An overview of antibody–drug conjugates in oncological practice

Abstract

Antibody–drug conjugates (ADCs) are designed to manipulate the toxic efficacy of specific chemotherapeutic compounds, employing the high affinity of antibody-mediated delivery so as to drive them selectively to target cancer cells. These immunoconjugates encompass the general tendency towards precision medicine and avert the systemic toxicities of conventional chemotherapy, accomplishing an improved therapeutic index. Cumulative experience acquired from first-generation ADCs offers new perspectives to these promising therapeutic modalities for various hematological and solid cancers and propels their clinical development in a faster-than-ever pace, as indicated by the approval of four novel ADCs during the last year. This paper aims to provide an up-to-date overview of the eight ADCs approved by the US Food and Drug Administration and their current indications in oncological practice. Starting from their bio-pharmaceutical background, we track their clinical evolution, with an emphasis on the pivotal trials that led to their commercial release. Late-stage studies examining these eight ADCs in other-than-approved settings as well as the investigation of potential new candidates are also reviewed. In the close future, more data are expected to expand ADCs’ oncological utility and to further reshape their role in cancer therapeutics.

Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond

“…In the following sections, we elaborate on the functional principles and the characteristics the characteristics of these components (Box 1), with emphasis on the latest bioengineering advances, such as bispecific antibodies, multi-drug ADCs, non-internalizing ADCs, and ADC-antibody co-administration. Updating our previous report [1], all current oncological and non-oncological implications of ADC's technology are also recapped.…”

“…Table 1 summarizes all these approved oncological ADCs, presenting their main characteristics. The preclinical and clinical data that drove these ADCs to their regulatory approvals have been published recently by our team [1]. In addition to these indications, many other solid malignancies, including prostate cancer [121], gastric cancer [122], pancreatic cancer [123], and hepatocellular carcinoma [124] have been entered into the focus.…”

“…The regulatory approval of first-generation ADCs spurred a surge of interest in this biotechnology that has produced a total of ten FDA-approved agents and an ever-increasing panel of candidates in clinical and preclinical level. ADCs are essentially tripartite pro-drugs consisting of an antibody tethered via a chemical linker to a given payload [1]. (Figure 1) After their administration, these agents circulate as inactive assemblies which are eventually catabolized via endogenous cleavage mechanisms at the intracellular compartment of the targeted cell [2].…”

“…Exploiting the embedded properties of monoclonal antibodies (mAbs), these immunoconjugates achieve selective delivery and localized release of the attached payload, minimizing the "off-target" effects on normal tissues and improving the therapeutic index [3]. The clinical utility of ADCs has been mainly explored in hematological/oncological indications [1]. However, during the last decade, a constant flow of reports about the implementation of this technology outside the oncological sphere has been also observed.…”

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

“…Antibody-drug conjugates could be considered a bridge between conventional chemotherapy which eliminates all rapidly dividing cells and more targeted immunotherapy combining the best anti-tumor properties of each of them [ 6 ].…”