An overview of antibody-drug conjugates


Posted August 13, 2019 by Bonnibelle

An antibody-drug conjugate (ADC) can be defined as a prodrug. Antibodies recognize targets that expresse tumor antigens, and are coupled to a cytotoxin "warhead" by a linker to form a targeted delivery system for tumor cells.

 
1. Antibody-drug conjugate definition
An antibody-drug conjugate (ADC) can be defined as a prodrug. Antibodies recognize targets that expresse tumor antigens, and are coupled to a cytotoxin "warhead" by a linker to form a targeted delivery system for tumor cells. In an ideal state, the prodrug is not toxic when administered systemically, while when the antibody in the ADC drug binds to a target cell expressing a tumor antigen, the entire ADC drug is endocytosed by the tumor cell, and then the small cytotoxin component will be effectively released in a sufficient amount in a highly active form to kill tumor cells.
To design an ideal ADC is complex. In the careful selection of specific tumor antigens/targets and related indications, in addition to considering the characteristics and limitations of antibodies, linkers and cytotoxic drugs, it is more important to find the best combination among them. Because the three are coupled together and affect each other.

2. Antibody-conjugated drug recognition target/antigen
Target/antigen selection is the starting point for designing ADC drugs because it determines which tumor indications the ADC drug will target and potentially affects the choice of conjugated cytotoxic drugs. Furthermore, the choice of target has a decisive role in the selection criteria for targeting patient populations in tumor indications.
Many targets have been evaluated during the development of ADC drugs over the years. Previous studies of preclinical mouse models have showed the diversity of targets, single or multiple transmembrane structural proteins or anchored glycosylphosphatidylinositol (GPI) can cause endocytosis of ADC drugs, which delayed tumor grow and even cause it to subside.
The principle for target/antigen selection is the high expression of this antigen in tumor tissues, but only little expression in normal tissues, thereby limiting or focusing the toxicity of ADC drugs on target cells as much as possible. However, the probability that a specific tumor antigen is not expressed in normal tissues is very low, and in most cases the antigen is usually expressed on the surface of epithelial cells of a normal tissue/organ subpopulation. Therefore, when selecting a target, not only the organ type (such as vital organs and reproductive organs) expressing the antigen, but also the cell subtype and the cell cycle state (differentiated cells and differentiated quiescent cells) should be considered. Moreoer, a difference in expression of this tumor antigen between normal cells and tumor cells positive for the antigen should be considered.
It should be noted that the expression of tumor antigens in normal organs in clinical trials does not necessarily mean serious side effects. In several clinical trials of ADC drugs that cross-react with normal tissues, the patients showed good tolerance, and the toxicity of ADC drugs was not very low, controllable and reversible, for example, mokantozumab/IMGN242 (targeting CanAg antigen, a carbohydrate antigen structure on a mucin-like protein), BT-062 (ADC drug targeting CD138 antigen) or CDX-011 (ADC drug targeting gpNMB antigen). In contrast, in the case of mobivalizumab (an ADC drug targeting CD44v6 antigen), skin keratinocytes expressed CD44v6, which caused severe skin toxicity, including a fatal toxic epidermal necrolysis. Eventually the phase I clinical study was terminated in the early stage.
The target antigen should be expressed at a lower level in normal tissues, and higher on the surface of the tumor cells (antigen density), and the antigen-antibody complex can be internalized after the target antigen binds to the antibody. It is processed and degraded in a suitable cell chamber, and then a sufficient amount of cytotoxic active drug is released in the cytoplasm.
In the tumor cell model used in preclinical studies, if the tumor target antigen expression pattern and expression level are consistent with the tumor cells from the patient biopsy, the in vitro study model of the tumor cells can be effectively obtained in preclinical studies. The data is bridged to the efficacy of the corresponding ADC drug clinical study. The ADC drug AVE9633, which targets the CD33 antigen, did not show efficacy in its Phase I clinical study, suggesting that the drug candidate did not deliver sufficient toxin drugs that kill tumor cells in the cytoplasm. In contrast, the tumor cell model of its preclinical studies showed a good response to AVE9633 because the expression level of CD33 antigen in the tumor cell model was significantly higher than that of tumor cells from the biopsy tissue. (From unpublished internal data, Sanofi, 2009).
3. Cytotoxic drugs and linkers
Many traditional therapeutic drugs have been used for the coupling of antibody drugs, but it was soon discovered that these cytotoxic drugs were coupled to antibodies and could not achieve the expected anti-tumor activity in subsequent clinical use. Then subsequent research focused on those naturally occurring, cytotoxic small molecules with highly potent anti-tumor activity that are often not available as anti-tumor drugs because of their high clinical toxicity.
Reference
1.Goff LW, et al. (2009) A phase II study of IMGN242 (huC242-DM4) in patients with CanAg-positive gastric or gastroesophageal (GE) junction cancer. J Clin Oncol 27:e15625.
2.DiJoseph JF, et al. (2004) Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103:1807–1814.
3.Tse KF, et al. (2006) CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res 12:1373–1382.
-- END ---
Share Facebook Twitter
Print Friendly and PDF DisclaimerReport Abuse
Contact Email [email protected]
Issued By https://www.creative-biolabs.com/
Country United States
Categories Biotech
Last Updated August 13, 2019