Intratumoral Payload Concentration Correlates with the Activity of Antibody-Drug Conjugates

Area of Science:

• Pharmacology and Toxicology
• Oncology
• Bioconjugation Chemistry

Background:

• Antibody-drug conjugates (ADCs) are key targeted cancer therapeutics.
• Characterizing the exposure-response relationship for ADCs remains a challenge.
• Understanding payload delivery is crucial for optimizing ADC efficacy.

Purpose of the Study:

• To investigate the correlation between intratumor payload exposure and efficacy of disulfide-linked ADCs.
• To evaluate the role of linker design in determining intratumor payload concentrations.
• To establish a predictive model for ADC antitumor efficacy based on molecular mechanisms.

Main Methods:

• Utilized HER2-expressing xenograft models to assess efficacy of pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD)-based ADCs.
• Measured intratumor and systemic payload (PBD) concentrations.
• Performed dose-fractionation studies and mechanistic investigations on linker stability and immolation.

Main Results:

• Intratumor PBD concentrations strongly correlated with ADC efficacy, unlike systemic exposures.
• A threshold intratumor payload concentration was identified for sustained efficacy, with a plateau effect observed.
• Linker immolation and disulfide stability were key determinants of intratumor PBD levels.

Conclusions:

• Intratumor payload exposure is a critical determinant of antibody-drug conjugate (ADC) efficacy.
• Linker design significantly influences intratumor payload concentration and subsequent antitumor activity.
• Intratumor exposure serves as a quantitative predictor of ADC antitumor response.