Antibody-drug conjugates (ADCs) are among the fastest-growing drug modalities, driven by the rising global incidence of cancer, advances in technology and innovation, and a growing demand for targeted and precision therapies. There are over 800 active clinical trials, and the ADC market was estimated at $12-16 billion in 2025. However, ADCs pose challenges for researchers, as they can cause ocular toxicity, leading to costly delays and regulatory barriers.
The Prevalence of Ocular Toxicity in ADCs
To date, ocular toxicity has necessitated three black box warnings out of 15 approved ADCs:
- Belantamab mafodotin-blmf, which was approved for relapsed/refractory multiple myeloma, can cause ocular toxicity leading to changes in corneal epithelium, potentially ending in vision impairment, including severe loss, and corneal ulceration.
- Tisotumab vedotin-tftv, approved for recurrent or metastatic cervical cancer, can cause changes in corneal epithelium and conjunctiva.
- Mirvetuximab soravtansine-gynx, approved for folate receptor alpha (FRα)-positive, platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis.
According to research, ocular adverse events (AEs) were found to be more frequent in a belantamab group compared to a control group, by 76.85% vs 24.95%. Some of the most common specific AEs were dry eye (45.16% vs 6.69%), blurred vision (59.77% vs 10.14%), photophobia (36.95% vs 2.64%), eye irritation (37.27% vs 5.48%), eye pain (26.27% vs 3.04%), foreign body eye sensation (41.71% vs 4.26%), and cataract (16.58% vs 9.13%.)
Taken together, these examples highlight that ocular toxicity is not a rare or peripheral concern in ADC development. Rather, it is a clinically significant liability with direct implications for patient safety, trial continuity, and regulatory approval. Understanding the mechanisms behind these toxicities is essential to developing more effective strategies for early detection, risk reduction, and mitigation.
Mechanisms of Ocular Toxicity in ADCs
To understand ocular toxicity in ADCs, it’s essential to first grasp the structure of the drug type. They are designed to deliver a payload directly to cancer cells, thereby improving treatment efficacy while reducing off-target effects and systemic exposure. ADCs consist of three main parts: the monoclonal antibody (mAb), the payload, and a linker that connects the two. The mAB binds to its target, and the linker then releases the payload in sufficient concentrations to attack the target.
The structure of ADCs most likely contributes to ocular toxicity, but the mechanisms underlying it are not well understood. The ocular surface is likely susceptible to ADC-related toxicity due to a rapidly regenerating population of limbal stem cells, a rich blood supply, and a diverse array of cell-surface receptors.
ADC-related off-target toxicity includes:
- Non-specific endocytosis: “macropinocytosis” or “cell drinking.”
- Receptor-mediated endocytosis: Fc and C-type lectin receptors
- Premature release of payload due to linker instability or linker degradation by normal metabolism in the cell.
- Passive diffusion of payload into a cell due to non-charged, membrane-permeable residues
- The “Bystander effect”: payload released from a dead cell into the extracellular space kills neighboring cells.
- A higher drug-antibody ratio (DAR) is associated with an earlier onset and/or higher incidence of corneal toxicity.
Overall, current evidence suggests that ADC-associated ocular toxicity is driven predominantly by off-target mechanisms, especially non-specific uptake and payload-related cytotoxicity. On-target toxicity appears to be relatively rare and is more likely to occur only when the intended antigen is also expressed in ocular tissue.
Management of Ocular Toxicity in ADCs
Although ocular toxicity remains a persistent challenge in ADC development, several established management strategies can help reduce its incidence and limit its clinical impact. A proactive approach that combines prevention, monitoring, supportive care, dose modification, and specialist referral is essential to keeping these events manageable throughout treatment.
Prevention: Through baseline exams, prophylactic tears, steroids or vasoconstrictors, and patient education, developers can reduce the incidence of ocular toxicity.
Monitoring: Regular ophthalmic visits, on a cycle-based schedule, and symptom reporting can ensure that early detection prevents progression.
Supportive Care: Artificial tears, cool compresses, and topical steroids can help manage symptoms, which are reversible in most cases.
Dose Adjustment: Doses should be adjusted according to the severity of adverse effects. If they are too severe, the treatment should be discontinued. Developers must balance toxicity and efficacy.
Referral: Patients should be prompted to visit their ophthalmologist regularly to check for symptoms.
Taken together, these strategies can make ADC-associated ocular toxicities substantially more manageable in clinical practice. While ocular toxicity cannot always be avoided, consistent preventive measures and early intervention can reduce its severity, support treatment continuity, and improve the overall safety profile of ADC therapy.
A Final Word
ADCs are an extremely exciting drug class and hold great potential for cancer treatment. While ocular toxicity is common in ADCs and the precise mechanism is unknown, the effects are manageable. However, diligent testing and close monitoring is required. Researchers should be aware that animal models yield limited ocular findings and poor predictive value, and this type of toxicity is more prevalent in humans. Collaboration is also key to ensuring that ADCs are brought to market in the safest and most efficient manner possible, so this key medical innovation can continue to improve the lives of the patients who need them.
