Conducting preclinical safety evaluations for ADCs requires adherence to Good Laboratory Practice (GLP) standards, except for some exploratory studies in early development phases, which may proceed under non-GLP conditions if necessary, with impacts on data quality clearly indicated.
Shanghai Prisys Biotech Co., Ltd. specializes in the preclinical and translational evaluation of new drug technologies, focusing on non-human primate (NHP) disease models and proprietary techniques aligned with international pharmaceutical standards. Serving global pharmaceutical companies, biopharmaceutical firms, research institutes, clinical technology providers, and R&D organizations, Prisys Biotech offers robust solutions for the clinical application and translational advancement of novel therapies. The company leverages a unique platform dedicated to NHP models for major human diseases, aiming to bridge early-stage drug research with clinical applications on an industrial scale.
1. Analysis of ADC Test Formulation
ADC test samples should adequately represent the quality attributes of those intended for clinical trials. Comprehensive reports on their physicochemical properties should include information on source, batch number, purity, concentration, and composition. ADC drug-to-antibody ratio (DAR) significantly impacts toxicity; thus, DAR stability must be verified both in test solutions before administration and throughout handling. Concentrations should be measured prior to administration, and DAR reassessed if conditions permit.
2. Selection of Animal Species for ADC Safety Studies
ADC composition includes an antibody, linker, and cytotoxic payload, combining features of both biologics and chemical drugs. Therefore, selecting appropriate animal models is crucial, especially those with relevant receptors or antigens for ADC binding and pharmacological activity. If rodents are unsuitable, a single non-human primate species can be selected. For unknown small-molecule toxicities, short-term studies may be conducted in rodents to compare ADC toxicity before and after antibody conjugation.
In cases where only one relevant species is identified, single-species studies may be justified. If no relevant species exists, alternative molecules or animal models (such as transgenic animals expressing human targets) can be utilized, but results should be carefully evaluated for human predictive relevance.
3. General Toxicity Studies
Standard acute and repeated-dose toxicity studies provide the foundation for ADC safety evaluation. ADC studies generally involve the entire molecule, though separate studies may assess specific components depending on target engagement. If the small molecule is approved or has sufficient safety data, isolated studies may not be necessary. However, novel or under-researched small molecules may require standalone toxicity studies, typically in rodents, to assess toxicity at maximal tolerated doses.
Due to the long half-life of ADC antibodies, observation periods in single-dose studies can be extended to capture delayed toxicity responses. Typically, repeat-dose studies do not exceed three months.
4. Tissue Cross-Reactivity (TCR) Studies
TCR studies offer insights into antibody binding with target and non-target tissues, though recent guidelines have downplayed their necessity due to limitations in non-clinical predictive value. Regulatory requirements vary, but TCR studies in human or NHP tissues are advisable for ADCs with newly modified distribution profiles to evaluate potential off-target effects.
5. Toxicokinetics (TK) Studies
TK assessments are integrated with toxicity studies, providing ADC exposure data and supporting first-in-human (FIH) dose selection. TK measurements, including free small molecule and intact ADC levels, offer a view of PK parameters and stability in vivo. Combining TK with PK studies is often practical in non-rodent models.
6. Immunogenicity Evaluation
As ADCs include antibody components, they may trigger immune responses. A multi-tiered testing approach-covering screening, titering, neutralization, and subtype analysis-is recommended to assess immunogenicity. Immunogenicity studies are typically conducted alongside repeat-dose toxicity studies, collecting samples at different intervals to analyze anti-drug antibody (ADA) formation.
7. Genotoxicity Studies
ADC structural properties imply that genetic toxicity risk mainly stems from the small molecule, so standard genotoxicity testing of ADCs themselves may not be necessary. If the small molecule is novel or has uncertain mechanisms, comprehensive genotoxicity assessments should be conducted, focusing on relevant components based on ADC stability, activity, and degradation pathways.
8. Safety Pharmacology
For anti-cancer biologics, ICH guidelines generally do not require standalone safety pharmacology studies. If the small molecule is a novel cytotoxin, hERG testing may be necessary to assess potential cardiotoxicity.
Prisys Biotech stands at the forefront of biopharmaceutical innovation, committed to establishing an industrial platform for the development of NHP models for significant human diseases. By fostering collaborations across international and domestic sectors, as well as government-funded projects, Prisys Biotech combines scientific research with industrial capital to expedite biomedicine's clinical applications. This dedication to advancing biopharmaceutical translation creates new opportunities and technological support for the strategic growth of the industry, underscoring Prisys Biotech's role as a key player in the global life sciences ecosystem.
