So far, the FDA and EMA have approved six ADC drugs for patients with solid tumors. Fig. 1 depicts the composition of each ADC (targeting antigen, mAb type, Payload, and linker), currently approved indications, and the most common toxicities observed for each drug. The adverse reaction profile of each ADC is usually a mixture of on-target and off-target effects, the latter usually determining the maximum tolerated dose. Common adverse reactions observed to varying degrees in many Adcs include fatigue, alopecia, cytopenias, and gastrointestinal disturbances. Due to the large molecular weight, ADCs are usually administered intravenously. Data from in vivo experiments suggest that this route of administration may be associated with reduced activity and severe skin toxicity of certain ADCs. After injection, an ideal ADC should remain intact in circulation and release its cytotoxic payload only in or near the targeted tumor cells. Small changes in the structure of ADCs often lead to large changes in the pharmacokinetic and/or pharmacodynamic characteristics of the drug.
Mechanistically, once an ADC reaches the tumor microenvironment (TME), it is generally believed that it binds to target antigens expressed on the surface of cancer cells and internalizes in vivo. The ADC payload is then released through chemical or enzymatic cleavage in lysosomes, ultimately leading to tumor cell necrosis or apoptosis. The mechanism of action of the payload and the concentration achieved at the target site play a decisive role in the efficacy of the ADC. In general, intracellular hydrophobic payloads, such as monomethyl auristatin E (MMAE) and exatecan derivatives, can diffuse outside of target cells upon unconjugation from antibodies, resulting in bystander killing of antigen-negative cells, which enhances the antitumor activity of certain ADCs. In addition to the traditionally recognized mechanisms for targeted payload release within tumor cells, certain ADCs can release cytotoxic payloads without antigen engagement and internalization. For example, sacituzumab-govitecan was shown to release its SN-38 payload extracellularly within the TME.
Effect of Structure on ADC Toxicity
ADCs have a modular structure, and minor modifications to any of their key components can lead to major changes in clinical characteristics. The relative contribution of each ADC component and the role of patient characteristics in the type and severity of observed toxicity will be dissected next.
- ADC Payloads
According to the rationale behind ADC development, targeting the antigen is expected to determine the toxicity profile of the drug. Clinical experience has shown that most adverse events associated with ADCs are similar in incidence and severity to payload backbones, and that different ADCs with the same payload often have similar toxicity profiles regardless of differences in target antigens. These toxicities can be broadly divided into off-targets unrelated to the antigen targeted by the antibody, and on-targets resulting from binding of the antibody to a cognate antigen located in nonmalignant tissue.
The key mechanism of off-target, extratumoral toxicity of ADCs is thought to be related at least in part to premature uncoupling of payloads in the systemic circulation, which leads to the diffusion of free cytotoxic payloads into extratumoral compartments. This payload is usually a lipophilic molecule capable of penetrating the plasma membrane and entering untargeted non-malignant cells. In addition, part of the payload may also bind to serum albumin and other sulfhydryl-containing circulating plasma proteins, which can increase the half-life of the payload-linker complex and may lead to deposition of the payload in nonmalignant tissues. In addition to the mechanism by which the payload dissociates from the ADC, other mechanisms are also thought to mediate the exposure of non-malignant cells to the cytotoxic payload, including nonspecific endocytosis, the endocytosis of intact ADC in non-malignant cells; and off-target, receptor-mediated uptake, which results from the interaction of the Fc region of antibody with Fc receptors expressed by immune cells. The latter mechanism may be more relevant to highly stable ADCs that are associated with premature dissociation and limited release of the cargo into circulation, thus making it more likely that intact ADCs will be encountered in non-malignant tissues. Regardless of the mechanism, the degree of off-target exposure of non-malignant cells to the payload ultimately determines agent tolerance, making the choice of payload a critical decision in any ADC design.
- ADC Linker
The primary mechanism leading to off-target toxicity in patients receiving ADCs may be related to the timing and localization of payload release from the conjugate. These characteristics are largely dependent on the stability and pharmacological structure of the linker and thus may have a major impact on the toxicity profile of the ADC. An ideal linker should be stable enough to deliver the payload to the intended site, but also unstable enough to release an effective amount of the payload in or near the tumor.
