Preclinical Testing for
New Modalities

New therapeutic modalities often present unique challenges, such as ensuring stability, efficient delivery, and targeted action. Each modality, whether it’s a PROTAC, oligonucleotide, ADC, peptide, peptide drug conjugate, CAR-T, or mRNA, has specific properties that require tailored approaches to evaluate their pharmacological and toxicological profiles. Additionally, addressing immunogenicity, off-target effects, and scalability for clinical production are significant challenges.

Stability and bioavailability are ensured through rigorous testing under different conditions, including temperature, pH, and exposure to enzymes. Formulation studies are conducted to develop stable delivery systems (e.g., lipid nanoparticles for mRNA or ADC linkers). Bioavailability is assessed through pharmacokinetic studies that measure the absorption, distribution, metabolism, and excretion (ADME) of the therapeutic.

Preclinical testing must adhere to regulatory guidelines set by agencies such as the FDA (Food and Drug Administration) in the US, EMA (European Medicines Agency) in Europe, and other relevant authorities. These guidelines include conducting Good Laboratory Practice (GLP)-compliant studies, performing comprehensive toxicology assessments, and documenting all findings in detail. Specific guidance

documents outline requirements for different modalities.

Key considerations include:

• Target specificity: Ensuring the therapeutic precisely interacts with its intended target.
• Stability: Developing formulations that maintain stability in physiological conditions.
• Delivery: Creating effective delivery systems that reach target cells or tissues.
• Efficacy: Demonstrating the therapeutic effect in relevant disease models.
• Safety: Identifying and mitigating potential toxicities and adverse effects.

Potential off-target effects are addressed through comprehensive in vitro and in vivo studies. High-throughput screening and bioinformatics tools are used to predict and identify unintended interactions. Functional assays and advanced imaging techniques help monitor off-target effects. Proteomics and genomics analyses are conducted to assess the broader impact on biological systems.

For biologics, considerations include immunogenicity, stability, and complex manufacturing processes. Biologics often require specialized assays to assess protein folding, glycosylation, and biological activity. For small molecules, the focus is on chemical stability, metabolic pathways, and potential drug-drug interactions. Both require robust pharmacokinetic and toxicological evaluations, but biologics may need additional immunotoxicity and bioanalytical assessments.

The transition is handled by compiling all preclinical data into an Investigational New Drug (IND) application, which is submitted to regulatory authorities. This includes detailed reports on safety, efficacy, pharmacokinetics, and toxicology studies. Collaboration with clinical experts ensures the design of early-phase clinical trials that address potential risks identified in preclinical testing. A well-defined manufacturing and quality control process is also established to ensure consistent production of the therapeutic for human studies.