either received prior pertuzumab treatment or were pertuzumab-naïve. The study demonstrated that T-DM1 has lower activity in HER2 + breast cancer cell lines resistant to trastuzumab and pertuzumab. This reduced effectiveness of T-DM1 is attributed to the downregulation of HER2 expression on the cell membrane and its subsequent nuclear translocation, resulting from the previously acquired resistance to trastuzumab and pertuzumab. The downregulation of HER2 was further confirmed through patient biopsies from individuals who had undergone pretreatment with trastuzumab and pertuzumab. Additionally, the median overall survival from the diagnosis of advanced stage and the median progression-free survival to a second-line treatment were 52 and 6 months, respectively, for 177 patients who received trastuzumab/pertuzumab as first-line treatments. For 194 pertuzumab-naïve patients, the median overall survival was 74 months, and the median progression-free survival was ten months. The authors concluded that the combined administration of trastuzumab and pertuzumab reduced the availability of the plasma membrane HER2 receptor, thereby limiting the binding of T-DM1 to cancerous cells and resulting in decreased T-DM1 activity [113]. Gazzah et al. [112] conducted a phase 1 dose-escalation study to evaluate the safety, pharmacokinetics, and antitumoral activity of tusamitamab ravtansine in patients diagnosed with solid tumors. During the study, 31 patients received intravenous treatment every two weeks, progressively escalating doses. Dose-limiting toxicities were observed in 28 patients, including reversible grade 3 microcystic keratopathy in three patients at a dose of 120 mg/m² and two patients at a dose of 150 mg/m². Consequently, the maximum tolerated dose was established at 100 mg/m². Furthermore, 22 patients experienced treatment-emergent adverse events (TEAEs). Of these, seven patients underwent grade 3 or higher TEAEs, excluding three patients. The adverse events included decreased appetite, asthenia, keratopathy, and nausea. Pharmacokinetic analysis revealed that the maximum plasma concentration of tusamitamab ravtansine was reached at the end of intravenous administration, followed by a biphasic decline in concentrations. The study concluded that tusamitamab ravtansine demonstrated a favorable and safe profile characterized by reversible, dose-related keratopathy. The maximum tolerated dose was 100 mg/m² [112]. Dang et al. [111] assessed the efficacy of JBH492, a DM4-containing AMC that targets CC-chemokine receptor 7 (CCR7) in lymphoid cancers. This evaluation involved in situ hybridization on human and cynomolgus monkey normal tissue microarrays. Additionally, the expression of CCR7 was studied using RNA sequencing. In vitro and in vivo assays were performed on various preclinical models of these malignancies. The safety of this treatment was evaluated in repeat dose toxicity studies in cynomolgus monkeys. The authors found that CCR7 is strongly expressed in lymphoid cancers, while its expression is diminished in healthy tissue. JBH492 demonstrated potent, target-dependent cytotoxic activity, as evidenced by in vitro binding studies showing avidity-driven binding to CCR7-expressing cells compared to healthy immune cells. Notably, JBH492 exhibited a dual mechanism of action, combining payload-mediated cytotoxicity with the blockade of ligand-induced CCR7 signaling through antibody antagonistic functionality. In vivo studies indicated robust and long-lasting efficacy across various lymphoma models, with a favorable safety profile and no significant side effects. Thus, JBH492 has a high potential as an AMC for treating CCR7-expressing lymphoid tumors. Currently, the drug is under testing in clinical trials in patients with refractory/relapsed chronic lymphocytic leukemia and non-Hodgkin’s lymphoma [111].

Zhou et al. [110] created a mechanistic quantitative systems pharmacology model for HER2-positive metastatic breast cancer. This model predicts and quantifies the effects of different treatments by simulating signal transduction and tumor growth kinetics. The study comprehensively assessed various second-line therapies, including tyrosine kinase inhibitors (TKIs), ADCs, and chemotherapy. The model accurately predicted the efficacy of different drugs and dosing regimens, including various combinations. The model demonstrated the effectiveness of T-DM1 in combination with TKIs, such as lapatinib and pyrotinib, for treating HER2-positive metastatic breast cancer. The combination of these TKIs with T-DM1 was found to be more effective than TKIs combined with capecitabine. The model’s predicted dose–response relationship indicated a synergistic effect between the TKIs when combined with T-DM1. Interestingly, a lower dosage of pyrotinib sufficed when combined with T-DM1 to achieve adequate tumor growth inhibition compared to regular single-agent doses. Conversely, higher doses of lapatinib were necessary to achieve a similar level of tumor inhibition when used alongside T-DM1. Furthermore, the combination of lapatinib with capecitabine and T-DM1 resulted in sustained tumor regression. However, administering T-DM1 followed by lapatinib and capecitabine yielded an even more potent effect. Fundamentally, in vivo experiments using SKBR3 xenografted mice confirmed the model’s predictions, demonstrating increased eradication of tumor growth when pyrotinib and T-DM1 were coadministered. This study underscores the effectiveness of using different TKIs in combination with T-DM1 as a feasible therapeutic strategy against HER2-positive metastatic breast cancer, potentially reducing dosages and subsequent toxicity for patients [110]. The findings on HER2 + breast cancer resistance mechanisms, particularly HER2 downregulation and translocation to the nucleus, could inform future drug design. Novel AMCs might be engineered to counteract these resistance pathways by targeting nuclear HER2 or preventing its translocation. Additionally, dual-targeting approaches could be developed to simultaneously address membrane-bound and nuclear HER2, enhancing therapeutic efficacy in resistant cancers.

