Patrick Chames

Daniel Baty

Bispecific antibodies for cancer therapy: the light at the end of the tunnel?

Keywords: Animals, Antibodies, Bispecific, immunology, therapeutic use, Antibody-Dependent Cell Cytotoxicity, genetics, immunology, Drug Approval, Europe, Genetic Engineering, Humans, Immunoglobulin Fc Fragments, genetics, immunology, Neoplasms, immunology, therapy, United States antibodies, bispecific, cancer, therapy, clinical trials

With 23 approvals in the US and other countries and 4 approvals outside US, antibodies are now widely recognized as therapeutic molecules. The therapeutic and commercial successes met by rituximab, trastuzumab, cetuximab and other mAbs have inspired antibody engineers to improve the efficacy of these molecules. Consequently, a new wave of antibodies with engineered Fc leading to much higher effector functions such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity is being evaluated in the clinic, and several approvals are expected soon. In addition, research on a different class of antibody therapeutics, bispecific antibodies, has recently led to outstanding clinical results, and the first approval of the bispecific antibody catumaxomab, a T cell retargeting agent that was approved in the European Union in April 2009. This review describes the most recent advances and clinical study results in the field of bispecific antibodies, a new class of molecules that might outshine conventional mAbs as cancer immunotherapeutics in a near future.

Introduction

Monoclonal antibodies (mAbs) are endowed with exquisite specificities. Since 1975, when Kohler and Milstein published an efficient way of producing these molecules, they have raised many hopes for the development of novel therapies, particularly as cancer treatments. 1

However, extensive optimization through antibody engineering was required before effective IgG molecules could be produced; the first anti-tumor mAb, rituximab, was finally approved in 1997. Since then, a total of nine mAbs have been approved for cancer therapy in the US and other countries. These molecules are generally very well-tolerated and lead to significant clinical results, especially in the case of 2 hematologic malignancies, as seen with rituximab. Unfortunately, none of them are able to cure cancer as single agent. Several clinical outcomes and animal studies have highlighted major limitations in their modes of action, including redundancy of molecular pathways leading to cancer cell survival, effects of the microenvironment, suboptimal interaction with effector cells due to alternative Fc glycosylation or Fc receptor polymorphism, activation of inhibitory receptors, and competition with circulating IgG. However, as 2 hypothesized very early, many mAb shortcomings could be overcome by creating bispecific antibodies (bsAbs) capable of simultaneous 3 binding to two different targets. Such molecules would be capable of retargeting a large variety of payloads to cancer cells. The potential of this approach has been demonstrated by several studies over the years, but the difficulty of producing large amounts of homogenous bsAbs using the available techniques (e.g., hybrid hybridomas, chemical cross-linking) hindered wider adoption and development of this approach. However, using advanced antibody engineering, new recombinant formats have been designed and validated to a certain extent.

These formats include tandem scFv, diabodies, tandem diabodies, dual variable domain antibodies, and heterodimerization using a motif such as CH1/Ck domain or the Dock and Lock motif (reviewed in Ref.

). The development of single domain antibodies from Camelid 4 antibodies or engineered VH domain should also facilitate design of improved antibody therapeutics. However, few candidates based on 5 these formats have reached the clinic. This review focuses on novel antibody formats of particular interest, highlighting triomabs and BiTEs, which are two formats that have yielded outstanding results in recent clinical trials.

First generation bsAbs: chemically cross-linked bispecific antibodies

The potential of using bispecific antibodies to retarget effector cells toward tumor cells was demonstrated in the 1980s, , , and, 3 6 7 several Phase 1clinical studies were launched in the early nineties. These early bispecific molecules were mainly generated using either of two approaches, chemical cross-linking, or hybrid hybridomas or quadromas. Despite some obvious biological effects, none of these approaches led to a significant impact in the clinical course of the disease. The first studies of bsAbs highlighted two major limitations of 8 the first generation molecules, including the difficulty of producing large, homogeneous batches, and the lack of efficacy of murine antibody fragments. Human anti-mouse antibody (HAMA) responses were seen in most treated patients, which severely decreased the efficacy of the murine molecules and excluded the possibility of multiple administrations.

A series of clinical trials were also performed with chemically linked bispecific (Fab )2 molecules targeting the breast and ovarian ′ cancer tumor antigens HER2 or EGFR, which are overexpressed in many epithelial tumors such as colorectal, head and neck, 9 -12 bladder, renal, non-small cell lung carcinoma. The second specificity of these bsAbs was directed against Fc RI (CD64), which is notably γ expressed on monocytes and macrophages and up-regulated upon activation on neutrophils. Since this last population represents 60 70 -% of leukocytes, co-administration of granulocyte-colony stimulating factor (G-CSF) was thought to enhance the activity of the injected bsAb. Biological effects were seen in some clinical trials of bsAbs MDX-210 (targeting Her2 and CD64), MDX-H210 (humanized version of MDX-210) and MDX-447 (targeting EGFR and CD64), but none of these treatments led to consistent antitumor activity. These 9 -12 results might be explained by preclinical data for MDX-210 indicating that measurable tumor-cell lysis required high bsAb concentrations (0.1 1 mg.mL ) and effector-to-target cell ratios of at least 40:1, even when human neutrophils that had been prestimulated with IFN- (CR) and one partial remission (PR) in a group of 15 treated patients; this was followed by one CR and three PR in a second clinical 14 trial. The construct was the first instance of bsAb treatment leading to a complete remission. However, the low production yield (2.8 g 15 of bsAb obtained from 44 g of IgG) and the high immunogenicity of this bsAb precluded further clinical studies.

A different approach, and indeed the most obvious application of bsAb, is T cell retargeting. Cytotoxic T cells are considered the most potent killer cells of the immune system. They are abundant, efficiently proliferate upon activation, capable of killing multiple times, 16

and efficiently infiltrate tumors, but do not express Fc receptors. The idea of using T cells to efficiently kill tumor cells using bsAb γ emerged in the 1980. Bispecific antibodies directed against a tumor marker and CD3 have the potential to redirect and activate any 3 circulating T cells against tumors. However, T cells have a major drawback. Without the secondary signal given by the interaction between CD28 and one of its ligands (e.g., B7), T cells are not fully activated, and might even become anergic. The first anti-CD3 bsAbs were 17 thus administered in combination with anti-CD28 antibodies, but the combination yielded mixed results.18

Alternatively, it should be possible to pre-stimulate the effector T cells. Surprisingly, treatment with bsAbs of the most basic format, i.e., chemical cross-linking of full size monoclonal antibodies, yielded some success in clinical studies. Such antibodies were primarily developed for use with polyclonally activated T cells (PACTs); bsAb-loaded PACTs were generated ex vivo and then administered to patients. . Specifically, the patient s T cells are purified, expanded and activated in vitro to very large amount (>300 10 ). Next, these

' × 9
cells are incubated with an anti-CD3 tumor target bispecific antibody, before being administered to the patient. This approach has the × advantage of avoiding a direct systemic injection of bsAb in the patient, thereby significantly minimizing toxicity associated with free murine Fc bearing molecules. The approach also provides a large amount of activated and armed T cells artificially redirected to tumor 19 cells, and has been applied to arm patient PACTs for targeting breast and hormone-refractory prostate cancers, non-Hodgkin lymphoma (NHL), EGFR cancers, and CA-125 ovarian cancers.

+ +

Interestingly, it was shown that bsAb-retargeted PACTs can divide and secrete cytokines upon restimulation with target cells, while retaining their specificity and cytotoxicity for more than two weeks, which might be an important feature for therapeutic settings. A 20

Phase 1/2 clinical trial using Her2Bi (OKT3 trastuzumab)-armed activated T cells for the treatment of breast cancer and prostate cancer × has resulted in partial responses persisting for two months following completion. In addition, a new Phase 1 clinical study of autologous activated T cells retargeted by CD20bi (OKT3 rituximab) in combination with chemotherapy for the treatment of multiple myeloma was × recently designed. The treatment will be followed by autologous peripheral blood stem cell transplantation to replace the blood-forming cells that were destroyed by the chemotherapy (ClinicalTrials.gov Identifier NCT00938626).

TriomAbs

Triomabs probably represent one of the most impressive and unexpected success in the field of bispecific antibodies. In 1995, Lindhofer and collaborators published a paper describing a major improvement of the classical quadroma approach to produce bsAbs.21

By using an original subclass combination (mouse IgG2a and rat IgG2b), they demonstrated a preferential species-restricted heavy/light chain pairing, in contrast to the random pairing in conventional mouse/mouse or rat/rat quadromas, as well as use of sequential pH elution on protein A to easily separate the desired bsAb from the parental mAb. Surprisingly, the resulting hybrid rat/mouse Fc portion efficiently interacted with activating human Fc receptors (Fc RI and Fc RIII), but not inhibitory ones (Fc RIIB), thereby reaching the goal that other γ γ γ groups had hoped to achieve using human Fc engineering. , The investigators used this approach to create an anti-CD3 22 23 × anti-EpCAM bsAb, and demonstrated that this antibody was capable of binding to target cells and human T cells, but was also capable of activating dendritic cells (DC), inducing NK-dependent ADCC and stimulating tumor cell phagocytosis by macrophages. , In short, 22 23 this Fc adds two crucial functions to regular anti-CD3 target bsAbs: additive tumor killing capabilities through the efficient recruitment × of macrophages and NK cells, and, most importantly, efficient co-stimulation of T cells through direct contact with accessory cells such as macrophages and DC (B7/CD28, CD40/CD40L, LFA3/CD2) or cytokine secretion (IL-2, IL-6, IL-12).

