Development, efficacy and side effects of antibody‑drug conjugates for cancer therapy (Review)

Abstract

Antibody-drug conjugates (ADCs) are anticancer drugs that combine cytotoxic small-molecule drugs (payloads) with monoclonal antibodies through a chemical linker and that transfer toxic payloads to tumor cells expressing target antigens. All ADCs are based on human IgG. In 2009, the Food and Drug Administration (FDA) approved gemtuzumab ozogamicin as the initial first-generation ADC. Since then, at least 100 ADC-related projects have been initiated, and 14 ADCs are currently being tested in clinical trials. The limited success of gemtuzumab ozogamicin has led to the development of optimization strategies for the next generation of drugs. Subsequently, experts have improved the first-generation ADCs and have developed second-generation ADCs such as ado-trastuzumab emtansine. Second-generation ADCs have higher specific antigen levels, more stable linkers and longer half-lives and show great potential to transform cancer treatment models. Since the first two generations of ADCs have served as a good foundation, the development of ADCs is accelerating, and third-generation ADCs, represented by trastuzumab deruxtecan, are ready for wide application. Third-generation ADCs are characterized by strong pharmacokinetics and high pharmaceutical activity, and their drug-to-antibody ratio mainly ranges from 2 to 4. In the past decade, the research prospects of ADCs have broadened, and an increasing number of specific antigen targets and mechanisms of cytotoxic drug release have been discovered and studied. To date, seven ADCs have been approved by the FDA for lymphoma, and three have been approved to treat breast cancer. The present review explores the function and development of ADCs and their clinical use in cancer treatment.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

“…Drug conjugates are chemotherapeutic or cytotoxic agents covalently linked to targeting ligands such as antibodies or peptides via a linker. They have recently gained notoriety as an important class of anticancer therapeutics, and while antibody-drug conjugates (ADCs) are well established in cancer treatment, peptide-drug conjugates (PDCs) are emerging as a new approach for targeted drug delivery with better efficacy and limited side effects [161][162][163][164]. In these conjugates, the linker plays a key role in the drug circulation time as well as in the accurate release of the active entity at the target site for an optimum activity.…”

“…While early technologies relied on random conjugation to either lysine or cysteine residues, often leading to heterogeneous ADCs, the latest approaches enable the synthesis of homogeneous ADCs via a conjugation at specifically engineered cysteines, glycosylated amino acids, or bioorthogonal unnatural amino acids [165,166]. As a result, targeted thera-pies based on polysaccharide-drug or protein-drug conjugates have gained prominence in recent years due to their superior efficacy and limited side effects [161][162][163][164][165][166].…”

Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies

“…The research and development of antibody drugs have seen continuous advancements, leading to the classification of marketed ADC drugs into three generations. 9 The first‐generation ADCs had limitations such as insufficient toxicity in the payload, unstable structure, and easy detachment of the toxin, resulting in a narrow therapeutic window and a high rate of failure. 4 The second‐generation ADCs, utilizing humanized monoclonal antibodies and more potent cytotoxic drugs, showed reduced immunogenicity, improved drug efficacy, and a wider therapeutic window compared with the first generation.…”