Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Li, Xinrui; Wu, Jianming; Ptacek, Travis; Redden, David T.; Brown, Elizabeth E.; Alarcón, Graciela S.; Ramsey‐Goldman, Rosalind; Petri, Michelle; Reveille, John D.; Kaslow, Richard A.; Kimberly, Robert P.; Edberg, Jeffrey C.

doi:10.1126/scitranslmed.3007097

Cited by 49 publications

(69 citation statements)

References 47 publications

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“…Further evidence for FcgR effector mechanisms came from the observations that hFcgRIIIa and hFcgRIIa polymorphisms correlate with clinical efficacy, 21,22 although roles for complement activation and apoptosis induction have also been proposed. 1,23 Multiple cell types express FcgR with variable expression patterns: With the exception of a minor proportion of the human population who express an open reading frame for hFcgRIIc, 24 B cells express only the inhibitory hFcgRIIb (mFcgRII), natural killer (NK) cells express only hFcgRIIIa (mFcgRIII), and macrophages variably express the full repertoire of FcgR. 25 Here we assessed the potential effector functions employed by type I and II mAbs, how they are affected by the internalization process, and, through the use of isotype variants, identified the key effector mechanisms involved in B-cell depletion.…”

Section: Introductionmentioning

confidence: 99%

Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies

Tipton

Roghanian

Oldham

et al. 2015

Blood

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Key Points• Antigenic modulation significantly impacts natural killer cell and macrophage ability to mediate Fc g receptor-dependent killing.• hIgG1 mAbs are unable to elicit natural killer-mediated ADCC in the mouse, supporting ADCP as the dominant effector mechanism.Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo. (Blood. 2015;125(12):1901-1909

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Section: Introductionmentioning

confidence: 99%

Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies

Tipton

Roghanian

Oldham

et al. 2015

Blood

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“…Further, mice do not possess the IgA FcαR1 receptor that specifically binds IgA in humans. They also lack homologs to the human FcγRIIA and FcγIIC receptors, which serve to mediate binding of immunoglobulin G isotype 2 (IgG 2 ) and IgG 3 to neutrophils and ultimately affect susceptibility to infectious and autoimmune diseases in humans (Li et al, 2013;Wolf et al, 2006;van Schie and Wilson, 2000).…”

Section: Immunological Considerations: Disparities Between Rodents Anmentioning

confidence: 99%

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

Grow¹,

McCarrey²,

Navara³

2016

Stem Cell Research

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The derivation of dopaminergic neurons from induced pluripotent stem cells brings new hope for a patient-specific, stem cell-based replacement therapy to treat Parkinson's disease (PD) and related neurodegenerative diseases; and this novel cell-based approach has already proven effective in animal models. However, there are several aspects of this procedure that have yet to be optimized to the extent required for translation to an optimal cell-based transplantation protocol in humans. These challenges include pinpointing the optimal graft location, appropriately scaling up the graft volume, and minimizing the risk of chronic immune rejection, among others. To advance this procedure to the clinic, it is imperative that a model that accurately and fully recapitulates characteristics most pertinent to a cell-based transplantation to the human brain is used to optimize key technical aspects of the procedure. Nonhuman primates mimic humans in multiple ways including similarities in genomics, neuroanatomy, neurophysiology, immunogenetics, and age-related changes in immune function. These characteristics are critical to the establishment of a relevant model in which to conduct preclinical studies to optimize the efficacy and safety of cell-based therapeutic approaches to the treatment of PD. Here we review previous studies in rodent models, and emphasize additional advantages afforded by nonhuman primate models in general, and the baboon model in particular, for preclinical optimization of cell-based therapeutic approaches to the treatment of PD and other neurodegenerative diseases. We outline current unresolved challenges to the successful application of stem cell therapies in humans and propose that the baboon model in particular affords a number of traits that render it most useful for preclinical studies designed to overcome these challenges.

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“…Lastly, an intriguing host genetic correlate was also recently identified; namely, a premature stop codon variant of the FcγRIIc receptor occasionally found on natural killer (NK) cells and B cells [26] was associated with reduced risk of infection [40]. However, whether or how this polymorphism may hold mechanistic significance remains unclear.…”

Section: Recent Evidence Of the Importance Of Antibody Effector Functmentioning

confidence: 99%

Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life

Boesch

Alter

Ackerman

2015

Current Opinion in HIV and AIDS

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Purpose of review A wealth of recent animal model data suggests that as exciting possibilities for the use of antibodies in passive immunotherapy strategies continue to develop, it will be important to broadly consider how antibodies achieve anti-HIV-1 effect in vivo. Recent findings Beyond neutralization breadth and potency, substantial evidence from natural infection, vaccination, and studies in animal models points to a critical role for antibody Fc receptor (FcR) engagement in reducing risk of infection, decreasing postinfection viremia, and delaying viral rebound. Supporting these findings in the setting of HIV, the clinical maturation of recombinant antibody therapeutics has reinforced the importance of Fc-driven activity in vivo across many disease settings, as well as opportunely resulted in the development and exploration of a number of engineered Fc sequence and glycosylation variants that possess differential binding to FcRs. Exploiting these variants as tools, the individual and concerted effects of antibody effector functions such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement-dependent cytotoxicity, antibody half-life, and compartmentalization are now being explored. As exciting molecular therapies are advanced, these studies promise to provide insight into optimal in-vivo antibody activity profiles. Summary Careful consideration of recent progress in understanding protective antibody activities in vivo can point toward how tailoring antibody activity via Fc domain modification may enable optimization of HIV prevention and eradication strategies.

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Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Cited by 49 publications

References 47 publications

Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies

Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life

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