Overcoming the On-Target Toxicity in Antibody-Mediated Therapies via an Indirect Active Targeting Strategy

Area of Science:

• Biomedical Engineering
• Immunotherapy
• Drug Delivery Systems

Background:

• Antibody-based therapies face challenges due to target receptor expression on non-target sites, leading to on-target toxicity.
• Clinical applications of antibody therapies are limited by specificity issues and associated adverse effects.

Purpose of the Study:

• To develop a novel strategy, indirect active targeting (INTACT), to improve the specificity of antibody-based therapies.
• To mitigate on-target toxicity by exploiting receptor expression differences between target and non-target sites.

Main Methods:

• Proposed a biomimetic INTACT strategy involving prebinding antibodies with cell membrane vesicles.
• Utilized receptor expression disparities to filter interactions at non-target sites and ensure targeted release via competitive binding.
• Validated the strategy using a CD47 antibody in various animal models, including humanized patient-derived xenografts.

Main Results:

• Demonstrated significant alleviation of CD47 antibody-induced hematotoxicity in preclinical models.
• Observed improved therapeutic effects alongside reduced toxicity.
• Showcased the broad applicability of the INTACT strategy for antibodies, antibody-drug conjugates, and other targeted delivery systems.

Conclusions:

• The INTACT strategy effectively enhances the specificity of antibody-based therapies by minimizing off-target interactions and on-target toxicity.
• This approach offers a promising platform for refining the safety and efficacy of advanced antibody-related treatments.
• INTACT strategy shows potential for broad application in various targeted therapy systems.