Unlocking the potential of antibody–drug conjugates for cancer therapy

Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment

“…The CAST therapy was thus reported as a new mode of cancer therapy, especially for refractory, stromal-rich cancers. Since the first CAST therapy was reported over 10 years ago, there have been several appreciated experimental studies and review works supporting and promoting CAST therapy [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Preclinical evaluation of a novel antibody-drug conjugate targeting DR5 for lymphoblastic leukemia therapy

“…ADC internalization is one of the key requirements to facilitate its druggability. 11 As demonstrated in Figure 3 A, Oba01 induced a significant time-dependent decrease in the expression of cell-surface DR5. In addition, Oba01 (green) was visible on the cells at 4°C and could be distinguished from lysosome-specific LAMP-1 that stained the lysosomes (red) in the cells ( Figure 3 B).…”

“…Moreover, targeting antibody-drug conjugates (ADCs) could specifically bind to the tumor-related antigen on the cell surface, and then could be endocytosed into lysosomes, where the payload of a small-molecule toxin coupled to the antibody could be effectively released by proteinase digestion and specifically kill the tumor cells. 7 , 8 , 9 , 10 , 11 Thus, ADCs have become an important strategy in development of the novel cancer therapeutics. As of now, several ADCs have been approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA), for example, gemtuzumab ozogamicin (Mylotarg, Pfizer) for the treatment of CD33-expressing acute myelogenous leukemia, 12 brentuximab vedotin (Adcetris, Seattle Genetics) for the therapy of CD30-positive Hodgkin’s lymphoma, 13 ado-trastuzumab-emtansine (Kadcyla, Genentech) for the treatment of Her2-positive breast cancer, 14 inotuzumab ozogamicin (Besponsa, Pfizer) for the management of CD22-expressing relapsed and refractory B cells and ALL, 15 polatuzumab vedotin (Polivy, Roche) for the therapy of CD79B-expressing relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL), 16 trastuzumab deruxtecan (Enhertu, AstraZeneca/Daiichi Sankyo) for the treatment of Her2-positive breast cancer, 17 and enfortumab vedotin (Padcev, Seattle Genetics/Astellas) for the therapy of Nectin-4-positive bladder cancer.…”

“… 18 Currently, more than 10 ADCs are undergoing phase III clinical trials in cancer patients. 11 However, there remains an unmet need to a great extent for the development of effective therapeutics against various malignant tumors, including ALL.…”

The Chemistry Behind ADCs

“…Although they are widely applied, the use of most chemotherapies is limited by undesired side effects, mostly through action on cells beyond the tumor and its environment, resulting in systemic toxicity and a narrow therapeutic window. The discovery of the unique composition of cancer cell surfaces combined with the understanding of the strong and selective interaction between antibodies and cell-surface antigens opened the way to exploit antibodies as targeted delivery agents for chemotherapies, including highly toxic drugs [ 1 , 2 , 3 ]. The resulting molecular entities, also known as antibody–drug conjugates (ADC) consist of three main parts: the antibody responsible for the selective recognition of the cancer cell surface antigen capable of internalizing the ADC, the drug payload responsible for killing the cancer cell once released inside it, and the linker connecting the antibody and payload parts.…”