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WO1998035697A1 - Procede ameliore permettant de reduire la formation de cellules neointimes apres une angioplastie - Google Patents

Procede ameliore permettant de reduire la formation de cellules neointimes apres une angioplastie Download PDF

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Publication number
WO1998035697A1
WO1998035697A1 PCT/EP1998/000837 EP9800837W WO9835697A1 WO 1998035697 A1 WO1998035697 A1 WO 1998035697A1 EP 9800837 W EP9800837 W EP 9800837W WO 9835697 A1 WO9835697 A1 WO 9835697A1
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WO
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Prior art keywords
pdgf
stent
antibody
reduction
angioplasty
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Application number
PCT/EP1998/000837
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English (en)
Inventor
Ulrich Martin
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Roche Diagnostics Gmbh
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Publication date
Application filed by Roche Diagnostics Gmbh filed Critical Roche Diagnostics Gmbh
Priority to AU64971/98A priority Critical patent/AU6497198A/en
Publication of WO1998035697A1 publication Critical patent/WO1998035697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Coronary artery disease is caused by atherosclerotic narrowing of the coronary arteries leading to stable and unstable angina and finally to myocardial infarction associated with high morbidity and mortality.
  • interventional procedures such as percutaneous transluminal coronary angioplasty (PTCA) as one form of percutaneous revascularization are widely used to enlarge the vessel lumen. It is estimated that about 800,000 patients worldwide per year are undergoing coronary percutaneous interventional procedures.
  • PTCA percutaneous transluminal coronary angioplasty
  • the initial success of these techniques for reestabhshment of long-term patency of stenosed coronary vessels is hampered by the iatrogenic complication of restenosis.
  • Restenosis can be defined angiographically as a renarrowing of the lumen of the vessel or clinically as reoccurence of coronary symptoms (stable or unstable ungina), acute myocardial infarction, death, need for repeat angioplasty or coronary artery bypass grafting (CABG).
  • CABG coronary artery bypass grafting
  • restenosis The pathophysiology of restenosis is complex and incompletely understood. Complementary data from animal models, human atherectomy, angioscopic and postmortem studies have provided valuable insights into the possible mechanisms involved. All these data suggest that the pathogenesis of restenosis is a multifactorial process depending on an inadequate initial result, elastic recoil, unfavourable remodeling, mural thrombus and neointimal hyperplasia. The importance of each factor varies from patient to patient and lesion to lesion. The prevailing approach has been to regard restenosis as a "response to injury" (Erickson and Topol, Vessels 2 (1996) 22-32).
  • abciximab The chimeric monoclonal antibody c7E3 (abciximab) is directed against the platelet glycoprotein Ilb/IIIa receptor which represents the final common pathway of platelet aggregation.
  • Abciximab is an effective antithrombotic agent by irreversible blockade of platelets, thereby preventing platelet aggregation.
  • Stents are mechanical devices supporting the vessel wall and mechanically preventing narrowing of the lumen of the vessels. Stents can be distinguished by their type of delivery system (self-expanding, balloon expandable), their composition (metallic-stainless steel, cobalt based alloy or tantalum, biodegradable, polymeric) and their configuration (mesh structure, slotted tube, coil). Most of them are placed definitively in coronary vessels, but there is also one temporary retrievable bailout stent (Eeckhout et al., J Am Coll Cardiol 27 (1996) 757-765).
  • stents examples include the Wallstent (Scheider AG), the Flexstent (Gianturco-Roubin, Cook), the Palmaz-Schatz stent (Johnson & Johnson Interventional Systems), the Wiktor stent (Medtronic Interventional Vascular), the Micro stent (Applied Vascular Engineering Inc.), the Cordis stent (Cordis), the Multi Link stent (Advanced Cardiovascular Systems) and others.
  • EGF epidermal growth factor
  • FGF fibroblast growth factor
  • TGF transforming growth factor
  • IGF insulin like growth factor
  • PDGF platelet derived growth factor
  • PDGF seems to play a particularly important role.
  • PDGF exists as a homo- (AA or BB) or hetero- (AB) dimer in which the two chains are disulfide-linked.
  • the A-chain binds to only the ⁇ -receptor while the B-chain binds to both the oc- and ⁇ -receptors with high affinity.
