Biofunctional coatings

Abstract

The present invention provides compositions and methods for an improved coating for medical devices. The coating is an interfacial biomaterial ("IFBM") which comprises at least one binding module that binds to the surface of a device ("surface-binding module") and at least one binding module that performs another function ("affector module") and which acts to inhibit biofilm formation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 60/580,019, filed Jun. 16, 2004; U.S. Provisional Application No. 60/651,338, filed Feb. 9, 2005; and U.S. Provisional Application No. 60/651,747, filed Feb. 10, 2005, each of which is hereby incorporated by reference herein.

FIELD OF THE INVENTION

[0003] The present invention provides materials and methods for coating surfaces with a coating that reduces adsorption by, and/or biochemically interacts with, biological cells, viruses and/or macromolecules. Generally, the present invention finds use in providing improved medical implants, catheters, and similar items.

BACKGROUND OF THE INVENTION

[0004] The fouling of polymer surfaces by biological materials is a common problem that can compromise safety and hygiene as well as appearance. Often the fouling involves formation of a "biofilm." Particularly serious problems result when fouling occurs in the context of medicine or medical care. In the context of medical care, for example, every year over 5 million patients in United States hospitals are implanted with a "central line catheter." In these catheterizations, a polyurethane or polyvinylchloride hose is implanted into the patient's chest while the other end of the hose remains exposed to the hospital room environment and therefore to a variety of pathogens, including drug-resistant pathogens (McGee & Gould (2003) N. Engl. J. Med. 348: 1123-1133). Frequently, this catheterization results in the life-threatening complication of system-wide infection of the blood. Research suggests that up to 90% of such cases originate in films of bacteria that adhere to catheter walls (Donlan (2001) Emerg. Infect. Dis. 7: 277-281).

[0005] Pathogenic bacterial biofilms form on both outer and inner walls of catheters and may be detected on catheter surfaces within twenty four hours of catheter insertion. Bacteria in these biofilms are thickly embedded in a mostly polysaccharide substance known simply as "matrix" which protects the bacteria from administered antibiotics as well as the immune system. These biofilms also provide an environment in which bacteria can exchange drug-resistance genes. The selective pressures on bacteria in these environments give rise to bacteria which are resistant not only to commonly-used antibiotics but also to drugs which are treatments of "last resort."

[0006] Other types of catheters that are frequently used include urinary catheters, which are typically used with incontinent elderly patients and are typically made of silicone and latex. Unfortunately, virtually all patients who have urinary catheters in place for 28 days or more develop urinary tract infections (Donlan (2001) Emerg. Infect. Dis. 7: 277-281). Nearly all hospital-acquired systemic infections that are not associated with central line catheters are associated with urinary catheters (Maki & Tambyah (2001) Emerg. Infect. Dis. 7: 342-347). Treatment of urinary catheter-associated infections alone costs an estimated $1.8 billion annually (Platt et al. (1982) N. Engl. J. Med. 307: 637-642).

[0007] Polymer surfaces can also be "fouled" and their usefulness negated by the adherence of non-bacterial cells and/or protein. For example, receptacles that are used for collecting and storing blood for use in transfusion can be "fouled" and destroy the blood stored in them unless they deter the natural tendency of various blood components to clot and to adhere to surfaces. Similarly, receptacles that are used for storing proteins of interest are often made from synthetic polymers such as, for example, plastic tubes, syringes, etc. Once proteins begin to adhere to a receptacle wall, the process often continues until no protein remains in solution. Thus, these receptacles should ideally prevent adhesion of the proteins to the receptacle surface in order to preserve the quality of the proteins stored in them.

[0008] Similar problems currently exist with orthopedic implants. The long-term effectiveness of an implanted medical device is extremely dependent upon the appropriate integration of the implant with the patient's tissues. Nowhere is this more true than in the field of orthopedics, particularly for procedures such as total knee arthroplasty and total hip arthroplasty. According to the National Center for Health Statistics, currently there are over 150,000 new hip replacements and 300,000 knee replacements performed in the U.S. each year. These numbers are expected to continue to increase as the baby boom generation ages. With orthopedic implants, failure usually results in surgical removal of the faulty implant and replacement with a new implant, a process known as revision. The revision rate for total joint replacements remains a significant burden to the health care economies of Western countries and varies between 10-20% depending upon the country. See, e.g., Malchau et al. (2002) "Prognosis of total hip replacement: Update of results and risk-ratio analysis for revision and re-revision from the Swedish National Hip Arthroplasty Registry, 1979-2000," 69th Annual Meeting of the American Academy of Orthopaedic Surgeons, Scientific Exhibition; Fitzpatrick et al. (1998) Health Technol. Assess. 2: 1-64; Mahomed et al. (2003) J. Bone Joint Surg. Am. 85-A: 27-32).

[0009] In the United States, Medicare data for patients aged 65 years and older suggests that revision procedures occur at a yearly rate of about 18% relative to the number of primary surgeries (Mahomed et al. (2003) J Bone Joint Surg. Am. 85-A: 27-32). Main causes of implant failure include host inflammation responses and infection due to the formation of bacterial biofilms on the surface of the implants. This has led to an increase in the failure of orthopedic implants. In a study by Charnley and Cupic ((1973) Clin. Orthop. 95: 9-25), it was reported that 4-6% of total hip arthroplasty revision surgeries were due to infection, typically as a result of the formation of bacterial biofilms on the surface of the implants. Once present, these infections are extremely difficult to treat and may lead to removal and replacement of the implant, amputation, or even death. In contrast, the same study revealed that only 1-2% of the revision surgeries were performed due to mechanical loosening of the implant. With the use of prophylactic antimicrobial agents and improved operating room techniques, the rates of deep infection in total hip arthroplasty has dropped to approximately 1% over the last 20 years (Tang et al. (2003) J. Arthroplasty 18: 714-718; Gaine et al. (2000) J. Bone Joint Surg. Br. 82: 561-565; An and Friedman (1998) J. Invest. Surg. 11: 139-146). However, with over 450,000 new hip and knee arthroplasty surgeries each year, infections may affect 4000 to 5000 patients.

[0010] Furthermore, studies have shown that infections are very common at the site of pin insertion (Parameswaran et al. (2003) J. Orthop. Trauma 17: 503-507), and infection associated with external fixators may be as high as 85% (Sims and Saleh (1996) Prof. Nurse 11: 261-264). Because metal pins and wires are being used more often in the treatment of orthopedic trauma, primarily for external fixation of bone fractures (Davis (2003) Nurs. Times. 99: 46-48), any device improvements that decreased the rate of infections from joint prostheses or other metallic implants could have a significant impact on the quality of orthopedic healthcare.

[0011] The biofilm "life cycle" from the adhesion of bacteria to a surface to the maturation of a biofilm and subsequent release of cells has been the focus of many recent basic research studies. Using a variety of molecular genetic techniques, genes required for biofilm formation and maturation have been identified in a broad range of Gram-positive and Gram-negative microbes. While similar themes have been elucidated among microbes in terms of biofilm development (i.e., a role for surface adhesion and quorum sensing), no universal "biofilm genes" have yet been identified that are conserved among the many opportunistic pathogens.

[0012] Biofilm formation is-regulated via the exchange of chemical signals between cells in a process called quorum sensing. Staphylococci bacteria, which are a common cause of nosocomial infections related to biofilm formation on implanted catheters, use two peptide-based quorum sensing systems. The first system is composed of the autoinducer RNA-III activating protein (RAP) and its target receptor TRAP (target of RNA-III activating protein). When the concentration of RAP reaches a threshold concentration, it induces the phosphorylation of TRAP, which in turn leads to increased cell adhesion and the activation of the second quorum sensing system, agr. The agr system controls toxin production (Balaban et al. (2001) J Biol Chem 276: 2658-67). S. aureus virulence can be inhibited by the heptapeptide YSPWTNF, which is called RIP (RNA-III inhibiting peptide). RIP is a competitive inhibitor of RAP binding to TRAP, and thus inhibits TRAP phosphorylation, leading to reduced expression of the agr system, which leads in turn to suppression of the virulence phenotype (Gov et al. (2001) Peptides 22: 1609-1620; Vieira-da-Motta et al. (2001) Peptides 22: 1621-1627). Among Gram-negative bacteria, quorum sensing is accomplished using N-acyl-homoserine lactone signaling molecules (AHLs), LuxI-type signal synthetases and LuxR-type signal receptors. The AHL-dependent sensing system mediates the regulation of a number of genes, including those involved in biofilm formation and production of virulence factors (Eberl (1999) Syst. Appl. Microbiol. 22(4): 493-506).

[0013] While research into the use of quorum sensing antagonists as a means of controlling biofilm formation appears promising, it has not yet been reduced to practice (Ehrlich (2004) ASM News 70(3): 127-133). Efforts to reduce the incidence of infection due to biofilms on medical devices, including implants and catheters, have focused on two approaches. The first is the development of antibacterial compounds that retain efficacy on bacteria in biofilms (Shih and Huang (2002) J. Antimicrob. Chemother. 49: 309-314). Unfortunately, it is not yet understood how bacteria within a biofilm become resistant to antibiotics, which makes development of antibiotics with efficacy for treatment of biofilms virtually unattainable. Due to the difficulties of this approach, the main strategy that has been used to combat this problem is to modify the surface or composition of the article to prevent biofilm formation.

[0014] Surface modification technologies that have been tested for use with medical devices include diffusion, laser and plasma processing, chemical grafting, and bombardment with high-energy particles. These treatments have traditionally been used to alter the physical or mechanical properties of materials but are not proving to be effective in reducing infection rates (Katz (1997) Medical Device & Diagnostic Industry Magazine, April 1997). More recently, new treatments designed to reduce infection rates have been investigated, including hydrogel encapsulation and impregnation of the catheter or other article surface with antimicrobial agents (Raad and Hanna (1999) Support. Care Cancer 7: 386-390; DiTizio et al. (1998) Biomaterials 19: 1877-1884; Maki et al. (1997) Ann. Intern. Med. 127: 257-266). This approach seeks to kill the bacteria prior to, or shortly after, adhesion to the surface of the article. Representative examples of patents involving articles that have been coated or impregnated with anti-microbial drugs include U.S. Pat. No. 5,520,664 ("Catheter Having a Long-Lasting Antimicrobial Surface Treatment"), U.S. Pat. No. 5,709,672 ("Silastic and Polymer-Based Catheters with Improved Antimicrobial/Antifungal Properties"), U.S. Pat. No. 6,361,526 ("Antimicrobial Tympanostomy Tubes"), U.S. Pat. No. 6,261,271 ("Anti-infective and antithrombogenic medical articles and method for their preparation"), U.S. Pat. No. 5,902,283 ("Antimicrobial impregnated catheters and other medical implants") U.S. Pat. No. 5,624,704 ("Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent") and U.S. Pat. No. 5,709,672 ("Silastic and Polymer-Based Catheters with Improved Antimicrobial/Antifungal Properties").

[0015] Some recent studies and review articles have suggested that impregnating catheters with antibiotics may help prevent colonization by killing organisms when they come in close proximity to the surface, before they can establish a biofilm. There are, however, several other limitations to that approach. For example, although chlorhexidine-impregnated catheters showed limited efficacy in preventing infections, they are also believed to cause hypersensitivity reactions (Knight et al. (2001) Intern. Med. J. 31: 436-437). Furthermore, impregnating catheters with antibiotics may be counter-productive because as the concentration of antibiotics released from the catheter inevitably falls, bacteria are exposed to sublethal levels of antibiotics, a condition that promotes the development of antibiotic resistance (Rachid et al. (2000) J. Bacteriol. 182: 6824-6826; Rachid et al. (2000) Antimicrob. Agents Chemother. 44: 3357-3363; Rupp and Hamer (1998) J. Antimicrob. Chemother. 41: 155-161). Moreover, several studies have demonstrated that sublethal levels of antibiotics actually stimulate biofilm formation by Staphylococcus strains, one of the key organisms involved in implant infections.

