Antibody-drug conjugates: the clinical development in gastric cancer

Abstract

Gastric cancer (GC) is a prevalent malignant tumor of the digestive system worldwide, ranking among the top five in terms of incidence and mortality. However, the clinical efficacy of conventional treatments for gastric cancer remains limited, with a median overall survival of approximately eight months for advanced cases. In recent years, researchers have increasingly focused on antibody-drug conjugates (ADCs) as a promising approach. ADCs are potent chemical drugs that selectively target cancer cells by binding to specific cell surface receptors with antibodies. Notably, ADCs have demonstrated promising results in clinical studies and have made significant strides in the treatment of gastric cancer. Currently, several ADCs are under investigation in clinical trials for gastric cancer patients, targeting various receptors such as EGFR, HER-2, HER-3, CLDN18.2, Mucin 1, among others. This review offers a comprehensive exploration of ADC drug characteristics and provides an overview of the research progress in ADC-based therapies for gastric cancer.

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target

“…ADCs are a novel drug design in which antibodies are chemically linked to cytotoxic therapy [15,[23][24][25]. The antibody component exerts its anti-tumor effects by recognizing the antigen on the target cells, facilitating the formation of an antigen-antibody conjugate, which allows the cytotoxic payload to be rapidly internalized, leading to release of the cytotoxic component [25].…”

“…ADCs are a novel drug design in which antibodies are chemically linked to cytotoxic therapy [15,[23][24][25]. The antibody component exerts its anti-tumor effects by recognizing the antigen on the target cells, facilitating the formation of an antigen-antibody conjugate, which allows the cytotoxic payload to be rapidly internalized, leading to release of the cytotoxic component [25]. Ideally, this mechanism should reduce off-target toxicity; however, as mentioned previously, trastuzumab deruxtecan, an ADC that consists of trastuzumab with a topoisomerase inhibitor, carries substantial toxicity [10,11].…”

“…RC48 is an ADC composed of hertuzumab, an anti-HER2 mAb conjugated to a microtubule inhibitor, monomethylauristatin E (MMAE) [26,27]. A phase 2 trial in ICH 2+/3+ advanced GAC patients in the refractory setting showed an ORR of 24.8%, median PFS of 4.1 months, and median OS of 7.9 months [25][26][27]. Those with HER2 IHC 2+/FISH− showed an ORR of 16.7%.…”

“…ARX788 was granted orphan drug status with the FDA in 2021 [32]. Examples along with their cytotoxic payload include MRG002 (microtubule disrupting agent monomethyl auristatin E), SYD985 (duocarmyicin), PF-06804103 (Aur0101), FS-1502 (monomethyl auristatin F), GQ1001 (DM1), A166 (microtubule cytotoxic agent), XMT-1522 (auristatin), BDC-1001 (toll-like receptor), ALT-P7 (monomethyl auristatin E), and SBT6050 (toll-like receptor) [15,24,25]. Trial examples of these agents are described in Table 2 [28,[33][34][35][36][37][38][39][40][41].…”

Claudin 18.2 as a New Biomarker in Gastric Cancer—What Should We Know?

“…Overall, the main limitations of ADCs are antigen modifications on tumor cells (heterodimerization, mutation, downregulation) and activity dependent on the level of expression of CLDN18.2. New strategies to enhance the specificity of the antibodies in order to create an effective strategy in the scenario of low CLDN18.2 expression are being studied [96].…”