  • PDGF also provides a potent chemoattractant signal for the subintimal migration of SMCs, modulates the inflammatory response and possesses vasoconstrictory activity (Newby et al., Cardiovasc Res 27 (1993) 1173-1183).
  • Intimal vascular SMC proliferation in a baboon graft model was associated with intimal PDGF-mRNA expression and release of PDGF-like proteins (Golden et al., J Clin Invest 87 (1991) 406-414).
  • Biologically active PDGF along with receptor protein is present in both the neointima and graft matrix in a primate graft model (Kraiss et al., J Clin Invest 92 (1993) 338-348).
  • Vascular lesion after balloon catheter angioplasty and carotid artery endarterectomy in the baboon showed significant expression of PDGF receptors in neointima cells (Wilcox et al., Circulation 86 (1992) 1-84).
  • This compound (2-bromomethyl-5-chlorobenzene sulfonylphthalimide) reduced in vivo at 100 mg/kg per day orally neointimal lesion area by 36 % in the rat model of carotid balloon injury (Mullins et al., Atheroscler Thromb 14 (1994) 1047-1055).
  • Terbinafme which is a specific inhibitor of squalen epoxidase activity but also inhibits the mitogenic activity of PDGF reduced after oral administration in vivo neointimal lesion by 40 % after balloon catheterization in the rat (Nemecek et al., J Pharmacol Exp Ther 248 (1989) 1167-1174).
  • a PDGF receptor tyrosine kinase inhibitor was also shown to reduce restenosis in rats (G. Golomb et al., Atherosclerosis 25 (1996) 171-182).
  • Other PDGF receptor tyrosine kinase inhibitors have been characterized in vitro (Sawutz et al., Biochem Pharmacol 51 (1996) 1631-1638).
  • Trapidil which is a weak phosphodiesterase inhibitor also antagonizes the mitogenic actions of PDGF.
  • trapidil reduced neointimal lesion formation by 51 % (Ohnishi et al., Life Sci 31 (1982) 2595-2621).
  • inhibitors of the PDGF- ⁇ receptor have been evaluated in vivo on their effectiveness in animal models of restenosis.
  • a murine monoclonal antibody against the human PDGF- ⁇ receptor was tested in the rat carotid injury model. Systemic administration of this antibody inhibited neointimal hyperplasia by 60 % (Guzman et al., Restenosis Summit VII, Cleveland, Ohio, May 16-17, 1996).
  • a mouse/human chimeric anti-PDGF ⁇ receptor antibody has been investigated at intravenous administration in the baboon model of saphenous artery injury following balloon angioplasty.
  • results showed a 40 % decrease of neointimal hyperplasia when evaluated by intimal/media area ratios (Hart et al., Restenosis Summit VII, Cleveland, Ohio, May 16-17, 1996).
  • a neutralizing monoclonal antibody directed against the ⁇ receptor of PDGF was evaluated in a baboon model of carotid artery injury by endarterectomy and of femoral artery injury by balloon dilation. Systemic administration of this antibody caused a reduction in neointima formation of 29 % and 42 % following carotid endarterectomy and femoral balloon dilation, respectively (Giese et al., Restenosis Summit VII, Cleveland, Ohio, May 16-17, 1996).
  • WO 94/19016 and WO 92/12734 it is known to use an antibody against PDGF receptor or PDGF to reduce restenosis after PTCA.
  • a combination with the intracoronary placement of stents is not mentioned therein.
  • WO 96/40112 describes the use of a non- peptide PDGF-antagonist to reduce restenosis after PTCA, without the use of stents.
  • EP-A 0 734 721 a general method for the coating of stents with monoclonal antibodies such as, for instance, antibodies against PDGF-receptors is described.
  • coating stents with an antibody is a laborious technique.
  • the object of the invention is to provide an improved method for the reduction of neointima formation after angioplasty.
  • the present invention provides a solution of the still unresolved problem of a high neointima formation after coronary angioplasty.
  • Treatment with antagonists of PDGF or PDGF- receptors alone only confers submaximal efficacy. It was surprisingly found that the combination of a systemically applied anti-PDGF- ⁇ receptor antibody with intracoronary placement of stents as a mechanical therapy results in a synergistic improvement of the reduction of neointima formation.
  • the invention comprises a method for improvement of the reduction of neointima formation wherein an anti-PDGF- ⁇ receptor antibody is administered to the patient, the method being characterized in that said inhibitor is administered concomitantly to the placement of a medical device in the blood vessel (coronary artery) supporting mechanical prevention of narrowing of the lumen of said vessel.
