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The key to successfully develop an ADC drug

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Anti-drug conjugate (ADC) is an antibody that binds to cytotoxic drugs and targets cytotoxic drugs to tumors through the targeting of antibodies, thereby reducing the non-specific systemic toxicity of drugs commonly found in chemotherapy. The study of antibody-drug conjugate (ADC) can date back to 1980s.

A successful antibody drug conjugate drug includes four main parts: a suitable target (tumor antigen), a highly specific antibody, an ideal linker, and a highly cytotoxic drug.

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Firgure. The model of ADC action

  1. The basis for target selection

Nowadays, ADC drugs are mainly used for anti-tumor. When selecting a target, the ideal target antigen should be overexpressed on the surface of tumor cells, but no expression or very low expression in normal tissues. Moreover, when the antibody and the target are aggregated in the ADC drug, it can be effectively internalized, and the drug is released into the cell to kill the target cell.

  1. Antibody specificity, affinity, and pharmacokinetics

The high affinity of the antibody and the target antigen is the core of the effective targeting of the ADC. It is generally believed that the affinity index KD 10 nM is a basic requirement for the antibody. On the basis of this, antibodies that are low in immunogenicity, long in half-life, and stable in blood are screened.

  1. Selection and intracellular drug release

The ideal linker can maintain stability in the blood and effectively release the drug in the target cells. The commonly used Linkers can be divided into two categories: cleavable linkers and non-cleavable linkers. The current study found that seven B cell receptors (CD19, CD20, CD21, CD22, CD79b, and CD180) have effective effects by cleavable linkers. In contrast, when non-cleavable linkers are used, only CD22 and CD79b antigens can bind to the antibody, effectively transport ADC to lysosomes, and release the drug to kill target cells. Therefore, when choosing which linker to be uses, the nature of the target should be considered.

  1. Selection of cytotoxic drugs

Since the antibody enters the body and can effectively enter the tumor site by about 0.003–0.08% of the total amount, it is necessary to have a highly effective and highly sensitive killing effect on the target cells (free drug IC50: 10-1 1–10-9M). ). There are two main types of commonly used drugs at present - microtubule inhibitors and DNA-damaging agents.

ADC development trend

  1. Site-specific conjugation

At present, the most advanced ADC drugs are using traditional no-specific conjugation. The biggest disadvantage is that the product obtained is a mixture of different drug molecules per antibody. Site-specific conjugated drugs, and more importantly, uniform data (eg, PK) for clinical evaluation is difficult to obtain. In oder to solve these shortcomings, site specific conjugation technology has become a hot spot for major companies. Using site specific conjugation techniques, the same number of drug molecules can be carried on each antibody to obtain a uniform ADC drug. It is conducive to pharmacodynamic research and evaluation. And in the clinical can get more stable and effective results. Among them, A mbrx's Unatural Amino acid (pAcPhe) technology has more applications and promotion prospects.

  1. Multivalent ADC drugs

The development of antibody drugs and vaccines has progressed from monovalent drugs to multivalent drugs. ADC might also follow this development process, that is, to link several small molecules that are synergistic with each other in the same antibody to improve the drug's efficacy. This requires a more sophisticated conjugation technology, to integrate two or more technologies. But now, the site-specific technology, excessively pursuits the coupling of a specific molecules at a specific site and neglects the diversity of coupling.

Practical and traditional techniques for multivalent coupling of drugs require simultaneous coupling of multiple drugs on one antibody. In this case, the singularity of the antibody itself to modify the linking group will result in a mixed product, and there is no guarantee that each antibody carries a different drug at the same time.

This problem can be solved by Site-specific techniques. When performing Site-specific modification, a variety of different coupling groups can be designed, which can use a group to carry out drug couples for the linker with the corresponding group.

Monoclonal antibodies and their conjugates are macromolecular substances. Large drug molecules are difficult to penetrate deep into the solid tumor through the capillary endothelium and through the extracellular space of the tumor. The use of antibody fragments, such as Fab, to prepare conjugates with lower molecular weight, may increase the permeability to the extracellular space and increase the amount of drug reaching deep tumor cells. "Small size or moderate miniaturization is an important way to develop ADC drugs."

Reference

  1. Beck, Alain, et al. "Strategies and challenges for the next generation of antibody–drug conjugates." Nature reviews Drug discovery 16.5 (2017): 315.
  2. Okeley NM, et al. (2010) Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res 16:888–897.
  3. Wu AM, Senter PD (2005) Arming antibodies: Prospects and challenges for immunoconjugates. Nat Biotechnol 23:1137–1146.
  4. Nagayama, Aiko, et al. "Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments." Targeted oncology 12.6 (2017): 719-739.
  5. Polakis P (2005) Arming antibodies for cancer therapy. Curr Opin Pharmacol 5:382–387.
  6. Dan, Nirnoy, et al. "Antibody-drug conjugates for cancer therapy: chemistry to clinical implications." Pharmaceuticals 11.2 (2018): 32.
  7. Lambert JM (2005) Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol 5:543–549.
  8. Sau, Samaresh, et al. "Advances in antibody–drug conjugates: a new era of targeted cancer therapy." Drug discovery today (2017).
  9. Vater CA, Goldmacher VS (2010) Antibody-cytotoxic compound conjugates for oncology. Macromolecular Anticancer Therapeutics, Part 4:331–369.
  10. Zhou, Qun. "Site-specific antibody conjugation for ADC and beyond." Biomedicines 5.4 (2017): 64.
  11. Kovtun YV, Goldmacher VS (2007) Cell killing by antibody-drug conjugates. Cancer Lett 255:232–240.

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