Developmental and peri-postnatal study in cynomolgus monkeys with belimumab, a monoclonal antibody directed against B-lymphocyte stimulator

Auyeung-Kim, Diana J.; Devalaraja, Matt; Migone, Thi‐Sau; Cai, Wendy; Chellman, Gary J.

doi:10.1016/j.reprotox.2009.07.002

Cited by 58 publications

(45 citation statements)

References 34 publications

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“…Golimumab was detectable in the infant serum for up to 6 months after birth (64). Belimumab was detected in umbilical cord blood and amniotic fluid in a study on cynomolgus monkeys treated with belimumab throughout pregnancy, confirming that transplacental transfer resulted in fetal exposure (65). Case reports on rituximab given during the second and third quarter showed cord blood levels similar to or higher than maternal levels at delivery (16)(17)(18)(19).…”

Section: N Biological Therapies In the Pregnant Patientmentioning

confidence: 91%

Are biological drugs safe in pregnancy?

et al. 2015

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The introduction of biological therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age, some concerns have been voiced as to the safety of these drugs in relation to reproduction and pregnancy. Data from many hundreds of pregnancies in patients affected by inflammatory bowel disease and inflammatory arthritis have suggested that exposure to anti-TNF therapies at conception and/or during pregnancy is not associated with adverse pregnancy outcomes or any increase in congenital abnormalities. However, the exposure to anti-TNFα agents, particularly to monoclonal antibodies, in late pregnancy is associated with high drug levels in the newborn and their long-term effects on children remain unknown. Therefore, limiting the use of anti-TNFα to the first 30 weeks of pregnancy is recommended to reduce fetal exposure. Live-virus vaccines should be given only when levels of anti-TNFα drugs are undetectable in the serum of infants. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which the infant absorbs them is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies at the time of conception. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab and belimumab are limited and their use in pregnancy cannot currently be recommended.

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Section: N Biological Therapies In the Pregnant Patientmentioning

confidence: 91%

Are biological drugs safe in pregnancy?

et al. 2015

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Section: Introductionmentioning

confidence: 99%

“…B-cell depletion by means of anti-CD20 mAb [12][13][14][15], or inhibition of B-cell activation and proliferation by anti-CD22 mAb Epratuzumab have been applied to lupus patients [16]. The human Lymphostat-B mAb that blocks another important costimulatory receptor, B-cell activating factor (BAFF), has been also successfully introduced [17][18][19].An alternative approach for specific targeting of B-cell response is the delivery of negative signals. The cross-linking of surface immunoglobulin receptors with the inhibitory Fc-gamma IIb (FcgIIb) receptors by IgG-containing immune complexes is a natural negative feedback mechanism of Ab production [20][21][22].…”

mentioning

confidence: 99%

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

Kerekov¹,

Mihaylova²,

Grozdev³

et al. 2011

Eur J Immunol

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Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B-cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well-established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA-specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B-cell activation and proliferation after co-cross-linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human-like system, we used immune-restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re-established after administration of a chimeric molecule consisting of a CR1-specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein-engineered chimera was able to co-cross-link selectively native DNA-specific BCR with the B-cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.Key words: Chimeric molecules . Inhibitory B-cell receptors . SCID models of SLE IntroductionThe pathogenesis of systemic lupus erythematosus (SLE) is characterized by the formation of autoantibodies against a wide range of self-antigens. Development of this multi-system autoimmune syndrome in many severe cases leads to mortality. SLE patients develop high-titered anti-nuclear antibodies (ANA), the majority of them against double-stranded (ds) DNA. Multiple organs can be involved in human SLE (skin, lung, heart, arteries, nervous system), but kidneys being most severely affected. The pathological changes are provoked by deposition of immune complexes into renal glomeruli, followed by kidney structure damages and development of nephritis and proteinuria [1]. 3301The pathogenetic role of self-specific B cells has been attributed not only to the generation of autoreactive antibodies, but also to their antigen-presenting functions [2,3]. A number of studies have clearly documented the strong correlation between the level of these B cells and disease severity. The efficacy of B-cell depletion therapy further supports the key role of B cells in the pathology of SLE. Activity of any self-specific B cells is regulated by the interplay of multiple factors controlling B-cell proliferation and differentiation. BCR-mediated activation may be counteracted by a number of inhibitory receptors: CD32 (FcgRIIb), CD22, CD5, CD72, CD66a, ILT2, PIR-B, CD279 (PD-1), LAIR-1, as well as the complement receptor type 1 (CR1, CD35). While a reduced expression of these receptors can result in uncontrolled B-cell activation [4,5] and autoimmunity, their cross-linking inhibits B-cell activation and proliferation and may serve for targeted suppressive signal delivery [6,7].Non-specific immunosuppressive drugs are by now the most frequent therapy for autoimmune diseases, including SLE. Their effects are purely symptomatic while most of them are associated with severe side ef...

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“…There is insufficient evidence to prove absolute safety of using biologics such as belimumab during pregnancy given the lack of controlled trials and insufficient human data 4 . In a study where belimumab was given supratherapeutically to pregnant monkeys and followed throughout gestation, effects attributed to therapy were limited to decreased B lymphocytes in the mothers and infants, but demonstrated recovery on cessation of exposure 5 . With regards to humans, it has been shown that passage across the placenta of monoclonal antibody-based TNF inhibitors is not seen in the first trimester, but is notable in the third trimester.…”

Section: To the Editormentioning

confidence: 99%