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Current anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models. Nonetheless, no therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes. In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively.In vitro human IgG1 and IgG3 did not show any differences in opsonisation ability of B16F10-gp75 mouse melanoma cells. IgG1, however, was superior in inducing phagocytosis of tumour cells by mouse macrophages. Similarly, in a mouse peritoneal metastasis model we did not detect an improved effect of IgG3 in preventing tumour outgrowth. Moreover, replacing the arginine at position 435 for a histidine in IgG3 to enhance half-life did not result in better suppression of tumour outgrowth compared to wild type IgG3 when injected prior to tumour cell injection.In conclusion, human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model.

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 FcgammaRI. This important finding documents the capacity of FcgammaRI to mediate potent antimalaria immunity and supports the development of FcgammaRI-directed therapy for human malaria.