Immunosuppressive monoclonal antibody to CD64 from patients with long-term stable multiple sclerosis

Annunziata, Pasquale; Cioni, Carla; Cantalupo, Loredana; Genova, Giuseppa Di; Savellini, Gianni Gori; Cusi, Maria Grazia

doi:10.1016/j.jneuroim.2012.12.007

Cited by 4 publications

(3 citation statements)

References 44 publications

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“…One such example comes from multiple sclerosis (MS), where high intrathecal levels of anti‐myelin basic protein (MBP) antibodies have been found to be positively correlated with a favorable course in these patients . It turns out that one such antibody, recognizing amino acids 105–120 of MBP, was found to cross‐react with a discrete epitope of the FcγRI . A mAb recognizing this epitope was found able to inhibit proliferation of MS‐derived T‐cell lines in the presence of FcR‐bearing monocytic cells and was generally immunosuppressive via induction of IL‐10 and reduction of IL‐12 secretion in monocytes.…”

Section: Fcγri In Infection and Inflammatory Diseasementioning

confidence: 99%

The many faces of FcγRI: implications for therapeutic antibody function

Swisher

Feldman

2015

Immunological Reviews

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Fcγ receptor I (FcγRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcγRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcγRI that is necessary for full interferon γ receptor signaling in the same cell. Interaction of FcγRI with larger high-avidity complexes can result in phagocytosis, the generation of reactive oxygen species, as well as the synthesis and release of inflammatory cytokines. However, numerous reports also document potent anti-inflammatory effects brought about by FcγRI engagement with immune complexes such as the inhibition of IFNγ and TLR4 signaling, and secretion of interleukin-10. This has led to conflicting hypotheses regarding the function of FcγRI, especially with regard to its role in the efficacy of several therapeutic monoclonal antibodies. While many of these issues are still unclear, continued characterization of the regulation and context dependence of FcγRI function, as well as the molecular mechanisms responsible for these various outcomes, will improve our understanding of FcγRI biology as well as the therapeutic strategies designed to harness or constrain its actions.

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Section: Fcγri In Infection and Inflammatory Diseasementioning

confidence: 99%

The many faces of FcγRI: implications for therapeutic antibody function

Swisher

Feldman

2015

Immunological Reviews

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“…When a mAb to MBP 105-120 recognizing the 222-228 epitope of the extracellular domain of high affinity immunoglobulin gamma Fc-receptor I (CD64) was isolated from EBV + B cell clones of long-term stable RRMS patients, the mAb exerted immunosuppressive activity on MS-derived T cell lines through induction and release of high amounts of IL-10 and decreased levels of IL-12 from activated monocytes 93 . It is remarkable that B cell clones isolated from patients with long-term stable MS can induce a monoclonal IgM to MBP with immunosuppressive activity.…”

Section: Non Fda-approved Monoclonal Antibodies For the Treatment mentioning

confidence: 99%

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

Wootla

Watzlawik

Stavropoulos

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients. Areas Covered Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells. Expert Opinion Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.

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“…On the other end of the Ig spectrum, anti-MBP IgMs are associated with a more benign course. Interestingly, these Ig target a shared epitope antigen between MBP and the extracellular loop of CD64, which is one of the IgG Fc receptors responsible for the immunologic properties of macrophages [229].…”

Section: Does the Microheterogeneity Of Its Translate Into Disease Hementioning

confidence: 99%

Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal

Bonnan¹

2016

Trending Topics in Multiple Sclerosis

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Multiple sclerosis (MS) is characterized by the intrathecal synthesis (ITS) of immunoglobulins (Igs), which, although nonspecific, is the strongest biological marker. Since no specific target has been elucidated, this synthesis is considered to be disease-irrelevant. We demonstrate that this synthesis provides pertinent information about the pathophysiological processes involved. Quantification of ITS is based on an approximation intrinsically underestimating its level and it remains constant in MS, albeit sometimes at a low level. B-cell maturation seems to be initiated within the cervical lymph nodes and B-cells traffic on both sides of the blood-brain barrier by rounds of bidirectional traffic. During this process, they undergo somatic hypermutation, which is the hallmark of antigen-driven antibody maturation, suggesting that most of the ITS is probably directed against as yet unknown targets. Alternatively, examining"non-disease-relevant" ITS in the light of meningeal tertiary lymphoid organs provides new insights into the pathophysiology of MS. Although no specific target has yet been identified in MS, recent developments in the search for targeted antigens point to non-conventional antigens (posttranslationally modified proteins or oxidized products) of which a few are promising for future research.

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Immunosuppressive monoclonal antibody to CD64 from patients with long-term stable multiple sclerosis

Cited by 4 publications

References 44 publications

The many faces of FcγRI: implications for therapeutic antibody function

The many faces of FcγRI: implications for therapeutic antibody function

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal

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