Targeted delivery of therapeutic molecules into cancer cells is considered as a promising strategy to tackle cancer. Antibody-drug conjugates (ADCs), in which a monoclonal antibody (mAb) is conjugated to biologically active drugs through chemical linkers, have emerged as a promising class of anticancer treatment agents, being one of the fastest growing fields in cancer therapy. The failure of early ADCs led researchers to explore strategies to develop more effective and improved ADCs with lower levels of unconjugated mAbs and more-stable linkers between the drug and the antibody, which show improved pharmacokinetic properties, therapeutic indexes, and safety profiles. Such improvements resulted in the US Food and Drug Administration approvals of brentuximab vedotin, trastuzumab emtansine, and, more recently, inotuzumab ozogamicin. In addition, recent clinical outcomes have sparked additional interest, which leads to the dramatically increased number of ADCs in clinical development. The present review explores ADCs, their main characteristics, and new research developments, as well as discusses strategies for the selection of the most appropriate target antigens, mAbs, cytotoxic drugs, linkers, and conjugation chemistries.
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
The tumor microenvironment is a complex and heterogeneous milieu in which multiple interactions occur between tumor and host cells. Immunosuppressive cells which are present in this microenvironment, such as regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), play an important role in tumor progression, via down-regulation of antitumor responses. MDSCs represent a heterogeneous group of cells originated from the myeloid lineage that are in the immature state. These cells markedly accumulate under pathologic conditions, such as cancer, infection, and inflammation, and use various mechanisms to inhibit both adaptive and innate immune responses. These immunosuppressive mechanisms include deprivation of T cells from essential amino acids, induction of oxidative stress, interference with viability and trafficking of T cells, induction of immunosuppressive cells, and finally polarizing immunity toward a tumor-promoting type 2 phenotype. In addition to suppression of antitumor immune responses, MDSCs can also enhance the tumor metastasis and angiogenesis. Previous studies have shown that increased frequency of MDSCs is related to the tumor progression. Moreover, various drugs that directly target these cells or reverse their suppressive activity can improve antitumor immune responses as well as increase the efficacy of immunotherapeutic intervention. In this review, we will first discuss on the immunobiology of MDSCs in an attempt to find the role of these cells in tumor progression and then discuss about therapeutic approaches to target these cells.
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