Antibody-Drug Conjugates as a Targeted Therapeutic Approach Across Entities in Oncology

Abstract

Background: Cancer is no longer treated on the basis of its histological lineage alone; more and more drugs are being developed that are directed toward specific molecular and immunological features. Monoclonal antibodies are one type of selectively acting therapeutic agent. As part of this development, antibody-drug conjugates ("ADCs") have been approved in recent years for the treatment of hematologic and solid malignancies.

Methods: This review is based on pertinent articles retrieved by a selective search in PubMed, as well as on papers presented at international congresses of specialist societies such as the European Society for Medical Oncology, the American Society of Clinical Oncology, and the American Association for Cancer Research, and information published on the websites of the European Medicines Agency, the Food and Drug Administration, and the German Joint Federal Committee.

Results: The efficacy of the nine ADCs currently approved in the European Union (as of 12/2022) is derived from technical improvements in the conjugation process, the introduction of novel linkers for the covalent binding of cytotoxic agents to the Fc portion of the antibody, and the development of new, potent cytotoxic agents. Compared to conventional cancer therapies, the approved ADCs improve treatment outcomes with respect to tumor remission, time to tumor progression and, in some cases, overall survival by specifically channeling cytotoxic agents into the malignant target cells and thereby limiting, at least to some extent, the exposure of healthy tissue to adverse effects. Various potential side effects still require attention, including venous occlusive disease, pneumonitis, ocular keratopathy, and skin rash. The development of effective ADCs requires the identification of tumor-selective targets to which ADCs can bind.

Conclusion: ADCs are a novel category of drugs for the treatment of cancer. Their approval is mainly, but not exclusively, based on the favorable findings of randomized, controlled phase III trials. ADCs are already helping to improve the outcomes of treatment for cancer.

Figure 1

Structure of an antibody-drug conjugate (ADC) An ADC is composed of an immune protein that recognizes and binds to structures on the tumor target cell. Typically, this is a complete monoclonal antibody which is usually coupled in the constant region to a highly potent cytotoxic agent via a cleavable or non-cleavable linker. In the ADCs currently in clinical use, up to eight active substances are coupled to one monoclonal antibody (3).

Figure 2

Cellular uptake routes for an antibody-drug conjugate (ADC) containing a diffusible cytotoxic agent. The mechanism involves (a) binding of the ADC to the target antigen and (b) internalization. After uptake, the ADC is typically found in the endo-/lysosomal compartment of the target cell. This is where the drug is released intracellularly, either via cleavage of the linker or after proteolysis of the monoclonal antibody. The diffusible drug can cross the intracellular membranes (c) to reach the target site (for example, nucleus or microtubules), thereby exerting the cytotoxic effect (d). The free drug can then diffuse out of the target cell (e), penetrate into surrounding cells and induce their cell death (bystander effect). Alternatively, the drug can be released extracellularly by cleavage after binding of the ADC, but before internalization, by extracellular enzymes (for example, the protease cathepsin B) (f). Subsequently, the drug can also diffuse into neighboring bystander cell. With this mechanism of extracellular drug cleavage, it is important that the relevant releasing enzymes do not occur in the systemic circulation, but are only produced in the tumor microenvironment by the tumor cells themselves or, for example, tumor-associated macrophages (TAMs), in order to prevent intolerable systemic toxicity.