Antibody-drug conjugates (ADCs) are among the most exciting drugs being developed to fight cancer, as sponsors leverage their unique design and laser-like precision. However, ADCs also pose ocular safety challenges that must be addressed to avoid costly delays or regulatory setbacks.
ADCs are designed to deliver a payload directly to a target, typically cancer cells, improving treatment efficacy and reducing systemic exposure and off-target effects. But if developers are to capitalize on the enormous potential of ADCs, they must consider ocular safety at the earliest opportunity. The following tips can help ensure ocular safety remains at the forefront of the developer’s mind as they seek to bring this crucial new mode of drug delivery to market.
1. Understand the Effects of Ocular Toxicity
ADCs are associated with several adverse effects and toxicities, including hematologic side effects such as neuropathy, lymphopenia, and neutropenia. Ocular toxicities are among the most clinically impactful during development and require early planning and active monitoring during therapy.
These toxicities often affect the cornea or ocular surface and can manifest as a foreign-body sensation and blurred vision. Other clinical signs include blurred vision, dry eye, foreign body sensation and cataract, among others.
ADCs such as enfortumab vedotin and tisotumab have been associated with common ocular side effects and are examples of drugs which have suffered from both on-target and off-target ocular toxicity. Enfortumab vedotin carries a warning for ocular disorders, and the incidence of ocular toxicities when using the drug can reach as high as 46%, with dry eye symptoms being the most commonly reported.
The pathogenesis of ocular adverse effects in ADCs has been attributed to:
- The unique molecular structure of the drug type
- The cytotoxic mechanism of its payload
- The expression of target antigens on both tumor and healthy ocular cells.
The precise mechanisms causing these effects are still unknown, but it is thought that the ADCs cause ocular adverse effects through both on-target and off-target mechanisms. Growing evidence suggests that most of these adverse effects are target-independent and driven primarily by the payload rather than by antigen expression on normal eye tissue.
Armed with this research, scientists have developed strategies to reduce off-target uptake, presenting a path forward in the mission to reduce ocular toxicity.
Mitigate Ocular Toxicity Through Preclinical Testing and Study Design
Toxicology must become more adaptive and integrative to meet the safety demands of emerging modalities such as ADCs. One of the major challenges is that preclinical studies can’t predict ocular toxicity in humans, who are more sensitive than animals. Safety assessments should be embedded earlier in the development lifecycle to allow predictive tools to guide candidate selection and study design. Preclinical studies do not necessarily show eye abnormalities, and if they do, they are often mild and considered non-adverse. For example, non-adverse histopathology findings of increased mitotic figures and single cell necrosis in rats and rabbits treated with an ADC (belantamab mafadotin) that causes ocular toxicity in humans that requires a black box warning on the label.
Developers must carefully select the target, antibody, cytotoxic payload, and linker to ensure that the drug is as effective as possible while maintaining safety and reducing adverse effects. Researchers must also account for nuanced characteristics of ADCs and risks that are not always captured in conventional pre-clinical assays.
3. Pay Close Attention to Variability in the DAR
Variability in the drug-to-antibody ratio (DAR) is a primary and unique concern in ADC testing. DAR determines the amount of drug delivered, the duration of ADC circulation, and safety, and significantly affects a drug candidate’s efficacy, safety, and pharmacokinetics (PK).
Researchers are not seeking the highest possible DAR, but rather an appropriate ratio that balances safety, PK stability, and efficacy. Advanced bioanalytical methods can quantify free and conjugated payloads, as well as antibodies, to characterize the PK profile.
4. Establish Safety Parameters with MTD
Researchers must also determine a compound’s Maximum Tolerated Dose (MTD) to set an appropriate preclinical threshold, which will inform dose selection and risk mitigation strategies.
This crucial step also establishes safety parameters for advancing therapies into clinical trials. Developers who follow this advice will be better prepared to deliver safe and efficacious drugs.
5. Reduce Ocular Safety Risks Before Clinical Trials
By building eye safety into early development, scientists can better identify and reduce many ADC-related ocular toxicities. Steps to achieving eye safety include:
- Assessing whether the target antigen is present in healthy eye tissue.
- Testing ADCs and their payloads on human eye-surface (corneal epithelial) cells to determine if toxicity occurs in the absence of target expression.
- Examining how the drug enters cells via nonspecific uptake.
Developers can also reduce the ocular risk by modifying ADC design. This can be done by improving linker stability, lowering drug load, or reducing hydrophobicity (when a molecule is repelled from water).
6. Consistent Monitoring at the Clinical Stage and Beyond
ADCs require continuous monitoring during the clinical stage and beyond due to their high risk of adverse effects. Diagnosis involves thorough clinical assessment, imaging, and functional testing through the treatment period.
Once in the clinical setting, a few strategic tests should be administered regularly to establish efficient and responsible monitoring of side effects such as ocular toxicity.
Fluorescein and lissamine green staining can be used to identify corneal and conjunctival epithelial damage, and corneal microscopy offers high-resolution imaging of microcysts and nerve alterations. Schirmer’s test and tear breakup time can help evaluate ADC-induced dry eye. Finally, optical coherence tomography detects changes in the corneal structure.
A Final Word
ADCs hold tremendous potential for treating cancers, but adverse effects including ocular toxicity threaten to undermine their progress. Even when mild, these toxicities can derail treatments and reduce ADCs’ effectiveness.
For sponsors and developers, ocular safety should remain a priority throughout development and beyond clinical trials. By addressing this issue early, with a team or lab partner wielding the expertise and experience to handle this type of testing, developers can ensure future ADCs reach patients safely and efficiently.
