Advances and Limitations of Antibody Drug Conjugates for Cancer

Abstract

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

Cancer Immunotherapies: What the Perioperative Physician Needs to Know

“…Building on the efficacy of targeted, unconjugated mABs, ADCs were developed to take advantage of the antigen-specificity of mABs as a mechanism for delivering a cytotoxic substance (i.e., anti-mitotic drug, drug that causes DNA damage, exotoxin, or radionuclide) directly to tumor cells. The efficacy of the ADC relies not only on the mAB target and the cytotoxic payload, but also on the linker between them [44]. In 2000, the FDA approved the first ADC, gemtuzumab ozogamicin, for treatment of acute myeloid leukemia.…”

Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate

“…This disease is commonly treated by surgery [3], radiotherapy [4] and chemotherapy [5,6], the latter being the treatment most widely used due to its capacity to target rapidly dividing cancer cells [2]. However, the use of chemotherapeutic drugs faces constant limitations in terms of non-specificity, meaning that they kill not only the tumor cells but also healthy cells and cause serious adverse reactions, narrow therapeutic windows, and increased drug resistance [7][8][9][10][11][12][13]. Targeted drug therapy could potentially address these challenges, as it facilitates the delivery of drug agents to unhealthy cells without harming healthy ones [14][15][16][17][18][19][20].…”

A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

“… 10 Despite these advances, there continue to exist biological limits to AMD effectiveness, including receptor expression level, internalization rate, tissue penetration and circulation half-life. 11 These barriers have historically prevented all but the most potent of payloads and most highly expressed of antigens from being addressed with conventional ADCs. Innovations in antibody engineering, linker design and payload chemistry will likely be essential to expand the scope of payloads and antigens for which AMD will be successful.…”