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.
Highlights
The linker conjugates the payload to the Monoclonal antibodies (mAbs), which binds to the target that is over expressed on the tumor cell, and the payload potentiates the therapeutic action [1]
Triple negative breast cancer is defined by lack of expression of all three receptors generally found in breast cancer subtypes: the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) [34]
PBD has been used as a payload for the antibody drug conjugates (ADCs), Vadastuximab talirine or SGN-CD33A being developed by Seattle Genetics to treat acute myeloid leukemia (AML)
Summary
Conventional cancer therapy often entails a low therapeutic window and non-specificity of chemotherapeutic agents that affects normal cells with high mitotic rates and provokes an array of adverse effects, and in some cases leads to drug resistance [1]. Prior to the development of ADCs, mAbs attracted interest attributable to its target specificity, wide therapeutic index, and its affiliation with fewer side effects, in particular for cancer [3], compared to conventional therapy, which incorporates chemotherapy, radiation therapy and surgery [4]. The linker conjugates the payload to the mAb, which binds to the target that is over expressed on the tumor cell, and the payload potentiates the therapeutic action [1]. A narrow therapeutic index results in II, a few ADCs were linked to dose limiting toxicities [11].
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