Release date:2020/8/20 8:23:37
The development of anti-tumor drugs can be traced back to the middle of the twentieth century. It was discovered that nitrogen mustard destroys individual bone marrow and lymphatic tissues by targeting rapidly dividing cancer cells. These drugs include folic acid and purine analogs (methotrexate and 6-mercaptopurine), microtubule polymerization inhibitors/promoters (vinca alkaloids and taxanes), and DNA disruptors (anthracyclines and nitrogen mustard). Since early tumor treatment drugs not only target cancer cells but also kill all dividing cells in the body, serious side effects occur in patients, which greatly limits the dosage and the therapeutic index of the drug (maximum tolerated dose/minimum effective dose) is very low and the treatment window is narrow. Antibody-drug conjugates (ADC) drugs may achieve selective delivery of toxic compounds to specific cancer cells.

1. The First-generation ADC drugs
Among the first-generation ADC drugs, anti-tumor drugs such as mitomycin C, idarubicin, anthracyclines, N-acetylmarflan, doxorubicin, vinca alkaloids and methotrexate are mainly conjugated with the mouse monoclonal antibody by non-cleavable linkers (amide or succinimide) .

In 2000, the first antibody conjugate Gemtuzumab Ozogamicin (trade name: Mylotarg, Wyeth, Pfizer subsidiary) was approved by FDA, the target is CD33. This drus is endocytosed by the target cell, it will release calicheamicin by hydrolyzing linker, which induces double-stranded DNA breaks, leading to cell cycle arrest and apoptosis. This drug is used to treat CD33-positive acute myeloid leukemia.
 Gemtuzumab Ozogamicin
  The structure of Gemtuzumab Ozogamicin
It was subsequently found that Gemtuzumab Ozogamicin had no significant clinical advantage compared with other anticancer drugs and had severe hepatotoxicity. In 2010, a decade after it went public, Gemtuzumab Ozogamicin voluntarily withdrew from the market. The potential therapeutic defects of Gemtuzumab Ozogamicin include instability of the linker, which releases of 50% of the chemical in about 48 hours, the calicheamicin in the drug has high hydrophobicity, binding rate with monoclonal antibody is 50%, high toxicity, poor CMC. In addition, studies have shown that the monoclonal antibody Gemtuzumab can be removed from cells by efflux pump (MDR1 and MRP1), showing no significant clinical efficacy compared with other anticancer drugs.

2. The Second-generation ADC drugs
After the rapid development of monoclonal antibody drugs in the past 10 years and more effective small molecular anticancer drugs have been discovered, the Second-generation  ADC drugs have better CMC properties than the First-generation ADC drugs. Representatives of the Second-generation of ADC drugs included Brentuximab Vedotin, Ado- Trastuzumab Emtansine and InotuzumabOzogamicin.

However, the Second-generation drugs have a narrow therapeutic window, mainly due to low off-target toxicity,which competes with antibodies that do not bind small molecule drugs for tumor targets.The Second-generation ADC drugs has different drug antibody ratios (DAR) from 0-8. Commonly, it will show low tolerance, high plasma clearance efficiency and low in vivo efficacy when DAR over 4. For example, the DAR of Brentuximab Vedotin is 4, the DAR of Ado- Trastuzumab emtansine DAR is 3.5, and the DAR of InotuzumabOzogamicin is 6.
3. The Third-generation ADC drugs
The key to the Third-generation ADC drugs is site-specific binding, which ensures antibody conjugate drugs with a clear DAR. In addition, the Third-generation ADC drugs can significantly improve the therapeutic efficacy of ADC drugs in terms of antibody optimization, linkers, and binding of small-molecule drugs. The representative drugs are Polatuzumab vedotin, Enfortumab vedotin, and Fam-trastuzumab deruxtecan.
Through the specific binding of small molecule drugs and monoclonal antibodies, antibody-conjugated drugs with a DAR 2 or 4 can be developed without increasing drug toxicity and unbound monoclonal antibodies, significantly improving drug stability and pharmacokinetics, and increasing drugs activity and binding activity to cells with lower antigen levels.
4. 12 ADC drugs approved by FDA
Till now, a total of
12 ADC drugs have been approved by the FDA, they are ado-trastuzumab emtansine (Kadcyla™), brentuximab vedotin (Adcetris™), inotuzumab ozogamicin (Besponsa™), gemtuzumab ozogamicin (Mylotarg™) , Moxetumomab pasudotox (Lumoxiti™), polatuzumab vedotin-piiq (Polivy™), Enfortumab vedotin (Padcev™), Sacituzumab govitecan (Trodelvy), Trastuzumab deruxtecan (Enhertu™), belantamab mafodotin-blmf (Blenrep™) and loncastuximab tesirine-lpyl (ZYNLONTA™),  tisotumab vedotin-tftv (Tivdak).
In 2019, the FDA approved a total of 3 ADC drugs, which is the largest number of approvals for years, causing a lot of attention. ADC drugs use the specificity of antigens and antibodies to deliver toxic small molecule drugs to target cells with high precision. At the same time, ADC's industry technical barriers are higher than chemical drugs and general biological drugs. After decades of development, a total of 8 drugs have been approved by FDA.

In the future, ADC drugs will have a huge potential in the anti-tumor market. Biochempeg, a world-class R&D base for the development of PEG Derivatives. We offer the full range of PEG derivative development services and provide the most comprehensive media for conjugation research.
[1] Peters, C., & Brown, S. (2015).
Antibody–drug conjugates as novel anticancer chemotherapeutics. Bioscience Reports, 35(4),e00225.
[2] Abdollahpour‐Alitappeh, M, Lotfinia, M, Gharibi, T,et al. (2019).
Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes. J Cell Physiol , 234: 5628– 5642.
[3] Nolting, B. (2013). Linker technologies forantibody–drug conjugates. Methods in Molecular Biology, 1045, 71–100.
[4] Kyoji Tsuchikama, Zhiqiang An. (2018).
Antibody-drugconjugates: recent advances in conjugation and linker chemistries.
Protein Cell,9(1), 33–46.
Related articles:

Anti-Cancer ADC Drugs: 3 Design Elements, 11 Approved ADCs, Multiple Clinical Trials
[2] Overviews of the Antibody-drug conjugates (ADCs)
[3] ADCs Against Cancer: Clinical Landscape and Challenges
[4] History and Development of Antibody Drug Conjugates (ADCs)
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