[0016] Another alternative for preventing biofilm formation is the development of a coating that prevents adherence of bacterial cells to the catheter surface. Such coatings could be used alone or in combination with antibacterial impregnation of the catheter to further prevent biofilm formation. The most commonly used coatings to prevent biological fouling on surfaces-include those generated using plasma treatment, biotin-avidin conjugation strategies, phospholipids, self-assembled monolayers on transition metal coatings, and chemically grafted poly(ethylene glycol) (Kingshott et al. (1999) Anal. Biochem. 273(2): 156-62; Ratner (1993) J. Biomed. Mater. Res. 27: 837-50).

[0017] Of these approaches, coating a surface with poly (ethylene glycol) has met with some success for preventing cell and protein adhesion (Dalsin et al. (2003) J. Am. Chem. Soc. 125(14): 4253-8). However, chemically grafting this macromolecule to a surface often requires special preparation of the surface and multi-step chemical procedures (Golander et al. (1992) J. Biomater. Sci. Polym. Ed. 4(1): 25-30). Investigators who have derivatized a percentage of PLL side chains with poly (ethylene glycol) ("PEG") report both that the polymer so modified retains affinity for surfaces and that surfaces coated with it inhibit adhesion by proteins (Tosatti et al. (2003) Biomaterials 24: 4949; Huang et al. (2001) Langmuir 17(2): 489) as well as bacteria (Harris et al. (2004) Biomaterials 25: 4135; Wagner et al. (2004) Biomaterials 25: 2247). In addition, Hubbell et al. have described a method to suppress the interaction, adsorption or attachment of proteins or cells to a biomaterial surface through a polymer coating comprised of a polyionic backbone with poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO) side chains (U.S. Patent Application No. 20020128234). Still another non-covalent means of associating PEG with metal surfaces includes linkage to mussel adhesive protein (Dalsin et al. (2003) J. Am. Chem. Soc. 125: 4253-8). For negatively charged metal oxides (TiO.sub.2, Ta.sub.2O.sub.5, Nb2O.sub.5, SiO.sub.2), an alternative method for coating the surface is the use of polycationic polymers such as poly-L-lysine. This type of polymer spontaneously adsorbs to metal oxides based on the interaction of the positively charged amino groups on the polymer with the negatively metal oxide surface (Huang et al. (2001) Langmuir 17(2): 489). Unfortunately, these current methods of coating surfaces also often require special preparation of the surface and multi-step chemical procedures.

[0018] Another disadvantage of current methods to coat medical device surfaces is that, in general, the conditions necessary for attachment of the coating threaten to modify the relatively labile chemical groups or macromolecular folds that are typical of bioactive agents such as antimicrobial compounds. The extra steps and costs necessary to preserve the function of bioactive agents in a surface coating often render the project cost-prohibitive. In principle, each new material and each new agent that is identified for use as a coating presents a different chemical engineering challenge that will require an unknown investment of time, money, personnel and infrastructure in order to obtain a final product.

[0019] Thus, existing methods to modify medical devices to prevent protein adsorption, cell adhesion, or biofilm formation suffer from various shortcomings: surface modification is often unreliable, incomplete, and requires specialized equipment; impregnating with traditional antibiotics can lead to increases in antibiotic resistance among bacteria and is often ineffective against bacteria in biofilms; and many of the surface coatings require multiple steps and are prohibitively expensive. Thus, the need remains in the art for a stable coating that can be applied simply, quickly, and in a cost-effective manner to the surface of a medical device.

SUMMARY OF THE INVENTION

[0020] The present invention provides materials and compositions for an improved coating for surfaces of medical devices, including implants and catheters. The coating is an interfacial biomaterial ("IFBM") which comprises at least one binding module that specifically binds to a surface ("surface-binding module") and at least one binding module that performs another function ("affector module"). The affector module can: inhibit binding to the polymer surface by an organism, cell, or protein ("adhesion-resistance module"); modify the behavior of cells and/or organisms which bind to it ("behavior modification module"); and/or bind to a moiety which is a compound or molecule of interest ("moiety-binding module"). The modules are connected by a linker. In some embodiments, the affector module inhibits biofilm formation. The compositions and methods of the invention improve the performance of medical devices, for example, by preventing unwanted adsorption and/or growth of bacterial cells on the surface of the device.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides compositions for an improved coating for medical devices and methods of coating medical devices using those compositions. The term "medical device" as used herein refers to any article used as an implant in the body of a patient (including both human and non-human patients), any article used as a conduit (e.g., a catheter) related to medical treatment or for biological materials, or any container used as a storage device for biological materials, for example, for proteins or solutions containing cells. Medical devices may be made of any material, including metal and/or polymers. The coating of the invention is an interfacial biomaterial ("IFBM") which comprises at least one binding module that specifically binds to a surface of a medical device ("surface-binding module") and at least one binding module that performs another function ("affector module"). The binding modules are connected by a linker. The affector module acts to inhibit formation of a biofilm by any suitable mechanism. For example, the affector module may inhibit formation of a biofilm by inhibiting binding of an organism, cell, or compound (e.g., a protein) to the surface of the medical device ("adhesion-resistance module"). Alternatively, the affector module inhibit formation of a biofilm by modifying the behavior of cells and/or organisms which come into contact with it or bind to it ("behavior modification module"); and/or it may function to specifically bind to a moiety which is a compound or molecule of interest ("moiety-binding module"). Any affector module is suitable for use in an IFBM of the invention so long as an IFBM comprising it acts to inhibit formation of a biofilm. Affector modules may have more than one function; thus, for example, a single affector module may have both adhesion-resistance function and behavior modification function. Any affector module may be used in an IFBM of the invention so long as it accomplishes the objective of the invention to inhibit biofilm formation. In some embodiments, at least one binding module (i.e., surface-binding module or affector module) is a peptide or comprises a peptide. Exemplary binding modules are set forth in SEQ ID NOs: 1-10, 39-43, 95-96, and 97-558.

[0022] The compositions and methods of the invention improve the performance of medical devices including those made from polymeric materials. The term "polymer" or "polymeric material" as used herein refers to any of numerous natural and synthetic compounds of usually high molecular weight consisting of up to millions of repeated linked units, each a relatively simple molecule. Generally, wherever the surface of a medical device is to interface with biochemical solutions or biological tissue, such a surface is susceptible to microbial growth, attachment, and biofilm formation. In medical devices that are inserted into a patient's body, said microbial organisms include non-pathogenic microbes that are ordinarily present in non-sterile areas as well as pathogenic microbes that are present as a result of extant disease or due to accidental introduction during the insertion of the device. The IFBM coatings of the invention are useful for improving the performance of medical devices such as, for example, implants, catheters, and endotracheal tubes. In some embodiments, these coatings prevent unwanted adsorption of and/or growth of bacterial cells to the surface of the device.

[0023] The surface-binding module of the IFBM of the invention is selected to specifically bind to the material of which the surface of the medical device is made. Typically, this binding is non-covalent. The affector module of the IFBM of the invention is chosen so as to confer to an IFBM-coated surface a desired property such as, for example, resistance to adhesion of bacteria. The IFBMs of the invention comprise at least one surface-binding module and at least one affector module which are connected by a linker. A linker may be chosen for particular properties, such as a specific susceptibility to modification and/or to allow affector modules flexibility of orientation at a distance from the binding modules so linked. In some embodiments, the linker itself may also have activities similar to those of the binding module or affector module; that is, the linker may act to enhance binding to a particular surface or to have anti-adhesive properties such as inhibiting cell attachment, etc. For example, an IFBM comprising a poly (ethylene glycol) ("PEG") linker to join the surface-binding module to the affector module may help to prevent non-specific protein and/or cell adherence to the surface of the medical device coated with that IFBM.

[0024] In some embodiments, the affector module inhibits biofilm formation. In some embodiments, an affector module inhibits biofilm formation due to its anti-adhesive properties; that is, the affector module is a molecule or moiety that does not bind to biomolecules and/or biomolecular constituents of cells. In some embodiments, an affector module inhibits biofilm formation by damaging cells so that they do not adhere to the surface or by affecting a regulatory mechanism of cells that is involved in biofilm formation. Any combination of affector modules may be linked to any combination of surface-binding modules to create an IFBM of the invention so long as the IFBM comprises at least one affector module and at least one surface-binding module.

[0025] A surface-binding module is a peptide that binds to the surface of a medical device. A surface-binding module may bind to any material which is used to make a medical device, including a metal, a metal oxide, a non-metal oxide, a ceramic, a polymer, such as, for example, a synthetic polymer such as a polyurethane, a rubber, a plastic, an acrylic, a silicone, and combinations thereof. Suitable materials are known in the art. Binding modules (i.e., surface-binding modules and/or affector modules) can be peptides, antibodies or antibody fragments, polynucleotides, oligonucleotides, complexes comprising any of these, or various molecules and/or compounds. Binding modules which are peptides may comprise sequences disclosed in this application or known in the art, such as the peptides described in pending U.S. patent application Ser. No. 10/300,694, filed Nov. 20, 2002 and published on Oct. 2, 2003 as publication number 20030185870. Binding modules can also be identified using the methods described in pending U.S. patent application Ser. No. 10/300,694 and/or other methods known in the art. In some embodiments, binding modules may be identified by screening phage display libraries for affinity to materials such as titanium, stainless steel, cobalt-chrome alloy, polyurethane, polyethylene, acrylic, latex or silicone. Exemplary binding modules which are peptides which exhibit specific binding to particular materials are set forth in SEQ ID NOs: 1-10 (showing specific binding to titanium), 39-43 (showing specific binding to stainless steel), 95-96 (showing specific binding to Teflon), and 97-558. By "binds specifically" or "specific binding" is intended that a binding module binds to a selected surface, material, or composition. In some embodiments, a binding module that binds specifically to a particular surface, material or composition binds at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or a higher percentage more than the binding module binds to an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.

[0026] The term "antibody" as used herein with reference to a binding module encompasses single chain antibodies. Thus, an antibody useful as a binding module may be a single chain variable fragment antibody (scFv). A single chain antibody is an antibody comprising a variable heavy and a variable light chain that are joined together, either directly or via a peptide linker, to form a continuous polypeptide. The term "single chain antibody" as used herein encompasses an immunoglobulin protein or a functional portion thereof, including but not limited to a monoclonal antibody, a chimeric antibody, a hybrid antibody, a mutagenized antibody, a humanized antibody, and antibody fragments that comprise an antigen binding site (e.g., Fab and Fv antibody fragments).

[0027] In some embodiments, the IFBM comprises an affector module that is an anti-adhesive or that binds to a protein which is an anti-adhesive. In such embodiments, the surface-binding module of the IFBM binds to the surface of the device and the anti-adhesive forms a dense structure that prevents the adsorption of biological cells, viruses and macromolecules onto that surface. Suitable anti-adhesives are "non-interactive" polymer and/or functional groups that resist adhesion to protein and/or to cells. The term "non-interactive" as used herein with regard to coating polymer articles means a polymer that reduces the amount of non-specific adsorption of molecules to a coated surface, such as, for example, inorganic ions, peptides, proteins, saccharides and cells such as mammalian cells, bacteria and fungi. In embodiments using non-interactive polymers, an IFBM may comprise an affector module which is a non-interactive polymer or an IFBM may comprise an affector module which binds to a non-interactive polymer. Suitable non-interactive polymers which have adhesion-resistant function are known in the art and include, for example: albumin, poly(ethylene glycol) (PEG) (see, e.g., Wagner et al. (2004) Biomaterials 25: 2247-2263; Harris et al. (2004) Biomaterials 25: 4135-4148); mixed polyalkylene oxides having a solubility of at least one gram/liter in aqueous solutions such as some poloxamer nonionic surfactants; neutral water-soluble polysaccharides; poly(vinyl alcohol); poly(N-vinyl pyrrolidone); non-cationic polymethacrylates such as poly(methacrylic acid); many neutral polysaccharides, including dextran, Ficoll.TM., and derivatized celluloses; non-cationic polyacrylates such as poly(acrylic acid); and esters, amides, and hydroxyalkyl amides thereof, and combinations thereof. For example, an IFBM can comprise an affector module that binds human serum albumin, a native protein present in the blood of people and animals which is known to reduce bacterial adherence to coated surfaces (see, e.g., Keogh and Eaton (1994) J. Lab. Clin. Med. 124: 537-545; U.S. Pat. No. 5,073,171; Sato et al. (2002) Biotechnol. Prog. 18: 182-192). IFBMs comprising an affector module which has affinity for albumin can be coated onto polymer surfaces such as catheters or containers for blood, serum or other tissue, or solutions containing bacteria; albumin present in physiological solutions will then bind to the affector module, effectively providing a coating of albumin to the polymer surface, e.g., of the catheter or container.