  • Concomitant administration of the anti-PDGF- ⁇ receptor antibody within the meaning of the present invention can be that systemic administration of the inhibitor of PDGF or PDGF- receptor starts briefly before, during or after the interventional procedure in the coronary artery by intravenous administration, preferably by bolus injection.
  • Systemic administration is characterized in that the stent is not coated with the inhibitor of PDGF or PDGF-receptor, but in that the inhibitor of PDGF or PDGF-receptor is given via oral, intravenous, intramuscular, subcutaneous or intraarterial route.
  • Another object of the invention is a method for the production of a therapeutic agent which can be administered in the manner described above.
  • a further object of the invention is a therapeutic agent for use in the manner described above.
  • Antibody as used herein is understood as a protein that is composed of one or several polypeptide chains which are essentially encoded by antibody genes.
  • the antibody genes code for the antigen-specific variable regions and may also code for the genes for the constant regions.
  • Antibodies within the scope of the invention are also understood as various derivatives and fragments of antibodies such as Fv, Fab and F(ab)2, individual antibody chains or chimeric antibodies or fragments.
  • the antibodies may be polyclonal or monoclonal.
  • the invention encompasses antibodies which are non-human, e.g., murine antibodies (muAb), humanized antibodies (HuAb) or human antibodies.
  • a HuAb comprises a humanized heavy chain variable region and a humanized light chain region.
  • the humanized light chain variable region comprises complementarity determining regions (e.g. CDR1 , CDR2, CDR3) having amino acid sequences from the light chain of a muAb and having a variable region framework sequence substantially identical to a human light chain variable region framework sequence.
  • the humanized heavy chain variable region comprises complementarity determining regions (e.g. CDR1, CDR2, CDR3) having amino acid sequences from the corresponding muAb heavy chain, and having a variable region framework sequence substantially identical to a human heavy chain variable region framework sequence.
  • the antibodies optionally contain constant regions substantially identical to human constant regions.
  • Especially preferred antibodies encompassed by the present invention are humanized antibodies directed against the ⁇ -receptor of PDGF, thereby mediating their inhibitory effect on PDGF-mediated biological activity.
  • antibodies encompassed by the present invention may be directed against the ⁇ - receptor and the ⁇ -receptor of PDGF.
  • the effect of the antibodies may be achieved by inhibition of binding of PDGF to its receptor or by other mechanisms of interference with the interaction of PDGF with its receptor, e.g. by influencing receptor dimerization.
  • Antibodies against the ⁇ -receptor of PDGF have recently been disclosed: a mouse/human chimeric antibody (Hart et.al., Restenosis Summit VII, Cleveland, Ohio, May 16-17, 1996) and a neutralizing murine monoclonal antibody (Giese et al., Restenosis Summit VII, Cleveland, Ohio, May 16-17, 1996).
  • the systemic administration of the pharmacological agent inhibiting PDGF-mediated biological activity may require single or multiple applications depending on the potency, bioavailability, and the half life of the pharmacological agent.
  • Possible routes of administration are, e.g., oral or parenteral; modes of administration are, e.g., single or multiple bolus injection, infusion or oral ingestion.
  • a preferred embodiment of the present invention is to achieve presence of the pharmacological agent in an effective amount in the body for about 10 to 14 days after placement of the stent because this time period represents the PDGF-sensitive phase in the development of the neointimal hyperplasia. This time period may be longer in case that pharmacological agents against other growth factors or growth factor receptors different from PDGF or PDGF receptor are used.
  • a preferred embodiment of the present invention encompasses humanized antibodies against PDGF-mediated biological activity. These antibodies are known to have a long half life in humans which is in the range of 2 to 21 days. Especially preferred are humanized antibodies against the ⁇ -receptor of PDGF. An effective amount of these antibodies is an amount sufficient to effect the desired beneficial result which is reduction of neointima formation. Therapeutically effective amounts will generally range from about 0.01 mg/kg to 100 mg/kg per treatment, with dosages from 0.1 mg/kg to 10 mg/kg of antibody per dose being more commonly used. The humanized antibodies are suitable for intravenous single or multiple bolus injections due to their long half life.
