Antibody-Drug Conjugates (ADCs) combines the high specificity of monoclonal antibody drugs with the high activity of small molecule cytotoxic drugs to improve the targeting of cancer drugs and reduce toxic side effects. The mechanism of action involves using monoclonal antibodies to specifically target cancer cells, and kill the cancer cells by coupled small molecule drugs. BOC Sciences has an extensive catalog of ADC cytotoxins, including commercially available compounds and custom synthesis options. We offer a wide range of potent cytotoxic drugs that can be combined with antibodies for targeted cancer therapy.
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Fig. 1. Antibody drug conjugate structure.
Cytotoxins are toxic substances that can cause cell damage or death, typically by directly affecting the internal structures or functions of cells, thereby disrupting their physiological activities. Cytotoxins can specifically target cells, leading to dysfunction, membrane rupture, or programmed cell death (such as apoptosis or necrosis). These toxins are widely found in various organisms, including bacteria, fungi, plants, animals, and some animal venom secretions. ADC cytotoxin, also known as ADC payload, is an important component of ADC drugs. As shown in Fig. 1, ADC-antigen complexes are formed after ADC drugs generally enter the blood circulation and bind to target antigens on the surface of tumor cells. The ADC-antigen complex is then internalized into the cell, and the complex after lysosomal degradation releases the payload and induces tumor cell death. It can be said that the activity and physicochemical properties of the payload will directly affect the anti-tumor efficacy of ADC drugs.
Requirements for ADC linked toxins include: 1. Sufficient water solubility and stability in serum, because ADC may circulate in the body for several days; 2. Toxins must have functional groups that can be used to couple with the linker; 3. Toxins must be insensitive to enzymatic degradation reactions of lysosomes; 4. Toxins can reduce the aggregation effect (lipophilic substances tend to occur) and alter the interaction between ADC and pGp (permeability glycoprotein), which is the main cause of multipotent drug resistance (MDR) in tumor cells. In addition, for cleavable linker ADC, the side effect is that the toxin kills the target cells and then enters and exits the cell membrane to kill the surrounding cells. Such cleavable linker ADC requires a toxin with a certain lipid-water partition coefficient (LogP) and a positive/neutral charge.
Cytotoxins are drugs used to treat cancer and other diseases, primarily by disrupting cell functions or inducing cell death. They are commonly used in anticancer drugs, particularly in antibody-drug conjugates (ADCs). The following are classifications of several common cytotoxins:
These are a class of microtubule inhibitors that prevent cell division by disrupting the dynamic balance of microtubules, often used in cancer therapy.
These cytotoxins induce cell death by damaging the DNA double helix structure and are known for their potent antitumor activity.
They inhibit the activity of topoisomerase I, interfering with DNA replication and transcription, leading to DNA damage. They are commonly used for the treatment of various cancers.
These anthracycline antibiotics intercalate into DNA, inhibiting transcription and replication, and are widely used in the treatment of leukemia and other cancers.
These drugs bind to DNA and form cross-links, inhibiting DNA synthesis and exerting anticancer effects.
These drugs inhibit microtubule assembly, preventing cell division and are commonly used in targeted drug delivery systems.
These drugs bind to DNA and form cross-linking structures that cause DNA damage and induce cell death.
Traditional cytotoxins, such as platinum-based chemotherapy drugs, cross-link DNA to inhibit DNA replication and transcription, and are widely used in cancer chemotherapy.
Common toxins used in ADC drugs are extremely toxic and with little selectivity, which makes them difficult to use alone as small molecule drugs. These toxins have often been studied as chemical drugs in the past but have been abandoned due to their later emerged toxicity. The most commonly used cytotoxic drugs at present can be divided into several categories according to their mechanisms of action:
Fig. 3. DNA damage and DNA repair (Cancer Genet. 2021, 252-253: 6-24).
Tubulin inhibitors are currently the most widely used type of "warhead" in ADC drug development. The payload of 8 of the 15 ADC drugs on the market is tubulin inhibitors. Tubulin inhibitors interfere with the dynamic combination of microtubules by binding to tubulin, causing cells to stagnate in the G2/M phase of the cell cycle, ultimately leading to cell apoptosis. According to their different mechanisms of action, tubulin inhibitors can be further divided into tubulin polymerization enhancers and tubulin polymerization inhibitors.