Catumaxomab (Removab )

® CatumaxomAb, which targets the tumor antigen EpCAM, was the first triomab produced. EpCAM (CD326) is expressed on essentially all human adenocarcinoma, certain squamous cell carcinoma, retinoblastoma, and hepatocellular carcinoma. EpCAM is also expressed in normal cells, but is predominantly located in intercellular spaces where epithelial cells form very tight junctions. It is thought that EpCAM is sequestered on epithelia, and thus much less accessible to antibodies compared to EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface. Moreover, EpCAM is very often on cancer stem cells, a very attractive feature for a tumor marker. [START_REF] Munz | The emerging role of EpCAM in cancer and stem cell signaling[END_REF] In vitro and in vivo preclinical data demonstrated that a mouse surrogate of this triomab, targeting mouse CD3 and human EpCAM, was able to kill tumor cells very efficiently, at low concentration (10 pM range), without any additional costimulation of effector cells. In animal studies, 100 of mice administered an injection of 4 g of triomabs survived after intraperitoneal (IP) injection of a lethal dose of % μ

EpCAM melanoma cells. Moreover, initial treatment of the tumor with this bsAb led not only to total tumor eradication, but also to the 2009 for the treatment of malignant ascites in patients with EpCAM positive carcinomas in cases where standard therapy is not available or no longer feasible. This first marketing approval clearly represents an important milestone in the field of bispecific antibodies. It is also interesting to note that the high immunogenicity of this rat/mouse hybrid molecule did not constitute a major issue. Moderate anti mouse and anti rat responses were seen in the majority of the patients but they do not seem to affect the efficiency of the treatment. This is 26

probably due to the extremely small amounts administered to the patients (around 100 g, compared to 3 g for rituximab, i.e., 30,000 fold μ less), the short duration of the treatment (10 days), and probably to the IP route of administration. However, Intravenous injections will be required for other indications. In a phase I study for the treatment of non-small cell lung cancer patients, it was established that the maximum tolerated dose for multiple catumaxomab i.v. administration was 5 g, together with a pre-medication of 40 mg dexamethasone μ and antihistamines. This low amount probably reflects the mode of action of triomabs, potentially leading to tumor-cell independent 28 cross-linking of T-cells with accessory cells followed by cytokine release-related symptoms. At this dose, no patient developed HAMA or HARA within 28 days after the single dose treatment. Thus, repeated administration of the antibody can be considered in the future and must be investigated in further clinical trials. Although survival analysis was not the primary endpoint, the survival observed in this study was very favorable with several advanced patients still alive 28 months after catumaxomab treatment. Future randomized trials are needed to determine if these low amounts of bsAb will be enough to achieve a therapeutic effect in this setting.

Ertumaxomab (rexomun )

® Ertumaxomab is triomab targeting HER2, a well-characterized breast tumor marker that is also targeted trastuzumab (Herceptin). This triomab possesses the same hybrid Fc portion as catumaxomab, and displays the same efficiency in vitro. Ertumaxomab was also 29 compared to trastuzumab for its ability to kill tumor cells expressing various level of HER2. Exposure to ertumaxomab led to the efficient lysis of cells expressing very low amount of tumor antigen, whereas trastuzumab was completely ineffective even at high concentration.30

This difference can probably be explained by the mode of action of these antibodies. Trastuzumab triggers NK-mediated ADCC while ertumaxomab relies on T cell mediated killing and the interaction between T cells and accessory cells, as demonstrated by the release of proinflammatory cytokines such as IL-6, IFN-and TNF-. Of note, two other triomabs, targeting melanoma-associated proteoglycans or melanomaassociated gangliosides (GD2 and GD3),33 are in preclinicalstudies as potential treatments for malignant melanoma.

The new generation: recombinant bsAbs

In the nineties, advances in antibody engineering provided innovative solutions antibody design problems, allowing production of small antibody fragments recapitulating the entire binding activity of the parent molecule . One fragment, the single chain variable [Fig. 1 ] fragment (scFv), made by association of the heavy and light variable domain through a peptidic linker, has especially inspired antibody engineers. Two formats have been intensively studied. Tandem scFvs (TaFv) are two scFv fragments linked an extra peptide linker that via is expected to confer good flexibility to each fragment. Although difficult to produce in , this 60 kDa molecule is well-expressed by E. coli mammalian cells, and. By reducing the length of the peptide linker between variable domains so that these cannot assemble, it is possible to force the pairing of domains between two different polypeptides, leading to a compact bsAbs called diabody (Db). CD28 antibody induced systemic T-cell activation and severe cytokine release syndrome when injected into six healthy volunteers, and 42 since then concerns have been raised about the use of immunomodulatory molecules. However, it should be noted that a fundamental difference exists between TGN1412 and bispecific molecules such as rM28. Indeed, unlike the activity of TGN1412, supra-agonistic CD28 stimulation by rM28 was shown to be strictly target-cell restricted over a wide concentration range, i.e., not induced if NG2-expressing target cells are absent. This, in principle, should avoid side effects such as those observed after TGN1412 43 administration.

BiTEs: bispecific T cell Engagers

Another type of tandem scFvs aimed at activating T cells has met with more success in clinical trials. BiTEs, or bispecific T cell Engagers, are made by fusing an anti-CD3 scFv to an anti-TAA scFv via a short 5 residue peptide linker (GGGGS). In 1995, Kufer and collaborators produced such a tandem scFv targeting EpCAM (epithelial 17-1A antigen) and human CD3 in CHO cells. This new kind of bsAb proved to be highly cytotoxic at nanomolar concentrations against various cell lines, using unstimulated human PBMCs in the absence of co-signaling. Later, L ffler et al. published similar data obtained using a fusion between a murine anti-CD19 scFv and a 44 ö murine anti-CD3 scFv. This molecule demonstrated outstanding in vitro properties, including efficient cytotoxicity induced by 45 extremely low concentrations of bsAb (10 50 pg.mL , i.e. subpicomolar), at low effector:target ratio (2:1), and in only four hours, -1 without the need for pre-stimulation of T cells or, most surprisingly, the need of co-signaling (e.g., through CD28). These results were in marked contrast with the majority of published studies based on anti-CD3 bispecific constructs.

Since then, Baeuerle and collaborators have accumulated data demonstrating the properties of BiTEs. The most impressive property 46 of this class of molecules, beside the absence of requirement for any kind of pre or co stimulation of effector T cells, is the low concentration required to achieve anti-tumor activity. Indeed, most tumor cell lines can be lysed in the presence of 0.2 to 2 pM of BiTEs for half maximal target cell lysis. In some cases, up to 18 fM was shown to be enough to induce in vitro cell lysis, suggesting that a low two digit number of BiTEs bound between T and target cells is sufficient to induce lysis. Moreover, BiTEs are capable of inducing 47 efficient lysis at effector to target ratios (E:T) as low as 1:10. This suggests that BiTEs mediate serial killing of many target cells, and this was actually demonstrated using video assisted microscopy. Despite this extreme efficiency, the killing remains strictly target-cell dependent, and T cells cannot be activated in the absence of target cells, even at concentrations exceeding EC values by several 50 thousand fold.48

The biological properties of BiTEs are not yet clearly understood. In the case of molecules targeting CD19 on B cells, one cannot exclude a possible co-signal triggered by the interaction between CD28 and B7, known to be expressed on normal and malignant B cells.

However, BiTE molecules targeting EpCAM expressed on a variety of solid tumor of epithelial origin that do not express B7 show similar efficacy. The absence of a need for co-signaling through CD28 for these BiTEs might also be explained by the observation that among all T cell subtypes, CD8 effector memory cells CD45RO (TEM) and CD8 effector memory CD45RA (TEMRA) contribute the most to BiTE

BiTEs

+ + + +
activity, whereas na ve T cells do not contribute at all to the killing efficiency. It is believed that memory T cells do not require CD28 Other BiTEs in the pipeline MT111/MEDI-565 targets the carcinoembryonic antigen (CEA, also called CEACAM5), a widely expressed tumor antigen highly expressed in colorectal cancer, and also in a substantial proportion of carcinomas of the lung, pancreas, stomach, ovary, uterus, breast, and a subset of melanomas.

However, CEA can be shed by phospholipases from the cell surface through cleavage of its 58 glycosylphosphatidylinositol-linkage, which causes the protein to be released in the circulation. This soluble CEA (sCEA) might therefore interfere with antibody based therapies. To test this hypothesis, Lutterbuese et al. compared the activity of several anti-CEA anti-CD3 × BiTE in the absence or presence of sCEA, and found that the cytotoxic activity of some of these molecules was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. MT111 is therefore a promising molecule 59 soon to be tested in clinical trials.

DNL antibodies for radioimmunotherapy

The Dock and Lock (DNL) method was originally published in 2006, and represents a convenient and efficient way to create 61 bispecific antibodies. It relies on the spontaneous association of a dimer of the 45 amino acids peptide DDD2, derived from the regulatory subunit of human cAMP-dependent protein kinase (PKA) with the 21 residues peptide AD2, derived from the anchoring domains (AD) of human A kinase anchor proteins (AKAPs). Upon association, two disulfide bonds are created, resulting in a covalent complex that is stable for more than a week at 37 C in human serum. This approach can be used to efficiently create any kind of bsAb but was so far used to °create bispecific molecules dedicated to radioimmunotherapy.

TF2

The first described bsAb built using the DNL method was a molecule of 157 kDa, devoid of Fc fragment, comprising two Fab fragments derived from humanized anti-human CEA mAb hMN-14 and one Fab fragment from humanized mAb h679 that is able to strongly bind the hapten histamine-succinyl-glycine (HSG). This bispecific Tri-Fab molecule named TF2 was used for tumor imaging purposes in xenografted nude mice, based on a previously validated pretargeted approach where the bsAb is first injected, then the 99m Tc-labeled hapten is injected after the bsAb has cleared from the circulation. Exceptionally high tumor blood ratios were observed, ranging from 13 at 0.5 h to 395 at 24 h, with high tumor uptake of 30 ID/g, whereas the levels in blood and normal tissues, except kidney, were % <1 ID/g at1 h after injection. These outstanding results obtained in imaging approaches prompted the use of this bsAb for therapy. In % order to take advantage of possible dimerization of the bsAb on the surface of target cells (a process named affinity enhancement system) protection and patient-handling issues. Thus, the combination of bsAb-enabled pretargeting approaches and this radionuclide might have a high therapeutic potential.

