Patritumab deruxtecan induces immunogenic cell death.

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Antibody-drug conjugates (ADCs) are designed for targeted cancer therapy.
• Patritumab deruxtecan targets the Erb-B2 Receptor Tyrosine Kinase 3 (HER3).
• Understanding the precise mechanism of action for ADCs is crucial for optimizing their efficacy.

Purpose of the Study:

• To characterize the mode of action of patritumab deruxtecan.
• To investigate its effects on cancer cell viability and immunogenic cell death (ICD).
• To evaluate its potential to elicit antitumor immunity in vivo.

Main Methods:

• Utilized human osteosarcoma cells engineered to express HER3.
• Assessed cell viability and calreticulin exposure.
• Measured HMGB1 and ATP release as markers of ICD.
• Investigated DNA-to-RNA transcription inhibition by the payload DXd.
• Evaluated in vivo antitumor immunity in mouse models.

Main Results:

• Patritumab deruxtecan reduced cancer cell viability and induced calreticulin relocation.
• Both the ADC and its payload DXd induced key features of ICD, including calreticulin exposure, HMGB1 and ATP release.
• DXd rapidly inhibited DNA-to-RNA transcription, a predictor of ICD.
• DXd-treated cancer cells induced anti-tumor immunity and immune memory in mice, leading to tumor rejection upon rechallenge.

Conclusions:

• Patritumab deruxtecan's cytotoxic payload induces hallmarks of ICD in vitro.
• The ADC effectively elicits antitumor immunity and immune memory in vivo.
• These findings support the therapeutic potential of patritumab deruxtecan in cancer treatment.