[0028] In other embodiments, the IFBM comprises an affector module that has anti-microbial activity. For example, the affector module can be a peptide which has anti-microbial activity such as, for example, cationic antimicrobial peptides such as a magainin, defensin, bacteriocin, or microcin, all of which are known in the art (see, e.g., Lin et al. (2001) Medical Device Technology, October 2001 issue; Zasloff (2002) Nature 415: 389-395). Lactoferrin is also known to inhibit biofilm formation and is therefore useful as an affector module. While the invention is not limited to a particular mechanism of action of biofilm inhibition, the mechanism of action for many anti-microbial peptides is through disruption of the integrity of the bacterial membrane; most of these peptides do not affect the membranes of plant or animal cells. Because this disruption is mechanical in nature, it is unlikely that bacteria would develop resistance to these peptides (Zasloff (2002) Nature 415: 389-395).

[0029] In other embodiments, an affector module has biofilm inhibitor activity due to its interference with a regulatory mechanism of cells that is involved in their establishment of or participation in a biofilm. Suitable biofilm inhibitors for use as an affector module include compounds that are known in the art to interfere with bacterial quorum sensing such as RNA III inhibiting peptide (RIP), RIP analogs, antagonists of TRAP (Target for RNA III Activating Peptide), antagonists of N-acyl-homoserine lactone-based signaling, and furanone analogs.

[0030] The IFBMs of the invention can be coated onto a medical device and implanted into the body. The linkers used in such IFBMs can be, for example, a PEG linker which joins the binding module to the affector module and also may prevent non-specific protein and/or cell adherence to the surface of the medical device. When the IFBM-coated medical device is implanted in a patient, the affector module which has affinity for albumin will bind endogenous serum albumin, thereby specifically coating the surface of the medical device with albumin. A medical device coated with such IFBMs may also be coated with albumin by contacting the device with albumin-containing solutions in vitro prior to implantation of the device in a patient (see, e.g., Wagner et al. (2004) Biomaterials 25: 2247-2263; Harris et al. (2004) Biomaterials 25: 4135-4148).

[0031] Phage display technology is well-known in the art and can be used to identify additional peptides for use as binding modules in IFBMs of the invention. Using phage display, a library of diverse peptides can be presented to a target substrate, and peptides that specifically bind to the substrate can be selected for use as binding modules. Multiple serial rounds of selection, called "panning," may be used. As is known in the art, any one of a variety of libraries and panning methods can be employed to identify a binding module that is useful in the methods of the invention. For example, libraries of antibodies or antibody fragments may be used to identify antibodies or fragments that bind to particular cell populations or to viruses (see, e.g., U.S. Pat. Nos. 6,174,708, 6,057,098, 5,922,254, 5,840,479, 5,780,225, 5,702,892, and 5,667,988). Panning methods can include, for example, solution phase screening, solid phase screening, or cell-based screening. Once a candidate binding module is identified, directed or random mutagenesis of the sequence may be used to optimize the binding properties of the binding module. The terms "bacteriophage" and "phage" are synonymous and are used herein interchangeably. The term "bacteriophage" is defined as a bacterial virus containing a nucleic acid core and a protective shell built up by the aggregation of a number of different protein molecules.

[0032] A library can comprise a random collection of molecules. Alternatively, a library can comprise a collection of molecules having a bias for a particular sequence, structure, or conformation. See, e.g., U.S. Pat. Nos. 5,264,563 and 5,824,483. Methods for preparing libraries containing diverse populations of various types of molecules are known in the art, and numerous libraries are also commercially available. Methods for preparing phage libraries can be found, for example, in Kay et al. (1996) Phage Display of Peptides and Proteins (San Diego, Academic Press); Barbas (2001) Phage Display: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0033] A binding module that is a peptide comprises about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100, 200, or up to 300 amino acids. Exemplary binding modules that are peptides are set forth in SEQ ID NOs: 1-10, 39-43, and 95-558. Peptides that are useful as binding modules in IFBMs of the invention may differ from these exemplary peptides so long as the desired property of the binding module is retained. Peptides useful as a binding module can be linear, branched, or cyclic, and can include non-peptidyl moieties. The term "peptide" broadly refers to an amino acid chain that includes naturally occurring amino acids, synthetic amino acids, genetically encoded amino acids, non-genetically encoded amino acids, and combinations thereof. Peptides can include both L-form and D-form amino acids. A peptide of the present invention can be subject to various changes, substitutions, insertions, and deletions where such changes provide for certain advantages in its use. Thus, the term "peptide" encompasses any of a variety of forms of peptide derivatives including, for example, amides, conjugates with proteins, cyclone peptides, polymerized peptides, conservatively substituted variants, analogs, fragments, chemically modified peptides, and peptide mimetics. Any peptide that has desired binding characteristics can be used in the practice of the present invention.

[0034] Representative non-genetically encoded amino acids include but are not limited to 2-aminoadipic acid; 3-aminoadipic acid; .beta.-aminopropionic acid; 2-aminobutyric acid; 4-aminobutyric acid (piperidinic acid); 6-aminocaproic acid; 2-aminoheptanoic acid; 2-aminoisobutyric acid; 3-aminoisobutyric acid; 2-aminopimelic acid; 2,4-diaminobutyric acid; desmosine; 2,2'-diaminopimelic acid; 2,3-diaminopropionic acid; N-ethylglycine; N-ethylasparagine; hydroxylysine; allo-hydroxylysine; 3-hydroxyproline; 4-hydroxyproline; isodesmosine; allo-isoleucine; N-methylglycine (sarcosine); N-methylisoleucine; N-methylvaline; norvaline; norleucine; and ornithine. Representative derivatized amino acids include, for example, those molecules in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, chloroacetyl groups or formyl groups. Free carboxyl groups can be derivatized to form salts, methyl and ethyl esters or other types of esters or hydrazides. Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine can be derivatized to form N-im-benzylhistidine.

[0035] The term "conservatively substituted variant" refers to a peptide having an amino acid residue sequence substantially identical to a sequence of an exemplary peptide in which one or more residues have been conservatively substituted with a functionally similar residue such that the "conservatively substituted variant" will bind to the same binding partner with substantially the same affinity as the parental variant and will prevent binding of the parental variant. In one embodiment, a conservatively substituted variant displays a similar binding specificity when compared to the exemplary reference peptide. The phrase "conservatively substituted variant" also includes peptides wherein a residue is replaced with a chemically derivatized residue.

[0036] Examples of conservative substitutions include the substitution of one non-polar (hydrophobic) residue such as isoleucine, valine, leucine or methionine for another; the substitution of one aromatic residue such as tryptophan, tyrosine, or phenylalanine for another; the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, between glycine and serine; the substitution of one basic residue such as lysine, arginine or histidine for another; or the substitution of one acidic residue such as aspartic acid or glutamic acid for another.

[0037] Peptides which are useful as binding modules of the present invention also include peptides having one or more substitutions, additions and/or deletions of residues relative to the sequence of an exemplary peptide sequence as disclosed herein, so long as the binding properties of the original exemplary peptide are retained. Thus, binding modules of the invention include peptides that differ from the exemplary sequences disclosed herein by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids but that retain the ability of the corresponding exemplary sequence to bind to a particular material or to act as an affector module. A binding module of the invention that differs from an exemplary sequence disclosed herein will retain at least 25%, 50%, 75%, or 100% of the activity of a binding module comprising an entire exemplary sequence disclosed herein as measured using an appropriate assay. That is, binding modules of the invention include peptides that share sequence identity with the exemplary sequences disclosed herein of at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater sequence identity. Sequence identity may be calculated manually or it may be calculated using a computer implementation of a mathematical algorithm, for example, GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package of Genetics Computer Group, Version 10 (available from Accelrys, 9685 Scranton Road, San Diego, Calif., 92121, USA). The scoring matrix used in Version 10 of the Wisconsin Genetics Software Package is BLOSUM62 (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915). Alignments using these programs can be performed using the default parameters.

[0038] A peptide can be modified, for example, by terminal-NH.sub.2 acylation (e.g., acetylation, or thioglycolic acid amidation) or by terminal-carboxylamidation (e.g., with ammonia or methylamine). Terminal modifications are useful to reduce susceptibility by proteinase digestion, and to therefore prolong a half-life of peptides in solutions, particularly in biological fluids where proteases can be present. Peptide cyclization is also a useful modification because of the stable structures formed by cyclization and in view of the biological activities observed for such cyclic peptides. Methods for cyclizing peptides are described, for example, by Schneider & Eberle (1993) Peptides. 1992: Proceedings of the Twenty-Second European Peptide Symposium, Sep. 13-19, 1992, Interlaken, Switzerland, Escom, Leiden, The Netherlands.

[0039] Optionally, a binding module peptide can comprise one or more amino acids that have been modified to contain one or more halogens, such as fluorine, bromine, or iodine, to facilitate linking to a linker molecule. As used herein, the term "peptide" also encompasses a peptide wherein one or more of the peptide bonds are replaced by pseudopeptide bonds including but not limited to a carba bond (CH.sub.2--CH.sub.2), a depsi bond (CO--O), a hydroxyethylene bond (CHOH--CH.sub.2), a ketomethylene bond (CO--CH.sub.2), a methylene-oxy bond (CH.sub.2--O), a reduced bond (CH.sub.2--NH), a thiomethylene bond (CH.sub.2--S), an N-modified bond (--NRCO--), and a thiopeptide bond (CS--NH). See e.g., Garbay-Jaureguiberry et al. (1992) Int. J. Pept. Protein Res. 39: 523-527; Tung et al. (1992) Pept. Res. 5: 115-118; Urge et al. (1992) Carbohydr. Res. 235: 83-93; Corringer et al. (1993) J. Med. Chem. 36: 166-172; Pavone et al. (1993) Int. J. Pept. Protein Res. 41: 15-20.

[0040] In some embodiments, IFBMs of the invention comprise binding modules which comprise peptides that specifically bind to materials used in medical implants, such as peptides having an amino acid sequence as set forth in SEQ ID NOs:1-10, 39-43, and 95-558. While these exemplary peptide sequences are disclosed herein, one of skill will appreciate that the binding properties conferred by those sequences may be attributable to only some of the amino acids comprised by the sequences. Thus, a peptide which comprises only a portion of an exemplary amino acid sequence disclosed herein may have substantially the same binding properties as a peptide comprising the full-length exemplary sequence; thus, also useful as binding modules in IFBMs of the present invention are peptides that comprise only 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the amino acids in a particular exemplary sequence provided herein. Such amino acids may be contiguous or non-contiguous so long as the desired property of the binding module is retained as determined by an appropriate assay. Such amino acids may be concentrated at the amino-terminal end of the exemplary peptide (for example, 4 amino acids may be concentrated in the first 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids of the peptide) or they may be dispersed throughout the exemplary peptide.

[0041] Binding modules of the present invention that are peptides can be synthesized by any of the techniques that are known to those skilled in the art of peptide synthesis. Representative techniques can be found, for example, in Stewart & Young (1969) Solid Phase Peptide Synthesis, (Freeman, San Francisco, Calif.); Merrifield (1969) Adv. Enzymol. Relat. Areas Mol. Biol. 32:221-296; Fields & Noble (1990) Int. J. Pept. Protein Res. 35:161-214; and Bodanszky (1993) Principles of Peptide Synthesis, 2nd Rev. Ed. (Springer-Verlag, Berlin). Representative solid phase synthesis techniques can be found in Andersson et al. (2000) Biopolymers 55: 227-250, references cited therein, and in U.S. Pat. Nos. 6,015,561; 6,015,881; 6,031,071; and 4,244,946. Peptide synthesis in solution is described in Schroder & Lubke (1965) The Peptides (Academic Press, New York, N.Y.). Appropriate protective groups useful for peptide synthesis are described in the above texts and in McOmie (1973) Protective Groups in Organic Chemistry (Plenum Press, London). Peptides, including peptides comprising non-genetically encoded amino acids, can also be produced in a cell-free translation system, such as the system described by Shimizu et al. (2001) Nat. Biotechnol. 19: 751-755. In addition, peptides having a specified amino acid sequence can be purchased from commercial sources (e.g., Biopeptide Co., LLC of San Diego, Calif., and PeptidoGenics of Livermore, Calif.).