Other DNL based bsAbs in the pipeline

TF4 is a second bsAb built using the DNL method, directed against CD20 for the treatment of NHL. Studies performed in xenografted nude mice that compared TF4 as a pretargeting agent of an

In-HSG-peptide with a one step approach using the parental anti-CD20 mAb 111 (hA20) directly labeled with Y demonstrated an impressive 1600 fold improvement of the tumor-to-blood ratio, as well as a 1. In-PAM4-IgG (5:1 at 24 hours). The high therapeutic potential of this approach should thus soon be tested in the clinic.

Conclusion

After years of disappointment and frustrations, clinical trials of bsAbs are finally providing exciting results, with the most impressive ones being delivered by triomab and BiTE molecules. These results do not represent a mere improvement compared to those obtained by approved therapeutic antibodies, but are a real leap in terms of therapeutic efficiency. For the first time, the possibility of actually curing patients using antibodies seems within reach. Further randomized studies are eagerly awaited to demonstrate whether these encouraging results from Phase 1 and 2 trials will result in prolonged overall survival. Interestingly, after a race toward fully human antibody molecules experienced during the last decade, these impressive biological activities were obtained with fully murine molecules which, because of their high efficiency, can be injected in doses four to five log lower than those usually used by therapeutic mAbs. In the case of BiTEs, the short half life traditionally perceived as a limitation was actually exploited to achieve an exquisite control of drug levels in patients using mini-pump devices developed for insulin delivery.

By choosing to develop treatments for malignant ascites and acute lymphoblastic leukemia, Trion pharma, which produces triomabs, and Micromet, which produces BiTE molecules, have decided to pursue approval for niche indications. This approach is likely to be the fastest and safest route to approval. There is no doubt that both companies have promising candidates with very large potential markets, and that candidates against several malignancies will soon be tested in clinical trials. With these developments, it might well be that we are currently experiencing a turning point in the field of bispecific antibody, and more generally of cancer immunotherapy.

13 ′

 13 CSF were used. More encouraging results were obtained in two clinical trials involving HRS-3/A9, a bispecific F(ab )2 antibody targeting the CD30 antigen on Hodgkin and Reed-Sternberg cells in patients with Hodgkin Disease (HD), and receptor Fc RIII (CD16) γ expressed by natural killer and macrophages. Two Phase 1 clinical studies performed with this molecule led to one complete remission

+ 25 induction

 25 of immune protection. All mice rechallenged on day 144 after the primary challenge were still able to reject the tumor, indicating the high efficacy and long duration of the antitumor response. This effect was dependent on the presence of the hybrid Fc, and involved a humoral response directed against the non-transfected (EPCAM ) tumor cells. -In a Phase 1/2 clinical trial, patients in ovarian cancer patients with malignant ascites were treated with IP administration of triomab (4 to 5 doses of 5 to 200 g); 22/23 patients did not require paracentesis between the last infusion and the end of study at day 37. Tumor cell μ monitoring revealed a reduction of EpCAM-positive malignant cells in ascites by up to 5 logs. By early 2009, the results of a large 26 international Phase 2/3 pivotal study involving 258 patients demonstrated a statistically significant improvement of the primary endpoint, puncture-free survival. Patients receiving catumaxomab had a four-fold increase in puncture-free survival compared to those receiving paracentesis therapy only. Below the maximum tolerated dose (200 g), side effects, including fever, nausea and vomiting, were μ predictable, limited, manageable and mostly fully transient. Consequently, the European commission approved catumaxomab in April 27

  In an early clinical trial of patients with malignant ascites due to peritoneal carcinomatosis, administration of total doses of ertumaxomab as low as 40 140 g lead to a complete elimination of tumor cells in ascites, and disappearance of ascites accumulation in all μ patients. This antibody is currently in Phase 2 trials for the treatment of metastatic breast cancer. 29 Bi20 (Lymphomun or fBTA05) ™ Bi20 triomab utilizes the same hybrid Fc portion as catumaxomab and ertumaxomab, and targets CD20. Expressed on all stages of B cell development from pre-B cells through memory cells, but not on either pro-B cells or plasma cells, CD20 represents an attractive target for the treatment of B cell malignancies. Notably, CD20 is targeted by rituximab. In vitro, Bi20 was shown to mediate an efficient and specific lysis of Bcell lines and B cells with low CD20 expression levels that were derived from chronic lymphocytic leukemia (CLL) patients. Remarkably, T cell activation and tumor cell killing occurred in an entirely autologous setting, i.e., without additional effector administered to six patients with recurrent B cell malignancies, CLL or highly malignant lymphoma after allo-stem cell transplantation. All alemtuzumab-and rituximab-refractory patients showed a prompt but transient clinical and hematological response, highlighting the high therapeutic potential of this triomab. Bi20 is currently in Phase 1 clinical study.32

These molecules 34 can 37 ×

 3437 be expressed at high yields in bacteria, and have been shown by crystallography experiments to adopt several conformations. This 35 format has been improved by adding an extra peptide linker between the two polypeptides in order to further decrease the amount of homodimers, yielding fragments called single chain diabodies (scDb). Numerous studies have demonstrated the potency of these formats in preclinical studies. Examples of bsAb fragments with potential as therapeutic candidates include bispecific anti-CD19 CD3 and 36 × anti-CD19 CD16 diabodies that demonstrated a synergistic antitumor effect in a preclinical model of NHL, a promising anti-EGFR × CD3 diabody able to cure xenografted mice in combination with lymphokine activated killer cells, and the efficient treatment of 38 xenografted mice bearing prostate cancer cell induced tumors using an anti-PSMA CD3 diabody and peripheral blood lymphocytes. × 39 Surprisingly, no bispecific diabodies have been tested so far in clinical trials. Although no bispecific diabodies have been administered to humans, tandem scFvs have been studied in clinical trials. One atypical molecule was rM28, a bispecific tandem molecule targeting the co-stimulatory molecule CD28 expressed on T cells and NG2, a melanoma-associated proteoglycan. This molecule spontaneously forms stable dimers, and was shown to be capable of inducing T-cell activation and effective tumor-cell killing in vitro and in vivo without a signal through the TCR/CD3 complex, a so called targeted " supra-agonistic stimulation . This effective mode of action was recently extended to the cytolysis of lymphoma cells using an anti-CD28 " 40 CD20 bispecific tandem scFv endowed with the same supra-agonistic properties . In 2005, a Phase 1/2 clinical trial was conducted to × 41 analyze the safety and efficiency of intralesional administration of rM28 and autologous peripheral blood mononuclear cells in patients with metastatic stage III/IV melanoma and unresectable metastasis. However, in March 2006, TGN1412, a monospecific superagonistic ' '

  have been demonstrated to induce immunological cytolytic synapses identical to synapses induced by regular T cell stimuli,49 even in the absence of MHC class I molecules, as shown by the lysis of Ep-CAM-expressing K562 cells or transfected rodent cells expressing the target antigen by human effector cells. The small size (60 kDa) of BiTEs, which ensures close proximity of T cells and target cell membranes, might therefore be responsible for their high efficiency by leading to the active displacement of negative regulatory proteins from the forming synapse, as demonstrated in the case of CD45. It should be stressed that the possibility to efficiently form 47 cytolytic synapses by a mere interaction between CD3 and a target antigen via a BiTE molecule, in the absence of MHC class I/TCR interaction, has the potential to overcome many tumor cell escape mechanisms such as MHC class I, proteasome and intracellular peptide transporter (TAP1 and 2) down-regulation.

ï 50 costimulation 1 -

 501 for expansion during secondary responses, which could explain the efficiency of BiTEs. However, this dogma has recently been challenged.51Blinatumomab (MT103)Blinatumomab, a murine anti-human CD3 anti-human CD19 was the first BiTE developed and is the most advanced BiTE in clinical × trials. The candidate is being studied as a treatment of lymphoma and leukemia. In preclinical trials, Dreier et al. demonstrated that submicrogram amounts of this molecule were sufficient to prevent tumor growth in a mouse model. Later, studies performed in 52 chimpanzees showed that repeated 2 h treatments with doses as low as 0.1 g.kg were well-tolerated, and led to cumulative depletion of μ peripheral B cells due to fully reversible T cell activation. In 2008, the first result of a Phase 1 clinical study indicated that doses as low 53 as 5 g per square meter per day in relapsed NHL patients led to an elimination of target cells in blood. All seven patients treated at a dose μ level of 60 g experienced a tumor regression. Because of its small size (60 kDa), blinatumomab is characterized by a short serum half μ 54 life of several hours, and so continuous intravenous infusion by portable mini-pumps is required. It should be highlighted that cumulative doses of several milligrams were sufficient to lead to the notable response in patients, whereas conventional antibody treatments, such as rituximab, consume gram amounts per treatment cycle. MT103 is also currently being tested in a Phase 2 trial in patients with B-precursor acute lymphoblastic leukemia (B-ALL) having minimal residual disease in their bone marrow. The first results from an ongoing Phase 2 trial in patients with B-ALL indicate that T cells engaged by blinatumomab are able to locate and eradicate rare disseminated tumor cells in the bone marrow that can only be detected by quantitative PCR assays detecting tumor cell-specific genomic aberrations. Thirteen out of 16 evaluable patients (81 ) became minimum % residual disease (MRD) negative, with ongoing responses lasting for up to 47 weeks on May the 25 2009 (data presented in Recombinant th Antibodies meeting, June 2009, Cologne). This result is remarkable since MRD positive ALL patients have very limited treatment options, and around 60 of patients die within 2 years, with a median time to hematological relapse of only 4.1 months. Interestingly, this trial was % associated with significantly reduced toxicity compared to NHL patients at the same dose level, suggesting that toxicity might be correlated to the number of target cells present in patients, rather than to the BiTE molecule itself. MT110 MT110, an anti-human EpCAM anti-human CD3 TaFv, was the second BiTE tested in clinical trial, and the first directed to a wide × spectrum of solid tumors. In vitro characterizations of MT110 have recapitulated the results obtained with MT103 on tumor cell lines, thereby demonstrating the generality of the BiTE format. A study in NOD/SCID mice demonstrated that as little as 100 ng of MT110 55 can prevent tumor outgrowth after an injection of a 1:1 ratio of human colon carcinoma cells mixed with unstimulated human peripheral mononuclear cells. MT110 was also active against human ovarian metastatic tissues grafted in immunodeficient mice in the absence of human peripheral mononuclear cells. Since MT110 does not activate murine T cells, this result suggests that tumor resident human T cells, being tolerized or anergized, could be reactivated, and were present in sufficient number to eliminate the xenograft. Preclinical data 56 from studies with muS110, a BiTE surrogate targeting murine EpCAM and murine CD3 demonstrated that EpCAM-specific BiTE antibodies can effectively discriminate between target antigen expressed on tumor and normal epithelial tissue. MT110 is currently 57 being tested in a Phase 1 study with lung, colorectal and gastrointestinal cancer patients; initial results are expected by the end of 2009.