In general, less stable linkers lead to earlier release of free payload into the circulation, higher peak cytotoxic concentrations, and increased typical chemotherapy-related toxicities such as cytopenias, alopecia, and/or gastrointestinal toxicity. A more stable linker can lead to long cycles of the full ADC, with the payload released later. This aspect may explain the particular toxicity profile of certain highly stable ADCs, some of which have been found to have limited chemotherapy-related toxicity but an unexpectedly high incidence of ocular toxicity. These findings suggest that a balance should be maintained when attempting to determine ADC stability, and that both excessive release and retention of ADC payloads can lead to unintended toxicity. In addition to linker stability, the specific chemistry used to attach the payload to the antibody, as well as the drug-to-antibody ratio (DAR), may have an impact on the toxicity profile of the ADC.
- Antibody
Much of the toxicity of ADCs is determined by the linker-payload complex. But despite ADCs with the same payload and linker, their adverse effects can vary greatly due to on-target, non-tumor toxicity. These events are associated with the engagement of specific targets or the accumulation of payloads in non-malignant tissues expressing ADC targets. In some cases, on-target toxicity may dominate ADC safety. To minimize the risk of this on-target toxicity, ADC targets need to be carefully selected, with preference given to antigens expressed between tumor cells (ideally high expression) and non-malignant cells (ideally low or no expression). Although antibody-related toxicities generally do not dominate the adverse effects of ADCs, several serious on-target, off-tumor, or Fc-part-mediated toxicities have been observed. These observations highlight the complexity of the mechanisms of action of these compounds and the relevance of each ADC component to the tolerance profile.
- Patient Related Factors
In addition to the differences in the toxicity profile observed across ADCs, there is also a relevant degree of heterogeneity in the spectrum and grade of adverse reactions occurring in different patients receiving the same ADC. A variety of patient-related factors may affect the pharmacokinetics and pharmacodynamics of these drugs, including baseline organ function, the presence of comorbidities, polymorphisms in enzymes involved in ADC metabolism or its catabolism, etc. Finally, race has been found to affect ADC metabolism: for example, patients of Japanese ethnicity had a 20% increase in mean serum T-DXd concentrations compared with patients from other countries, a finding that may explain the observed ILD in this patient population high incidence.
Adverse Reactions Related to the Combination Strategy
ADCs offer multiple opportunities for combination strategies with the aim of achieving additive or synergistic antitumor activity. However, these combinations also carry the risk of increased regimen toxicity, possibly due to overlapping adverse effects or unexpected synergies.
- ADC Combined with Chemotherapy
Combining different types of chemotherapy is an established approach to overcome drug resistance and improve treatment efficacy. However, combining ADCs with chemotherapy presents several challenges related to overlapping toxicities. Data from most trials seem to indicate that there is a non-negligible increase in toxicity when ADCs are combined with conventional chemotherapy, possibly due to overlapping toxicities due to off-target, off-tumor effects of the ADC payload.
- ADC Combined with Endocrine Therapy
Endocrine therapy is a common therapeutic strategy whose overall goal is to inhibit the growth of hormone-dependent cancers by blocking hormone production or the ability of hormones to promote tumor cell growth. This agent is generally well tolerated and is frequently administered to patients with breast or prostate cancer. Overall, the combination of ADCs and endocrine therapy does not appear to be associated with increased toxicity.
- ADC Combined with Immunotherapy
ADCs have the potential to trigger immunogenic cell death with chemotherapy, and also have potential immunostimulatory functions through the Fc domain of the antibody, thus providing ideas for combination with immune checkpoint inhibitors (ICIs). To date, no signal of synergistic toxicity has been observed for combinations of ICIs and T-DXd, Dato-DXd, or sacituzumab-govitecan.
ADC Combined with Targeted Therapy
Among currently approved ADCs, T-DM1 is the agent with the most evidence of activity and safety when used in combination with targeted agents. The combination of T-DM1 with the HER2 tyrosine kinase inhibitor tucatinib was tested in a phase Ib trial and found to be tolerable, despite frequent gastrointestinal and hepatotoxicity. T-DM1 was also tested in combination with CDK4 and CDK6 inhibition in the phase Ib trial of HER2-CLIMB-02, and no DLTs were observed. In a phase Ib trial of patients with metastatic TNBC, the combination of cetuzumab govetecan and the PARP inhibitor tarazoparib resulted in multiple DLTs (most enrolled patients had febrile moderate granulocytopenia). Finally, in a phase Ib trial involving patients with platinum-resistant ovarian cancer, the addition of the anti-VEGFA antibody bevacizumab to mivirtuximab-solavirtansine produced toxicities comparable to ADC toxicity alone.
Emerging Strategies to Optimize ADC Safety
In clinical practice, several strategies have been employed to prevent or optimally manage ADC-related toxicity.
