Antibody-drug conjugates in lung cancer: dawn of a new era?

Abstract

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs' recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.

Fig. 1. Structure and components of typical antibody-drug conjugates, including monoclonal antibodies, linkers, and payloads.

Antibody: chimeric/humanized monoclonal IgG antibody targeting a protein preferentially expressed on the tumor cell surface. Linker: ensures payload is attached to antibody in plasma but is efficiently released in tumor cells. Linkers can be cleavable (via tumor-associated factors) or non-cleavable (lysosomal degradation); payload: enhances cytotoxicity, although variable drug:antibody ratio affects efficacy and clearance. The antibody component of ADCs engage with immune effector cells to elicit antitumor immunity, including complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and antibody-dependent cell phagocytosis (ADCP) effects. MC maleimidocaproyl, MCC maleimidomethyl cyclohexane-1-carboxylate; MoA mechanism of action.

Fig. 2. Mechanisms of action of antibody-drug conjugates.

ADCs selectively deliver toxic payload to tumor cells resulting in cell death. The “bystander effect” of ADCs alter stumor microenvironment to enhance cell killing.