Figure 1 A

 1 Figure 1 A conventional antibody is depicted in green (light for light chain, dark for heavy chain, blue triangle indicate the glycosylation site) and the derived fragments (shaded areas represent the binding sites). The orange color symbolizes a different specificity. The blue and red shapes represent the DDD2 and AD2 peptides of the dock and lock (DNL) method. All flexible linkers are in grey. bsAb: bispecific antibody. bsFab: bispecific Fab fragment. scFv: single chain Fv fragment. dAb: domain antibody.

  Two other approaches to rapidly generate new relevant BiTEs are also being pursued by Micromet. The company has elaborated a platform allowing the selection of human scFvs against new tumor antigens and against CD3. Interestingly, these new scFvs are directly selected to be cross-reactive with orthologous antigens of non-human primates, allowing straightforward assessment of the molecule safety and pharmacology. Examples of fully human BiTEs in discovery that were obtained this way include BiTEs that target CD33, a protein expressed in > 90 of acute myeloid leukemia, including cancer stem cells, and melanoma associated chondroitin sulfate proteoglycan, a % 450 kDa antigen expressed in >90 of all melanomas. Both BiTEs have already been investigated in studies with macaque monkeys that % have validating these new molecules, both in terms of efficacy and safety. A second approach involves the reformatting of approved 60therapeuticantibodies as BiTE molecules. Examples include trastuzumab, panitumumab (Vectibix), cetuximab (Erbitux) and omalizumab (Xolair), leading to efficient BiTEs against HER2, EGFR and IgE, that have EC values between 90 fM and 3.6 pM. These molecules 50 should rapidly enter preclinical phases.

  to increase tumor retention, a new peptide; called IMP-288, was designed to contain two HSG epitopes. The divalent peptide was 62 labeled with Lutetium 177 for use in a Phase 1 clinical study involving patients with CEA expressing advanced colorectal tumors that was initiated in July 2009.Lu is a very promising radionuclide for targeted radiotherapy because its relatively long half-life of 6.71 days 177 allows employment of sophisticated procedures to synthesize and purify the radiopharmaceutical, and allows transport to more distant customers. Furthermore, the emitted radiation with a maximum energy of 498 keV is effective in destroying small tumors and metastasis

	β
	while sparing normal tissue, and its -rays are of low energy (113 and 208 keV) and abundance (7 and 11 ), which simplifies radiation γ % %

  17 . Howland KC , Ausubel LJ , London CA , Abbas AK . The roles of CD28 and CD40 ligand in T cell activation and tolerance . J Immunol . 2000 ; 164 : 4465 -70 18 . Manzke O , Titzer S , Tesch H , Diehl V , Bohlen H . CD3 CD19 bispecific antibodies and CD28 costimulation for locoregional treatment of low-malignancy

× non-Hodgkin s lymphoma ' . Cancer Immunol Immunother . 1997 ; 45 : 198 -202 19 . Lum LG , Davol PA , Lee RJ . The new face of bispecific antibodies: targeting cancer and much more . Exp Hematol . 2006 ; 34 : 1 -6 20 . Grabert RC , Cousens LP , Smith JA , Olson S , Gall J , Young WB . Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation . Clin Cancer Res . 2006 ; 12 : 569 -76

Table 1

 1 Most recent clinical trials involving the use of bispecific antibodies.

	Name	Format	Target	Cancer type	Stage	Ref.
	MDX-210	(Fab )2 ′	HER2 CD64 ×	Breast/ovarian	Phase 1	13
	MDX-H210	(Fab )2 ′	HER2 CD64 ×	Breast/ovarian	Phase 1	9
	MDX-447	(Fab )2 ′	EGFR CD64 ×	Lung, colorectal…	Phase 1	12
	HRS-3/A9	(Fab )2 ′	CD30 CD16 ×	Hodgkin Disease	Phase 1	, 14 15
	Her2Bi	Cross-linked IgGs	HER2 CD3 ×	Breast/prostate	Phase 1/2	19
	CD20Bi	Cross-linked IgGs	CD20 CD3 ×	Multiple myeloma	Phase 1	*
	Catumaxomab	Triomab	EpCAM CD3 ×	Malignant ascites	EMEA appr.	27
	Ertumaxomab	Triomab	HER2 CD3 ×	Metastatic breast	Phase 2	29
	Bi20	Triomab	CD20 CD3 ×	B-cell malignancies	Phase 1	32
	rM28	Dimeric TaFv	NG2 CD28 ×	Melanoma	Phase 1/2	40
	Blinatumomab	BiTE	D19 CD3 ×	HL and B-ALL	Phase 1 and 2	54
	MT110	BiTE	EpCAM CD3 ×	Lung, colorectal…	Phase 1	55
	TF2	DNL triFab	CEA HSG ×	Colorectal	Phase 1	61

* ClinicalTrials.gov Identifier: NCT00938626

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

cells, in 5 of 8 samples. In comparison, rituximab demonstrated a significantly lower B cell eradication rate. In a pilot study, Bi20 was

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]

[START_REF] Repp | Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer[END_REF]


Francesca Musiani

Within broad debates on freedom, security and human rights on the Internet -carried on during recent years in national and international fora -the proposal for the creation and adoption of a Bill of Rights for the Internet has been the subject of uneven attention and mixed reviews. Taking stock of the renewed interest in the proposal showed by the Committee on Civil Liberties of the European Parliament, this article analyses the current state of the Internet Bill of Rights (IBR) project. The analysis briefly retraces the history and main promoters of the IBR proposal, outlines the rationale and perspectives behind it, and debates its promises, limits and future challenges, with a special focus on its potential as an instrument of reconciliation between natural freedoms and needs for regulation.

Introduction. The recognition of rights

Retracing the historical development of human rights and fundamental liberties, Gerhard Oestreich affirms that, enshrined in every basic right, are both the aims of the political and social ordering and the human understanding of self. 1 With this image, the German author intends to convey the complexity of ethical, social, economic, historical and cultural relationships that underlie the attribution and recognition of every basic right. Every time that a new principle, right, rule or institution is acknowledged, the identity of the world we live in acquires some new facets. This complexity is first revealed in the debate on the very existence of rights and on their foundations: the hypothesis that a core of inviolable, basic rights does exist carries with it a number of dilemmas. The natural eternity of such rights cannot be demonstrated, as their nature cannot, in fact, be defined; the essence of their existence cannot be shown; their intrinsic logic cannot be made explicit, as there is no one and only logic. However, it is not always true that if the existence of something cannot be affirmed, it has to be rejected only because proper instruments to categorically confirm it are lacking; the inviolability of the individual, moral and social is then seen as a historical and at the same time utopian value, a regulatory idea that must show the way ahead. 2 A second level of complexity concerns the recognition of rights, that is not a steady and clear-cut process, for at least two main reasons: the difficulty to cope with regional differences, inequalities and social exclusion phenomena, and the trouble in pragmatically identifying not only what has been called the essential content of basic rights, but their limits of vulnerability as well. Moreover, if, as we have seen, the content of a right is hardly identifiable a priori, it means that, at a practical level, the content of a right is rather the result of the implementation of this right according to the history and features of a specific national, regional or cultural reality. It is therefore often difficult to point out which restrictions or regulations entail its intangible, essential core.

This article means to contribute to the debates on fundamental freedoms and security on the Internet, currently engaging with renewed interest within the Committee on Civil Liberties of the European Parliament, 3 by attempting to locate the principles outlined above in the specific context of the "new" rights brought along by the diffusion of the Internet in today's society, in a variety of sectors that include governance, education, management. The article analyses the current state of the proposal for the creation and adoption of a Bill of Rights for the Internet, and debates promises, challenges and limits of the project.

What rationale behind a constitution for the Internet?