[0042] The linker that joins the binding module to at least one other module to form an IFBM can be any suitable linker. Linkers may be peptides or non-peptides. Suitable linkers are known in the art and can comprise, for example, a polymer, including a synthetic polymer or a natural polymer. In some embodiments, an IFBM is synthesized as a single continuous peptide comprising sequences originally identified as separate binding modules; in such embodiments, the linker is simply one of the bonds in the peptide. Representative synthetic polymers include but are not limited to polyethers (e.g., poly(ethylene glycol) ("PEG")), polyesters (e.g., polylactic acid (PLA) and polyglycolic acid (PGA)), polyamines, polyamides (e.g., nylon), polymethacrylates (e.g., polymethylmethacrylate; PMMA), polyacrylic acids, polyurethanes, polystyrenes, flexible chelators such as EDTA, EGTA and other synthetic polymers having a molecular weight of about 200 daltons to about 1000 kilodaltons. Representative natural polymers include but are not limited to hyaluronic acid, alginate, chondroitin sulfate, fibrinogen, fibronectin, albumin, collagen, calmodulin EF-hand domains and other natural polymers having a molecular weight of about 200 daltons to about 20,000 kilodaltons. Polymeric linkers can comprise a diblock polymer, a multi-block copolymer, a comb polymer, a star polymer, a dendritic polymer, a hybrid linear-dendritic polymer, or a random copolymer. A linker can also comprise a mercapto(amido)carboxylic acid, an acrylamidocarboxylic acid, an acrlyamido-amidotriethylene glycolic acid, and derivatives thereof. See, for example, U.S. Pat. No. 6,280,760. Linkers are known in the art and include linkers that can be cleaved and linkers that can be made reactive toward other molecular moieties or toward themselves, for cross-linking purposes. Fluorescent linkers are also known in the art.

[0043] Methods for linking a linker molecule to a ligand, binding module, or to a non-binding domain will vary according to the reactive groups present on each molecule. Protocols for linking using reactive groups and molecules are known to one of skill in the art. See, e.g., Goldman et al. (1997) Cancer Res. 57: 1447-1451; Cheng (1996) Hum. Gene Therapy 7: 275-282; Neri et al. (1997) Nat. Biotechnol. 19: 958-961; Nabel (1997) Current Protocols in Human Genetics, vol. on CD-ROM (John Wiley & Sons, New York); Park et al. (1997) Adv. Pharmacol. 40: 399-435; Pasqualini et al. (1997) Nat. Biotechnol. 15: 542-546; Bauminger & Wilchek (1980) Meth. Enzymol. 70: 151-159; U.S. Pat. Nos. 6,280,760 and 6,071,890; and European Patent Nos. 0 439 095 and 0 712 621.

[0044] The compositions and methods of the invention find particular use in coating any implantable or insertable medical device that is susceptible to microbial growth on and around the surfaces of the device. Implantable medical devices that can be improved with the compositions and methods of the invention include those adapted to remain implanted for a relatively long-term, i.e., for period of from about 30 days to about 12 months or greater, such as, for example, orthopedic implants. However, devices intended to remain implanted for about 30 days or less such as, for example, certain catheters, are also included within the scope of the present invention. "Medical device" as used herein refers to devices used in human patients as well as to devices used in non-human animals.

[0045] Examples of medical devices that are conduits and vessels made of polymers or that have polymeric surfaces include but are not limited to: medical conduits for insertion into a human or animal body, such as catheters and endotrachial tubes; vessels such as blood collection tubes, specimen containers and storage jars; vessels and conduits for the storage and transport of biochemical reagents in biomedical research or manufacturing; and tubing and containers for waste, water or combinations thereof. The polymer may be any suitable kind, including for example a synthetic polymer such as a plastic, rubber, a silicone material and combinations thereof. Suitable materials are known in the art and include polyurethane, polyethylene, polyvinylchloride, acrylic and latex. Examples of implantable medical devices include but are not limited to: prosthetic joints, plates, screws, pins, nails, rivets, bone fixation implants and artificial ligaments and tendons. Medical devices may be made of any suitable material, including for example a synthetic polymer, a plastic, a metal (such as titanium, stainless steel, or cobalt-chrome alloy), a metal oxide, a non-metal oxide, a silicone material, a ceramic material, and combinations thereof. Suitable materials are known in the art and include polyurethane, polyethylene, and silicone.

[0046] Medical devices that are coated with IFBMs of the invention will exhibit at least one superior property in comparison to an appropriate control, such as a similar medical device that is not coated with at least one IFBM; for example, a medical device coated with IFBMs of the invention will exhibit reduced formation of bacterial biofilms or show resistance to adhesion of protein or cells. Thus, an IFBM is considered to act to inhibit formation of a biofilm if a surface coated with that IFBM exhibits a detectable decrease in the tendency for a biofilm to form on that surface when compared to a suitable control surface or if a surface coated with that IFBM shows a detectable increase in resistance to adhesion of protein or cells when compared to a suitable control surface. An IFBM also acts to inhibit formation of a biofilm if a surface coated with that IFBM becomes coated with a biofilm which exhibits a detectable reduction in any of the characteristics of a biofilm. That is, an IFBM acts to inhibit formation of a biofilm if it decreases the frequency of biofilm formation or if it reduces a characteristic of a biofilm or resists adhesion of protein or cells by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 100% when a surface coated with that IFBM is compared to a surface that is uncoated or that is not coated with that IFBM. In this manner, a medical device which is coated with at least one IFBM has a superior property where that medical device has a measurable characteristic which differs in a statistically significant way from the same characteristic of an appropriate control medical device (such as, for example, a medical device that is not coated with at least one IFBM). Thus a property of a medical device which is coated with at least one IFBM will have a property which is superior to a property of an appropriate control medical device by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 100%, or more. Such a property may result from the performance of the IFBM or of its component modules. One of skill in the art is familiar with techniques that can be used to compare the performance of coated and uncoated medical devices or materials. For example, such techniques are described in the American Society of Testing and Materials (ASTM) Standard Method E-2196-02, entitled "Standard Test Method for the Quantification of Pseudomonas aeruginosa Biofilm Grown with Shear and Continuous Flow using a Rotating Disk reactor" and E1427-OOel, entitled "Standard Guide for Selecting Test Methods to Determine the Effectiveness of Antimicrobial Agents and Other Chemicals for the Prevention, Inactivation and Removal of Biofilm." Thus, for example, a medical device which is coated with at least one IFBM will inhibit biofilm formation by at least 5% when compared to a comparable uncoated medical device.

[0047] A medical device that is coated with at least one IFBM is coated by any suitable method, for example, by dipping or spraying the IFBM onto the device. The coating may be stabilized, for example, by air drying or by lyophilization. However, these treatments are not exclusive, and other coating and stabilization methods may be employed; one of skill in the art will be able to select the compositions and methods used to fit the needs of the particular device and purpose.

[0048] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0049] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claim(s).