  • the humanized antibodies may be given as a single intravenous bolus injection of 1 mg/kg to 10 mg/kg concomitantly to the interventional procedure in the coronary artery. It can be administered briefly before, during or briefly after the procedure. Briefly before or briefly after the procedure means a time period of up to 5 hours, preferably within one hour before or after the procedure for the single bolus or the first bolus. For humanized antibodies with a shorter half life repeated intravenous bolus injections may be required. The frequency of administration may be two to six times, preferably two to four times. The time interval between the bolus injections may be 1 day to 3 weeks, preferably 5 to 10 days, or most preferably 7 to 21 days.
  • oral administration may be feasible. Depending on potency, bioavailability and half life, one to five fold daily oral administrations of the pharmacological agent up to a time period of 3 weeks after the procedure can be required.
  • a single oral dose may range from 0.1 to 100 mg/kg. More preferred are single oral doses of 0.1 to 20 mg/kg.
  • the invention also encompasses methods of local administration of the pharmacological agent.
  • the composition containing the pharmacological agent can be directly coated onto the vessel wall during the procedure with a catheter in the coronary artery.
  • the methods of drug delivery are known in the art, e.g., described in Riessen and Isner, J Am Coll Cardiol 23 (1994) 1234-1244.
  • the desired effect to be achieved by the present invention means a reduction of neointima formation of more than 50 % as compared to the administration of the pharmacological agent alone or placement of the stent alone. Especially preferred is an effect of more than 60% reduction of neointima formation by the present invention.
  • the present invention is to be used in the setting of percutaneous revascularization procedure such as coronary angioplasty in order to improve prevention of neointima formation.
  • the clinical indications for performing revascularizations may be coronary artery disease such as stable and unstable angina, myocardial infarction and other acute coronary syndromes.
  • the procedures may be performed as emergency treatments and as elective interventions, i.e.. without need for acute intervention.
  • Stents in the meaning of the present invention are mechanical devices supporting the vessel wall and mechanically preventing narrowing of the lumen of the vessels after coronary angioplasty.
  • Stents can be distinguished by their type of delivery system (self-expanding, balloon expandable), their composition (metallic-stainless steel, cobalt based alloy or tantalum, biodegradable, polymeric) and their configuration (mesh structure, slotted tube, coil). Most of them are placed definitively in coronary vessels, but there is also one temporary retrievable bailout stent (Eeckhout et al., J Am Coll Cardiol 1996; 27: 757-765).
  • stents examples include the Wallstent (Scheider AG), the Flexstent (Gianturco-Roubin, Cook), the Palmaz-Schatz stent (Johnson & Johnson Interventional Systems), the Wiktor stent (Medtronic Interventional Vascular), the Micro stent (Applied Vascular Engineering Inc.), the Cordis stent (Cordis), the Multi Link stent (Advanced Cardiovascular Systems) and others.
  • the pharmacological therapy with PDGF-antagonism may consist of a systemic, e.g., intravenous, or regional, e.g., catheter-delivered intracoronary or -arterial, administration of the therapeutic agent or of a local drug delivery system for the therapeutic agent.
  • a systemic e.g., intravenous
  • regional e.g., catheter-delivered intracoronary or -arterial
  • administration of the therapeutic agent or of a local drug delivery system for the therapeutic agent e.g., a local drug delivery system for the therapeutic agent.
  • stents are placed in the conventional manner and the therapeutic agent is given separately before, during or briefly after stent placement.
  • the purpose of the present experimental study was to evaluate the effect of a humanized monoclonal antibody directed against the human ⁇ -recptor of platelet derived growth factor in a baboon model of neointima formation after balloon dilatation.
  • This antibody crossreacts with the baboon PDGF- ⁇ receptor and can inhibit baboon smooth muscle cell proliferation upon PDGF-BB stimulation in vitro.
  • the study consisted of two groups with 10 animals per group. All animals received angioplasty and stent placement in the carotid arteries and balloon angioplasty only in the femoral arteries. One group received treatment with the antibody and the other group placebo as negative control.
