Preclinical safety evaluation of ADCs is generally conducted under Good Laboratory Practice (GLP) standards. Some exploratory studies in early development phases may proceed under non-GLP conditions where necessary, provided the impact on data quality is 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. The company serves global pharmaceutical companies, biopharmaceutical firms, research institutes, clinical technology providers, and R&D organizations, and its platform is dedicated to NHP models for major human diseases. The intent behind that platform is to connect early-stage drug research with clinical application on an industrial scale.
1. Analysis of ADC Test Formulation
ADC test samples should adequately represent the quality attributes of the material intended for clinical trials. 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, so 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. In practice, DAR is a distribution rather than a single number: two batches with the same average value can differ in the proportion of unconjugated antibody, and that difference shows up in both potency and tolerability.
2. Selection of Animal Species for ADC Safety Studies
ADC composition includes an antibody, a linker, and a cytotoxic payload, which means the molecule combines features of both biologics and chemical drugs. Selecting appropriate animal models is therefore a central decision, especially those with relevant receptors or antigens for ADC binding and pharmacological activity. Antigen homology matters because the payload is delivered only after the antibody binds and the complex is internalized, so a species that lacks the epitope will underestimate both activity and toxicity. 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, though results should be carefully evaluated for human predictive relevance.
3. General Toxicity Studies
Standard acute and repeated-dose studies, the core of any Toxicology package, 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. 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, where off-target effects need to be evaluated. Such studies are usually run on a panel of frozen tissues at a small number of concentrations, and the readout is binding rather than function.
5. Toxicokinetics (TK) Studies
Toxicokinetics (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 Pharmacokinetics (PK) parameters and of stability in vivo. Combining TK with PK studies is often practical in non-rodent models, since the same sampling schedule can serve both purposes. The distinction is procedural as much as scientific: TK samples sit inside the GLP study and demonstrate exposure, while exploratory PK work can answer mechanistic questions on its own.
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. Baseline signals vary between animals, so pre-dose samples are needed if the post-dose response is to be read correctly.
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, broader 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 maintains an industrial platform for the development of NHP models for significant human diseases. By working with international and domestic partners, as well as government-funded projects, the company connects scientific research with industrial capital to move biomedicine toward clinical application. That combination is what sponsors draw on when a program needs translational data to support a regulatory submission.
