Innate immune regulation of mAb-induced infusion reactions - ABSTRACT The initial administration of therapeutic mAbs is frequently associated with the rapid onset of an array of symptoms, including chills, fever, hypotension, dyspnea, and rash. These reactions are termed infusion reactions (IRs) and are a subset of the larger family of immune-related adverse events (irAEs). mAb IRs range in severity, with most patients recovering with clinical support within hours to, in rare cases, very severe responses that result in hospitalization and death. The onset of mAb IRs occurs within 30-120min, and we and others have shown that in this time the circulating levels of inflammatory cytokines such as IL-6 and TNF are significantly increased. However, to date the pathophysiologic mechanisms that drive systemic cytokine release in mAb IRs remain poorly understood. While the frequency of IRs varies by mAb (ranging from 20-75%), nearly all therapeutic mAbs are associated with some level of IR. Given the widespread use of mAbs in cancer and non- cancer therapies, the treatment and monitoring of IRs represent a substantial cost to the U.S. medical system. Moreover, the need to monitor and treat patients for IRs following mAb therapy is a major factor that limits the application of these therapies in regions where such monitoring and care is prohibitively expensive. Thus, discovering the mechanisms that control mAb IRs will provide new avenues to avert these responses, which in turn will provide a major leap forward in the use of these therapies in the U.S. and globally. We and others have shown that the primary cytotoxic mechanism of αCD20 mAbs is via antibody-dependent cellular phagocytosis (ADCP) of mAb-opsonized B cells by Kupffer cell macrophages in the liver. However, there is currently no evidence that FcR on myeloid cells is the major source of IRs in vivo. Based on this and knowing that macrophages are major sources of inflammatory cytokines in settings of acute inflammation and tissue damage, we reasoned that macrophages could be a major source of the inflammatory cytokines in mAb IRs. Our in vitro preliminary studies using primary human macrophages have shown that ADCP can induce the production of some of the systemic cytokines seen in mAb IRs. In this project, we will use primary human and mouse macrophages as well as a new in vivo mouse model of mAb IR to investigate the role of macrophages in producing mAb IR cytokines and to determine the major signaling mechanisms responsible for the induction of these cytokines. This work will provide important new insights into avoiding and treating irAEs in the context of mAb immunotherapies.
