Antibody–drug conjugates in solid tumors: a look into novel targets

Abstract

Antibody–drug conjugates (ADCs) are a relatively new class of anticancer agents designed to merge the selectivity of monoclonal antibodies with cell killing properties of chemotherapy. They are commonly described as the “Trojan Horses” of therapeutic armamentarium, because of their capability of directly conveying cytotoxic drug (payloads) into the tumor space, thus transforming chemotherapy into a targeted agent. Three novel ADCs have been recently approved, i.e., trastuzumab deruxtecan, sacituzumab govitecan and enfortumab vedotin, respectively, targeting HER2, Trop2 and Nectin4. Thanks to progressive advances in engineering technologies these drugs rely on, the spectrum of diseases sensitive to these drugs as well as their indications are in continuous expansion. Several novel ADCs are under evaluation, exploring new potential targets along with innovative payloads. This review aims at providing a summary of the technology behind these compounds and at presenting the latest ADCs approved in solid tumors, as well as at describing novel targets for ADCs under investigation and new strategies to optimize their efficacy in solid tumors.

Trop2 Expression in Extramammary Paget’s Disease and Normal Skin

“…Sacituzumab govitecan is an ADC consisting of a fully humanized IgG1 anti-Trop2 antibody and the active metabolite of irinotecan (SN-38), a topoisomerase I inhibitor. The antibody is linked to SN-38 by a hydrolysable linker, which causes the release of drug molecules into the tumor microenvironment, thereby killing adjacent tumor cells (bystander effect) [ 45 , 46 ]. Sacituzumab govitecan was first approved by the US Food and Drug Administration for the treatment of triple-negative breast cancer and later authorized for treating lung cancer and urothelial carcinoma [ 45 ].…”

“…The antibody is linked to SN-38 by a hydrolysable linker, which causes the release of drug molecules into the tumor microenvironment, thereby killing adjacent tumor cells (bystander effect) [ 45 , 46 ]. Sacituzumab govitecan was first approved by the US Food and Drug Administration for the treatment of triple-negative breast cancer and later authorized for treating lung cancer and urothelial carcinoma [ 45 ]. Bardia et al recently reported the results of a phase III trial for relapsed or refractory metastatic triple-negative breast cancer (NCT02574455) [ 35 ].…”

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

“…Firstly, prior to Kadcyla ® , the treatment of solid tumors with ADCs fell short due to numerous biological barriers in the tumor microenvironment (e.g., poor vascularization, diffusion through dense stroma, overcoming tumor interstitial fluid pressure) which limited drug penetration. Secondly, unlike hematologic malignancies, the concept of lineage-specific antigen expression is not applicable to solid tumors, for which the antigens expressed are mainly “tumor associated” rather than “tumor specific” [ 70 ]. This implies both a share of on-target/off-tumor toxicity and thus reduced intra-tumoral drug delivery.…”

Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers

“…Antibody-drug conjugates (ADCs) represent a new generation of highly potent antineoplastic drugs (19). These drugs are built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody, using either a permanent or a labile linker.…”