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FDA-approved anti–PD-L1 monoclonal antibodies (mAbs) bear the IgG1 isotype, whose scaffolds are either wild-type (e.g., avelumab) or Fc-mutated and lacking Fcγ receptor (FcγR) engagement (e.g., atezolizumab). It is unknown whether variation in the ability of the IgG1 Fc region to engage FcγRs renders mAbs with superior therapeutic activity. In this study, we used humanized FcγR mice to study the contribution of FcγR signaling to the antitumor activity of human anti–PD-L1 mAbs and to identify an optimal human IgG scaffold for PD-L1 mAbs. We observed similar antitumor efficacy and comparable tumor immune responses in mice treated with anti–PD-L1 mAbs with wild-type and Fc-mutated IgG scaffolds. However, in vivo antitumor activity of the wild-type anti–PD-L1 mAb avelumab was enhanced by combination treatment with an FcγRIIB-blocking antibody, which was co-administered to overcome the suppressor function of FcγRIIB in the tumor microenvironment (TME). We performed Fc glycoengineering to remove the fucose subunit from the Fc-attached glycan of avelumab to enhance its binding to the activating FcγRIIIA. Treatment with the Fc-afucosylated version of avelumab also enhanced antitumor activity and induced stronger antitumor immune responses compared with the parental IgG. The enhanced effect by afucosylated PD-L1 antibody was dependent on neutrophils and associated with decreased frequencies of PD-L1+ myeloid cells and increased infiltration of T cells in the TME. Our data reveal that the current design of FDA-approved anti–PD-L1 mAbs does not optimally harness FcγR pathways and suggest two strategies to enhance FcγR engagement to optimize anti–PD-L1 immunotherapy. Tweaking the scaffold: Immune checkpoint blockade using anti–PD-L1 monoclonal antibodies (mAbs) is used for treatment of multiple cancers. Whether these mAbs have the optimal Fc scaffold to induce Fc-mediated effector functions is unclear. Here, Cohen-Saban et al. investigate how FcγR engagement by anti–PD-L1 contributes to antitumor immunity. They demonstrate that beneficial FcγR signaling pathways are not engaged by FDA-approved mAbs and use two approaches to increase the ratio of activating to inhibitory FcγR pathway activation. Blockade of the inhibitory FcγRIIB in combination with anti–PD-L1 improved antitumor responses. Similarly, afucosylation of the IgG1 Fc region improved antitumor responses, and this was due to alterations in the tumor microenvironment. These findings identify two approaches to improve anti–PD-L1 therapy and suggest that an afucosylated IgG1 scaffold renders anti–PD-L1 mAbs more effective. —HMI [ABSTRACT FROM AUTHOR]

The clinical use of anti-CD40 agonist monoclonal antibodies (mAbs) is aimed at recruiting the immune system to fight the tumor cells. This approach has been demonstrated to be effective in various preclinical models. However, human CD40 Abs displayed only modest antitumor activity in cancer patients, characterized by low efficacy and dose-limiting toxicity. While recent studies highlight the importance of engineering the Fc region of human CD40 mAbs to optimize their agonistic potency, toxicity remains the main limiting factor, restricting clinical application to suboptimal doses. Here, we discuss the current challenges in realizing the full potential of CD40 mAbs in clinical practice, and describe novel approaches designed to circumvent the systemic toxicity associated with CD40 agonism. [ABSTRACT FROM AUTHOR]

Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury. [ABSTRACT FROM AUTHOR]