Tissue-specific expression of IgG receptors by human macrophages ex vivo

Bruggeman, Christine W.; Houtzager, Julia; Dierdorp, Barbara; Kers, Jesper; Pals, Steven T.; Lutter, René; Gulik, Thomas van; Haan, Joke M. M. den; Berg, Timo K. van den; Bruggen, Robin van; Kuijpers, Taco W.

doi:10.1371/journal.pone.0223264

Cited by 35 publications

(23 citation statements)

References 48 publications

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“…CD32b CAR-T cells may cause B cell aplasia, which can be managed with immunoglobulin infusion. Previous reports have shown the expression of CD32b in some normal tissues and cells, including airway smooth muscle cells, liver sinusoidal endothelial cells, Kupffer cells and placenta [8,9], which may cause potential offtarget toxicities of CD32b CAR-T cell therapy. However, CD32b may still be an applicable target, since the potential off-target toxicity could be alleviated by decreasing CAR affinity for antigen or adopting a syn-Notch or zipper safety gate, which has been validated in various CAR-T cell studies [10][11][12].…”

Section: To the Editormentioning

confidence: 99%

Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia

et al. 2021

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CD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.

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Section: To the Editormentioning

confidence: 99%

Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia

et al. 2021

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“… 35 For example, liver endothelial and Kupffer cells, which express FcγRs, can phagocytose and degrade IgG. 35 , 36 Thus, in addition to circulating immune cells, avelumab could also be removed from circulation by other cell types.…”

Section: Discussionmentioning

confidence: 99%

Avelumab internalization by human circulating immune cells is mediated by both Fc gamma receptor and PD-L1 binding

et al. 2021

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Avelumab is an IgG1 anti–programmed death ligand 1 (anti–PD-L1) monoclonal antibody that has been approved as a monotherapy for metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. Avelumab is cleared faster and has a shorter half-life than other anti–PD-L1 antibodies, such as atezolizumab and durvalumab, but the mechanisms underlying these differences are unknown. IgG antibodies can be cleared through receptor-mediated endocytosis after binding of the antibody Fab region to target proteins, or via Fcγ receptor (FcγR)-mediated endocytosis. Unlike other approved anti–PD-L1 antibodies, avelumab has a native Fc region that retains FcγR binding capability. We hypothesized that the rapid clearance of avelumab might be due to the synergistic effect of both FcγR-mediated and PD-L1 target–mediated internalization. To investigate this, we performed in vitro and in vivo studies that compared engineered variants of avelumab and atezolizumab to determine mechanisms of cellular internalization. We found that both FcγR and PD-L1 binding contribute to avelumab internalization. While FcγR binding was the dominant mechanism of avelumab internalization in vitro , with CD64 acting as the most important FcγR, studies in mice and cynomolgus monkeys showed that both FcγR and PD-L1 contribute to avelumab elimination, with PD-L1 binding playing a greater role. These studies suggest that the rapid internalization of avelumab might be due to simultaneous binding of both PD-L1 and FcγR in trans. Our findings also provide a basis to alter the clearance and half-life of monoclonal antibodies in therapeutic development.

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“…As described above, macrophage phagocytosis requires not only sufficient expression of phagocytic receptors that recognize pathogens but also the coordinated action of intracellular molecules mediating subsequent engulfment. It should also be noted that the expression patterns of these receptors vary widely depending on the microenvironment where macrophages are differentiated, as has already been explored (Berger et al, 1994;A-Gonzalez et al, 2017;Bruggeman et al, 2019). Moreover, phagocytosis is affected by circadian metabolic regulation.…”

Section: Role Of Macrophage Phagocytosis In Acute Lrtis: Implication ...mentioning

confidence: 96%

Macrophage Meets the Circadian Clock: Implication of the Circadian Clock in the Role of Macrophages in Acute Lower Respiratory Tract Infection

Shirato

Sato

2022

Front. Cell. Infect. Microbiol.

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The circadian rhythm is a biological system that creates daily variations of physiology and behavior with a 24-h cycle, which is precisely controlled by the molecular circadian clock. The circadian clock dominates temporal activity of physiological homeostasis at the molecular level, including endocrine secretion, metabolic, immune response, coupled with extrinsic environmental cues (e.g., light/dark cycles) and behavioral cues (e.g., sleep/wake cycles and feeding/fasting cycles). The other side of the clock is that the misaligned circadian rhythm contributes to the onset of a variety of diseases, such as cancer, metabolic diseases, and cardiovascular diseases, the acceleration of aging, and the development of systemic inflammation. The role played by macrophages is a key mediator between circadian disruption and systemic inflammation. At the molecular level, macrophage functions are under the direct control of the circadian clock, and thus the circadian misalignment remodels the phenotype of macrophages toward a ‘killer’ mode. Remarkably, the inflammatory macrophages induce systemic and chronic inflammation, leading to the development of inflammatory diseases and the dampened immune defensive machinery against infectious diseases such as COVID-19. Here, we discuss how the circadian clock regulates macrophage immune functions and provide the potential risk of misaligned circadian rhythms against inflammatory and infectious diseases.

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Tissue-specific expression of IgG receptors by human macrophages ex vivo

Cited by 35 publications

References 48 publications

Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia

Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia

Avelumab internalization by human circulating immune cells is mediated by both Fc gamma receptor and PD-L1 binding

Macrophage Meets the Circadian Clock: Implication of the Circadian Clock in the Role of Macrophages in Acute Lower Respiratory Tract Infection

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