Sequence CWU 1

1

558 1 17 PRT Artificial Sequence isolated from phage display libraries 1 Ser Ser His Lys His Pro Val Thr Pro Arg Phe Phe Val Val Glu Ser 1 5 10 15 Arg 2 22 PRT Artificial Sequence isolated from phage display libraries 2 Ser Ser Cys Asn Cys Tyr Val Thr Pro Asn Leu Leu Lys His Lys Cys 1 5 10 15 Tyr Lys Ile Cys Ser Arg 20 3 22 PRT Artificial Sequence isolated from phage display libraries 3 Ser Ser Cys Ser His Asn His His Lys Leu Thr Ala Lys His Gln Val 1 5 10 15 Ala His Lys Cys Ser Arg 20 4 22 PRT Artificial Sequence isolated from phage display libraries 4 Ser Ser Cys Asp Gln Asn Asp Ile Phe Tyr Thr Ser Lys Lys Ser His 1 5 10 15 Lys Ser His Cys Ser Arg 20 5 22 PRT Artificial Sequence isolated from phage display libraries 5 Ser Ser Ser Ser Asp Val Tyr Leu Val Ser His Lys His His Leu Thr 1 5 10 15 Arg His Asn Ser Ser Arg 20 6 22 PRT Artificial Sequence isolated from phage display libraries 6 Ser Ser Ser Asp Lys Cys His Lys His Trp Tyr Cys Tyr Glu Ser Lys 1 5 10 15 Tyr Gly Gly Ser Ser Arg 20 7 14 PRT Artificial Sequence isolated from phage display libraries 7 His His Lys Leu Lys His Gln Met Leu His Leu Asn Gly Gly 1 5 10 8 14 PRT Artificial Sequence isolated from phage display libraries 8 Gly His His His Lys Lys Asp Gln Leu Pro Gln Leu Gly Gly 1 5 10 9 25 PRT Artificial Sequence isolated from phage display libraries 9 Ser Ser Ser Asp Lys Ser His Lys His Trp Tyr Ser Tyr Glu Ser Lys 1 5 10 15 Tyr Gly Gly Ser Gly Ser Ser Gly Lys 20 25 10 25 PRT Artificial Sequence isolated from phage display libraries 10 Ser Ser Ser Asp Lys Cys His Lys His Trp Tyr Cys Tyr Glu Ser Lys 1 5 10 15 Tyr Gly Gly Ser Gly Ser Ser Gly Lys 20 25 11 21 PRT Artificial Sequence isolated from phage display libraries 11 Ser Ser Asp Trp Gly Val Val Ala Ser Ala Trp Asp Ala Phe Glu Ala 1 5 10 15 Leu Asp Ala Ser Arg 20 12 21 PRT Artificial Sequence isolated from phage display libraries 12 Ser Ser Gly Ala Asp Phe Gly Tyr Gly Ser Trp Val Ser Phe Ser Ala 1 5 10 15 Leu Ser Ala Ser Arg 20 13 21 PRT Artificial Sequence isolated from phage display libraries 13 Ser Arg Gly Glu Ala Ser Gly Trp Glu Ala Phe Ser Ala Leu Glu Ala 1 5 10 15 Ala Val Val Ser Arg 20 14 21 PRT Artificial Sequence isolated from phage display libraries 14 Ser Arg Ser Ser Asp Ser Ala Phe Ser Ser Phe Ser Ala Leu Glu Gly 1 5 10 15 Ser Val Val Ser Arg 20 15 21 PRT Artificial Sequence isolated from phage display libraries 15 Ser Arg Asp Gly Ala Gly Ala Ala Ala Trp Gly Ala Phe Ser Ala Leu 1 5 10 15 Ala Ser Glu Ser Arg 20 16 21 PRT Artificial Sequence isolated from phage display libraries 16 Ser Arg Gly Gly Glu Ala Ala Ala Gly Ala Trp Val Ser Phe Ser Ala 1 5 10 15 Leu Glu Ser Ser Arg 20 17 21 PRT Artificial Sequence isolated from phage display libraries 17 Ser Arg Val Ser Gly Val Ala Ala Trp Glu Ala Phe Ala Gly Leu Ser 1 5 10 15 Val Ser Ser Ser Arg 20 18 21 PRT Artificial Sequence isolated from phage display libraries 18 Ser Arg Asp Gly Gly Ser Phe Ser Ala Phe Ser Ser Leu Val Trp Ala 1 5 10 15 Ala Asp Ser Ser Arg 20 19 21 PRT Artificial Sequence isolated from phage display libraries 19 Ser Ser Val Ala Gly Asp Val Gly Ser Ser Trp Ala Ala Phe Ala Ser 1 5 10 15 Leu Ala Ala Ser Arg 20 20 21 PRT Artificial Sequence isolated from phage display libraries 20 Ser Ser Trp Glu Val Phe Ser Ser Leu Glu Ser Gly Ser Val Gly Ala 1 5 10 15 Gly Ala Gly Ser Arg 20 21 21 PRT Artificial Sequence isolated from phage display libraries 21 Ser Ser Ser Ser Gly Ala Val Ser Ser Phe Glu Ser Leu Ser Gly Ser 1 5 10 15 Val Val Ser Ser Arg 20 22 21 PRT Artificial Sequence isolated from phage display libraries 22 Ser Arg Glu Gly Val Ala Trp Glu Ala Phe Gly Ala Leu Ser Ser Phe 1 5 10 15 Ala Ala Asp Ser Arg 20 23 21 PRT Artificial Sequence isolated from phage display libraries 23 Ser Ser Trp Gly Leu Ala Ser Glu Ala Ser Phe Phe Ser Phe Ser Ala 1 5 10 15 Leu Ser Ser Ser Arg 20 24 21 PRT Artificial Sequence isolated from phage display libraries 24 Ser Arg Glu Gly Ala Ala Trp Asp Ser Phe Phe Ala Leu Ser Gly Gly 1 5 10 15 Ser Ala Ala Ser Arg 20 25 17 PRT Artificial Sequence isolated from phage display libraries 25 Ser Ser Ser Val Asp Leu Tyr Phe Pro Leu Lys Gly Asp Val Val Ser 1 5 10 15 Arg 26 17 PRT Artificial Sequence isolated from phage display libraries 26 Ser Ser Phe Glu Pro Leu Arg Phe Pro Leu Lys Gly Val Pro Val Ser 1 5 10 15 Arg 27 7 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 27 Xaa Xaa Xaa Phe Xaa Xaa Leu 1 5 28 7 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 28 Xaa Xaa Phe Pro Leu Xaa Gly 1 5 29 39 PRT Artificial Sequence IFBM 29 Ser Ser Phe Glu Pro Leu Arg Phe Pro Leu Lys Gly Val Pro Val Ser 1 5 10 15 Arg Gly Ser Ser Gly Lys Asp Val Asn Ser Ile Trp Met Ser Arg Val 20 25 30 Ile Glu Trp Thr Tyr Asp Ser 35 30 39 PRT Artificial Sequence IFBM 30 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 Ser Gly Ser Ser Gly Lys Ser Ser Phe Glu Pro Leu Arg Phe Pro Leu 20 25 30 Lys Gly Val Pro Val Ser Arg 35 31 43 PRT Artificial Sequence IFBM 31 Ser Arg Ser Ser Asp Ser Ala Phe Ser Ser Phe Ser Ala Leu Glu Gly 1 5 10 15 Ser Val Val Ser Arg Gly Ser Ser Gly Lys Asp Val Asn Ser Ile Trp 20 25 30 Met Ser Arg Val Ile Glu Trp Thr Tyr Asp Ser 35 40 32 43 PRT Artificial Sequence IFBM 32 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 Ser Gly Ser Ser Gly Lys Ser Arg Ser Ser Asp Ser Ala Phe Ser Ser 20 25 30 Phe Ser Ala Leu Glu Gly Ser Val Val Ser Arg 35 40 33 39 PRT Artificial Sequence IFBM 33 Ser Ser Ser Val Asp Leu Tyr Phe Pro Leu Lys Gly Asp Val Val Ser 1 5 10 15 Arg Gly Ser Ser Gly Lys Asp Val Asn Ser Ile Trp Met Ser Arg Val 20 25 30 Ile Glu Trp Thr Tyr Asp Ser 35 34 39 PRT Artificial Sequence IFBM 34 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 Ser Gly Ser Ser Gly Lys Ser Ser Ser Val Asp Leu Tyr Phe Pro Leu 20 25 30 Lys Gly Asp Val Val Ser Arg 35 35 43 PRT Artificial Sequence IFBM 35 Ser Arg Gly Gly Glu Ala Ala Ala Gly Ala Trp Val Ser Phe Ser Ala 1 5 10 15 Leu Glu Ser Ser Arg Gly Ser Ser Gly Lys Asp Val Asn Ser Ile Trp 20 25 30 Met Ser Arg Val Ile Glu Trp Thr Tyr Asp Ser 35 40 36 43 PRT Artificial Sequence IFBM 36 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 Ser Gly Ser Ser Gly Lys Ser Arg Gly Gly Glu Ala Ala Ala Gly Ala 20 25 30 Trp Val Ser Phe Ser Ala Leu Glu Ser Ser Arg 35 40 37 43 PRT Artificial Sequence IFBM 37 Ser Ser Asp Trp Gly Val Val Ala Ser Ala Trp Asp Ala Phe Glu Ala 1 5 10 15 Leu Asp Ala Ser Arg Gly Ser Ser Gly Lys Asp Val Asn Ser Ile Trp 20 25 30 Met Ser Arg Val Ile Glu Trp Thr Tyr Asp Ser 35 40 38 43 PRT Artificial Sequence IFBM 38 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 Ser Gly Ser Ser Gly Lys Ser Ser Asp Trp Gly Val Val Ala Ser Ala 20 25 30 Trp Asp Ala Phe Glu Ala Leu Asp Ala Ser Arg 35 40 39 23 PRT Artificial Sequence isolated from phage display libraries 39 Ser Ser Ser Ser Tyr Phe Asn Leu Gly Leu Val Lys His Asn His Val 1 5 10 15 Arg His His Asp Ser Ser Arg 20 40 22 PRT Artificial Sequence isolated from phage display libraries 40 Ser Ser Cys His Asp His Ser Asn Lys Tyr Leu Lys Ser Trp Lys His 1 5 10 15 Gln Gln Asn Cys Ser Arg 20 41 23 PRT Artificial Sequence isolated from phage display libraries 41 Ser Ser Ser Cys Lys His Asp Ser Glu Phe Ile Lys Lys His Val His 1 5 10 15 Ala Val Lys Lys Cys Ser Arg 20 42 23 PRT Artificial Sequence isolated from phage display libraries 42 Ser Ser Ser Cys His His Leu Lys His Asn Thr His Lys Glu Ser Lys 1 5 10 15 Met His His Glu Cys Ser Arg 20 43 15 PRT Artificial Sequence isolated from phage display libraries 43 Ser Ser Val Asn Lys Met Asn Arg Leu Trp Glu Pro Leu Ser Arg 1 5 10 15 44 21 PRT Artificial Sequence isolated from phage display libraries 44 Ser Ser Ala Pro Leu Thr Glu Ser Glu Ala Trp Arg Gly Phe Ser Lys 1 5 10 15 Leu Glu Val Ser Arg 20 45 21 PRT Artificial Sequence isolated from phage display libraries 45 Ser Ser Ser Met Pro Val Gly Trp Asp Ser Trp Arg Gly Leu Glu Trp 1 5 10 15 Ser Asp Arg Ser Arg 20 46 21 PRT Artificial Sequence isolated from phage display libraries 46 Ser Ser Glu Gly Arg Gly Gly Trp Asn Ser Trp Glu Ala Phe Arg Glu 1 5 10 15 Leu Val Val Ser Arg 20 47 21 PRT Artificial Sequence isolated from phage display libraries 47 Ser Ser Gly Gly Gly Gly Ala Trp Glu Ser Trp Arg Gly Leu Ser Gly 1 5 10 15 Val Glu Leu Ser Arg 20 48 21 PRT Artificial Sequence isolated from phage display libraries 48 Ser Arg Asn Val Glu Gly Ser Trp Glu Ser Phe Ala Gly Leu Ser His 1 5 10 15 Val Arg Glu Ser Arg 20 49 21 PRT Artificial Sequence isolated from phage display libraries 49 Ser Arg Glu Asp Gly Gly Arg Trp Glu Ser Phe Leu Gly Leu Ser Ala 1 5 10 15 Val Glu Val Ser Arg 20 50 21 PRT Artificial Sequence isolated from phage display libraries 50 Ser Ser Val Glu Gly Ser Ala Trp Ser Ala Phe Lys Ser Leu Ser Ser 1 5 10 15 Glu Gly Val Ser Arg 20 51 21 PRT Artificial Sequence isolated from phage display libraries 51 Ser Arg Val Glu Gly Gly Ala Trp Gln Ala Leu Ala Gly Leu Thr Val 1 5 10 15 Glu Arg Val Ser Arg 20 52 21 PRT Artificial Sequence isolated from phage display libraries 52 Ser Ser Pro Pro Lys His Ala Trp Gly Ser Phe Asp Ala Leu Gly Gly 1 5 10 15 Gln Val Val Ser Arg 20 53 21 PRT Artificial Sequence isolated from phage display libraries 53 Ser Ser Glu Arg Gly Val Gly Trp Glu Val Phe Leu Ala Met Glu Gly 1 5 10 15 Ala Arg Met Ser Arg 20 54 21 PRT Artificial Sequence isolated from phage display libraries 54 Ser Ser Ser Ser Ser Gly Thr Trp Gln Ala Phe Thr Gly Leu Ser Gly 1 5 10 15 Glu Arg Val Ser Arg 20 55 21 PRT Artificial Sequence isolated from phage display libraries 55 Ser Ser Ser Pro Gly Gly Gly Ser Gly Gly Trp Asp Ala Phe Tyr Ser 1 5 10 15 Leu Val Gly Ser Arg 20 56 21 PRT Artificial Sequence isolated from phage display libraries 56 Ser Ser Gly Gly Gly Gly Gly Gly Glu Gly Phe Ser Ser Leu Ser Gly 1 5 10 15 Asn Gly Arg Ser Arg 20 57 21 PRT Artificial Sequence isolated from phage display libraries 57 Ser Ser Thr Gly Gly Gly Ser Trp Glu Glu Phe Lys Ala Met Thr Pro 1 5 10 15 Ser Trp Thr Ser Arg 20 58 21 PRT Artificial Sequence isolated from phage display libraries 58 Ser Ser Glu Gly Ser Gly Leu Trp Asp Ser Phe Ser Ser Leu Ser Val 1 5 10 15 His Glu Val Ser Arg 20 59 21 PRT Artificial Sequence isolated from phage display libraries 59 Ser Ser Gly Val Thr Gln Glu Ser Ala Ser Trp Ser Ser Phe Arg Thr 1 5 10 15 Leu Ala Val Ser Arg 20 60 21 PRT Artificial Sequence isolated from phage display libraries 60 Ser Ser Ser Lys Val Ala Pro Ser Gly Glu Trp Arg Ser Phe Ala Thr 1 5 10 15 Leu Glu Val Ser Arg 20 61 21 PRT Artificial Sequence isolated from phage display libraries 61 Ser Ser Glu Ala Gly Arg Gly Trp Glu Gly Phe Lys Ala Leu Glu Gly 1 5 10 15 Tyr Gln Val Ser Arg 20 62 21 PRT Artificial Sequence isolated from phage display libraries 62 Ser Ser Leu Gly Gln Thr Gly Trp Glu Ala Phe Glu Ser Leu Ser Gly 1 5 10 15 Thr Arg Gly Ser Arg 20 63 21 PRT Artificial Sequence isolated from phage display libraries 63 Ser Ser Val Ala Trp Asp Ala Phe Thr Val Phe Glu Ser Leu Glu Gly 1 5 10 15 Val Ala Thr Ser Arg 20 64 21 PRT Artificial Sequence isolated from phage display libraries 64 Ser Ser Glu Val Val Glu Pro Trp Glu Trp Trp Val Ala Leu Glu Arg 1 5 10 15 Ala Gly Gly Ser Arg 20 65 21 PRT Artificial Sequence isolated from phage display libraries 65 Ser Arg Val Ala Ala Val Ser Trp Glu Phe Phe Gly Ser Leu Ser Ser 1 5 10 15 Ala Gly Val Ser Arg 20 66 21 PRT Artificial Sequence isolated from phage display libraries 66 Ser Ser Ala Asp Leu Gly Val Ser Gly Ser Trp Glu Gly Phe Ala Leu 1 5 10 15 Met Arg Gly Ser Arg 20 67 21 PRT Artificial Sequence isolated from phage display libraries 67 Ser Ser Val Gly Gln Met Gly Trp Glu Ala Phe Glu Ser Leu Ser Gly 1 5 10 15 Thr Gly Gly Ser Arg 20 68 21 PRT Artificial Sequence isolated from phage display libraries 68 Ser Ser Gly Gln Gly Glu Thr Trp Glu Trp Phe Ala Gly Met Arg Gly 1 5 10 15 Ser Val Ala Ser Arg 20 69 21 PRT Artificial Sequence isolated from phage display libraries 69 Ser Ser Tyr Phe Asp Val Phe Ser Ser Met Thr Gly Thr Arg Ala Ala 1 5 10 15 Gly Ser Trp Ser Arg 20 70 21 PRT Artificial Sequence isolated from phage display libraries 70 Ser Ser Ala Tyr Ser Val Phe Ser Ser Leu Arg Ala Asp Asn Ser Gly 1 5 10 15 Gly Ala Val Ser Arg 20 71 19 PRT Artificial Sequence isolated from phage display libraries 71 Ser Ser Gly Gly Ile Ala Ser Leu Lys Tyr Asp Val Val Lys Thr Trp 1 5 10 15 Glu Ser Arg 72 16 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 72 Gly Gly Gly Ala Trp Glu Ala Phe Ser Ser Leu Ser Gly Ser Arg Val 1 5 10 15 73 7 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 73 Trp Xaa Xaa Phe Xaa Xaa Leu 1 5 74 15 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 74 Ser Ser Gly Ala Trp Glu Ser Phe Ser Ser Leu Ser Gly Ser Ser 1 5 10 15 75 40 DNA Artificial Sequence encoding consensus sequence 75 tcgagtggtg cttgggagtc tttttcgtca ctgagtggat 40 76 40 DNA Artificial Sequence partial complement of SEQ ID NO75 76 caccacgaac cctcagaaaa agcagtgact cacctagatc 40 77 21 PRT Artificial Sequence isolated from phage display libraries 77 Ser Ser Glu Gly Val Gly Gly Phe Pro Leu Lys Gly Ile Pro Gln Glu 1

