Five Tips for Building an Integrative Approach to Toxicology for Emerging Modalities
Novel therapeutic modalities like antibody-drug conjugates (ADCs), antisense oligonucleotides (ASOs), peptide-drug conjugates (PDCs), and others are advancing fast and reshaping the drug development landscape in the process. Each of these modalities bring new challenges, including distinct pharmacological behaviors, mechanisms of action (MoAs), and safety considerations. As a result, this cohort of new modalities creates new questions for toxicologists to answer. Although foundational toxicology remains essential, more traditional approaches must be integrated with modality-specific strategies to ensure a complete and accurate safety profile.
This evolving environment requires a harmonized, integrative approach that combines in vitro, in vivo, and computational models with emerging analytical tools to ensure scientific rigor and regulatory alignment in the most efficient way possible. A few key best practices can help drug developers get there.
1. Ensure Modality-Specific Toxicology
Drug safety assessment has previously relied on frameworks designed around small molecules or conventional protein biologics. However, the emergence of new modalities has challenged conventional assumptions. Drugs that are more complex and mechanistically targeted interact with biological systems in ways that diverge from known patterns.
For example, an ADC’s safety profile is primarily driven by target specificity, linker stability, payload potency, drug-to-antibody ratio (DAR), and bystander effects in addition to pharmacokinetics (PK). By contrast, the safety profiles of ASOs are shaped less by traditional metabolism and more by sequence-specific hybridization, tissue accumulation, and immunostimulatory potential. To ensure thorough toxicity assessment, researchers must account for these nuances and develop different approaches to nonclinical study design.
For the industry, risk assessment must evolve beyond a one-size-fits-all model. A new standard of tailored toxicology programs, informed by mechanism and platform behavior, is emerging. These programs require revamped methodologies and new approaches to interpreting data and translational contexts. Drug developers must proactively plan and tailor their programs to address the challenges this new paradigm presents.
2. Address Challenges in Evaluating Next-Generation Modalities
Each emerging modality introduces its own nuanced risks that conventional assays cannot adequately capture. These factors span PK off-target effects, immunogenicity, and tissue biodistribution.
ADCs The primary challenge for ADCs (antibody-drug conjugates) is variability in DARs. This has a significant bearing on drug efficacy, safety, and PK. The goal is not to achieve the highest DAR but rather to use a DAR that balances safety, PK, and efficacy. Hydrophobic-interaction chromatography (HIC), liquid chromatography with mass spectrometry (LC-MS)-based intact and subunit analyses, ligand-binding assays (LBAs), hybrid LBA-LC-MS approaches, and other bioanalytical methods can quantify conjugated payloads, free drug, and antibodies to characterize the PK profile of an ADC.
ASOs
Low circulating concentrations, extensive tissue binding, and the presence of chain-shortened metabolites further complicate analytical characterization of ASOs (antisense oligonucleotides).
Researchers must use targeted biomarker monitoring to detect early signs of toxicity resulting from accumulation in specific tissues, particularly the liver and kidneys. ASOs can also elicit innate immune responses, posing risks for systemic inflammation or complement activation.
Peptide-based therapies
These therapies are highly susceptible to rapid enzymatic degradation, leading to short half-lives and limited bioavailability. This makes frequent and complex dosing a regular necessity. In these cases, understanding a drug’s PK to pharmacodynamics (PD) relationship is crucial to strike a balance between safety and efficacy.
Targeted protein degraders (TPDs)
TPDs are designed to eliminate disease-causing proteins by catalyzing their degradation via the ubiquitin-proteasome system. They fall into three classes: PROTACs, molecular glues, and lysosome-based degraders. Conventional plasma PK is necessary, but insufficient, and robust PD biomarkers are required to demonstrate target degradation and PK-PD response in targeted protein degraders.
mRNA-based therapies Generally well tolerated, but in a toxicological sense, mRNA-based therapies are limited primarily by a potential for innate immune activation and lipid nanoparticle (LNP)-related toxicity. Regulators usually expect full immunotoxicity assessment, careful dose selection, robust control of mRNA and LNP components, and long-term follow-up.
3. Embed Safety Assessments Earlier in Product Development
The development of emerging modalities requires adaptive, integrative toxicology methods. This begins with embedding safety assessments earlier in the product development than is customary, using predictive tools to guide candidate selection and study design.
A proactive, modality-specific, and integrative approach can vastly improve program progress. For example, early genotoxicity screening can help flag off-target effects for ASOs or mRNA therapies before they progress to costly in vivo studies. Utilizing a multimodal toolkit is also crucial. LBAs, LC-MS techniques, and high-sensitivity flow cytometry can now be used in tandem to monitor drug levels, active metabolites, and PD biomarkers.
New-approach methodologies (NAMs) can further enhance translational relevance.
4. Consider NAMs to Enhance Translational Relevance
NAMs reduce reliance on in vivo testing models and can be combined with traditional safety paradigms to meet the distinctive challenges of new modalities. NAMs include the following:
- Cytotoxicity panels
- Human ether-a-go-go-related gene (hERG) patch-clamp assays
- Tests using hiPSC-derived cardiomyocytes
- Assays using 3D liver spheroids/organoids
- In chemico bacterial reverse-mutation assays
- In vitro micronucleus (MNvit) assays
- Lung-on-chip models
- Gut-organoid testing
- Zebrafish-embryo assays.
NAMs are already being translated into real-world drug development scenarios. In ASO development, for example, monitoring liver and kidney biomarkers is now standard in early safety studies.
5. Make Strategic Considerations When Approaching Regulation
In this evolving landscape, sponsors must rethink how and when they approach toxicology. Early engagement with regulators is vital, as novel modalities may not fit within existing frameworks, requiring sponsors to justify study design, species selection, and biomarker strategies.
Cross-functional collaboration is crucial. Toxicologists, drug metabolism (DM) and PK scientists, and regulatory affairs teams must work closely to ensure study goals, data interpretation, and regulatory messaging are aligned. And timing matters. Integrating toxicology insights early in the IND-enabling process informs candidate advancement, and proactive sponsors are more likely to navigate regulatory complexity successfully and avoid last-minute surprises.
A Final Word As the therapeutic landscape transforms, sponsors and developers must stay ahead of the shift. Integrative toxicology approaches that combine traditional rigor with innovative methodologies are no longer optional. Adaptive, fit-for-purpose strategies allow sponsors to navigate the complexities of development and regulatory pathways and to bring therapies to patients safely and efficiently.
A Final Word
As the therapeutic landscape transforms, sponsors and developers must stay ahead of the shift. Integrative toxicology approaches that combine traditional rigor with innovative methodologies are no longer optional. Adaptive, fit-for-purpose strategies allow sponsors to navigate the complexities of development and regulatory pathways and to bring therapies to patients safely and efficiently.
