Antibody-Drug-Conjugate

Antibody-Drug Conjugate or ADCs are a class of drugs designed as a targeted therapy for treating disease. At the moment most of them are useful for treating cancer. ADCs are consisting of an antibody linked to a cytotoxic payload. They are able to deliver selectively different types of cytotoxic agents to the tumor target by increasing efficiency and reducing toxicity.This method kill tumor cells without harming the healthy cells and characterized by lower immunogenicity and higher potency. Currently ten ADCs have been approved by the FDA.Antibody: Most ADCs are built from IgG۱ compared to other antibody subclasses. It combines solubility, a long serum half-life and a high binding affinity. Linker technology: linkers are biochemical compounds connecting the antibody to the payload and they can be classified into cleavable and non-cleavable according to their chemical properties. In Non-cleavable linkers cleavage occurs only after lysosome internalization. while, cleavage of cleavable linkers can depend on external pH.Payload: Payloads belong to two major families: Tubulin inhibitors and DNA-damaging agents. The most important payload macro categories are agents that destabilize microtubules, drugs capable of generating DNA damage and protein toxins. They cause apoptosis or microtubule disruption. In addition, drug can exported from the target tumor cell, cross the cell membrane to kill neighboring tumor cells, including those that may not express the relevant antigen on its cell surface or they are less accessible from the circulatory system.Enfortumab vedotin is an ADC developed to target nectin-۴, conjugated to a MMAE payload via a protease-cleavable linker . Nectin-۴ is a type I transmembrane polypeptide member of the nectin family encoded by the NECTIN۴ gene, that is widely expressed and associated with poor prognosis in metastatic UC.It is anticipated that, in the future, more safe ADCs will be developed, and they can also be used for other diseases beyond cancer.Cytotoxic agents are able to promote cell death, causing release of tumor antigens. These effects allow the activation of the immune system and the increase of antigen-presenting cells. Moreover, ICIs counteract the immunosuppression generated in the tumor microenvironment by modulating regulatory T cells and cytokines. The combination of chemotherapy and ICIs is a new method already approved in several cancers. In addition, subsequent studies in mouse models have shown that tumor regression was greater with the combination of Brentuximab vedotin and a PD۱ inhibitor, confirming the therapeutic synergy of these two drugs.