5 10 15 Ala Trp Ala Ser Arg 20 78 21 PRT Artificial Sequence isolated from phage display libraries 78 Ser Ser Pro Ser Gly Val Val Phe Pro Leu Arg Gly Glu Leu Leu Gly 1 5 10 15 Val Xaa Lys Ser Arg 20 79 21 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 79 Ser Ser Gly Gly Phe Val Pro Phe Pro Leu Arg Gly Glu Val Trp Asp 1 5 10 15 Gly Val His Ser Arg 20 80 21 PRT Artificial Sequence isolated from phage display libraries 80 Ser Ser Glu Gly Ser Leu Ser Phe Pro Leu Lys Gly Gln Val Tyr Ser 1 5 10 15 Gly Trp Gly Ser Arg 20 81 21 PRT Artificial Sequence isolated from phage display libraries 81 Ser Ser Gly Lys Pro Leu Glu Phe Pro Leu Arg Gly Thr Leu Ala Glu 1 5 10 15 Trp Pro Val Ser Arg 20 82 21 PRT Artificial Sequence isolated from phage display libraries 82 Ser Arg Gly Glu Ala Leu Gly Phe Pro Leu Thr Gly Gln Leu Met Glu 1 5 10 15 Ala Ala Glu Ser Arg 20 83 21 PRT Artificial Sequence isolated from phage display libraries 83 Ser Ser Met Trp Asp Val Gly Phe Pro Leu Lys Gly Arg Trp Ile Asp 1 5 10 15 Gly Ala Asp Ser Arg 20 84 21 PRT Artificial Sequence isolated from phage display libraries 84 Ser Ser Ser Asn Ser Leu Trp Phe Pro Leu Arg Gly Ser Thr Val Glu 1 5 10 15 Val Gly Ala Ser Arg 20 85 21 PRT Artificial Sequence isolated from phage display libraries 85 Ser Ser Gly Pro Ala Leu Arg Leu Pro Leu Arg Gly Thr Val Val Ser 1 5 10 15 Asp Val Pro Ser Arg 20 86 21 PRT Artificial Sequence isolated from phage display libraries 86 Ser Ser Ala Asp Arg Val Ala Trp Pro Leu Lys Gly Ala Pro Val Trp 1 5 10 15 Val Lys Glu Ser Arg 20 87 21 PRT Artificial Sequence isolated from phage display libraries 87 Ser Ser Gly Leu Ala Leu Gly Leu Pro Ile Lys Gly Trp Thr Val Ser 1 5 10 15 Gly Lys Asp Ser Arg 20 88 21 PRT Artificial Sequence isolated from phage display libraries 88 Ser Ser Gly Tyr Thr Leu Gly Phe Pro Leu Ser Gly Gln Thr Ile Lys 1 5 10 15 Asp Trp Pro Ser Arg 20 89 21 PRT Artificial Sequence isolated from phage display libraries 89 Ser Ser Glu Gly Trp Val His Phe Pro Leu Lys Gly Asp Val Met Gly 1 5 10 15 Gly Pro Phe Ser Arg 20 90 21 PRT Artificial Sequence isolated from phage display libraries 90 Ser Ser Gly Arg Tyr Val Ser Leu Pro Leu Lys Gly Glu Val Val Pro 1 5 10 15 Gln Thr Ala Ser Arg 20 91 21 PRT Artificial Sequence isolated from phage display libraries 91 Ser Ser Glu Gly Gly Val Gly Phe Pro Leu Lys Gly Ile Pro Gln Glu 1 5 10 15 Ala Trp Ala Ser Arg 20 92 21 PRT Artificial Sequence isolated from phage display libraries 92 Ser Arg Val Asp Ser Val Asn Phe Pro Leu Arg Gly Glu Thr Val Thr 1 5 10 15 Ser Met Val Ser Arg 20 93 17 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 93 Gly Gly Ala Leu Gly Phe Pro Leu Lys Gly Glu Val Val Glu Gly Trp 1 5 10 15 Ala 94 7 PRT Artificial Sequence consensus sequence from comparing peptides isolated from phage display libraries 94 Leu Xaa Phe Pro Leu Lys Gly 1 5 95 22 PRT Artificial Sequence isolated from phage display libraries 95 Ser Ser Cys Trp Ser Arg Phe Arg Leu Phe Met Leu Phe Cys Met Phe 1 5 10 15 Tyr Leu Val Ser Ser Arg 20 96 22 PRT Artificial Sequence isolated from phage display libraries 96 Ser Arg Cys Ile Lys Tyr Pro Phe Leu Tyr Cys Cys Leu Leu Ser Leu 1 5 10 15 Phe Leu Phe Ser Ser Arg 20 97 18 PRT Artificial Sequence isolated from phage display libraries 97 Cys Ala Glu Lys Trp Trp Trp Trp Ile Gln Tyr Ala Trp Gly Gly Val 1 5 10 15 Leu Cys 98 18 PRT Artificial Sequence isolated from phage display libraries 98 Cys Asp Asp Ile Asp Tyr Ile Lys Glu Ala Pro Ile Asp Ala Met Met 1 5 10 15 Cys Cys 99 18 PRT Artificial Sequence isolated from phage display libraries 99 Cys Asp Phe Phe Asn Arg His Gly Tyr Asn Ser Gly Cys Glu His Ser 1 5 10 15 Val Cys 100 18 PRT Artificial Sequence isolated from phage display libraries 100 Cys Asp Phe His Ser Asn Lys Tyr Tyr Ile Asn Gln Ile Ala Gly Ser 1 5 10 15 Asp Cys 101 18 PRT Artificial Sequence isolated from phage display libraries 101 Cys Asp Asn Gly Leu Asp Asp Cys Phe Glu Pro Cys Tyr Trp Ile Gln 1 5 10 15 Leu Cys 102 18 PRT Artificial Sequence isolated from phage display libraries 102 Cys Phe Glu Ile Ser Ser Ser Ser Thr Pro Ile Glu Leu Trp Glu Ser 1 5 10 15 Val Cys 103 18 PRT Artificial Sequence isolated from phage display libraries 103 Cys Phe Glu Ser Asp Phe Pro Asn Val Arg His His Val Leu Lys Gln 1 5 10 15 Ser Cys 104 18 PRT Artificial Sequence isolated from phage display libraries 104 Cys Phe Phe Phe Arg Arg Gln Ile Glu Ile Tyr Tyr Ala Arg Phe Gly 1 5 10 15 Phe Cys 105 18 PRT Artificial Sequence isolated from phage display libraries 105 Cys Phe Leu Phe Phe Ser Met Cys Asn Met Ala Cys Thr Lys Ala Lys 1 5 10 15 Glu Cys 106 18 PRT Artificial Sequence isolated from phage display libraries 106 Cys Phe Tyr Gln Asn Val Ile Ser Ser Ser Phe Ala Gly Asn Pro Trp 1 5 10 15 Glu Cys 107 18 PRT Artificial Sequence isolated from phage display libraries 107 Cys Gly Asp His Met Thr Asp Lys Asn Met Pro Asn Ser Gly Ile Ser 1 5 10 15 Gly Cys 108 18 PRT Artificial Sequence isolated from phage display libraries 108 Cys His Arg Tyr Asp Arg Arg Trp Thr Met Tyr Thr Arg Ala Arg Leu 1 5 10 15 Arg Cys 109 18 PRT Artificial Sequence isolated from phage display libraries 109 Cys Ile Met Thr Ser Asp Met Val Asn Ala Ala Ile Trp Asn Glu Val 1 5 10 15 Gln Cys 110 18 PRT Artificial Sequence isolated from phage display libraries 110 Cys Leu Phe Phe Phe Ser Met Ile Met Asn Phe Asp Phe Pro Asn Phe 1 5 10 15 Glu Cys 111 18 PRT Artificial Sequence isolated from phage display libraries 111 Cys Leu Pro Pro Pro Tyr Glu Pro Lys Gln Leu Ala Glu Pro Cys Asp 1 5 10 15 Gly Cys 112 18 PRT Artificial Sequence isolated from phage display libraries 112 Cys Leu Pro Trp Tyr Tyr Tyr Tyr Lys Ala Gln Gln Leu Tyr Asp His 1 5 10 15 Tyr Cys 113 18 PRT Artificial Sequence isolated from phage display libraries 113 Cys Met Arg Arg Trp Asp Arg Trp Val Arg Trp Ala Trp Ser Arg Gln 1 5 10 15 Lys Cys 114 18 PRT Artificial Sequence isolated from phage display libraries 114 Cys Met Trp Trp Trp Gln Trp Gly Ser Tyr Ile Tyr Gly Glu Leu Trp 1 5 10 15 Ile Cys 115 18 PRT Artificial Sequence isolated from phage display libraries 115 Cys Asn Glu Asp Val Asn Asn Phe Pro Pro Arg Met Asn Thr Glu Leu 1 5 10 15 Gly Cys 116 18 PRT Artificial Sequence isolated from phage display libraries 116 Cys Asn Met Leu Leu Asn Ser Leu Pro Leu Pro Ser Glu Asp Trp Ser 1 5 10 15 Ala Cys 117 18 PRT Artificial Sequence isolated from phage display libraries 117 Cys Asn Asn Asn His Arg Asp Val Asn Trp Asn Leu Arg Asp Asn Thr 1 5 10 15 Ala Cys 118 18 PRT Artificial Sequence isolated from phage display libraries 118 Cys Asn Asn Asn Val Asn Trp Tyr His Tyr Met Phe Ile Pro Trp Ala 1 5 10 15 Lys Cys 119 18 PRT Artificial Sequence isolated from phage display libraries 119 Cys Asn Asn Val Asn Ala Cys Gln Asn His Glu Asn Asn Met His Asn 1 5 