Pinocytosis inhibitory nanoparticles enhance aPD-1 antibody delivery and efficacy while avoiding toxicity in the treatment of solid tumors

While monoclonal antibodies have significantly improved cancer treatment, their accumulation in off-target tissues not only limits efficacy, but also induces toxicity. A major contributor to this problem is the mononuclear phagocyte system (MPS). This collection of innate immune cells is a critical regulator of immune homeostasis that effectively scavenges nanoparticles and biologics, preventing their therapeutic effects within solid tumors. Here, pinocytosis inhibitory nanoparticles are demonstrated to safely and temporarily disable the MPS <i>via</i> enhanced delivery of the small molecule actin inhibitor latrunculin A (LatA). This "indirect targeting" strategy is applied to improve anti-programmed death receptor 1 (aPD-1) antibody administration in mice bearing melanoma and colon carcinoma, decreasing aPD-1 interaction with the MPS, avoiding liver toxicity, increasing engagement with target cells, and modulating the immune microenvironment of solid tumors. The resulting change in biodistribution significantly improved safety, anticancer efficacy, and overall survival. Our methodology may be employed to enhance a wide range of monoclonal antibody therapies.