The Importance of Human FcγRI in Mediating Protection to Malaria

Abstract

The success of passive immunization suggests that antibody-based therapies will be effective at controlling malaria. We describe the development of fully human antibodies specific for Plasmodium falciparum by antibody repertoire cloning from phage display libraries generated from immune Gambian adults. Although these novel reagents bind with strong affinity to malaria parasites, it remains unclear if in vitro assays are predictive of functional immunity in humans, due to the lack of suitable animal models permissive for P. falciparum. A potentially useful solution described herein allows the antimalarial efficacy of human antibodies to be determined using rodent malaria parasites transgenic for P. falciparum antigens in mice also transgenic for human Fc-receptors. These human IgG1s cured animals of an otherwise lethal malaria infection, and protection was crucially dependent on human FcγRI. This important finding documents the capacity of FcγRI to mediate potent antimalaria immunity and supports the development of FcγRI-directed therapy for human malaria.

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…been associated with protection against blood-stage infection in humans (16), possibly through the induction of Ab-dependent cellular inhibition (23,60) or Ab-dependent respiratory burst (22) mechanisms via interaction with FcgRs on innate effector immune cells (61). Although little is known about how rhesus IgG1-4 isotype function corresponds to their human counterparts, this study has highlighted the need for the development of rhesusspecific reagents to assess these.…”

Functional Characteristics of the High Affinity IgG Receptor, FcγRI

“…Contribution of FcgRI to Ab treatment was shown in a liver metastases model using TA99 and a model using CD20 mAb (48,49). Treatment with human IgG1 mAbs in a malaria model was completely dependent on transgenic expression of FcgRI (50). …”

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

“…5 Nevertheless, several in vivo studies documented a role for Fc␥RI, varying from a contribution during inflammation and autoimmune reactions, [6][7][8] or, during monoclonal antibody (mAb)-based immunotherapy in melanoma and B-cell lymphoma models, 9,10 to a malaria model in which transgenic expression of human Fc␥RI was central for effective mAb treatment. 11 Furthermore, Fc␥RI can induce potent proinflammatory signaling compared with Fc␥RIIa, 12 and can efficiently mediate both major histocompatibility complex class II (MHC-II) antigen presentation and cross-presentation. [13][14][15][16] It remains unclear how Fc␥RI contributes to immune complex clearance in the presence of high IgG levels.…”