10 15 Asp Cys 120 18 PRT Artificial Sequence isolated from phage display libraries 120 Cys Asn Pro Gly Tyr Asn Asn Met Met Asn Asp Ser Met Val Met Trp 1 5 10 15 Arg Cys 121 18 PRT Artificial Sequence isolated from phage display libraries 121 Cys Pro Phe Thr His Ser Leu Ala Leu Asn Thr Asp Arg Ala Ser Pro 1 5 10 15 Gly Cys 122 18 PRT Artificial Sequence isolated from phage display libraries 122 Cys Pro His Trp Pro Pro Pro Trp Cys Glu Trp Tyr Pro Glu Asn Trp 1 5 10 15 Cys Cys 123 18 PRT Artificial Sequence isolated from phage display libraries 123 Cys Pro Asn Pro Phe Pro Glu Pro Leu Asn His Asp Ala Ile Asp Trp 1 5 10 15 Cys Cys 124 18 PRT Artificial Sequence isolated from phage display libraries 124 Cys Pro Asn Val Pro Arg Pro Ala Gln Leu Ser Ile Cys Gly Asn Leu 1 5 10 15 Pro Cys 125 18 PRT Artificial Sequence isolated from phage display libraries 125 Cys Pro Pro Met Tyr Pro Gln Trp Glu Gly Asp Pro Asn Gln Arg Tyr 1 5 10 15 Asp Cys 126 18 PRT Artificial Sequence isolated from phage display libraries 126 Cys Pro Pro Pro Gly Gln Val Pro Pro Trp Pro Pro Ser Pro Pro Pro 1 5 10 15 Pro Cys 127 18 PRT Artificial Sequence isolated from phage display libraries 127 Cys Pro Arg Arg His Lys Arg Tyr Asn Trp Phe Ala His Asn Ala Arg 1 5 10 15 Met Cys 128 18 PRT Artificial Sequence isolated from phage display libraries 128 Cys Arg Gln Tyr Arg Phe Arg Pro Ile Val Arg Ala Arg Arg Leu Asn 1 5 10 15 Lys Cys 129 18 PRT Artificial Sequence isolated from phage display libraries 129 Cys Arg Arg Phe Arg Ser Arg Cys Pro Gly Glu Trp Arg Ser Trp Thr 1 5 10 15 Thr Cys 130 18 PRT Artificial Sequence isolated from phage display libraries 130 Cys Arg Val Gly Val Arg Arg Lys Glu Gly Gly Phe Arg Pro Trp Tyr 1 5 10 15 Lys Cys 131 18 PRT Artificial Sequence isolated from phage display libraries 131 Cys Arg Val Arg Arg Glu Pro Arg Met Arg Lys Ile Lys Lys Met Ala 1 5 10 15 Leu Cys 132 18 PRT Artificial Sequence isolated from phage display libraries 132 Cys Arg Tyr Ser Thr Ser Ser Trp Ser Asp Met Thr Cys Gly Cys Gly 1 5 10 15 Gln Cys 133 18 PRT Artificial Sequence isolated from phage display libraries 133 Cys Ser Gly Trp Lys Trp Trp Val Phe His Val Cys Trp Lys Gln Val 1 5 10 15 His Cys 134 18 PRT Artificial Sequence isolated from phage display libraries 134 Cys Ser Asn Ser Ser Cys Thr Ser His Thr Leu Tyr Ser Ser Val Met 1 5 10 15 Gly Cys 135 18 PRT Artificial Sequence isolated from phage display libraries 135 Cys Ser Ser Phe Met Ser Met His His Trp His Val Val Val Asp Ser 1 5 10 15 Cys Cys 136 18 PRT Artificial Sequence isolated from phage display libraries 136 Cys Ser Ser Ile Asn Ser Ser Tyr Val His Cys Leu Gly Cys Thr Glu 1 5 10 15 Ser Cys 137 18 PRT Artificial Sequence isolated from phage display libraries 137 Cys Ser Ser Arg Tyr Ser Thr Ala Tyr His Met Ala Ser Asn Ser Ile 1 5 10 15 Phe Cys 138 18 PRT Artificial Sequence isolated from phage display libraries 138 Cys Thr Glu Arg Arg Arg Arg Phe Asn Arg Asn Arg Pro Ala Lys Met 1 5 10 15 Arg Cys 139 18 PRT Artificial Sequence isolated from phage display libraries 139 Cys Thr Pro Arg Pro Pro Val Pro Val Tyr Ile Pro Tyr Ser Ser Ser 1 5 10 15 Pro Cys 140 18 PRT Artificial Sequence isolated from phage display libraries 140 Cys Val Asp Phe Lys Ser Lys Glu Lys Thr Glu Ile Met Leu Arg His 1 5 10 15 Ala Cys 141 18 PRT Artificial Sequence isolated from phage display libraries 141 Cys Val Phe Asp Ser Lys His Phe Ser Pro Thr His Ser Pro His Asp 1 5 10 15 Val Cys 142 18 PRT Artificial Sequence isolated from phage display libraries 142 Cys Val Tyr Lys Ile Tyr Tyr Leu Tyr Cys His Pro Tyr Leu Thr Phe 1 5 10 15 Pro Cys 143 18 PRT Artificial Sequence isolated from phage display libraries 143 Cys Trp Lys Ser Ser Ser Ser Met Met Thr Ile Val Trp Trp Asn Lys 1 5 10 15 Met Cys 144 18 PRT Artificial Sequence isolated from phage display libraries 144 Cys Trp Met Trp Trp Pro Glu Trp Trp Trp Gln Cys Ala Val Gln Cys 1 5 10 15 Asn Cys 145 18 PRT Artificial Sequence isolated from phage display libraries 145 Cys Trp Tyr Thr Trp Trp Cys Gln Ala Ser Thr Met Gly Gln Ile Tyr 1 5 10 15 Glu Cys 146 18 PRT Artificial Sequence isolated from phage display libraries 146 Cys Tyr Tyr Asp Ser Tyr Pro Ser Val Pro Tyr Tyr Tyr Gln Asn Pro 1 5 10 15 Ser Cys 147 18 PRT Artificial Sequence isolated from phage display libraries 147 Cys Tyr Tyr Phe Tyr Gln Ala Leu Gln Gly Leu Ile Lys Asn His Trp 1 5 10 15 Ala Cys 148 18 PRT Artificial Sequence isolated from phage display libraries 148 Cys Tyr Tyr Lys Pro Tyr Tyr Pro Cys Ser Ala Tyr Met Asn Phe Pro 1 5 10 15 Leu Cys 149 18 PRT Artificial Sequence isolated from phage display libraries 149 Cys Tyr Tyr Asn Gly Leu Val Val His His Ser Asn Ser Gly His Lys 1 5 10 15 Asp Cys 150 17 PRT Artificial Sequence isolated from phage display libraries 150 Cys Ala Asn Phe Leu Ser Phe Val Asn Asn Ser Tyr Cys Ile Asp Ser 1 5 10 15 Asn 151 17 PRT Artificial Sequence isolated from phage display libraries 151 Cys Ala Arg Arg Arg His His His His Pro Pro Met Pro His Phe Arg 1 5 10 15 Arg 152 17 PRT Artificial Sequence isolated from phage display libraries 152 Cys Cys Asp Gly Leu Ile Thr Ser Ser Trp Leu Asn Trp Phe Ala Arg 1 5 10 15 Gly 153 17 PRT Artificial Sequence isolated from phage display libraries 153 Cys Cys Glu Trp Trp Trp Cys Trp Lys Trp Trp Gln Cys Leu Trp Trp 1 5 10 15 Cys 154 17 PRT Artificial Sequence isolated from phage display libraries 154 Cys Cys Phe Asn Phe Phe Thr Ser Phe Asn Gln Gly Lys Asp Asn Phe 1 5 10 15 Val 155 17 PRT Artificial Sequence isolated from phage display libraries 155 Cys Cys Ser Ser Cys Glu Ser His Trp Lys Lys Phe Glu His Asn Arg 1 5 10 15 Gln 156 17 PRT Artificial Sequence isolated from phage display libraries 156 Cys Asp Asp Phe Val Leu Asp Tyr Asp Asp Glu Tyr Met Val Met Asn 1 5 10 15 His 157 17 PRT Artificial Sequence isolated from phage display libraries 157 Cys Asp Asp Met Gly Asp Asp Val Lys Asp Pro Glu Asp Tyr Ile Asp 1 5 10 15 Gln 158 17 PRT Artificial Sequence isolated from phage display libraries 158 Cys Asp Phe Cys Phe Thr Asn Val Leu Phe Asp Ala Phe Gly Ser His 1 5 10 15 Val 159 17 PRT Artificial Sequence isolated from phage display libraries 159 Cys Asp Tyr Phe Ser Phe Leu Glu Cys Phe Ser Asn Gly Trp Ser Gly 1 5 10 15 Ala 160 17 PRT Artificial Sequence isolated from phage display libraries 160 Cys Phe Phe Phe Gly Gln Gly Asp Phe Met Cys Trp Ile Cys Leu Thr 1 5 10 15 Val 161 17 PRT Artificial Sequence isolated from phage display libraries 161 Cys Phe Phe Asn Ser Phe Asn Cys Thr Pro Asn Glu Met Trp Tyr Trp 1 5 10 15 Phe 162 17 PRT Artificial Sequence isolated from phage display libraries 162 Cys Phe Phe Ser Tyr Cys Phe Ser His Asp Val Ser Thr Tyr Asn Thr 1 5 10 15 Ala 163 17 PRT Artificial Sequence isolated from phage display libraries 163 Cys Phe Phe Ser Tyr

