In recent years, the development of antibody-drug conjugate (ADC) therapies has flourished, leading to significant advancements in treating solid tumors. The FDA has approved six solid tumor ADCs so far—Sacituzumab govitecan (SG), Trastuzumab Deruxtecan (T-DXd), Trastuzumab emtansine (T-DM1), Mirvetuximab soravtansine (MS), Tisotumab Vedotin (TV), and Enfortumab Vedotin (EV). Common adverse effects of these ADCs include varying degrees of fatigue, hair loss, bone marrow suppression, and gastrointestinal disturbances, often closely linked to ADC stability and payload composition.
From a molecular design perspective, the approved ADCs can be viewed as “targeted chemotherapy” agents. Although there are significant differences among various ADCs, they all consist of three components: a monoclonal antibody targeting tumor-associated antigens, a cytotoxic payload, and a linker. The primary mechanism involves the precise binding of the monoclonal antibody to tumor cells, enabling efficient delivery of the cytotoxic drug. Within this design framework, the cytotoxic effects of the payload and the antibody-dependent cellular cytotoxicity (ADCC) effects of the antibody are preserved, reflecting both efficacy and safety in treating solid tumors.
Regarding cytotoxic payload structures, ADCs with the same payload often exhibit similar profiles of adverse reactions. For instance, ADCs containing microtubule inhibitors like DM1 often lead to hepatotoxicity and thrombocytopenia. ADCs containing topoisomerase I inhibitors like DXd and SN-38 tend to cause hair loss, diarrhea, and neutropenia. The adverse effects attributed to the cytotoxic payload are mainly due to off-target effects on non-tumor cells and on-target effects on tumor cells. Clinical manifestations primarily involve the former, often resulting from premature dissociation of ADCs within the circulatory system. The patient’s tolerance to the cytotoxic payload exposure determines ADC tolerability, underscoring the significance of payload selection in ADC design.
In linker design, a balance is sought between sufficient stability for proper target delivery and adequate instability to enable payload release within the tumor microenvironment or tumor cells. Overly stable linkers can cause prolonged circulation, resulting in non-specific binding to non-tumor sites and subsequent adverse reactions unrelated to the payload. Conversely, excessively labile linkers can trigger premature payload release, leading to payload-related adverse effects. Additionally, whether the drug-antibody ratio is optimal and whether the linker conjugation is random or site-specific also impacts the spectrum and incidence of adverse reactions.
When selecting monoclonal antibodies, binding to antigens outside of tumor cells can lead to accumulation of the drug in non-tumor tissues, triggering unique off-target reactions. Furthermore, ADCs can interact with FcγRs through their Fc regions, potentially leading to toxicity in non-malignant cells. Hence, optimizing antibody selection, favoring those that bind highly to tumor cells and minimally to normal tissues, and avoiding unnecessary ADCC effects are common strategies in ADC design.
Apart from the ADC drugs themselves, patient-specific factors such as organ function and comorbidities can influence the spectrum and incidence of adverse reactions when applying ADC therapies. For instance, kidney impairment and lowered oxygen saturation are associated with lung toxicity related to T-DXd. Liver damage can enhance the cytotoxic effect of Enfortumab Vedotin. UGT1A1 gene polymorphisms can increase the incidence of neutropenia in SG. Even patient weight, albumin concentration, and race can impact how adverse reactions manifest with ADCs, necessitating clinical vigilance.
One of the primary aims of ADC design is to enhance the efficacy of traditional chemotherapy, often achieved through cytotoxic payloads. Standardized analysis of payloads has revealed that the maximum tolerated dose and minimum effective dose of ADC drugs are similar to those of their unconjugated cytotoxic payloads, as are their adverse reaction profiles. Over 90% of adverse events in clinical ADC use are associated with the cytotoxic payload. Due to their large molecular weight, ADCs are typically administered intravenously. After entering the circulation, ADC drugs exist as complete ADC molecules, unconjugated cytotoxic agents, and dissociated antibodies. During the process of transitioning from the circulation to the tumor microenvironment, approximately 0.1% of the drug can successfully reach the solid tumor. Most ADC drugs are cleared through targeted clearance or FcγR-mediated macrophage phagocytosis, and the dissociated “cytotoxic-linker” complex binds to serum albumin, further extending the activity and toxic characteristics of certain ADCs.