Antibody–drug conjugates: targeted weapons against cancer

Abstract

Antibody-drug conjugates (ADCs) are formed by a targeting antibody conjugated to a chemotherapeutic molecule through a linker. Recent data demonstrate that ADCs represent a valuable advancement for the clinics and, despite their recent appearance in medicine, they are already undergoing an innovation wave aimed at targeting all three ADC building blocks. Thus, new antibody formats are being engineered, site-specific linkers are being designed, and highly toxic molecules, like RNA polymerase inhibitors, are starting to be used for conjugation. These molecules were previously considered extremely toxic and could not be used as chemotherapeutic drugs. In this review, we will present an overview of current cancer treatments and their limitations, and the logic that has led to the generation of ADCs. Their mechanism of action will be outlined, and the most recent novelties in linker design and optimization will be discussed, along with present and near future discoveries in the current ADC research pipeline.

Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

“…While the receptor is recycled back to the cell surface, the delivered cytotoxic components induce apoptosis in tumor cells. One cavity of application is the fact that ADCs might be extracellularly released because of the proteolytic labile linker or ADCs are recycled back to the cell surface without delivering the cytotoxic component, leading to a reduced drug concentration in the cell (Polson et al, 2009;Peters and Brown, 2015;Scotti et al, 2015). The recycling mechanism of ADCs is caused by the high affinity of ADCs to neonatal Fc receptors (FcRns) within early endosomes that reach the cell surface recurrently, where ADCs are released from the FcRn under physiological pH.…”

“…The ADCs are often DNA alkylating agents, inhibitors of tubulin polymerization, or enediyne antibiotics which lead to DNA double-strand breaks (Scotti et al, 2015). Limitations of ADC application is indicated by the restriction of available specific tumor-associated antigens (TAA), downregulation of TAAs, and the transport of ADCs to the brain (Phillips et al, 2016;Miyauchi and Tsirka, 2018).…”

“…Certainly, a specific antigen for targeting glioblastoma is needed; however, tumor heterogeneity or reduced levels of antigens are one of several reasons for therapy resistance (Gan et al, 2017). An additional limitation of this approach is an acquired resistance to the cytotoxic agent of ADC, namely active efflux of the internalized drug is possible through transporters of the adenosine triphosphatebinding cassette family (Scotti et al, 2015).…”

Principles of Immunotherapy: Implications for Treatment Strategies in Cancer and Infectious Diseases

“…(A) Anticancer antibodies eliminate cancer cells and cause tumor destruction by targeting cancer antigens. (B) Antibody-conjugates – (i) Immunotoxins: bind to a surface receptor of an infected cell, undergo endocytosis and intracellular trafficking to the cytosol where most toxins induce cell death; (Becker and Benhar, 2012) (ii) ADCs: combine the specificity of mAbs with the cytotoxic potential of drugs and binds to internalizing receptors on target cell and are taken up by endocytosis; Once in the cell, ADCs undergo cellular trafficking to a lysosome where lysosomal degradation results in the cleavage and release of the active drug into the cellular cytoplasm where the drug induces apoptosis; (Scotti et al, 2015) (iii) Radioimmunoconjugates: antibodies attached to a radioactive molecule, once the antibody binds the target cell, the radio-particle’s radiation interacts with target cells, resulting in cell death. (C) Anti-viral antibodies – to eliminate a viral inhibition of cell infection, viral replication, cell-cell transmission, viral release as well as mediated killing of infected cells needs to occur; Palivizumab is a neutralizing antibody that binds to RSV preventing virus-host cell interactions (Groothuis and Nishida, 2002).…”

Marine Antibody–Drug Conjugates: Design Strategies and Research Progress

“…The antibody efficiently carries cytotoxins to targets via specific antigen-antibody reactions, and the ADC-antigen complex is internalized by endocytosis [ 2 ]. Once internalized, the ADC moves into cancer cells and experiences further degradation to release drugs for killing tumor cells ( Figure 2 ) [ 3 ]. Additionally, the conjugation strategy has an essential impact on the pharmacokinetics (PK) of cytotoxic drugs and can increase the half-life of these cytotoxins from hours to days [ 4 ].…”