DNA inhibitors are a class of cytotoxic agents that interfere with the integrity, replication, and repair of DNA. These inhibitors function through various mechanisms to prevent DNA synthesis or damage DNA directly, leading to cell cycle arrest and ultimately inducing cell death. DNA inhibitors are widely utilized in the treatment of cancers and certain infectious diseases, as rapidly dividing cells (such as tumor cells and bacteria) are particularly susceptible to DNA damage. Common DNA inhibitors include topoisomerase I inhibitors, calicheamicin and antromycin.
RNA polymerase inhibitors are a class of cytotoxins that specifically target the enzyme RNA polymerase, which is essential for the process of transcription in cells. Transcription is the process through which messenger RNA (mRNA) is synthesized from a DNA template, and it is crucial for the production of proteins that govern cell functions. By inhibiting RNA polymerase, these inhibitors block RNA synthesis, which prevents the production of proteins required for cell survival and proliferation. Amikacin is a typical RNA polymerase inhibitor, commonly used in antibacterial therapy.
DNA topoisomerases are essential enzymes involved in maintaining the topology of DNA during processes like replication, transcription, and recombination. These enzymes work by introducing temporary single- or double-strand breaks into the DNA helix, allowing it to unwind and untangle. After the DNA is unwound, the topoisomerase reseals the breaks, ensuring the DNA remains intact for further cellular processes. There are two main types of topoisomerases: Type I topoisomerases, which make single-strand cuts, and Type II topoisomerases, which make double-strand cuts.
The synthesis of cytotoxins can be carried out through various methods, including natural and synthetic approaches. Naturally occurring cytotoxins are typically produced by microorganisms, plants, or animals, such as snake venom, bacterial toxins, and fungal toxins. These natural toxins are synthesized through complex biochemical pathways involving enzyme-catalyzed reactions and metabolic processes. For example, certain bacteria produce toxins through the synthesis of peptide chains, which can bind to cell membranes via receptors and ultimately disrupt cellular structures. In laboratory settings, cytotoxins can also be artificially synthesized using genetic engineering techniques. Researchers can employ recombinant DNA technology to insert cytotoxin genes into host cells, utilizing expression systems to produce the desired toxins. These synthetic toxins can be used for research purposes or drug development, such as in immunotoxins for cancer therapy. During the synthesis of cytotoxins, it is often necessary to optimize the synthesis pathway to improve yield, purity, and activity.
Cytotoxin detection is an important method for assessing the impact of toxic substances on cell function. Commonly used methods include cell viability assays, enzyme-linked immunosorbent assays (ELISA), and chromatography techniques. Cell viability assays, such as the MTT assay and Cytotoxicity Assay, primarily evaluate the potency of cytotoxins by measuring cell survival rates. The MTT assay assesses cell viability by detecting the activity of intracellular reductases, which convert tetrazolium salts into purple products, reflecting cell survival. ELISA uses the specific binding of antibodies to cytotoxins to quantitatively detect toxin concentrations in serum or culture media. Chromatographic techniques (such as liquid chromatography and gas chromatography) effectively separate and quantify cytotoxins, providing structural information about the toxins. Additionally, fluorescence labeling techniques are widely used for real-time monitoring of changes in cells under toxin exposure, such as membrane integrity and cell death. These detection methods provide reliable technical support for toxin screening, drug development, and environmental monitoring.
Cytotoxin linkers, also known as cytotoxic drug linkers, are chemical entities used in the design of targeted therapies such as ADCs. These linkers play a crucial role in attaching a cytotoxic or anti-cancer drug to a monoclonal antibody (mAb), enabling the targeted delivery of the drug to specific cancer cells while minimizing damage to healthy tissues. The linker acts as a bridge, connecting the cytotoxic payload (usually a highly potent toxin) to the antibody, allowing for its selective release upon internalization by the targeted cell.
