Anti-CD95-induced Lethality Requires Radioresistant FcγRII+ Cells

Jodo, Satoshi; Kung, John T.; Xiao, Sheng; Chan, Derek V.; Kobayashi, Seiichi; Tateno, Masatoshi; Lafyatis, Robert; Ju, Shyr‐Te

doi:10.1074/jbc.m211229200

Cited by 20 publications

(8 citation statements)

References 30 publications

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“…Alternately, the BsAb structure could be mistaken as 'antigen loaded', imparting some 'specific' unintended non-specific binding to FcgRIIb, or other Fcg receptors, that are expressed on LSECs and play a role in clearing soluble immune complexes. [39][40][41] While the exact, and perhaps case-by-case, biochemical interaction(s) has not been defined, this mechanism of clearance is consistent with the physiological role of LSECs in the liver.…”

Section: Discussionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

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(2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys, mAbs, 8:5, 969-982, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACT Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgGscFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.

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Section: Discussionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

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“…This lethal effect was originally attributed to the toxicity of hepatocytes. We demonstrated that FcRII knockout mice are resistant to Jo2 treatment [18]. In addition, anti-Fas mAb lacking FcRII binding activity also failed to induce lethality [18].…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that FcRII knockout mice are resistant to Jo2 treatment [18]. In addition, anti-Fas mAb lacking FcRII binding activity also failed to induce lethality [18]. Moreover, sFasL was extremely ineffective in inducing lethality due to its inability to form aggregates on the target cells that lacked FcRII.…”

Section: Discussionmentioning

confidence: 99%

A recombinant scFv-FasLext as a targeting cytotoxic agent against human Jurkat-Ras cancer

Chan

Sharma

et al. 2013

J Biomed Sci

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BackgroundTargeted therapy of human cancers is an attractive approach and has been investigated with limited success. We have developed novel cytotoxic agents for targeted therapy of human cancers based on the extracellular cytotoxicity domain of CD178 (FasL) and the specificity offered by single chain antibodies (scFv) against dominant human tumor Ag TAG-72 (cc49scFv) and TAL6 (L6scFv).ResultsThe cc49scFv-FasLext is highly effective in in vitro killing of human TAG-72+ Jurkat-Ras tumor cells with a 30,000 fold greater cytotoxicity as compared to soluble FasL (sFasL). On the other hand, L6scFv-FasLext only increased cytotoxicity 500-fold as compared with sFasL against TAL6+ HeLa cells in in vitro assays. The high specificity and strong cytotoxicity of cc49scFv-FasLext made it feasible to cure IP-implanted Jurkat-Ras tumors in SCID mice.ConclusionOur study demonstrated that scFv-FasLext with a strong cytotoxicity against sensitive human tumor targets may be useful as effective chemotherapeutic agents.

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“…On the other hand, Jodo et al reported that Jo2 delivers a Fas-mediated apoptosis signal to sinusoidal lining cells prior to hepatic parenchymal cells and this apoptosis signal is dependant on FccRII expression on sinusoidal lining cells. The destruction of sinosoids, which was induced by apoptosis of sinusoidal lining cells and subsequent liver hemorrhage, leads to damage of the hepatic parenchymal cells (Jodo et al 2003). Since Jo2 induced apoptosis in isolated mouse hepatocytes and HFE7A inhibited an apoptosis in vitro assay system which contained neither infiltrated neutrophils and activated cytotoxic lymphocytes nor FccRII positive sinusoidal lining cells, it is suggested that the hypothetic mechanism of the direct Fas-mediated apoptosis of hepatic parenchymal cells is certainly involved in Jo2-induced fulminant apoptotic liver damage in mice.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2

et al. 2009

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Anti-CD95-induced Lethality Requires Radioresistant FcγRII+ Cells

Cited by 20 publications

References 30 publications

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

A recombinant scFv-FasLext as a targeting cytotoxic agent against human Jurkat-Ras cancer

Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2

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