AS3288802, a highly selective antibody to active plasminogen activator inhibitor-1 (PAI-1), exhibits long efficacy duration in cynomolgus monkeys

Kashiwagi, R.; Sato, Ryugo; Masumoto, Mari; Yoshino, Masayasu; Tanaka, Hiroaki

doi:10.1016/j.biologicals.2020.08.001

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…The interaction between the ‘bait’ peptide (R369–M370) bound in the RCL and the target proteases results in the cleavage of the bound, after which the proteases are irreversibly translocated to the opposite site of the PAI-1 module, with the rapid insertion of the amino terminal part of the RCL into beta sheet A 45 . Recently developed anti-PAI-1 monoclonal antibodies (MEDI-579 and AS3288802) to the RCL efficiently block PAI-1 activity and show nephroprotective effects in mouse models of diabetic nephropathy and lupus nephritis 46 , 47 . Considering these facts, we considered the RCL as a plausible epitope for our PAI-1 vaccine.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Nakayama

Azegami

Kiso

et al. 2023

Sci Rep

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Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

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Section: Discussionmentioning

confidence: 99%

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Nakayama

Azegami

Kiso

et al. 2023

Sci Rep

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“…These antibodies prevented PAI-1 from binding to uPA or tPA by neutralizing effect, and used in thrombolytic therapy 34 , 35 . Since the discovery of the PAI-1 in promoting tumor growth and metastasis, small molecule inhibitors of PAI-1 had been developed, including PAI-039, Tiplaxtinin, TM 5275, XR5967, and AS3288802 42 , 43 , 44 . These inhibitors were demonstrated anti-tumor activity in mouse tumors.…”

Section: Discussionmentioning

confidence: 99%

Anti-PAI-1 Monoclonal Antibody Inhibits the Metastasis and Growth of Esophageal Squamous Cell Carcinoma

Zheng¹,

Meng²,

Qu³

et al. 2023

J. Cancer

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Plasminogen activator inhibitor (PAI-1) is highly expressed in esophageal squamous cell carcinoma (ESCC) and strongly contributes to metastasis, making it a potential target for ESCC therapy. However, the antibodies and inhibitors targeting PAI-1 have not shown good therapeutic effect in the in vivo experiments yet. Here, we generated a panel of novel monoclonal antibodies (mAbs) against PAI-1. Analysis of PAI-1 expression in 90 tissue specimens and 128 serum specimens from ESCC patients with these mAbs confirmed that PAI-1 levels was significantly correlated with metastasis and poor survival. In addition, we found that high PAI-1 expression contributed to the enhanced motility and invasiveness of two ESCC cell lines. Next, mAb-1E2 and mAb-2E3, which have highest affinity with PAI-1, were shown to possess strong inhibitory effects on ESCC migration and invasion. Anti-tumor and anti-metastatic effects of mAb-2E3 were further demonstrated in the experimental animal models. Finally, LRP1 was identified as key factor mediating the pro-invasive function of PAI-1 and the anti-invasive capacity of mAb-2E3 in ESCC cells. The mAb-2E3 markedly decreased STAT1 phosphorylation levels and blocked the binding between PAI-1 and LRP1-ClusterII domain. Collectively, mAb-2E3 developed by our lab may be an effective antibody drug which can be used for anti-metastatic therapy in ESCC.

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AS3288802, a highly selective antibody to active plasminogen activator inhibitor-1 (PAI-1), exhibits long efficacy duration in cynomolgus monkeys

Cited by 2 publications

References 40 publications

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Anti-PAI-1 Monoclonal Antibody Inhibits the Metastasis and Growth of Esophageal Squamous Cell Carcinoma

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