Acute Systemic Reaction and Lung Alterations Induced by an Antiplatelet Integrin gpIIb/IIIa Antibody in Mice

Nieswandt, Bernhard; Echtenacher, Bernd; Wachs, Frank-Peter; Schröder, Josef; Gessner, J. Engelbert; Schmidt, Reinhold; Grau, Georges E.; Männel, Daniela N.

doi:10.1182/blood.v94.2.684

Cited by 68 publications

(33 citation statements)

References 43 publications

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“…Although antiplatelet antibodies can activate human platelets in vitro , causing platelet aggregation and degranulation (Horsewood et al ., 1991), we have failed to detect such aggregation (by means of aggregometry) using platelet‐rich plasma (PRP) exposed to various concentrations of OVA (data not shown). A similar nonresponsiveness of mouse PRP to a monoclonal antibody to fibrinogen receptors (gpIIb/IIIa) has also been reported by Nieswandt et al . (1999).…”

Section: Resultssupporting

confidence: 82%

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Accumulation of platelets in the lung and liver and their degranulation following antigen‐challenge in sensitized mice

Yoshida

Ohba

et al. 2002

British J Pharmacology

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1 Mast cells and basophils are believed to trigger allergic reactions and anaphylaxis. They rapidly release histamine (H), a typical mediator of in¯ammation, in response to antigens. In the mouse, platelets contain much 5-hydroxytryptamine (5HT), an additional in¯ammatory mediator, while human platelets contain both H and 5HT. Here, we examined the response of platelets in sensitized mice to antigen challenge. 2 Platelets accumulated in the lung and liver almost immediately after intravenous injection of ovalbumin (OVA), in mice sensitized to it, and platelet degranulation occurred during these reactions. 3 These responses of platelets preceded H release from mast cells and/or basophils, occurred at doses of OVA lower than those inducing H release, and contributed to the signs of shock. 4 We reported previously that intravenous injection into mice of LPS (a membrane constituent of gram-negative bacteria) induces a similar platelet response (accumulation of platelets in the lung and liver) and shock. 5 Blood that has passed through the body (other than the digestive tract) passes ®rst to the lungs before being recirculated by the heart, and blood that has passed through the digestive tract passes next to the liver. Thus, our ®ndings suggest that in addition to their role in haemostasis, platelets, tiny anuclear cytoplasts, may be important in both innate and acquired immunity, and that the lung and liver may be the fronts at which platelets wage war on pathogens.

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Section: Resultssupporting

confidence: 82%

“…Thus, it is of particular interest to know whether this type of receptor is present on platelets in mice. In fact, murine platelets, have been reported to lack FcγRII (CD32) (Kato et al ., 1998), and Nieswandt et al . (1999) reported that mouse platelets were not stained by an anti‐FcγRII/III monoclonal antibody.…”

Section: Resultsmentioning

confidence: 97%

Accumulation of platelets in the lung and liver and their degranulation following antigen‐challenge in sensitized mice

Yoshida

Ohba

et al. 2002

British J Pharmacology

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“…A newly generated mAb against mouse αIIbβ3 (JON/A, IgG2b) was used in the current study. JON/A, like the well‐established anti‐αIIbβ3 mAb MWReg30 (10), precipitated αIIbβ3 from the lysate of surface‐biotinylated platelets (Fig. 1a).…”

Section: Resultsmentioning

confidence: 92%

“…MWReg30 and p0p6 antibodies were generated, produced, and modified in our laboratories: MWReg30 (anti‐ αIIbβ3, IgG1; ref. 10) and p0p6 (anti‐GPIX, IgG1; ref. 11).…”

Section: Methodsmentioning

confidence: 99%

Flow cytometric detection of activated mouse integrin αIIbβ3 with a novel monoclonal antibody

et al. 2002

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Background Integrin αIIbβ3 mediates platelet adhesion and aggregation and plays a crucial role in thrombosis and hemostasis. αIIbβ3 is expressed in a low affinity state on resting platelets. Upon platelet activation, αIIbβ3 shifts to a high affinity conformation that efficiently binds its ligands. On human platelets, the high affinity conformation of αIIbβ3 is detected by the monoclonal antibody (mAb), PAC‐1. However, a reagent with binding specificity to high affinity mouse αIIbβ3 has not been described so far. Methods A novel rat mAb directed against mouse αIIbβ3 (JON/A) was generated and characterized. JON/A was conjugated with fluorescein isothiocyanate (JON/AFITC) or with R‐phycoerythrin (JON/APE) and used for flow cytometric analysis of mouse platelets. Results Although JON/AFITC bound to resting and activated platelets, virtually no binding of the larger JON/APE to resting platelets was detectable. However, strong binding of JON/APE occurred on platelet activation in a dose‐dependent manner. Binding of JON/APE required extracellular free calcium and was irreversible, thereby stabilizing the high affinity conformation of αIIbβ3. Conclusion JON/APE is the first tool for direct assessment of integrin αIIbβ3 activation in mice. Furthermore, JON/AFITC and JON/APE provide the first examples of fluorescent antibody derivatives with identical antigenic specificitiy that allow the discrimination between the resting and the activated state of an integrin. Cytometry 48:80–86, 2002. © 2002 Wiley‐Liss, Inc.

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“…Pharmacology/toxicity of surrogate molecules. Administration of a surrogate anti‐murine GP IIb/IIIa antibody (MWReg30) to mice resulted in FcγRIII and TNF‐α‐dependent hypothermia, engorgement of alveolar septal vessels and acute lung injury (Nieswandt et al ., 1999). In vitro , MWReg30 inhibited platelet aggregation and did not induce morphological signs of platelet activation.…”

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confidence: 99%

Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets

Bugelski

Martin

2012

British J Pharmacology

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Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found. AbbreviationsADCC, antibody-dependent cellular cytotoxicity; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic T lymphocyte antigen 4; CMV, cytomegalovirus; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICAM-1, intercellular adhesion molecule-1; LFA, lymphocyte function associated antigen; JCV, human polyoma JC virus; mAb, monoclonal antibody; NHP, non-human primate; NK, natural killer; PML, progressive multifocal leukoencephalopathy; RBC, red blood cell; SCID, severe combined immunodeficiency; SIV, simian immunodeficiency virus; SLE, systemic lupus erythematosus; TCR, T-cell receptor; USPI, United States Prescribing Information; VLA-4, very late antigen-4; WBC, white blood cell IntroductionMonoclonal antibodies (mAb) and soluble receptors (fusion proteins) make an important contribution to the treatment of a variety of diseases. Over 30 mAb or fusion proteins have been approved for clinical use and more than 200 more are in various stages of clinical development (Dimitrov and Marks, 2009). Because species cross-reactivity is usually highly BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012) restricted to humans and non-human primates (NHPs), mAbs directed towards human targets are usually pharmacologically inactive in rodents (Cavagnaro, 2008). As a consequence, preclinical studies with many of the mAbs or mAb-like molecules need to be conducted in NHPs (ICH, 2011). However, there are some notable exceptions, for example abatacept (...

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Acute Systemic Reaction and Lung Alterations Induced by an Antiplatelet Integrin gpIIb/IIIa Antibody in Mice

Cited by 68 publications

References 43 publications

Accumulation of platelets in the lung and liver and their degranulation following antigen‐challenge in sensitized mice

Accumulation of platelets in the lung and liver and their degranulation following antigen‐challenge in sensitized mice

Flow cytometric detection of activated mouse integrin αIIbβ3 with a novel monoclonal antibody

Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets

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