Antibody-Drug Conjugates: A Review on the Epitome of Targeted Anti- Cancer Therapy

Abstract

Cancer is one of the deadly diseases which is characterized by unchecked cell division or abnormal cell growth due to the incapability of cell cycle arrest. As the treatment for this is to kill the cancerous cells the main challenge for scientists is to direct the cell killing to cancerous cells while leaving the normal cells unharmed. Antibody-drug conjugates (ADC) are one such targeted anti-cancer therapy. It is an effective drug delivery system that utilizes the targeting action of antibody along with cell death by potent cytotoxic agent, linked up with one another by a linker molecule and thus helps to reduce toxicity to non-target cells, ensure broad therapeutic window and overcome multi-drug resistance. Multiple parameters like total antibody (conjugated and unconjugated antibody), conjugated antibody, conjugated drug, unconjugated antibody and unconjugated (free) drug are needed to be analyzed to find out the behavior as well as safety and efficacy of ADCs. With 2 FDA approved drugs (Kadcylca and Adcetris) and more than 40 drugs undergoing clinical trial this field has gained pace in recent years. Some challenges still persist in this field like reducing immunogenic response to antibodies, ensuring the ADC homogeneity and antibody-drug ratio, selection of appropriate targets, successful conjugation of drug to antibody, securing the stability of linkers in systemic circulation as well as improvement of oral bioavailability. With the advent of stable linkers, cytotoxic drugs having higher potency and better conjugation capability with the linker and antibodies having high specificity, these ADCs can overcome the limitations of cancer treatment. This review focuses on the criteria for proper construction of ADC, conjugation techniques, the target choices, the underlying mechanism of action and pharmacokinetic considerations associated with ADC.

Considerations for setting occupational exposure limits for novel pharmaceutical modalities

“…The mechanistic basis for the ADC activity includes its specific binding to the cellular target, triggering ADC cellular internalization by pinocytosis, followed by the intracellular release of the payload ( Roberts et al, 2013 ). Therefore, after administration into the systemic circulation, the antibody fragment guides the complex to the targeted tumor antigen where it becomes internalized into the cancer cell ( Hasan et al, 2018 ). The intracellular release of the payload in its active form results in cell death.…”

“…The intracellular release of the payload in its active form results in cell death. The three components of ADCs, namely the antibody, the linker and the cytotoxic drug, have their own inherent characteristics, limitations, and influence on each other, thus finding the best combination of these components to design an ideal ADC is a complicated task ( Hasan et al, 2018 ). Although this targeted approach appears straightforward, its translation to clinical practice has been problematic when initial attempts failed due to inappropriate linker systems or insufficiently potent cytotoxins, resulting in unfavorable therapeutic indices.…”

“…Genotoxicity, and reproductive and developmental toxicities are also associated with exposure to these highly potent cytotoxic drugs, and neurotoxicity is a known adverse effect of the tubulin disruptors ( Remesh, 2012 ). Radio-nucleotides were also historically used as ADC payloads, but have been replaced in modern ADCs by the use of these highly potent cytotoxic drugs ( Hasan et al, 2018 ).…”

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

“…Because of their high affinity to target proteins, antibodies are traditionally considered perfect carriers for the intracellular delivery of therapeutic agents in cancer therapy. [ 75 ] Although the antitumor activity of an antibody‐drug conjugate (ADC) is mainly caused by drug toxicity, the degradation of target proteins induced by an antibody may also play an important role in suppressing tumorigenesis. In fact, target protein degradation is a common phenomenon in ADC‐mediated cancer therapy, as the protein‐ADC complex needs to be degraded before toxic agents are released into cells.…”

Anti-CD24 Antibody–Nitric Oxide Conjugate Selectively and Potently Suppresses Hepatic Carcinoma

“…The FDA-approved brentuximab vedotin and trastuzumab have validated this design of an "armed" antibody, which forms the next generation of antitumor antibodies (15)(16)(17)(18)(19). The development of ADC technology has attracted the attention of researchers in the biological and chemical synthesis fields in recent years, which has resulted in more than 50 ADCs in clinical trials (20,21). Improved conjugation methods have shown a remarkable advantage over traditional techniques; various types of toxin payloads have emerged, which are crucial components of ADCs.…”