Bystander effect of antibody-drug conjugates: fact or fiction?

Area of Science:

• Oncology
• Pharmacology
• Cancer Therapeutics

Background:

• Solid tumors present challenges for antibody-drug conjugates (ADCs) due to heterogeneous antigen expression.
• The bystander effect, where ADCs release payloads to antigen-negative cells, may overcome this limitation.
• This effect involves payload diffusion from antigen-positive to antigen-negative tumor cells.

Purpose of the Study:

• To review preclinical and clinical evidence of the bystander effect in antibody-drug conjugates (ADCs) for solid tumors.
• To explore the role of ADC pharmacological characteristics in mediating the bystander effect.
• To assess the clinical relevance of the bystander effect in heterogeneous solid tumors.

Main Methods:

• Review of preclinical studies investigating ADC bystander activity.
• Analysis of clinical data from ADCs used in solid tumors with variable antigen expression.
• Evaluation of the impact of payload hydrophobicity and linker type on bystander effects.

Main Results:

• Preclinical data strongly support the existence of the bystander effect in ADCs.
• Certain ADC properties, like hydrophobic payloads and cleavable linkers, appear crucial for this effect.
• Clinical observations in heterogeneous tumors suggest the bystander effect's potential importance.

Conclusions:

• The bystander effect is a significant, albeit debated, feature of ADCs in solid tumors.
• Further investigation is required to determine if the bystander effect is essential for potent ADC activity.
• Understanding this mechanism could optimize ADC design and application in oncology.