💉 ADC Immunogenicity Analysis

🔎 What It Is

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. However, their immunogenic potential—the ability to trigger unwanted immune responses—poses risks to safety, efficacy, and pharmacokinetics.
Immunogenicity analysis is therefore a critical component of ADC development, from preclinical research to clinical translation.

⚠️ Why It Matters

• Anti-drug antibodies (ADAs) can reduce ADC efficacy by neutralizing antibody binding or accelerating clearance.

• Hypersensitivity or immune toxicities may be induced by the antibody, linker, or payload.

• Regulatory requirement: Agencies (FDA, EMA) expect thorough immunogenicity risk evaluation for ADCs.

🧪 Typical Analysis Strategies

1. In Silico Immunogenicity Prediction

   • Epitope mapping & T-cell epitope prediction (antibody + linker + payload).

2. In Vitro Assays

   • Human PBMC assays for T-cell activation.

   • Cytokine release assays to assess immune stimulation.

   • Dendritic cell activation tests.

3. In Vivo Models

   • Rodent or non-human primate studies for immunogenicity profiling.

4. Clinical ADA Assays

   • Screening: detect anti-drug antibodies.

   • Confirmatory: competitive binding assays.

   • Characterization: neutralizing antibody (NAb) assays, titer, and persistence.

📊 Data Interpretation

• Frequency and severity of ADA responses.

• Impact on ADC PK/PD, efficacy, and safety.

• Risk mitigation strategies (humanized antibodies, linker optimization).