Antibody Bioconjugates Incorporating Bacterial formyl-Met Peptides Engage Neutrophils in Targeted Cell Killing

Abstract

Abstract Immune-oncology therapies targeting adaptive immunity have transformed cancer therapy. In contrast, therapies targeting the innate immune response have received less attention. Here we describe an antibody drug conjugate (ADC) capable of engaging neutrophils in targeted cell killing. These initial ADCs, which we term bactabodies, consist of a targeting antibody conjugated to formyl-Met peptides via a short polyethylene glycol linker to activate formyl peptide receptor-1 (FPR-1) on neutrophils. A trastuzumab (Tmab) bactabody stimulated human neutrophil migration, degranulation and reactive oxygen production. Her2+ tumor cells opsonized with Tmab bactabody were rapidly killed by primary human neutrophils and antibody targeted killing was more effective than FPR-1-mediated bystander killing. In vivo, Tmab bactabody activated intratumor neutrophils and reduced tumor growth in a mouse xenotransplant model. Molecular design elements required for translation to humans and mice are described. Our results establish a modular strategy for engineering novel ADCs to engage neutrophils in targeted cell killing.