| Types | Description |
| MMAE and MMAF | MMAE is essentially demethylated auristatin E (auristatin E), that is, the N-terminal amino group has only one methyl substituent instead of two methyl substituents like auristatin E itself. MMAE contains four amino acids: monomethyl valine (MeVal), valine (Val), doleisoleucine (Dil) and doraproline (Dap), and the carboxyl-terminal amino demethylephedrine. In MMAF, the C-terminus of monomethylvaline is replaced by phenylalanine, and its cellular activity is significantly reduced. The current clinical applications are represented by Brentuximab vedotin, Polatuzumab vedotin, and Bellantumab vedotin. |
| Maytansine | Maytansine was first isolated from maytansine in the Americas in 1972 as a nineteen-membered macrolactam structure. Although the anti-proliferative effect of maddenin on most cancer cell lines at the sub-nanomolar concentration level is obvious, the lack of selectivity to cancer cells has caused serious side effects in patients in early clinical trials and has not been applied in clinical practice. Until the emergence of the concept of ADC in the early 1980s, some medicinal chemistry researchers artificially modified maytansine and successively synthesized maytansine derivatives. Among them, DM1 and DM4 are the two most commonly used maytansine derivatives in clinical applications. Both are thio derivatives in which the C-3 position of maytansine has been modified. The difference lies in the group connected to the sulfhydryl group. DM1 is -CH2-CH2-S-, and DM4 is -CH2-CH2-C(CH3)2-S-. The current clinical use of the two drugs is represented by Kadcyla and Elahere respectively. |
| Tubulysins | Tubulysins (Tubulysin A, Tubulysin B, Tubulysin M, etc.) is a polypeptide antimitotic drug isolated from myxobacteria. It can inhibit the aggregation of tubulin during mitosis, induce cell death, and avoid efflux related to DM1 resistance. The structures of these compounds all have carboxyl functional groups. This hydrophilic group increases the polarity of the toxin small molecule and avoids the efflux effect of the P-gp pump. The toxin plays a killing effect after entering the tumor cells with the ADC molecule. However, at the same time, due to the decrease of cell membrane penetration ability, it cannot spread to the surrounding tumor tissue, so it does not have a bystander effect. |
| Camptothecin | Topoisomerase I inhibitors are represented by camptothecin, which forms a cleavable complex with DNA in the form of a covalent bond, thereby generating a single-stranded nick; the other undamaged single strand rotates back from the gap, relaxing the supercoiled DNA to facilitate replication and transcription; when the unwinding is completed, topoisomerase I breaks away and promotes the recovery of the DNA chain. Clinically used camptothecins are represented by DXd and SN-38. |
| DXd | DXd, a DX-8951 derivative, is a new, highly membrane-permeable topoisomerase I inhibitor. By acting on topoisomerase I, it inhibits the spatial structure changes required by chromosomal DNA during the replication process, thereby blocking the DNA replication process and causing cell death. DXd has strong anti-tumor activity, nearly 10 times higher than that of SN-38. The short half-life in the blood is beneficial to reducing the occurrence of toxic side effects. In addition, DXd has strong cell membrane penetration ability, produces a bystander effect, can kill nearby tumor cells, and has a shortened half-life. Among the ADC drugs currently on the market, AstraZeneca/Daiichi Sankyo’s DS-8201 selects Dxd as the payload. |
| SN-38 | SN-38, also known as 7-ethyl-10-hydroxycamptothecin, is a semi-synthetic camptothecin. SN-38 is a metabolite of irinotecan and its main anti-tumor component. Its inhibitory activity is 2 to 3 orders of magnitude stronger than that of irinotecan. However, due to its high hydrophobicity and toxicity issues, it can only be administered in the form of prodrugs. The hydroxyl group at the C-20 position of SN-38 has the effect of reducing the degradation rate of the lactone ring in vivo, and can also be connected to a linker for the development of ADC. Among the ADC drugs currently on the market, Sacituzumab govitecan, developed by Immunomedics, uses SN38. |
| Calicheamicin | Calcheamicins (CLM) is an enediyne anti-tumor antibiotic isolated from rare actinomycetes and is one of the most cytotoxic natural products. Calchinomycin mainly binds to the minor groove of specific sequences of cellular DNA, inducing cellular DNA fragmentation, thereby leading to tumor cell apoptosis. However, calicheamicin can also cause damage to normal cell DNA. Based on this, the clinical application of calicheamicin is limited. Nonetheless, calicheamicin's high cytotoxicity, small molecular weight, and well-defined mechanism of action make it an attractive ADC payload. Among the currently marketed ADC drugs, Gemtuzumab Ozogamicin (trade name Mylotarg) and Inotuzumab Ozogamicin (trade name Besponsa) both use N-acetyl-γ1I calicheamicin. |