Clinical studies

Several maytansinoid derivatives, mainly AMCs, are currently under clinical trials for the treatment of a variety of cancers (i.e., auristatin E and auristatin F) [62, 112, 114–116] (Table 2). Massard et al. evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC) [115]. The most frequently observed adverse events included thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). AMG 172 demonstrated a favorable pharmacokinetic profile despite these side effects in this patient population. Additionally, there was evidence of limited antitumor activity associated with this AMG. Notably, the safety and tolerability of AMG 172 aligned with expectations for this class of compounds [115]. Mirvetuximab soravtansine (MIRV) represents another AMC wherein the antibody is conjugated to the maytansinoid ravtansine (DM4) [116]. MIRV is undergoing a phase III randomized clinical trial involving platinum-resistant epithelial ovarian cancer patients. The study by Moore et al. revealed that MIRV did not yield significant improvements in primary endpoints compared to standard chemotherapy. However, intriguingly, MIRV demonstrated more favorable outcomes in secondary endpoints, particularly among patients exhibiting high folate receptor alpha (FRα) expression. Fundamental ly, MIRV exhibited a well-tolerated safety profile, which was comparatively more convenient than traditional chemotherapy [116]. As mentioned in the preceding section, preclinical investigations revealed promising outcomes for SAR408701 in treating CEACAM5-positive tumors [117]. Building upon these findings, Gazzah et al. conducted a series of clinical studies to assess the efficacy, safety, and anticancer activity of SAR408701 in patients with CEACAM5-positive solid tumors [112, 114]. The initial study evaluated the efficacy and safety of this AMC in patients with non-squamous non-small cell lung cancer (NSQ NSCLS) [114]. Among the 92 NSQ NSCLS analyzed patients, 28 exhibited moderate CEACAM5 expression, while 64 had high expression. Treatment involved intravenous administration of 100 mg/m² of SAR408701 every two weeks. Notably, the overall response rate was 7.1% in the moderate expression group, whereas the high expression cohort demonstrated partial responses in 13 patients, resulting in an overall response rate of 20.3%. Fundamental ly, patients previously treated with anti-PD1/PD-L1 therapies achieved an overall response rate of 17.8%. Additionally, 27 patients maintained stable disease, while 6 discontinued the trial due to TEAEs. Overall, SAR408701 exhibited promising antitumor activity in advanced NSQ NSCLS patients with high CEACAM5 expression, and its safety profile was more favorable than conventional chemotherapy. Notably, hematological toxicity was minimal, and keratopathy was reversible and manageable with dose adjustments [114]. In a subsequent phase I dose-escalation study, Gazzah et al. further explored the safety, pharmacokinetics, and preliminary antitumor effects of SAR408701 in patients with advanced solid tumors [112]. The authors emphasized that, among the 31 patients, the AMC demonstrated a favorable safety profile, with only limited instances of hematologic toxicity compared to docetaxel, a standard anti-tubulin treatment [112]. Currently, two AMCs, Kadcyla® and Elahere®, have received FDA approval for cancer treatment. Kadcyla® (trastuzumab emtansine), approved in 2013, is utilized to treat HER2-positive breast cancer, while Elahere® (mirvetuximab soravtansine-gynx) obtained FDA approval in 2022 for the treatment of adult patients with folate receptor alpha (FRα) positive, platinum-resistant, epithelial ovarian, fallopian tube, or primary peritoneal cancer [53, 118]. These AMCs have demonstrated efficacy in patients who have not responded to other treatments and have been associated with improved survival rates [118]. In summary, clinical trials have contributed valuable insights into the potential therapeutic applications of maytansinoid derivatives, emphasizing their role in advancing cancer treatment strategies. Further investigations are warranted to fully elucidate their clinical impact and optimize their use in oncology.

Table 2.

Preliminary clinical studies suggest the efficacy of maytansinoid derivatives in managing diverse cancers

Compound	Cancer type	Phase trial	Number of patients receiving the treatment	Positive outcomes	Side effects	References
AMG 172 (maximum tolerated dose 1.6 mg/kg)	Cell renal cell carcinoma (ccRCC)	1	10	favorable pharmacokinetic profile, limited antitumor activity	Thrombocytopenia, nausea, decreased appetite, vomiting, fatigue	[115]
AMG 172 (0.3–2.4 mg/kg)	Cell renal cell carcinoma (ccRCC)	1	21	six patients exhibited no substantial change in their condition, whereas two individuals recovered partially	13 patients had progressive disease	[115]
Mirvetuximab soravtansine (MIRV)	Epithelial ovarian cancer (EOC)	3	243	well tolerated, safe, favorable outcome in secondary endpoint, FDA approved	No significant improvement in progression-free survival	[116]
SAR408701 (doses of 100 mg/m2)	Non-Small Cell Lung Cancer (NSQ NSCLS)	2 (phase 3 underway)	92	promising, well tolerated, low hematological toxicity		[114]
SAR408701 (dose escalation)	NSQ NSCLS	1	31	favorable safety profile	Limited cases of hematologic toxicity	[112]