  • This study design allows to compare the effect of the antibody on reduction of neointimal hyperplasia after balloon angioplasty alone with that of the antibody on reduction of neointimal hyperplasia after balloon angioplasty in combination with placement of intracarotid stents.
  • the antibody was given systemically, i.e. by intravenous administration.
  • a # 7 F femoral sheath was advanced into the femoral artery and a # 7 F multipurpose guide catheter advanced round the arch of the aorta and the carotid arteries were intubated.
  • Vessels were sized using a Scimed Intravascular ultrasound system (IVUS).
  • Stents were placed bilaterally in the proximal carotid arteries and balloon angioplasty was performed in the iliac artery.
  • the stents were placed in the intrathoacic portion of the carotid artery, a sites which has not been associated with "crush" injury, i.e. stent deformation due to muscular activity or external pressure.
  • Stent implantation was performed using standard angioplasty techniques and over-the-wire technology.
  • the Johnson & Johnson Interventional Systems non-coated stents were manually crimped onto the appropriately sized balloon catheters by the operator.
  • the deployment balloon cathers to be used depended upon the diameter of the vessel to be stented. For smaller diameter vessels, the 3.5 mm or 4.0 mm PAS catheter (20 mm balloon length) was used. For larger diameter vessels, the 4.5 mm or 5.0 mm Jupiter catheter (20 mm balloon length) was used.
  • the preferred balloon : artery ratio was 1.1 : 1 to 1.2 : 1, but not greater than 1.3 : 1. Heart rate and blood pressure were monitored during the procedure.
  • a final angiogram was performed to document vessel and stent patency and intravascular ultrasound was performed and compared to one obtained at 30 day, just prior to sacrifice. No therapeutic pharamcologic agents were administered post-procedurally. The animals were maintained in cages until sacrifica at day 30 after the procedure.
  • Intravascular ultrasound was performed using an automated pullback system.
  • a monorail (SciMed) IVUS catheter was introduced through each stent to be imaged and then the automated pullback was initiated.
  • Neointimal area, vessel area, and stent areas were quantified using standardized clinical IVUS image analysis techniques.
  • Two pullbacks were performed per stented segment post implantation and at 30 days (pre-harvesting). Thus, final IVUS was performed on all vessels prior to explantation. Volumetric analysis of the neointima was performed and this was correlated with the histological section analysis. Animals were treated with intravenous nitroglycerin during angiography and IVUS procedures to achieve maximal vasodilatation before and during imaging.
  • Stents from all animals in this study were harvested at 30 days. Each animal had received two stents and the stents were harvested and pressure perfusion fixed at 100 mm Hg with buffered formalin. Samples were immersed in the same fixative overnight at 4°C, then processed for histornorphometric analysis. Samples were dehydrated in graded ethanol and embedded in methyl me hacrylate resins. Two to four 300 ⁇ m thick sections (from proximal and distal stent halves) were cut and ground to approximately 30 ⁇ m and stained with a modified toluidine blue stain. The number of sections cut were determined on the basis of initial intra- stent variability. Small segments of selected stents were also fixed in buffered glutaraldehyde and processed for scanning electron microscopy to document endothelial cell coverage of the neointima.
  • Toluidine-blue stained sections were analyzed on a Nikon Labphot microscope coupled to a CCD camera, digitizing pad, and 486 DX IBM PC. Images were acquired using Image Pro Plus software. Measurements included the luminal perimeter, luminal area, vessel perimeter and area (defined by the external elastic lamina), neointimal area (defined by the lumen, internal elastic lamina, and excluding the area of embedded stent elements).
  • the main endpoint of this study was the neointima area formation after injury to the vessel wall.
  • the antibody employed in this study was Hu M4TS.22 (described in WO 97/37029) which is crossreacting with the baboon ⁇ -receptor of PDGF.
  • Anti-PDGF- ⁇ R achieved a 23% statistically significant reduction of neointima area in balloon-injured femoral arteries without stent placement as compared with placebo (see Table 1).
  • Anti-PDGF- ⁇ R significantly reduced neointimal area by 42% in balloon-injured carotid arteries with stent placement in comparison with placebo (see Table 2).
  • this example provides evidence that reduction of neointima formation can be considerably improved by combining a systemically administered anti-PDGF- ⁇ R-antibody with the medical device stents.

