Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Abstract

Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

“…The linker can be cleaved inside the cancer cells, after ADC internalization, typically at the level of the lysosomes. There are not yet ADCs approved for the treatment of HCC, though there is experimental work supporting their potential [ 25 ]. In this respect, two targets have been explored so far: the cell surface membrane-bound glypican-3 (GPC3), a heparan sulfate proteoglycan protein, and the cell membrane-bound CD24, which is a mucin-like molecule that is overexpressed in a range of human carcinomas, including HCC [ 26 ].…”

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

“…The structure of T-DXd/DS8201. In 2020, T-DXd was approved and became the second ADC for HER2 + therapy (66). Similar to T-DM1, T-DXd was also designed for HER2-positive patients.…”

Use of Amatoxin Conjugates in Antibody Drug Conjugates, One of the Current Treatment Approaches: Systematic Review

“…Amatoksinlerin suda iyi çözünmeleri nedeniyle sulu çözeltilerde tamponlanmaları kolaylaşır ve immünojenite potansiyelleri azalır. 32 Amatoksinler, izolösin, prolin ve triptofan amino asitlerinden oluşan siklik oktapeptidlerdir. Hidroksil yan zincirler, molekülün suda çözünürlüğünü ve hücresel makromoleküllere afinitesini artırmaktadır.…”