| Antromycin | Antromycin is an anti-tumor antibiotic isolated from Streptomyces refuineus in the 1860s by Leimgruber et al. It belongs to the pyrrolobenzodiazepine (PBD) family. PBD compounds are composed of aromatic A ring, 1-4-diaza-5-1 B ring and pyrrolidine C ring. The mode of action is selective alkylation in the small grooves of DNA. The amino group at the C-2 position of guanine in the DNA minor groove forms a covalent bond with the electrophilic imine group at the N-10/C-11 position of the diazacyclo, fixing the spiral structure of DNA, blocking the cell division process, arresting the cell cycle in the G2/M phase and leading to apoptosis. |
| Docarmycin | Docarmycin is a powerful cytotoxic substance that binds to the minor groove of DNA through its highly active cyclopropane ring and alkylates adenine at the N3 position. The acyclic, halomethyl form of docarmycin has significantly reduced cytotoxic activity. Since the phenol group in the molecule can act as a meso activator, thereby forming an electrophilic cyclopropane, the connection strategy in the development of docarmycin ADC focuses on the linker connection of the phenolic functional group. |
Cytotoxins are most widely used in cancer treatment. By targeting cancer cells, cytotoxins effectively inhibit tumor growth. Traditional chemotherapy drugs, such as cisplatin and paclitaxel, are also cytotoxins, and their mechanisms of action typically involve interfering with DNA replication or cell division in cancer cells, thereby triggering cell death. These drugs have been widely applied in the treatment of various types of tumors, including lung cancer, breast cancer, and ovarian cancer.
In recent years, cytotoxins have been combined with monoclonal antibodies to form ADCs, a treatment modality that shows great potential. ADCs precisely deliver cytotoxins to cancer cells, overcoming the toxic effects of traditional chemotherapy drugs on healthy cells. Cytotoxins, as the "toxic payload" of ADCs, are specifically targeted to tumor cell surfaces via antibodies, where they release the cytotoxins to directly kill cancer cells. Commonly used cytotoxins in ADCs include mitotic inhibitors like Mertansine and DNA-damaging agents like Doxorubicin.
Cytotoxins also play an important role in immunotherapy. For example, cytotoxins can activate T cells or other immune system cells to exert cytotoxic effects, effectively combating tumor cells. Additionally, some genetically engineered bacteria or viruses have been designed to produce cytotoxins, which activate the immune system and directly attack cancer cells, thereby enhancing the efficacy of cancer immunotherapy.
In addition to their widespread use in cancer treatment, cytotoxins also hold potential in combating infections. Natural cytotoxins produced by certain bacteria, fungi, or viruses can exert antimicrobial effects by inhibiting or killing pathogenic microorganisms. For instance, certain bacterial toxins (such as diphtheria toxin and tetanus toxin) target specific cells, inhibiting their biosynthetic functions, thus eliminating invading pathogens. Furthermore, some cytotoxins are being used in the development of antiviral therapies to help control infections caused by viruses like HIV and influenza.
Gene therapy uses the cell-killing ability of cytotoxins to treat genetic diseases. For example, by introducing genes that encode cytotoxins into target cells, cytotoxins can be released in specific cells to selectively kill diseased cells. This approach is not limited to cancer treatment but has also been explored in the treatment of genetic immune deficiencies. By directing the expression of cytotoxins, diseased or infected cells can be removed while minimizing the impact on normal cells.
Cytotoxins also have important applications in vaccine development. Through genetic engineering, scientists can modify cytotoxins to serve as vaccine carriers. These modified toxins can trigger immune responses while reducing their toxicity to the human body. Such vaccines effectively enhance the immune system's defense against pathogens while minimizing side effects and adverse reactions.
A neurotoxin is a type of toxin that affects the nervous system by damaging the structure or function of nerve cells, typically interfering with nerve conduction or causing nerve damage. A cytotoxin, on the other hand, is a toxic substance that harms or kills cells directly, with effects that are not limited to nerve cells and may impact various types of cells.
An exotoxin is a toxin secreted by bacteria into the external environment, typically with high specificity, disrupting the host's immune system or cellular functions. A cytotoxin is a toxin that directly damages or disrupts the structure or function of cells and can be produced by bacteria, viruses, or other organisms, with effects not limited to bacterial secretion.
An enterotoxin is a toxin that affects the function of the gastrointestinal tract, often secreted by bacteria like Escherichia coli or Salmonella, and can cause diarrhea or gastrointestinal discomfort. A cytotoxin is a type of toxin that directly damages cells, and its effects are not limited to the gastrointestinal tract but can impact various types of cells.
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