Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy

Abstract

Cytotoxic small-molecule drugs have a major influence on the fate of antibody-drug conjugates (ADCs). An ideal cytotoxic agent should be highly potent, remain stable while linked to ADCs, kill the targeted tumor cell upon internalization and release from the ADCs, and maintain its activity in multidrug-resistant tumor cells. Lessons learned from successful and failed experiences in ADC development resulted in remarkable progress in the discovery and development of novel highly potent small molecules. A better understanding of such small-molecule drugs is important for development of effective ADCs. The present review discusses requirements making a payload appropriate for antitumor ADCs and focuses on the main characteristics of commonly-used cytotoxic payloads that showed acceptable results in clinical trials. In addition, the present study represents emerging trends and recent advances of payloads used in ADCs currently under clinical trials. K E Y W O R D S antibody-drug Conjugate (ADC), auristatin, calicheamicin, cytotoxic small molecules, maytansine, payloads, warheads

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

“…Rapid cell proliferation and insufficient oxygen supply due to increased oxygen demand and slow new vascularization network formation develop a hypoxic microenvironment in the most solid tumors. This hypoxic microenvironment with low nutriment regulates behaviors, differentiation, and function of TME cells such as tumor cells, inflammatory immune cells, and stromal cells . Tumor‐infiltrating lymphoid cells, tumor‐associated macrophages (TAMs), dendritic cells, myeloid‐derived suppressor cells represent the most important immune cells in TME.…”

ErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1

“…Kadcyla is made of trastuzumab conjugated via a non-cleavable linker to the microtubule disrupting agent emtansine and it is approved for the treatment of metastatic ErbB2-expressing breast and gastric cancer. There are several factors affecting efficacy and tolerability of ADCs including antibody target relevance and binding properties, cellular uptake, release of the active moiety, and relevance of the targeted molecular pathway in the maintenance of tumor malignancy (28). The role of the antibody appears to be particularly important, in fact ADCs made of two different antibodies targeting the same antigen (i.e., CD79b) and conjugated to the same toxin can exhibit different safety and efficacy profiles in patients (26).…”

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

“…There are at least four mechanisms of action exerted by DNA-damaging agents, which are as follows: (a) DNA double-strand breakage, (b) DNA alkylation, (c) DNA intercalation, and (d) DNA cross-linking. The most used DNA-damaging payloads are pyrrolobenzodiazepine, duocarmycins, doxorubicin, and calicheamicins [ 61 ] ( Figure 8 ).…”

“…The spliceosome is an attractive target in cancer therapy, and thailanstatins have been shown to inhibit RNA splicing by the binding to different spliceosome subunits [ 61 ]. Thailanstatin A in fact was demonstrated to bind to the SF3b subunit of the spliceosome blocking RNA splicing and was used in the generation of an ADC (anti-Her2-thailanstatin).…”