1. Dose Optimization Strategy
Considering the dose-dependence of toxicity associated with ADCs, researchers have paid considerable attention to the optimization of doses and dosing regimens in an attempt to increase the therapeutic index of ADCs. To this end, five classic dose optimization strategies have been employed, including body weight dose capping, treatment duration capping, dose frequency optimization, response-guided dose adaptation, and randomized dose-finding studies.
2. Optimize ADC Design
ADC engineering and other optimization strategies are important approaches to maximize the efficacy and safety of a formulation. Indeed, design innovations of each ADC component can enable fine-tuning of pharmacological properties with potential impact on tolerability.
3. Antibody Innovation
Most currently approved and investigated ADCs target targets that are heterogeneously expressed to varying degrees in nonmalignant tissues. The generation of probe-drug conjugates (PDCs) provides an example of engineering that may reduce the incidence of on-target, non-tumor toxicity. In addition to masking the binding region of antibodies, attempts are currently being made to silence antibody Fc domains to reduce off-target and extratumoral toxicity associated with Fc-mediated ADC uptake by immune cells. Another strategy to improve the delivery of ADCs to tumor sites and potentially reduce the incidence of on-target toxicity is to conjugate the payload to bispecific antibodies instead of conventional antibodies. Compared with conventional antibodies, bispecific antibodies have higher selectivity and better internalization in tumor cells.
4. Linker Innovation
Several strategies are currently being developed to improve the stability of ADCs in system cycles to optimize safety. These approaches enable the preparation of homogenous ADCs with predictable DAR and payload attachment sites, which may be associated with improved tolerability and more predictable pharmacokinetics. Preclinical data suggest that these combination strategies improve safety. Furthermore, ADCs developed using this strategy retain activity and have improved pharmacokinetic properties and are currently undergoing clinical testing.
5. Payload Innovation
To improve the therapeutic index of single-payload ADCs, new constructs with two different types of payloads linked to the same mAb have been developed. Preclinical data have confirmed the feasibility and high anti-tumor activity of this approach, and its constructs such as HER2-targeting antibody conjugated to MMAE and MMAF and FGF2-targeting antibody conjugated to MMAE and α-amanitin. Furthermore, new payloads are being explored in addition to microtubule agents, topoisomerase I inhibitors, and DNA intercalators. These payloads include other cytotoxic molecules such as topoisomerase II inhibitors or agents that inhibit transcription or translation as well as ADCs with unconventional payloads such as immunostimulatory molecules, heterobifunctional protein degraders, and tyrosine Kinase inhibitors. Co-administration of ADCs with payload-neutralizing antibody fragments is another innovation aimed at improving the tolerability of ADCs. Preclinical data demonstrated that when a HER2-targeted MMAE-based ADC was administered in combination with humanized anti-MMAE Fab fragment ABC3315 in a xenograft model, chemotherapy-related toxicity was reduced, body weight loss was improved in a mouse model, and activity is retained.
6. Pharmacogenomics
Identifying patients at greatest risk of adverse events following ADC therapy is an important step toward improving the clinical management of such patients. The data suggest that pharmacogenomic parameters may have a relevant impact on the safety profile of some ADCs. As novel ADCs are developed, consideration of pharmacogenomic profiling when designing early trials may be a reasonable approach to ensure safety is not unduly affected by genetic variation in specific populations and/or between individuals.
7. Diagnostic Tools
Another potential approach for early detection and better management of ADC-induced adverse events involves the use of wearable biosensors (WBS). The rapid development of these technologies may facilitate the early diagnosis of ILD in at-risk patients, help identify acute exacerbations of ILD, and support real-time clinical decision-making.
ADCs improve the activity of conventional chemotherapy regimens in a range of solid tumors. Despite their ideal on-target mechanism of action, most ADCs suffer from frequent and sometimes life-threatening toxicity. Given the rapid expansion of its indications, awareness of these adverse effects and their management and efforts to prevent and mitigate ADC-related toxicities are critical. These include careful attention to the risk of synergistic or overlapping toxicity when using ADCs in combination with other anticancer agents. And caution in developing and testing novel ADCs in early-stage disease, where each indication requires a unique balance of risks and benefits. Innovations in ADC design, pharmacogenomic testing, and WBS, as well as increased focus on ADC dose optimization through dedicated prospective trials, may help harness the potential of this highly promising class of cancer drugs, which remains far from being fully explored.
References
- Tolaney, S.M. et al. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol. 2023, 20(8): 558-576.
