Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to Increase In...

Area of Science:

• Oncology
• Pharmacology
• Immunology

Background:

• Antibody-drug conjugates (ADCs) targeting highly expressed tumor antigens show clinical promise in solid tumors.
• Antigen expression in normal tissues can lead to target-mediated drug disposition (TMDD) and increased ADC clearance.
• The impact of ADC cross-reactivity with normal tissue antigens on tumor response is not fully understood.

Purpose of the Study:

• To investigate the impact of a cross-reactive antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα) in a model with normal tissue antigen binding.
• To evaluate the effect of a 'carrier' dose of unconjugated antibody on the clearance, distribution, and efficacy of a cross-reactive ADC.

Main Methods:

• Generated a cross-reactive anti-FRα antibody tested in an animal model where it binds both human tumor FRα and murine FRα in normal tissue.
• Employed a carrier dose of unconjugated anti-FRα antibody co-administered with the anti-FRα ADC.
• Assessed ADC clearance, systemic exposure, tumor penetration, normal tissue uptake, and overall efficacy.

Main Results:

• Co-administration of unconjugated anti-FRα antibody with the ADC improved efficacy, even in low-expression models.
• The carrier dose reduced target-antigen-mediated clearance in normal tissue, increasing systemic exposure and tumor penetration.
• Optimal carrier dosing enhanced efficacy, while excessive doses reduced efficacy, highlighting the importance of payload potency and antigen saturation.

Conclusions:

• Co-administering unconjugated antibody can mitigate target-mediated clearance in normal tissues, thereby improving ADC systemic exposure, tumor penetration, and efficacy.
• Judicious use of higher antibody doses, via lower drug-to-antibody ratio (DAR) or carrier doses, can enhance the therapeutic window by increasing efficacy and reducing normal tissue toxicity.
• This strategy offers a potential method to improve the therapeutic index of ADCs targeting antigens with normal tissue expression.