ADCs Cytotoxin

ADCs Cytotoxin

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Antibody-drug conjugate (ADC) 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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More information About ADCs Cytotoxin

Cytotoxin Definition

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.

structure of antibody drug conjugate Fig. 1. Antibody drug conjugate structure.

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.

Types of ADC Cytotoxin

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:

mechanism of action of ADCs Fig. 2. Possible mechanism of action of ADCs (Br J Cancer. 2017, 117(12): 1736-1742).

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.

  • Tubulin Polymerization Enhancer (Auristatins)

Tubulin polymerization enhancers refer to cytotoxins represented by the auristatin compounds MMAE and MMAF. Usually acts on the β subunit of α and β tubulin dimers, causing unregulated growth of microtubules. 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.

  • Tubulin Polymerization Inhibitor (Maytansine)

Tubulin polymerization inhibitors refer to a class of cytotoxins represented by the maytansinoid compounds DM1 and DM4. Blocking the polymerization of tubulin dimers usually occurs by inhibiting the formation of mature microtubules. 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.

Compared with tubulin inhibitors, DNA inhibitors can destroy DNA through double-strand breaks, alkylation, chimerism, cross-linking, etc., act on the entire cell cycle, produce cytotoxic effects, and have good therapeutic effects on solid tumors. Common DNA inhibitors include topoisomerase I inhibitors, calicheamicin and antromycin.

DNA damage and DNA repair Fig. 3. DNA damage and DNA repair (Cancer Genet. 2021, 252-253: 6-24).

  • DNA Inserting Agent (Camptothecin)

Topoisomerase I inhibitors inhibit DNA replication and transcription by acting on DNA topoisomerase, leading to tumor cell death. 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, 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, 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.

The chemical structure of the DNA double-strand destroying agent contains an enediyne fragment. After entering the nucleus, this fragment undergoes a Bergman cyclization reaction to form a benzene ring diradical transition state, inducing DNA double bond cleavage. The representative of this type of toxin small molecule is calicheamicin γ1.

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. N-acetyl-γ1I-kachimycin, a derivative of kachimycin γ1I, is acetylated on the ethyl amino sugar structure of kachimycin γ1I. At the same time, in order to realize the connection with the amide type or hydrazone linker, its trisulfide bond structure is modified into a disulfide bond. Compared with other analogues isolated from fermentation broth (α2I, α3I, β1I, β1Br, γ1Br, δ1I), calicheamicin γ1I is the most cytotoxic.

  • DNA Alkylating Agent (PBD and Duocarmycin)

After binding to the DNA minor groove, DNA alkylating agents generally use functional groups that are easy to react with amino groups in the molecule, such as carbon-nitrogen double bonds or cyclopropane structures, to undergo nucleophilic reactions with guanine or adenine, forming inter-chain or intra-chain cross-linking in DNA to prevent its replication and transcription, leading to tumor cell death.

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. Among the ADC drugs currently on the market, loncastuximab tesirine-lpyl (Zynlonta) developed by ADC Therapeutics is an ADC drug targeting CD19 and consists of humanized IgG1κ mAb conjugated with SG3199. Among them, SG3199 is a cytotoxic PBD dimer alkylating agent. It is a PBD dimer composed of PBDs connected to each other through the C-8 position. Compared with a single PBD, the PBD dimer has a larger interaction area with DNA and can form two covalent bonds with guanine to fix the DNA more firmly. This also makes it have stronger cytotoxicity, and the effective inhibitory concentration against various tumor cells can reach the picomolar level.

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.

In Conclusion

In addition to the types of loaded toxins used in the above two types of marketed ADC drugs, toxins with various mechanisms of action have also been gradually used in ADC drug development, such as Bcl-xL inhibitors, RNA shearing enzyme inhibitors, RNA polymerase inhibitors, etc. Another type of novel toxin small molecules acts on cell membrane surface targets or tumor tissue matrix targets, and is used for the development of non-endocytic ADC drugs, such as sodium potassium ion pump ATPas (Na+/K+-ATPase) inhibitors, matrix metalloproteinases (MMP) inhibitors and immune agonists, etc.


  1. Staudacher, A.H. et al. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017, 117(12): 1736-1742.
  2. de Almeida, L.C. et al. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. Cancer Genet. 2021, 252-253: 6-24.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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