Evaluation of RBC Targeting As a Strategy to Extend Half-Life and Reduce Nonspecific Tissue Uptake of Biologics

Delivery strategies exploiting red blood cells (RBCs) have been widely pursued, particularly for the purpose of achieving sustained systemic exposure to small molecule drugs. However, limited efforts have been focused on applying RBC-inspired delivery strategies to biologic therapies. We aimed to evaluate RBC binding as a potential strategy to achieve systemic half-life extension or reduced tissue accessibility of antibodies, including those having intravascular targets or safety liabilities within peripheral tissues. The effects of RBC targeting on systemic pharmacokinetic (PK) properties was evaluated by measuring exposures of bispecific antibodies targeting a murine RBC surface target, the TER119 antigen, with or without point mutations that diminish binding to the neonatal Fc receptor (FcRn). Additionally, the effects of RBC targeting on specific (tumor) and nonspecific (normal) peripheral tissue uptake of a bispecific antibody targeting the TER119 antigen and a tumor cell surface tumor target (HER2) was assessed by noninvasive imaging and gamma counting. HER2 was used solely as a surrogate peripheral antigen to model potential safety-relevant tissue engagement rather than as a target expected to benefit from RBC binding. Results from an imaging study in tumor bearing mice revealed that RBC binding reduced peripheral uptake in both tumor and normal tissues but increased uptake in the spleen, which acts as both a reservoir for viable RBCs and a site for hemolysis of senescent RBCs. Furthermore, PK and biodistribution studies in normal mice indicated that RBC binding significantly increased the antibody half-life by ∼14-fold in the absence of FcRn-binding. These efforts lay an initial foundation for developing a next generation of biologic therapies with improved PK and therapeutic windows by taking advantage of the unique properties of RBCs.