Ever since the inception of the Web twenty years ago, a number of voices have been raised to define the Internet as the widest global public space of today's world, due to the millions of people every day exchanging messages, producing and receiving knowledge, building political and social participation, playing, selling and buying through and on it. 4 An argument has also been made that the Internet, as the facility that ensures global interconnectivity, has to be treated as a common good. Alongside these arguments, sometimes blamed for their excessive "technological optimism", a discourse has developed on what it takes for the public space created by the Internet to be preserved. Is it necessary to actively try and prevent its privatisation or control by specific lobbies? Is the absence of regulation ultimately a way to leave the Internet at the mercy of authoritarian regimes or market laws? It should be taken into account, these "mild sceptics" warn, that what was originally the space of boundless possibilities and untamed freedom5 is increasingly also becoming a conflict arena that impacts upon individual and collective rights, where freedom is depicted as the enemy of security, and vice-versa. 6 Regardless of the position one assumes in this controversy, it seems safe to acknowledge that these conflicts do exist -and they prompt, now more than ever, a thorough reflection on the opportunity for the Internet to find its rules and produce its institutions, and what it means and takes at a more practical level to "guarantee the respect of freedoms and rights for all its users",7 despite the appealing but rather vague choice of words. A key contribution to the discussion of these issues is provided by the work of American scholars such as Jack Balkin on freedom of expression,8 John Palfrey on access9 and, especially, Lawrence Lessig (accessed 20 Apr 2009).

on the delicate balance between innovation and control.10 However, the birth and development of the Internet Bill of Rights (IBR) proposal has added a more specifically European dimension to the debate, in particular thanks to the contributions of Italian scholar Stefano Rodotà. The remainder of this section will outline the perspective and vision fostered by the IBR promoters -in order to subsequently assess the feasibility and opportunity to translate those principles into a constitution-like document.

The promoters of a charter for the rights of the Internet argue that while information and communication technologies (ICTs) offer, on one hand, the possibility of increasingly wide participation to the Information Society11 and unprecedented sharing of ideas and contents, they give on the other hand room to issues of information control and manipulation from particular groups or individuals. Technologies of freedom and technologies of control live side by side.

Delivering the future to absence of rules and natural evolution might expose the global public network created by the Internet to the law "of the strongest" -not only in the sense of a progressively higher level of control by governments in the name of security,12 but also as a gradual self-imposition of the logics of the market (often the only source of rules when an institutional framework of guarantees is lacking). 13 It is therefore argued that a truly accessible, both individually and collectively, public space should not be subjected to private owning, nor to public control. Object of special attention within the Internet's creation and organisation of a public space should be the new modalities of intervention and interaction, like the progressive organisation of public structures (networks), the access to online information and services, the introduction of new possibilities of control by citizens of their representatives and thus a wider availability of possibilities to intervene in decisionmaking processes, the creation of new social spaces for knowledge and information sharing. 14 At the same time, the focus on positive aspects should not lead to the neglect of the "sins of the digital age,"15 such as inequality, commercial exploitation, exposure of misleading information, threats to privacy and the "tyranny" of access control. 16 Interestingly, IBR discourses on these aspects seem to focus exclusively on the rights of human beings, while discussions on the rights of companies, legal entities in their own right, are absent -including for those issues in which the promotion of the rights of one group does not (necessarily) go to the detriment of the other (e.g. net neutrality).

The main argument of the IBR promoters can then be summarized as following. All those who see in the Internet either only the freedoms it naturally enables, or the need for regulations and constraints in the name of security, are missing a vital part of the picture: only a collective and capable use of ICTs can avoid the transformation of the Net into a controlled realm, dominated by a few actors. Furthermore, the very relevance of the Internet inasmuch as the birth of a global public space is concerned makes it necessary to guarantee and safeguard citizens' rights within that same public space through appropriate instruments.

Basic principles between new and old rights: privacy as a case study

The predictable next step of the discussion concerns the features that these "appropriate instruments" should have. As the promoters of the Bill themselves consider the right to privacy as being of crucial importance, it will be given particular attention here as a case study which will put in context the rationale behind the IBR. The instrument would, however, be aimed at protecting a number of other rights, such as: the right to be online in the first place (freedom of access and use); the right to create and share knowledge; and last, but not least, freedom of expression -a controversial theme which is central to the present debates and comes with a long history. 17 An issue which has, thus far, been neglected in the IBR debate (but heavily discussed in other settings and potentially interesting to address in this one) is the realm of rights in virtual worlds and avatar rights; the question whether avatars -being the manifestation of actual people in an online medium -should have their utterances, actions, thoughts, and emotions considered to be as valid and endowed with rights as their equivalent in any other forum or through another medium. 18 Rodotà argues repeatedly that the primary aspect a discipline of the Internet should take into account is privacy. 19 He is followed by other prominent supporters of the IBR, who argue that In an ideal world the right to privacy would be protected by an entity with full understanding of the priorities of rights and capable in each situation to decide which right is more important. This entity also needed total knowledge of the context to be considered in order to produce the ethically correct or at least most suitable solution. Because this is impossible from a practical point of view, the basic need is to find a middle way between auto-regulation and institutionalized control. 20 As the promoters of the Bill themselves consider the right to privacy as being of crucial importance, it is taken here as a case study of the following aspects: the ways in which this right is enshrined in existing national and international instruments; whether and how an update according to the content and communication features of the Net is required; the extent to which a new instrument would be able to move from a negative to a positive conception of the right; what authorities are and should be involved in the protection of this right, and with what functions.

It is proposed that uses of personal data should be further clarified for the specific context of the Internet, with particular focus on the responsibilities of everyone concerned; the purpose(s) for which data and personal information are collected; and the acknowledgment and informed consent of the interested party. Furthermore, it should grant that the storage of personal information does not exceed a strictly necessary period of time, and allow the possibility of the interested parties to access the data in order to correct errors at any time.

Any further regulation on privacy concerns can benefit from already existent, widely ratified conventions. For example, the right to protection of personal data is enshrined in Article 8 of the Charter of Fundamental Rights of the European Union (EU). At paragraph 2, the article reads: Such data must be processed fairly for specified purposes and on the basis of the consent of the person concerned or some other legitimate basis laid down by law. Everyone has the right of access to data which has been collected concerning him or her, and the right to have it rectified. 21 Interestingly, paragraph 3 of the same article underlines the necessity of an independent authority with oversight functions. 22 The rights are thus located in a realm in which public institutions are asked to fulfil a function of guarantee and control. 23 This further underlines the overcoming of the negative concept of the right to privacy (as might be a "right to be left alone"), and moves it forward to a positive conception, that involves the public institutions being proactive in order to guarantee that freedom. 24 Such a discipline also implies the safeguard of the right to privacy of communications, as it is already set in many national constitutions. The Italian one, for example, reports at Article 15 that "the freedom and secrecy of communications and correspondence are inviolable." 25 The extension of such principles of freedom and secrecy should arguably be extended to the Internet-created public space, especially considering that communications and correspondence increasingly take place in virtual spaces and less often in "real" ones. Once again, this necessity is acknowledged in most national legal orders, at least within EU borders. It is argued, however, that these norms are inadequate as the competence and jurisdictions of national legal systems cannot apply to the Internet and more generally to transnational networks. If agreements and forms of judicial cooperation are lacking, it may prove difficult e.g. to find a national of one country liable for the violation of the privacy of a national of a different country. 26 These remarks are considered to be all pointing in one direction: the need to reaffirm those liberties that are enshrined in international conventions and national constitutions, whilst updating them according to the content and communication features of the Net. In doing this, special care should be paid to formalise them in such a way that increases their certainty and applicability. This would best be translated pragmatically into the creation of an IBR.

...Towards an Internet Bill of Rights?

For the good and for the bad, the unprecedented change in power balances that the Internet is supporting prompts the establishment of the basic principles of the new "global citizenship": freedom of access, freedom of use, right to knowledge and to share it freely, respect to privacy, identification of new common goods. 27 The idea of an IBR is born out of a desire to face and respond to the challenges posed by the evolution of the technical architecture and to legally ensure the respect of principles deemed as fundamental and intrinsically linked to the evolution of a global, "networked" public space. 28 To the objection that even before considering how the IBR should be done, one should consider whether it can be done or not, its promoters respond that it is the Internet itself that suggests the way forward. Of course, the IBR will not be achieved by summoning a Constituent Assembly; innovative ways are needed, able to take into account the multiplicity of actors involved in Internet governance (i.e. states, individual citizens, providers, producers, entrepreneurs) -translating, into practice, a multi-stakeholder approach. [START_REF] Padovani | From Lyon to Geneva. What Role for Local Authorities in the WSIS Multistakeholder Approach?[END_REF] The very nature of the Internet opposes the adoption of regulation forms according to traditional, "vertical" models involving a single authority, or multiple authorities in intergovernmental fora. Rodotà points out that the Internet is the place of pervasive discussion, universal initiatives, elaboration and sharing of contents and ideas. 30 It is thus hard to imagine that the adoption of an IBR would follow the traditional procedures pertaining to international conventions.

In the intentions of the IBR promoters, however, this should not mean that the content of precedent legal instruments is to be deemed as obsolete. In fact, as mentioned previously, a good starting point for any IBR is to be found in the Charter of Fundamental Rights of the European Union, due to its recognition of personal data protection as an autonomous, fundamental right, together with the overcoming of the traditional conception of privacy and the acknowledgement that the freedom of human beings cannot be achieved without the preservation of personal data. 31

The ongoing debate on the IBR: from the Internet Rights & Principles coalition to the European Parliament

The project of creating an IBR, already outlined during the World Summit on the Information Society in November 2005, [START_REF]WSIS Tunis Agenda for the Information Society[END_REF] has taken a more tangible form at the Internet Governance Forum (IGF)'s first meeting of October 2006, in Athens, Greece. 33 Many commentators have viewed this step as a sign of "maturity," 34 finally giving the "freedom on the Net" theme the spotlight it deserves among the wide spectrum of Internet governance issues.

The Dynamic Coalitions were born as groups "of institutions or people who agree to pursue an initiative started at the inaugural IGF meeting," 35 throughout the following year and in preparation for the second meeting that took place in November 2007 in Rio de Janeiro, Brazil. 36 They can be seen as working groups on relevant subjects for Internet governance, delving into specific themes and fostering ideal contexts for research into a variety of issues.

