Antibody-drug conjugates for cancer therapy

Abstract

Antibody‑drug conjugates (ADCs) are drugs designed to target specific anticancer treatment. ADCs are immunoconjugates comprised of a monoclonal antibody attached to the cytotoxic drug via a chemical linker. ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumor‑associated target antigens and deliver a highly potent cytotoxic agent. ADCs were designed to enhance the therapeutic index and minimize the toxicity of anticancer agents and overcome multidrug resistance in target cells. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor‑ mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic death of the cancer cell. The three components of ADCs (mAb, linker, and cytotoxin) affect the efficacy and toxicity of the conjugate. mAB should ensure high tumor specificity, target affinity, and low immunogenicity. Linkers are designed to be stable in the bloodstream and labile at the cancer site to allow rapid release of the cytotoxic drug. Cytotoxin should be soluble in the aqueous environment of mAb, stable in the bloodstream and the acidic environment of the lysosome, high potent at low concentrations, and its structure should allow for conjugation. The structure of ADC is dominated by the antibody backbone, and consequently, its properties determine the majority of ADME processes. ADCs are characterized by poor oral bioavailability, the long half‑life, neonatal Fc receptor‑dependent recycling, slow clearance, low volume of distribution, nonlinear pharmacokinetics, and immunogenicity. The toxicity of ADCs in healthy tissue is mostly caused by cytotoxin. The uptake of ADCs into normal cells is mediated by target‑dependent or target‑independent mechanisms. Currently, eleven ADCs were approved for clinical use by FDA, and more than ninety were still during clinical trials in June 2020. In this paper pharmacokinetic properties of ADCs were discussed in detail, and also their structure, anti‑tumor activity, and toxicity.