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  • Immunology (AREA)
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Abstract

L'invention concerne un procédé amélioré permettant de réduire la formation de cellules néointimes. Ce procédé consiste à administrer au patient un anticorps récepteur anti-PDGF-beta, ce procédé se caractérisant par le fait d'administrer cet inhibiteur par voie générale et conjointement à un dispositif médical que l'on place dans le vaisseau, de manière à empêcher mécaniquement que la lumière dudit vaisseau ne rétrécisse.
PCT/EP1998/000837 1997-02-14 1998-02-13 Procede ameliore permettant de reduire la formation de cellules neointimes apres une angioplastie WO1998035697A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64971/98A AU6497198A (en) 1997-02-14 1998-02-13 Improved method for the reduction of neointima formation after angioplasty

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97102365.0 1997-02-14
EP97102365 1997-02-14

Publications (1)

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WO1998035697A1 true WO1998035697A1 (fr) 1998-08-20

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PCT/EP1998/000837 WO1998035697A1 (fr) 1997-02-14 1998-02-13 Procede ameliore permettant de reduire la formation de cellules neointimes apres une angioplastie

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012734A1 (fr) * 1991-01-17 1992-08-06 The Board Of Regents Of The University Of Washington Anticorps contre les facteurs de croissance dans le traitement de la stenose vasculaire
WO1994019016A1 (fr) * 1993-02-25 1994-09-01 Zymogenetics, Inc. Inhibition de l'hyperplasie de l'intima par anticorps des recepteurs du facteur de croissance derive des plaquettes
EP0734721A2 (fr) * 1995-03-30 1996-10-02 Advanced Cardiovascular Systems, Inc. Procédé pour incorporer des médicaments dans un composant polymère des endoprothèses autoexpansives
WO1997037029A1 (fr) * 1996-03-22 1997-10-09 Protein Design Labs, Inc. ANTICORPS MONOCLONAUX SPECIFIQUES DU RECEPTEUR DU FACTEUR DE CROISSANCE DERIVE DES PLAQUETTE β ET PROCEDES D'UTILISATION DE CES ANTICORPS

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012734A1 (fr) * 1991-01-17 1992-08-06 The Board Of Regents Of The University Of Washington Anticorps contre les facteurs de croissance dans le traitement de la stenose vasculaire
WO1994019016A1 (fr) * 1993-02-25 1994-09-01 Zymogenetics, Inc. Inhibition de l'hyperplasie de l'intima par anticorps des recepteurs du facteur de croissance derive des plaquettes
EP0734721A2 (fr) * 1995-03-30 1996-10-02 Advanced Cardiovascular Systems, Inc. Procédé pour incorporer des médicaments dans un composant polymère des endoprothèses autoexpansives
WO1997037029A1 (fr) * 1996-03-22 1997-10-09 Protein Design Labs, Inc. ANTICORPS MONOCLONAUX SPECIFIQUES DU RECEPTEUR DU FACTEUR DE CROISSANCE DERIVE DES PLAQUETTE β ET PROCEDES D'UTILISATION DE CES ANTICORPS

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