At the last IGF, the following coalitions were listed as active: Stop Spam Alliance, Privacy, Open Standards, Internet Bill of Rights, Access to Knowledge, Online Collaboration, Freedom of Expression, Access and Connectivity for Remote, Rural and Dispersed Communities, Linguistic Diversity, A2K@IGF, Gender and Internet Governance, Framework of Principles, Child Online Safety, Accessibility and Disability and Internet and Climate Change. 37 In January 2009, the Internet Bill of Rights and the Framework of Principles for the Internet Coalitions joined forces in what has been re-baptised as the Internet Rights & Principles Coalition, 38 whose mission is to:

[C]reate a platform for the emergence and agreement on definitions of Internet Rights (a notion which encompasses all (human) rights on the Internet), an Internet Rights watch (implying the build-up of a repository of precedences and coverage of Internet Rights cases), as well as a means to translate and mainstream these Internet Rights standards into "human readable" standardized formats so users and providers of services become more aware of the rights they have on any given website or when using services. [START_REF]IBR History[END_REF] The discussion on modalities, time schedule and features of the project is currently open online. Some principles have already been defined between Athens and Rio, such as the multi-stakeholder approach 40 and the respect of existing human rights instruments. [START_REF]Statement at the IGF Consultations in Geneva[END_REF] However, there is a common understanding that the continuous evolution of the technical architecture should translate into the flexibility of the Bill of Rights with respect to any preexisting, predefined model, both structure-and content-wise, in its double challenge of figuring out the best ways to "implement and better define human rights and duties in the Internet environment" and the "areas and types of rights and duties [that] should be part of this work and of its results."

Immediately after the IGF 2008 meeting in Hyderabad, India, the Coalition created a new website, with the stated aim of building a "stronger alliance with the related IGF coalitions and the secretariat in order to achieve a more prominent position of rights in the IGF agenda and mainstreaming human rights in the everyday work of the stakeholders." The new online environment is part of a larger marketing of the initiative to the public, as well as a facilitator for content contribution by the potential subjects of the IBR. While it seems clear that the road towards the Coalition's final goal is still long, its quest to increase its legitimacy as a proponent of a crucial issue, as well as its efforts to reinvent and update itself, are equally noteworthy.

Interestingly, the nexus between rights, principles and the Internet was the subject of increased attention in the early phases of the preparation of the IGF's fourth meeting, about to be held in Egypt in November 2009. The post-Hyderabad Synthesis Paper reports that "[r]ights and the Internet was recommended as the overarching theme" for the Egyptian meeting, so as to "clarify and attempt to reach consensus on how rights with respect to the Internet were defined, and how they relate to pre-existing definitions of human rights." 42 The meeting of the IGF Multistakeholder Advisory Group held in February 2009 did not subsequently build on this recommendation ("Internet rights and principles was another proposal for an overall theme, but the view was held that this would be too specific"). [START_REF]IGF Multistakeholder Advisory Group[END_REF] This does, however, further confirm that the interest in the issue and the perception of its importance are present in transnational and international discussions and is, likely, a guarantee of the fact that the IBR proposal will be thoroughly reviewed and assessed.

Such interest seems to be alive in European venues as well. A request by the European Parliament's Committee on Civil Liberties, Justice and Home Affairs (LIBE) to Steve Peers, professor at the University of Essex, to produce a study on "the human rights aspects of the Internet," [START_REF] Peers | Strengthening Security and Fundamental Freedoms on the Internet -an EU Policy on the Fight Against Cyber Crime[END_REF] published in January 2009, has been followed by the LIBE's unanimous vote of a recommendation on "strengthening security and fundamental freedoms on the Internet", proposed by Stavros Lambridinis, in February 2009, 45 and by a public hearing of the same title held by the LIBE the following month. 46 The project of creating a European IGF, hypothesized for some years, is now on its way in the form of the European Dialogue on Internet Governance (EuroDIG), whose second meeting was held in September 2009 and identified the "protection of human rights" as a key priority for today's Internet governance. 47 However, it should be noted that as of now, it is hard to identify the seeds of innovation, either content-or procedure-wise, anywhere in the final press release -besides the increasingly institutionalized recognition of a possible European specificity in the Internet governance landscape that needs to be further investigated:

The protection of human rights, ensuring universal access to the Internet as a public service and promoting media literacy should be key priorities for Internet governance [...]EuroDIG supported that the Council of Europe […] provides the secretariat to ensure the sustainability of EuroDIG, which should continue to be organised in cooperation with other organisations and stakeholders, including the European Parliament (EP). There was consensus among participants on the importance of maintaining a multistakeholder approach to Internet governance related issues.48

What challenges and open issues for the IBR?

This article has outlined the current state of the proposal for the creation and adoption of a Bill of Rights for the Internet, with a special focus on the rationale behind it as well as its promises. This concluding section is, instead, aimed at pointing out the challenges and open issues it faces, which are not to be overlooked for an impartial assessment of its likelihood of success.

Possible?

First of all, there is the question of whether creating an IBR is possible. The objection to this is that the affirmation of the need for public regulation(s) collides with the planetary character of the Net. This eliminates the possibility to individuate one and only regulatory authority or body. But even discarding unlikely options like a single state or organisation, who would be -if someone has to be -the creators and "owners" of an IBR? Existing intergovernmental organisations would probably suffer from the same in-built unbalances, occasional lack of credibility and problems of enforcement they have to face in other domains, as I have argued elsewhere. 49 The signature of a baseline treaty by all, or an overwhelming majority of, countries in the world seems an unlikely outcome, and an impossible one to enforce, especially if the ratification process is to happen outside existing institutional settings.

What IBR promoters see as the alternative way to go, the multi-stakeholder approach -and its chances to preserve the open and public nature of the Internet, safeguard citizens' access to online services and foster their effective, practical and agile participation -is an interesting one; one which is, however, showing flaws alongside potential, even in the most prominent examples of its application. 50 Can it be successfully applied to the case at stake, which looks especially problematic in this regard? How would this be carried out in practice? Such questions have not yet been answered satisfactorily.

Needed?

Second comes the question of whether an IBR is needed. According to the most "libertarian" voices, the Net is in itself endowed with features that enable it to maintain its overall condition of openness in face of and for a variety of actors, contents and forms of knowledge organisation. Given freely, collective contributions make possible the establishment of equally accessible, democratically organised online resources, which overcomes the barriers posed by other forms of communication ("interpret censorship as damage, and route around it") 51 and increase the possibility of a collective critical evaluation of information. There has never been a moral structure or culture to the Internet, and it is useless to try and artificially create one at the present stage.

According to this position, what is needed is rather a bottom-up "self-enforcement" of good practices: the construction of user awareness vis-à-vis the machines they own, what they can do, how they can be exploited if taken over -and a consequent shift to an increased attribution of responsibility to oneself as a user in the first place. Kleinrock even envisages the possibility of a "slowdown in Internet use and acceptance" unless a "diminished influence by government and industry" is pursued, so as to maintain the basic concepts that were contained in the original philosophy of the Internet, namely, that it was founded on a heritage of openness and freedom, of open research, of shared ideas and works, with no overbearing control structure, and with trust in the members of the community. 52 So, why not let the Internet decide for itself? The response of the Bill's promoters is that the Internet is too much of a reality on the move to argue that its natural, sine qua non condition 50 F Musiani, "Le présent de l'IGF et de la gouvernance d'Internet : une mise à jour après Hyderabad, une évaluation à mi-chemin" (2009) Vox Internet II Article 267, available at http://www.voxinternet.fr/spip.php? article267&lang=fr (accessed 23 April 2009). 51 Quote attributed to, and then confirmed by John Gilmore of the Electronic Frontier Foundation (EFF). See http://cyber.law.harvard.edu/people/reagle/inet-quotations-19990709.html (accessed 22 April 2009). 52 L Kleinrock, "The Internet Rules of Engagement: Then and Now" (2004), Technology in Society 26(2-3): 19-207 of space of freedom can only be safeguarded if no regulation is established at all. The very natural freedoms fostered by the evolution of the Net are in parallel leading to an increasing number of initiatives and instruments aimed at controlling online behaviours by impeding access, supervising data, filing end users' profiles -and creating new needs, such as the safeguard of privacy on the net, that were non-existent only a handful of years ago.

Suitable?

Without detracting from the validity of this point, another relevant issue with the creation of an IBR lies in its suitability as an answer to these types of threats. It is possibly naïve of those I have called the "libertarians" to neglect the control and centralisation drives that are present in today's Internet; but it might be equally naïve of the Bill's promoters to underplay a valid counterargument, i.e. that a protection system for the majority of the issues to be covered by the IBR is basically already in place, in a plurality of legal systems and norms. Moreover, this plurality of norms is often inherent in technical devices themselves: devices that are constantly bound to change at the rapid pace of technological progress and innovation, and that might be ultimately more damaged than protected by legal measures based on a "snapshot of technology at any given time". 53 This system is already difficult enough to sort through and eventually act upon -and in front of it, the proposal of harmonisation with existing human rights instruments, rather than being a promise of increased clarity, seems more like an argument for irrelevancy. Unless it reaches an incredibly delicate balance between local and global, public and private, technical and political, the Bill is constantly risking being turned into the upper layer of this very complex scenario -an all-encompassing container that can, for the same reason, easily become very thin and rapidly fall into uselessness.

Protecting users?

A final point of debate concerns the argument that an IBR is needed to counter the progressive exclusion of end users from the possibility to be exclusive managers, through their individual capacities of access and research, of their relationship with the Net and with other users. As of today, the IBR promoters argue, we could not do without forms of mediation such as the Google or Yahoo! portals that organise the enormous quantity of available information and make them, in fact, available to end users. Without them, research on the Internet would be almost impossible, as in an uncharted continent: portals perform the function traditionally fulfilled by libraries and museums, and have probably outgrown their success, but also carry issues of information selection criteria, that are decided by few for the many.

