A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy

Abstract

Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment of hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, that are mainly associated with modest specificity and therapeutic benefit, the three key components that form an ADC (a monoclonal antibody bound to a cytotoxic drug via a chemical linker moiety) achieve remarkable improvement in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tumor toxicity. Based on their beneficial mechanism of action, 15 ADCs have been approved to date by the market approval by the Food and Drug Administration (FDA), the European Medicines Agency (EMA) and/or other international governmental agencies for use in clinical oncology, and hundreds are undergoing evaluation in the preclinical and clinical phases. Here, our aim is to provide a comprehensive overview of the key features revolving around ADC therapeutic strategy including their structural and targeting properties, mechanism of action, the role of the tumor microenvironment and review the approved ADCs in clinical oncology, providing discussion regarding their toxicity profile, clinical manifestations and use in novel combination therapies. Finally, we briefly review ADCs in other pathological contexts and provide key information regarding ADC manufacturing and analytical characterization.

Keywords: antibodies; antibody-drug conjugate; cancer treatment; linkers; payloads; target therapy.

FIGURE 1

Schematic representation of the modular components of an Antibody-Drug Conjugate (ADC). ADC consists of a monoclonal antibody (blue), a linker (blue lines) and the cytotoxic drugs (gray/red). In this picture, the representative ADC on the left has a Drug-to-Antibody ratio equal to 4. A brief description of the basic function of each module is indicated on the right.

FIGURE 2

Mechanism of action of ADC strategy. The major steps of the process are indicated on the figure. Basically, following ADC-target interaction on the surface of cancer cell (step 1), this complex undergoes receptor-mediated endocytosis and enters the endosomal/lysosomal pathway until the payload is released in the cytoplasm (steps 2, 3a and 4). Then, the drug can exert its killing activity either damaging DNA structure in the nucles or derange mitotic fuse polymerization (step 5), leading to cell death by apoptosis. A fraction of ADCs binds to FcRn receptors in the early step on endosomal/lysosomal pathway and get transported out of the cell (step 2a and 3b).

FIGURE 3

Overview on the tumor-targeting ADCs. Taking advantage of blood circulation, ADCs reach the tumor microenvironment (TME), which is composed by cancer-associated fibroblasts (CAFs) and other cell types and interact with malignant cells that exposed the tumor associated/specific antigen on their surface. In addition to their canonical mechanism of action, ADCs can potentiate their positive response against the tumor mass. To this aim, ADCs hydrophobic payloads may diffuse through the cell membrane inducing the killing of neighborhood antigen-negative cells via bystander killing effect (black arrows) and/or the ADCs antibody Fc fragment may elicit anti-tumor immunity (ADCC, CDC, and ADCP) by engaging immune effector mechanisms, such as complement system, macrophages and NK cells. All together, these mechanisms aim to induce the death of the cellular component of the tumor mass via apoptosis.