Optimization Strategies for Dose Adjustment
Due to the dose-dependent nature of adverse reactions in ADC therapies, optimizing safety can be achieved through dose adjustment strategies. These include setting dose limits, maximum treatment duration, optimizing dosing frequency, dose adjustment guided by clinical response, and randomized dose confirmation studies.
The strategy of dose limits involves determining the maximum dose based on patient weight and pharmacokinetics to avoid excessive drug exposure and unnecessary adverse effects. For example, in populations weighing ≥ 100 kg using Enfortumab Vedotin, three treatment-related deaths prompted the use of a dose limit of 125 mg to control dosing.
The maximum treatment duration strategy controls drug exposure by limiting the treatment duration to reduce chronic and potential permanent adverse events. In treating relapsed or refractory diffuse large B-cell lymphoma with Polatuzumab Vedotin, an 8-course regimen increased ≥ Grade 2 peripheral neuropathy by over 50% compared to a 6-course regimen. While this strategy has not been verified for solid tumor ADC applications, it remains a consideration for control.
The dosing frequency optimization strategy adjusts peak blood concentration (Cmax) under the same cumulative dose to mitigate Cmax-driven adverse events. Gemtuzumab Ozogamicin’s original dosing regimen of 9 mg/m² q2w led to high rates of hepatotoxicity and veno-occlusive disease, resulting in its withdrawal in 2010. A revised regimen with doses of 3 mg/m² on days 1, 4, and 7 of each induction cycle reduced adverse reactions and gained approval in 2017.
Patient response-guided dose adjustment adapts doses based on individual treatment responses to maximize efficacy and minimize toxicity. In blood cancer therapy, Inotuzumab Ozogamicin’s initial dose of 1.8 mg/m² decreased to 1.6 mg/m² upon achieving complete remission, demonstrating a mature application of this strategy.
Randomized dose confirmation studies prospectively evaluate multiple doses of a drug to determine the optimal dose that maximizes therapeutic index. In exploring T-DXd’s application in HER2-positive non-small cell lung cancer, a comparison of 5.4 mg/kg and 6.4 mg/kg found similar efficacy, with higher doses having more adverse reactions, leading to the determination of a 5.4 mg/kg dose. Such dose exploration studies hold valuable references for other ADC dose development.
Optimization Strategies for ADC Design
Every structural innovation in ADC drug design can fine-tune pharmacological properties, impacting tolerability. Optimizing ADC’s structure is a fundamental approach to addressing adverse reactions.
At the antibody innovation level, most ADCs currently target antigens with high expression in tumor cells and low expression in normal cells. The design concept of the next-generation antibody-drug conjugates (probody-drug conjugates, PDCs) brings more possibilities. PDCs have an antibody part that acts as a probody, shielded by a cleavable peptide in the antigen-binding region. It selectively activates and exposes the binding region in the tumor microenvironment, avoiding off-target effects and enhancing efficacy and safety. Another strategy involves developing bispecific antibodies to enhance ADC’s tumor cell targeting for reduced adverse reactions.
In linker technology innovation, the current focus lies in achieving homogeneity by specifically bridging the cytotoxic payload and antibody parts, thereby improving pharmacokinetics. Additionally, adding polyethylene glycol structures to the linker enhances hydrophilicity, reducing non-specific uptake and off-target effects.
At the payload innovation level, novel ADCs with the same monoclonal antibody binding two different payloads are under development. Combining multiple mechanisms of cytotoxic payloads can enhance tolerability and anti-tumor activity, even when utilizing immune-stimulating agents and tyrosine kinase inhibitors as payloads. Furthermore, introducing neutralizing antibody fragments into payloads can bind free cytotoxic payloads in the circulatory system, reducing off-target effects and improving tolerability.
Optimization Strategies for Safety Monitoring
After clinical ADC use, recognizing risk factors for adverse reactions, effectively monitoring patients’ clinical presentations, and preventing, detecting, and treating adverse reactions in a timely manner are effective safety optimization strategies.
On the one hand, patients’ pharmacogenomic characteristics help predict the risk of adverse reactions after ADC application. Post-analysis of the ASCENT study revealed that UGT1A1 gene polymorphism causes UGT1A1 deficiency and correlates with adverse events of SG. Prior studies showed that UGT1A128 homozygosity is associated with neutropenia induced by irinotecan and SG. While routine testing of UGT1A1 gene polymorphism is not recommended due to the low frequency (<10%), closer toxicity monitoring is advised for known UGT1A128 homozygous patients. Early inclusion of pharmacogenomic profiles in clinical research design provides security for future clinical safety prediction as newer ADCs are developed.
On the other hand, early monitoring better manages adverse reactions in ADC. Wearable biosensors (WBS) that monitor patient health status are under development. These devices offer real-time, continuous, non-invasive monitoring of metrics like oxygen saturation, heart rate, and respiratory rate, facilitating early detection of adverse reactions.