  17 W Fisher, "Freedom of Expression on the Internet" (2001) Berkman Center for Internet and Society at Harvard Law School, available at http://cyber.law.harvard.edu/ilaw/Speech/ (accessed 2 June 2009).

18 R Koster, "Declaring the Rights of Players" (2000) Raph Koster's Website, available at http://www.raphkoster.com/gaming/playerrights.shtml (accessed 2 June 2009).

19

See notes 5, 6 and 14 above.

P Di Maggio et al, "Social Implications of the Internet" (2001) 27 Annual Review of Sociology, 307-336.

S Rodotà, "Una Costituzione per Internet" (2006) La Repubblica, available at http://www.repubblica.it/2006/06/sezioni/scienza_e_tecnologia/regole-internet/regole-internet/regoleinternet.html (accessed 20 Apr 2009).

6 S Rodotà, "Perchè Internet ha bisogno di una carta dei diritti" (2006) La Repubblica, available at http://www.repubblica.it/2006/11/sezioni/scienza_e_tecnologia/internet-30-milioni/carta-dirittiinternet/carta-diritti-internet.html (accessed 20 Apr

2009).7 See note

5 above. 8 J Balkin, "Digital Speech and Democratic Culture: A Theory of Freedom of Expression for the Information Society" (2004) 79 New York University Law

Review, 42-47. 9 J Palfrey, Access Denied: The Practice and Politics of Internet Filtering (Cambridge, MA: MIT Press, 2008).

L Lessig, The Future of Ideas (New York: Vintage Books, 2002).

D Lyon, The Information Society: Issue and Illusion (Oxford: Polity Press, Blackwell, 1988).

E.g., the fight to terrorism has often been the reason for Western countries' governments, in recent years, to retain -for long periods of time -data regarding every form of electronic communication by their citizens and to deliver sensitive information to police authorities in order for them to create and archive profiles.

See note 5 above.

S Rodotà, Tecnopolitica. La democrazia e le nuove tecnologie della comunicazione (Roma-Bari: Laterza, 1997), at 36 and 82.

L Brown, The Seven Deadly Sins of the Digital Age (Intermedia, 1994), at32-37.

H Schiller, Information Inequality: The Deepening Social Crisis in America (New York: Routledge, 1996), at 54.

D Casacuberta, M Senges and J-M Duart, "Privacy and the need for an Internet Bill of Rights: Are there new rights in Cyberspace?" (2007) Paper presented at the GigaNet Second Annual Symposium, Rio deJaneiro, Brazil, November 11, 2007

Charter of Fundamental Rights of the European Union 2000, art 8.2, available at http://www.europarl.europa.eu/charter/pdf/text_en.pdf (accessed 20 Apr 2009).

Ibid, art 8.3, "Compliance with these rules shall be subject to control by an independent authority".

S Rodotà, "Il buio dei diritti" (2007) La Repubblica, available at http://www.repubblica.it/2007/09/sezioni/cronaca/privacy-ufficio/commento-rodota/commento-rodota.html (accessed 20 Apr 2009).

See Rodotà, note 14 above, at29-30.

Costituzione della Repubblica Italiana, art 15, available at http://www.quirinale.it/costituzione/costituzione.htm (accessed 20 April 2009, my translation).

E Gelbstein and J Kurbalija, Internet Governance: Issues, Actors and Divides (Malta: The Information Society Library, 2005), at 75.

See note 5 above.

See note 6 above.

The dynamic coalitions are to be found at: http://www.stopspamalliance.org/; http://igf2006.info/wiki/Privacy, http://www.cptech.org/a2k/igf/athens110206/keydocs.html;

European Dialogue on Internet Governance, 2009 Final Press Release, available at http://www.eurodig.org/ (accessed 30 September 2009).

See note 47 above.

F Musiani, "War, Security and Humanitarian Intervention in the United Nations Reform Agenda" (2008) Peace & Conflict Review 3(1).

N Elkin-Koren, "Making Technology Visible: Liability of Internet Service Providers for Peer-to-Peer Traffic" (2006) NYU Journal of Legislation and Public Policy (9):15-61

This is hardly deniable: but is a top-down imposition of rules to existing actors necessarily the way to go about it? Maybe not, according to the many practitioners of the "alternative" that are starting to populate the Internet with fully decentralised, alternative search engines, 54 social online storage and exchange mechanisms, 55 multifunctional platforms, 56 mapping utilities 57 -with potentially far-reaching implications for a "counter-evolution" of end users as not only producers, but managers and hosts of their own content.

Concluding remarks

In conclusion, aside and beyond its eventual translation into a regulatory instrument for the rights of Netizens, the IBR project opens interesting paths of reflection on the process of identification and recognition of rights, and on the nature of the challenges to citizens' liberties inside the global technical architecture. Its success or failure are likely to depend on the ability of its proponents to translate the complex balance between existing normativities, current viewpoints and visions of the future, into words and practice. Future discussions of the proposal should not overlook the fact that technology is a "dynamic parameter" 58 in the process of recognition of rights into written law; thus, it is possible for it to evolve and innovate at too fast a pace, and too unpredictable a direction, for any regulator to be able to follow them and avoid being either invasive or irrelevant -whatever the intended aim of the regulation: to restrict, or to protect. It is however clear that, now more than ever, all concerned parties should keep an interested eye on Internet rights debates within relevant venues, from the IGF and its dynamic coalitions to the European Parliament and its committees.

54 http://maay.netofpeers.net/. 55 http://www.wuala.com/; http://www.movenplay.com/. 56 http://www.tribler.org/; http://paripari.it. 57 http://www.openstreetmap.fr/. 58 See note 53 above.


F Hétroy

Constriction Computation using Surface Curvature

Keywords: (according to ACM CCS): I, 3, 5 [Computer Graphics]: Computational Geometry and Object Modeling

This paper provides a curvature-based algorithm to compute locally shortest geodesics on closed triangulated surfaces. These curves, which are called "constrictions", are useful for shape segmentation. The key idea of the algorithm is that constrictions are almost plane curves; it first finds well-located simple, plane, closed curves, and then slides them along the surface until a shortest geodesic is reached. An initial curve is defined as a connected component of the intersection between the surface and a plane going through an initial vertex. Initial vertices and planes are determined using approximations of surface curvature.

Introduction and related work

Automatic detection of particular, well-defined, object features can be of great interest for many applications. For example, detection of the narrow parts of an object defined by its boundary surface (usually represented as a triangulated mesh) has been applied to solve at least three different problems. In [START_REF] Dey | Shape segmentation and matching with flow discretization[END_REF], such parts are defined as subsets of the object volume, and called "stable manifolds". They are used for shape segmentation and, subsequently, shape matching. Another approach is to define these parts as simple, closed curves on the surface. Such curves correspond to bottlenecks of the object if they locally minimize length (that is to say, if every other simple, closed curve in a tubular neighborhood has greater length). Figure 1 gives an example of such a curve. This approach has been developed in [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF], in which these curves are called "constrictions". They are closed geodesics, and the angle of a constriction at each of the vertices it goes through is at least π. Such constrictions can be used to segment shapes; but computing constrictions can also be useful in order to detect medical diseases, such as so called airway or vascular constrictions [START_REF] Bischoff | Snakes on triangle meshes[END_REF]. As far as we are concerned, we plan to apply constriction detection to character animation in a future work. The algorithm given in [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF] to find simple, closed curves near constrictions, and then to slide them to reach constrictions [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF], has several drawbacks. First, its computation time seems prohibitive, since it requires progressive surface simplification. Second, it is unable to compute some special configurations of constrictions, such as orthogonal constrictions (see Fig. 4). This is because finding a seed curve during the surface simplification stage sometimes prevents to find other neighboring seed curves, since surface cannot be simplified anymore around these curves. In this paper, we propose a new algorithm to detect constrictions on closed triangulated surfaces which overcomes these problems. This algorithm first finds initial simple, closed curves on the surface, and then slides them to reach constrictions, using the algorithm of [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF]. Detection of initial curves must satisfy two major requirements:

1. the number of curves computed must be relevant for the application; 2. these curves must be located as close as possible to constrictions, in order to reduce the computation time of the sliding algorithm, and not to slide to a single vertex (degenerated constriction).

Our algorithm first chooses some special vertices on the surc The Eurographics Association 2005.

face, and then computes initial plane curves starting from these vertices. Selection of these vertices and of the underlying planes of the curves is based on surface curvature, and is detailed on section 3. We have chosen to make use of surface curvature because we believe there is a strong link between constrictions and surface curvature; in particular constrictions often follow principal curvature directions.

The following section recalls some definitions and properties about constrictions and curvatures. Section 3 then describes our algorithm. Results are shown and discussed in section 4, and we conclude in last section.

Constrictions and curvature

Constrictions on closed surfaces

Let P be a 2-manifold embedded in R 3 . Let α be a simple, closed curve on P. α is a constriction if there exists ε > 0 such that every simple, closed curve on P whose Hausdorff distance to α is lower than ε has greater length than α's [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF]. It follows that constrictions are closed geodesics on P.

We now only consider the case of polyhedral surfaces. A vertex through which a curve goes is called a pivot vertex.

The angle made by a curve α at a pivot vertex v is the minimum of the two angles made by α on the surface around v [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF]. If α is a constriction, then the angle made by α at each of its pivot vertices is at least π. As a consequence, for each pivot vertex v of a constriction, the angle of the surface at v (that is to say, the sum of the angles of the triangles which are adjacent to v at v) is at least 2π. Such vertices are called saddle vertices. Constrictions can be characterized as closed geodesics with angle at least π at each of their pivot vertices [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF].