Future perspectives and research directions

Since the initial discovery of maytansine, its extraordinary potential as an anticancer agent has been increasingly recognized. The complex molecular architecture of maytansine, characterized by a macrolide core, a strained cyclohexane ring, and a polyketide side chain, has been identified as a pivotal factor in its biological activity. All the maytansinoids exert their therapeutic effect by perturbing microtubule dynamics, culminating in inhibiting cancer cell proliferation. This disruption triggers a cascade of cellular responses, including cell cycle arrest, mitotic checkpoint activation, and the induction of programmed cell death. However, the robust anticancer efficacy exhibited by these compounds is accompanied by significant side effects. In response to these challenges, researchers have developed derivatives such as AMCs, which offer improved pharmacokinetics and enhanced targeting capabilities [119]. These derivatives exhibit refined pharmacokinetic profiles and superior specificity; thus, they represent a promising avenue in cancer therapeutics by mitigating drug resistance and optimizing clinical outcomes while minimizing the collateral toxicity associated with the parent compounds [120]. Looking ahead, the horizon of maytansinoid research offers exciting prospects. Ongoing clinical trials, particularly those evaluating novel AMCs, aim to translate preclinical success into tangible clinical benefits. Concurrently, innovations in synthesis techniques and linker chemistries are anticipated to yield more potent and selective derivatives [18]. In the vanguard of these advancements is the integration of nanotechnology, which has facilitated the creation of cutting-edge pharmaceuticals and delivery systems. These technological advancements allow for the targeted release of maytansinoids and their derivatives within specific anatomical sites, thereby preventing or minimizing undesirable side effects [121]. The integration of biomarkers and diagnostic tools offers new possibilities for personalized maytansinoid-based cancer treatments. Biomarkers can help identify patients likely to respond to specific AMCs, tailoring therapies to individual needs and minimizing side effects. Advanced diagnostic tools, such as liquid biopsies and sequencing technologies, allow real-time monitoring of treatment responses, enabling precise adjustments to dosage or regimens based on tumor characteristics. Together, these innovations aim to enhance treatment effectiveness and improve patient outcomes.

Conclusions

In conclusion, the potent anticancer properties of maytansinoids and AMCs underscore the importance of ongoing research into their metabolic pathways, pharmacokinetics, and clinical applications. The unraveling of complex cancer pathophysiology may reveal new molecular targets, expanding therapeutic strategies and improving outcomes for patients. The development of maytansinoid-based therapies requires a collaborative approach, combining the expertise of chemists, biochemists, and clinicians to refine these agents and bring them closer to clinical integration. Nanoscale drug delivery systems, including liposomes and nanoparticles, have already entered clinical trials, demonstrating their potential to improve the pharmacological profile of maytansinoids by enhancing stability, reducing toxicity, and enabling precise targeting of diseased tissues. These advancements bridge the gap between theoretical promise and practical application, underscoring their relevance in modern oncology. As research continues to unlock the potential of maytansinoids, their integration into oncological care may redefine how we approach and manage cancer therapy. Their unique molecular mechanisms and nanotechnology-enabled delivery systems position them at the forefront of a transformative era in cancer treatment, offering more effective and patient-focused solutions.

Abbreviations

ADAM9

ADAM metallopeptidase domain 9

ADCs

Antibody–drug conjugates

AMCs

Antibody-maytansinoid conjugate

ccRCC

Clear cell renal cell carcinoma

CCR7

CC-chemokine receptor

DAR

Drug-antibody ratio

DBCO

Dibenzocyclooctyne

DLBCL

Diffuse large B-cell lymphoma

DMs

Maytansinoids derivatives

DM1

Thiolated maytansine derivative, also named Mertansine

DM4

Maytansinoid ravtansine

Elahere®

Mirvetuximab soravtansine-gynx

EOC

Epithelial ovarian cancer

ErbB2

HER2 receptor tyrosine kinase

FRα

Folate receptor alpha

GN

Gold nanoparticles

Kadcyla®

Trastuzumab emtansine

mAbs

Monoclonal antibodies

MIRV

Mirvetuximab soravtansine

NAs

Nano self-assembled

NHL

Non-Hodgkin lymphomas

NSQ NSCLS

Non-squamous non-small cell lung cancer

PEG

Polyethylene glycol

PLA

Polylactide

PUFA

Polyunsaturated fatty acid

SAR408701

Tusamitamab ravtansine

T-DM1

Trastuzumab-emtansine

TEAE

Related treatment-emergent adverse events

TKIs

Tyrosine kinase inhibitors

Author contributions

MP, IC, MA, FF, RA-R, MLM, HC, MLDP-A, CN-C, AR-M, DB, GL-G, JS-R, DC made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas that is revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.