From Payload-First Toward Dual-Mechanism Antibody-Drug Conjugates

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic payloads to tumors.
• The native pharmacology of potent monoclonal antibodies can be diminished upon conjugation.

Purpose of the Study:

• Introduce the concept of "antibody exposure deficit" in ADCs.
• Analyze factors contributing to reduced antibody mass and systemic exposure in ADCs.
• Define a design landscape for optimizing ADC constructs.

Main Methods:

• Conceptual analysis of ADC design parameters.
• Evaluation of payload, drug-to-antibody ratio (DAR), linker properties, and conjugation architecture.
• Consideration of fragment crystallizable (Fc) activity modulation.

Main Results:

• Conjugation systematically reduces antibody mass and systemic exposure (antibody exposure deficit).
• Payload type, DAR, linker hydrophobicity, and conjugation architecture influence this deficit.
• Site-specific DAR 1 formats mitigate the deficit, unlike higher-DAR constructs.

Conclusions:

• The antibody exposure deficit is a critical factor in ADC design.
• Optimizing ADC constructs involves balancing payload delivery with antibody pharmacology.
• Strategies like site-specific conjugation and Fc activity modulation offer pathways to improved ADC therapies.