Geodesics and surface curvature

Constrictions seem to be closely related to surface curvature. In particular, experience shows that constrictions are special lines of curvature. The algorithm described in next section thus constructs constrictions on closed, triangulated surfaces using surface curvature. But instead of computing principal curvature directions on the whole surface, which can be time prohibitive, it uses the following property for smooth surfaces, which can be for example found as an exercise in [dC76], p. 260:

• if a curve on a smooth surface is both a line of curvature and a geodesic, then it is a plane curve; • if a (nonrectilinear) geodesic on a smooth surface is a plane curve, then it is a line of curvature.

Since, in computer graphics, polyhedral surfaces often approximate smooth surfaces, we hope to find constrictions as approximations of plane curves.

Algorithm

Our algorithm relies on the idea that a constriction on a polyhedral surface approximates a plane curve. Thus, if we find both a vertex through which the constriction goes and the corresponding plane, we can theoretically construct a constriction. In fact, since this is just an approximation, we need to slightly move the curve to find a constriction. Our algorithm proceeds in three successive stages:

1. we find candidate vertices to construct the curves; 2. we compute the corresponding planes and the intersections between these planes and the surface, which give us the initial curves; 3. we slide these curves to reach constrictions, using the algorithm of [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF].

Note that, theoretically, a very huge number of constrictions can exist on a polyhedral surface, including constrictions very close to others. The goal of this algorithm is to compute only a few relevant ones.

Choice of initial vertices

The first stage of the algorithm is to find vertices (hopefully) belonging to constrictions. We can think of interactive selection of vertices [START_REF] Bischoff | Snakes on triangle meshes[END_REF]; however it can take a long time, and if the shape of the surface is complex (this can be the case in some medical applications, for example), some constrictions may be forgotten. That is why we prefer an automatic solution, even though some parameters must be selected by hand. Since each pivot vertex of a constriction is a saddle vertex, the simplest idea is to choose, as initial vertices, the saddle vertices of the surface. Unfortunately, on a standard triangulated surface, about half of the vertices are saddle vertices, which is far too much for our purpose. Another idea can be to choose only vertices on which the surface angle is locally maximum. But such vertices also are too numerous. Actually, the problem is that we only need one vertex to construct a constriction, and not all vertices through which it goes. Since constrictions correspond to concave areas on the surface, we decided to select initial vertices according to the (oriented) angles made between successive adjacent faces around a vertex: if the sum of these angles is lower than a user-defined (negative) threshold, the vertex is selected as an initial vertex. More formally, let v be a vertex on the surface, and let f 1 , f 2 , . . . , fn, f n+1 = f 1 be the successive faces which are adjacent to v. Let θ i , 1 ≤ i ≤ n, be the oriented angle between f i and f i+1 . θ i is positive if the oriented edge e i incident to f i and f i+1 is convex, and negative if e i is concave.

Then v is selected as initial vertex if, and only if,

n ∑ i=1 θ i < T ,
where T is a user-defined threshold. θ i is sometimes used as a coarse approximation of the mean curvature of the surface around e i . For sake of simplicity and in order to speed up the algorithm, we did not choose to compute other more precise approximations of mean curvature, such as those defined in [START_REF] Cazals | Estimating differential quantities using polynomial fitting of osculating jets[END_REF][START_REF] Cohen-Steiner D | Restricted delaunay triangulations and normal cycle[END_REF], although it would be interesting to compare results.

Computation of initial curves

An initial curve c is defined as a connected component of the intersection between the surface and a plane p to which an initial vertex v belongs. In order to define a plane, since we know a point on this plane (the initial vertex v), we need to choose two directions. These directions are computed using principal curvature directions, as follows:

• first, maximum (or minimum) principal curvature direction at v is computed, using the algorithm described in [CSM03, ACSD * 03]. • Then, this direction is projected on a plane p to which v belongs. p is defined by its normal, which is the average sum of the normals of the incident faces f i , with respect to the angles made by the faces at v. This normal can be seen as an approximation of the normal of the surface at v. • Each face f i is also projected on p . The projected face to which the projected maximum curvature direction belongs is selected, and the maximum curvature direction is re-projected on the corresponding face, to a segment vw which gives us the first of our two directions. This method ensures that we get one, and only one, projection of the direction on the surface. • Maximum (or minimum) principal curvature direction at w is computed, as the weighted average between maximum (or minimum) principal curvatures at the two endpoints of the edge to which w belongs. • This direction is also projected onto the surface, in order to get our second direction. This case is simpler than the previous one, since we know to which face of the surface the projected direction belongs: it is the face which is incident to the edge to which w belongs, but not adjacent to v.

Instead of computing a second maximum principal curvature direction in order to define the plane p, another idea can be to choose the minimum principal curvature direction at v (which is orthogonal to the maximum one) as the normal of p. Since p is defined using only one vertex, this possibility gives results very sensitive to the accuracy of the curvature computation.

We have chosen to compute principal curvature directions with the algorithm of Cohen-Steiner et al. because it gives fast and accurate results. Accurate approximation of principal curvature directions is critical in order to get initial curves not too far from corresponding constrictions. Also, note that we do not compute curvature directions on every vertex, but only on initial vertices. This speeds up the algorithm.

The initial curve going through v is then computed as the connected component of the intersection between the surface and the plane, to which v belongs (actually, the curve is computed starting from v).

Once the initial curves have been computed, we slide them to exact location of neighboring constrictions using the algorithm described in [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF].

Results and discussion

We have tested our algorithm on several closed, triangulated surfaces. Figure 2 shows our mean curvature approximation computed on a bunny and a horse model (each model having 10,000 faces), together with the initial curves detected. "Hot" areas correspond to vertices with the lowest mean curvature, that is to say the vertices we are interested in as initial vertices. Of course, these areas correspond to concave areas. The threshold we used was -π/9 (i.e., -20 o ) for the bunny and -π/18 for the horse. We can observe that some initial curves seem to be close to constrictions, while other (the longest ones) seem not. This is mainly because the longest the curve, the more important the accuracy of principal curvature direction: in these cases, a small error in the direction leads to a curve which can be located far away from a constriction. Figure 3 shows the constrictions computed on both of these models. Several initial curves are slided to a degenerated constriction, i.e. to a single point, while several others are slided to the same constriction: the number of initial curves is greater than the number of computed constrictions, as in [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF]. Several neighboring constrictions are detected on the back left horse leg. This is because the surface is noisy in this area, mainly because the model has a low density of vertices there. What is important to point out is that this method is able to construct "complicated" constrictions, for example constrictions wrapping around several parts of a model (as the longest constriction of the bunny model does), while method described in [START_REF] Hétroy | Detection of constrictions on closed polyhedral surfaces[END_REF] constrictions can also be computed, as can be seen on Fig. 4. The choice of the threshold T is important: the lowest the threshold (in absolute value), the greatest the number of initial vertices, thus the greatest the number of constrictions. For example, Table 1 gives the number of initial curves and constrictions computed on a noisy or not star model (Fig. 4 left; several initial curves slide to the same constriction). If T is too low, irrelevant constrictions can be computed, slowing down the algorithm. But if T is too high, some relevant constrictions can be missed (e.g. left ear of the bunny and ankles of the horse on Fig. 3). Computation times for several models are given in Table 2. Tests were performed using a Pentium IV 2.4 GHz with 512 MB RAM. Note that code was not optimized. Differences between computation times for models with the same number of faces is due both to the number of initial curves and to their distance to a constriction. We think these times can be significantly improved if the choice of initial vertices and the position of corresponding planes are improved, because computing a geodesic is the slowest task; thus the less geodesics are to be computed using [START_REF] Hétroy | From a closed piecewise geodesic to a constriction on a closed polyhedral surface[END_REF], the fastest the algorithm will be.

Conclusion and future work

In this paper, we have proposed a new, simple algorithm to compute constrictions on closed, triangulated surfaces. The algorithm computes initial plane curves starting from selected vertices, and slides them to reach constrictions. Initial vertices are selected according to the sum of the angles of adjacent faces around them; planes are constructed starting from these vertices and projecting maximum principal curvature directions on the surface. First results are encouraging, but this algorithm can still be improved. For example, we can think of other choice of initial vertices. Another solution could be to create an ordered list of candidate vertices, according to some criterion (for example, the value of our approximation of mean curvature), which are proposed to the user. To speed up the computation of constrictions, more recent and fast geodesic computation algorithms, such as [SSK * 05], may be used. From a theoretical point of view, it would be interesting to deeply investigate relationship between constrictions and surface curvature. Finally, we plan to apply these results to character animation (constrictions will be used to detect articulation areas). In this case, we need to compute only some special constrictions, and not all of them. Hence further assumptions have to be made.

Figure 1 :

 1 Figure 1: Example of a constriction.

Figure 2 :

 2 Figure 2: Approximation of mean curvature and starting curves computed on two standard models.

Figure 3 :

 3 Figure 3: Constrictions computed on two standard models.

Figure 4 :

 4 Figure 4: Contrary to [HA03a], orthogonal constrictions can be computed with our algorithm.

Table 1 :

 1 cannot. Moreover, orthogonal c The Eurographics Association 2005. Number of initial curves and constrictions computed on a star model, using different threshold values.

	Model	T	Init. curves Constrictions
	Star	-π/36	19	2
	Star	-π/18	19	2
	Star	-π/9	0	0
	Noisy star -π/36	39	4
	Noisy star -π/18	10	3
	Noisy star	-π/9	1	1
	Model	Nb. faces Threshold Init. curves	Time
	Noisy star	5,120	-π/18	10	25 sec
	2 crescents	4,320	-π/18	7	10 sec
	Bunny	10,000	-π/9	14	80 sec
	Horse	10,000	-π/18	16	27 sec
	Cat	5,000	-π/18	31	60 sec
	Dino	10,000	-π/18	15	60 sec
	Dragon	10,000	-π/9	45	42 sec

Table 2 :

 2 Computation times.

c The Eurographics Association 2005.