Stepping forward in antibody-drug conjugate development

Abstract

Antibody-drug conjugates (ADCs) are cancer therapeutic agents comprised of an antibody, a linker and a small-molecule payload. ADCs use the specificity of the antibody to target the toxic payload to tumor cells. After intravenous administration, ADCs enter circulation, distribute to tumor tissues and bind to the tumor surface antigen. The antigen then undergoes endocytosis to internalize the ADC into tumor cells, where it is transported to lysosomes to release the payload. The released toxic payloads can induce apoptosis through DNA damage or microtubule inhibition and can kill surrounding cancer cells through the bystander effect. The first ADC drug was approved by the United States Food and Drug Administration (FDA) in 2000, but the following decade saw no new approved ADC drugs. From 2011 to 2018, four ADC drugs were approved, while in 2019 and 2020 five more ADCs entered the market. This demonstrates an increasing trend for the clinical development of ADCs. This review summarizes the recent clinical research, with a specific focus on how the in vivo processing of ADCs influences their design. We aim to provide comprehensive information about current ADCs to facilitate future development.

Keywords: Antibody-drug conjugates (ADCs); Cancer therapy; Clinical research; Metabolism.

Figure 1.

Structures of the approved ADC drugs listed in Table 1.

Figure 2.. Structure of ADCs.

An ADC consists of three parts: an antibody, a linker and a payload (not to scale). The payloads are covalently coupled to the monoclonal antibody using linkers. This figure is based on a figure from www.adcreview.com.

Figure 3.

Chemical structures of clinical ADC payloads.

Figure 4.

Chemical structures of commonly used ADC linkers.

Figure 5.. In vivo processing of a typical antibody drug conjugate.

(1) The ADC enters blood circulation through IV injection and then distributes throughout the body over time. (2) The ADC binds to targeted antigen on tumor cell surfaces by antigen-antibody specific binding. (3) The ADC is internalized into tumor cells via receptor-mediated endocytosis and then is transported to the lysosome. (4) Within the lysosome, cytotoxic payloads are released after ADC proteolysis or linker split. (5) Cytotoxic payloads destroy the tumor cell and nearby tumor cells through the bystander effect. The figure is based on figures in (Birrer et al., 2019) and (Lambert & Berkenblit, 2018).