eISSN: 1896-9151
ISSN: 1734-1922
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abstract:
Commentary

Antibody-drug conjugates: smart weapons against cancer

Seyed Mohammad Gheibi Hayat
,
Amirhossein Sahebkar

Online publish date: 2019/02/18
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The scientist Paul Ehrlich introduced the term ‘magic bullet’ for the first time. He envisioned that if a substance is capable of binding selectively to a pathogen, it might cause targeted drug delivery (toxin) to the pathogen by binding a toxic agent to this pathogen. He won the Nobel Prize in Medicine for this theory in 1908 [1–3].
Antibody-drug conjugates (ADCs) are a new class of drugs that have been designed to treat patients with cancer. ADCs are complex consisting an antibody and a drug (anticancer drug) that are connected to each other by a linker so that monoclonal antibodies in the Fab domain have paratopes dedicated to binding to the anticancer epitopes. Figure 1 depicts three components of ADCs [4, 5].
The ADC complex induces apoptosis in cancer cells in five stages.
First stage – cell surface binding: ADCs can bind to surface of cancer cells by binding of monoclonal antibody to its specific antigen (cancer antigen) and thus form the antigen-antibody complex.
Second stage – internalization: ADCs can be transported into cancer cells through receptor-mediated endocytosis.
Third stage – separation of antibody from drug: after endocytosis of ADCs into the cell, they are placed in primary vesicles and then by turning into secondary vesicles it results in disconnection of the linker and the drug is separated from the antibody.
Fourth stage – release: the drug is released into the cytoplasm.
Fifth stage – cell death: drugs can cause apoptosis in cancer cells through different mechanisms such as interaction with DNA, or inhibition of microtubules or enzymes involved in cell proliferation [6–8].
It is estimated that only about one percent of the ADCs can eventually find their way into the cancer cells, but even this small amount is more efficient than traditional treatments of cancer. One of the most important factors to increase endocytosis is choosing an appropriate epitope antigen for cancer. Affinity between antibodies and antigens plays an important role in increasing internalization of ADCs into the cancer cell. Internalization is performed via three mechanisms involving clathrin, caveolae or pinocytosis; the first and second mechanisms are receptor-mediated while the third one is receptor-independent.
Following endocytosis, ADCs are placed inside the primary vesicles of the cell and at the next stage turn into secondary vesicles after binding to lysosomes. The...


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