Trp Asn Cys Leu Thr Asn Asn Ala Phe Val Lys 1 5 10 15 Pro 164 17 PRT Artificial Sequence isolated from phage display libraries 164 Cys Phe Gly Phe Ser Asp Cys Leu Ser Trp Phe Val Gln Pro Ser Thr 1 5 10 15 Ala 165 17 PRT Artificial Sequence isolated from phage display libraries 165 Cys Phe Gly Asn Phe Leu Ser Phe Gly Phe Asn Cys Glu Ser Ala Leu 1 5 10 15 Gly 166 17 PRT Artificial Sequence isolated from phage display libraries 166 Cys Phe Gly Asn Leu Gly Asn Leu Ile Tyr Thr Cys Asp Arg Leu Met 1 5 10 15 Pro 167 17 PRT Artificial Sequence isolated from phage display libraries 167 Cys Phe Gly Asn Val Phe Cys Val Tyr Asn Gln Phe Ala Ala Gly Leu 1 5 10 15 Phe 168 17 PRT Artificial Sequence isolated from phage display libraries 168 Cys Phe Thr Cys Phe Ser Phe Ala Phe Asn Phe Cys Phe Met Cys Trp 1 5 10 15 Met 169 17 PRT Artificial Sequence isolated from phage display libraries 169 Cys Phe Thr Phe Phe Lys Ala Ser Trp Ser Trp Trp His His Ala Met 1 5 10 15 Met 170 17 PRT Artificial Sequence isolated from phage display libraries 170 Cys Phe Val His Asn Phe Phe Trp Phe Leu Gly Lys Asn Ser Asn Cys 1 5 10 15 Arg 171 17 PRT Artificial Sequence isolated from phage display libraries 171 Cys Phe Trp Tyr Ser Trp Leu Cys Ser Ala Ser Ser Ser Asp Ala Leu 1 5 10 15 Ile 172 17 PRT Artificial Sequence isolated from phage display libraries 172 Cys Gly Tyr Phe Cys Ser Phe Tyr Asn Tyr Leu Asp Ile Gly Thr Ala 1 5 10 15 Ser 173 17 PRT Artificial Sequence isolated from phage display libraries 173 Cys His Arg Cys Lys Arg Arg His Leu Leu Arg Arg Lys Gln Ala Asn 1 5 10 15 Arg 174 17 PRT Artificial Sequence isolated from phage display libraries 174 Cys Ile Phe Asn Ser Tyr Phe Cys Ser Phe Gln Leu Thr Ser Tyr Gly 1 5 10 15 Ser 175 17 PRT Artificial Sequence isolated from phage display libraries 175 Cys Lys Ala Phe Phe Phe Asn Phe Gln Cys Phe Val Phe Val Phe His 1 5 10 15 Phe 176 17 PRT Artificial Sequence isolated from phage display libraries 176 Cys Lys Phe Ser Phe Asp Phe Phe Ala Arg Phe Asn Arg His Phe Tyr 1 5 10 15 His 177 17 PRT Artificial Sequence isolated from phage display libraries 177 Cys Lys Ser Lys Lys Ser Ser His Ser Glu Ser Glu His Lys Lys Ser 1 5 10 15 Ser 178 17 PRT Artificial Sequence isolated from phage display libraries 178 Cys Leu Phe Asn Cys Ser Gly Glu Ser Trp Pro Met Ser Ile Val Pro 1 5 10 15 Ser 179 17 PRT Artificial Sequence isolated from phage display libraries 179 Cys Leu Lys Asp Tyr Tyr Tyr Ser Pro Cys Ser Tyr Ser Cys Asp Gln 1 5 10 15 His 180 17 PRT Artificial Sequence isolated from phage display libraries 180 Cys Leu Leu Lys Tyr Cys Tyr Ser Asp Leu Ala Ser Ser Ser Leu Ser 1 5 10 15 Ile 181 17 PRT Artificial Sequence isolated from phage display libraries 181 Cys Leu Val Phe Met Arg Pro Tyr Phe Leu Leu Val Phe Leu Met Cys 1 5 10 15 Trp 182 17 PRT Artificial Sequence isolated from phage display libraries 182 Cys Leu Tyr Cys His Leu Asn Asn Gln Phe Leu Ser Trp Val Ser Gly 1 5 10 15 Asn 183 17 PRT Artificial Sequence isolated from phage display libraries 183 Cys Leu Tyr Cys Leu Asn Tyr Ala Asn Phe Ser Asp Pro Met Thr Met 1 5 10 15 Phe 184 17 PRT Artificial Sequence isolated from phage display libraries 184 Cys Asn His Leu Gly Phe Phe Ser Ser Phe Cys Asp Arg Leu Val Glu 1 5 10 15 Asn 185 17 PRT Artificial Sequence isolated from phage display libraries 185 Cys Asn Ser Phe Met Phe Ile Asn Gly Ser Phe Lys Glu Thr Gly Gly 1 5 10 15 Cys 186 17 PRT Artificial Sequence isolated from phage display libraries 186 Cys Asn Ser Ser Ser Tyr Ser Trp Tyr Cys Trp Phe Gly Gly Ser Ser 1 5 10 15 Pro 187 17 PRT Artificial Sequence isolated from phage display libraries 187 Cys Arg Asp Arg Gln Arg Trp Val Arg Ile Phe Asn Arg Arg Cys Val 1 5 10 15 Thr 188 17 PRT Artificial Sequence isolated from phage display libraries 188 Cys Arg Met Lys Lys Arg Arg Arg Ala His Pro Pro Arg Asn Cys Met 1 5 10 15 Glu 189 17 PRT Artificial Sequence isolated from phage display libraries 189 Cys Arg Arg Met Arg Cys Arg Asp His Thr Gln Lys Trp Arg Arg Glu 1 5 10 15 Arg 190 17 PRT Artificial Sequence isolated from phage display libraries 190 Cys Arg Arg Arg Lys Asn Phe Gln Arg Cys Phe Arg Pro Leu Leu Tyr 1 5 10 15 Pro 191 17 PRT Artificial Sequence isolated from phage display libraries 191 Cys Arg Arg Arg Ser Gln Arg Arg Asn Arg Arg Gly Asn Asp Asp Ser 1 5 10 15 Ala 192 17 PRT Artificial Sequence isolated from phage display libraries 192 Cys Ser Phe Phe Met Pro Trp Cys Asn Phe Leu Asn Gly Glu Met Ala 1 5 10 15 Val 193 17 PRT Artificial Sequence isolated from phage display libraries 193 Cys Ser Phe Ser Val Ser Lys Ser Ser Gln Ile Phe Ala Val Ser Tyr 1 5 10 15 Ser 194 17 PRT Artificial Sequence isolated from phage display libraries 194 Cys Ser Leu Thr Gly Cys Leu Tyr Asp Tyr Val Ser Phe Gly Trp Gly 1 5 10 15 Ala 195 17 PRT Artificial Sequence isolated from phage display libraries 195 Cys Ser Ser Ser Met Thr Tyr Arg Thr Ser Ser Ser Trp His Leu Lys 1 5 10 15 Ile 196 17 PRT Artificial Sequence isolated from phage display libraries 196 Cys Ser Thr Ser Tyr Ser Trp Asn Lys Trp Gln Ile Ser Ile Ser Ser 1 5 10 15 Tyr 197 17 PRT Artificial Sequence isolated from phage display libraries 197 Cys Thr Cys Phe Asn Leu Phe Asp Met Lys Thr Cys Pro Ser Phe Cys 1 5 10 15 Thr 198 17 PRT Artificial Sequence isolated from phage display libraries 198 Cys Thr Phe Gly Phe Pro Cys Val Met Ser Leu Val Asn His Val Pro 1 5 10 15 Ser 199 17 PRT Artificial Sequence isolated from phage display libraries 199 Cys Thr Asn Ser Asn Leu Asn Ser Ser Ser Trp His Thr Met Val Asp 1 5 10 15 Arg 200 17 PRT Artificial Sequence isolated from phage display libraries 200 Cys Thr Trp Trp Trp Trp Trp Val Val Asn Arg Glu Pro Tyr Val Ala 1 5 10 15 Cys 201 17 PRT Artificial Sequence isolated from phage display libraries 201 Cys Trp Asp Trp Met Thr Trp Gly Asn Asp Val Leu Val Asn Thr Asp 1 5 10 15 Trp 202 17 PRT Artificial Sequence isolated from phage display libraries 202 Cys Trp Leu Asp Asp Asp Ser Asp Asp Tyr Asp Asp Asp Asp Met Met 1 5 10 15 Ala 203 17 PRT Artificial Sequence isolated from phage display libraries 203 Cys Trp Met Gly Leu Phe Glu Cys Pro Asp Ala Trp Leu His Asp Trp 1 5 10 15 Asp 204 17 PRT Artificial Sequence isolated from phage display libraries 204 Cys Trp Asn Ile Ser Cys Met Phe Gly Phe Gly Trp Gly Gly Gly Gly 1 5 10 15 Leu 205 17 PRT Artificial Sequence isolated from phage display libraries 205 Cys Tyr Ala Tyr Tyr Phe Phe Phe Tyr Ser Ser Gly Arg Gly Tyr His 1 5 10 15 Gln 206 17 PRT Artificial Sequence isolated from phage display libraries 206 Cys Tyr Phe Pro Phe Tyr Cys Tyr Asn Thr Ser Ser Leu Ser Leu Asp 1 5 10 15 Phe 207 16 PRT Artificial Sequence isolated from phage display libraries 207 Ala Asp Arg Val Trp Pro Arg His Thr Ser Ser Pro Tyr His Arg His 1 5 10 15 208 16 PRT Artificial Sequence isolated from phage display libraries 208 Ala Phe Ile Ser Asn Leu His Ala Ala Cys Ser Val Gly Ser Cys Lys 1 5 10 15 209 16 PRT Artificial Sequence isolated from phage display libraries 209 Cys His Thr Pro Trp Pro Pro Met Asn Arg Tyr Ala Ser Val Leu Ile 1 5 10 15 210 16 PRT Artificial Sequence isolated from phage display libraries 210 Cys Thr Arg Arg Arg Arg Phe Cys Val Ile Ile Phe Arg Arg Glu Met 1 5 10 15 211 16 PRT Artificial Sequence isolated from phage display libraries 211 Cys Thr Ser Ser Ser Gln Lys His Cys Tyr His Gly His Ser Ser Asp 1 5 10 15 212 16 PRT Artificial Sequence isolated from phage display libraries 212 Asp Cys Cys Cys Met Trp Asp Asp Gly Val Gly Asp Asp Val Asp Met 1 5 10 15 213 16 PRT Artificial Sequence isolated from phage display libraries 213 Asp Phe Cys Phe Met Met Met Asn Cys Thr Met Asn Ala His Tyr Phe 1 5 10 15 214 16 PRT Artificial Sequence isolated from phage display libraries 214 Asp Val Asn Ser Ile Trp Met Ser Arg Val Ile Glu Trp Thr Tyr Asp 1 5 10 15 215 16 PRT Artificial Sequence isolated from phage display libraries 215 Asp Trp Cys Asn Asn Ala Trp Asp Thr Tyr Ala Ile His Asn Asp Cys 1 5 10 15 216 16 PRT Artificial Sequence isolated from phage display libraries 216 Phe Leu Phe Phe Thr Asn Met Val Trp Tyr Phe Phe Ile Met Gly Ala 1 5 10 15 217 16 PRT Artificial Sequence isolated from phage display libraries 217 Phe Thr Val Ser Ser His Ile Ile Glu Trp Ser Ala Asp Ser Val Val 1 5 10 15 218 16 PRT Artificial Sequence isolated from phage display libraries 218 Gly Ala Gly Gly Phe Phe Leu Pro Cys Leu Trp Asn Pro Asp Arg Thr 1 5 10 15 219 16 PRT Artificial Sequence isolated from phage display libraries 219 Gly Lys Cys Val Phe Arg Arg Glu Asp Cys Phe Trp Tyr Tyr Met His 1 5 10 15 220 16 PRT Artificial Sequence isolated from phage display libraries 220 Gly Ser Ser Ser Cys Gln Gly Val Ser Gly Ser Asp Tyr Val Met Lys 1 5 10 15 221 16 PRT Artificial Sequence isolated from phage display libraries 221 His Ala Ser Ile His His Cys Ser Tyr Gln Gly Tyr Gly Gln Ser Gly 1 5 10 15 222 16 PRT Artificial Sequence isolated from phage display libraries 222 His Cys Asn Asn Glu Asn Arg Trp His His Asn Gly Ala Ile Gly Val 1 5 10 15 223 16 PRT Artificial Sequence isolated from phage display libraries 223 His Ile Ser Ser Cys Gln Met Val Gln Ser Trp Ser Arg Pro Ala His 1 5 10 15 224 16 PRT Artificial Sequence isolated from phage display libraries 224 Ile Trp Glu Trp Phe Glu Leu Glu Met Leu Tyr Val Asn Arg Tyr Cys 1 5 10 15 225 16 PRT Artificial Sequence isolated from phage display libraries 225 Leu Ile His Arg Tyr Cys Arg Arg Val Pro Cys Arg Arg Glu Leu Lys 1 5 10 15 226 16 PRT Artificial Sequence isolated from phage display libraries 226 Met Ser Asn Phe Leu Ile Glu Phe Thr Tyr Asp Asn Val Gly Val Arg 1 5 10 15 227 16 PRT Artificial Sequence isolated from phage display libraries 227 Asn Phe Phe Val Glu Trp Ala Phe Asp Thr Gln Asp Arg Glu Glu Leu 1 5 10 15 228 16 PRT Artificial Sequence isolated from phage display libraries 228 Asn Gly Asn Glu Asn Asp Thr Ile Asn Asp Asn Asp Ile Asn Ala Ser 1 5 10 15 229 16 PRT Artificial Sequence isolated from phage display libraries 229 Asn Ile Asn Ile Val Glu Glu Arg Phe Met Val Glu Trp Asp Val Gln 1 5 10 15 230 16 PRT Artificial Sequence isolated from phage display libraries 230 Asn Pro Trp Ala Ser Ser Leu Val Ala Ala Cys Tyr Leu Asp Glu Ser 1 5 10 15 231 16 PRT Artificial Sequence isolated from phage display libraries 231 Asn Trp Trp Met Val Asn Leu Ile Pro Asp Glu Trp Cys Trp Asn Ser 1 5 10 15 232 16 PRT Artificial Sequence isolated from phage display libraries 232 Pro Phe Leu Phe Glu Ala Ser Asp Arg His Pro Ala Phe Asn His Met 1 5 10 15 233 16 PRT Artificial Sequence isolated from phage display libraries 233 Pro Gly Ser Ser Thr Phe Tyr Ser Ile Thr Met Thr Trp Asp Leu Pro 1 5 10 15 234 16 PRT Artificial Sequence isolated from phage display libraries 234 Pro Pro Ser Ser Asn Ser Asn Phe Met Leu Glu Phe Ser Trp Asp Ser 1 5 10 15 235 16 PRT Artificial Sequence isolated from phage display libraries 235 Pro Gln Ser Glu His Ser Lys Ser Tyr Met Ser Trp Ala Arg Ser Ser 1 5 10 15 236 16 PRT Artificial Sequence isolated from phage display libraries 236 Pro Ser Ala Cys Ser Arg Arg Ile Ile Gln Asp Thr Phe Phe Phe Met 1 5 10 15 237 16 PRT Artificial Sequence isolated from phage display libraries 237 Gln Glu Leu Arg Val Arg Lys Arg Arg Arg Pro Lys Asp His Glu Arg 1 5 10 15 238 16 PRT Artificial Sequence isolated from phage display libraries 238 Gln Glu Met Leu Asn Phe Phe Phe His Asn Gly Asn Phe Phe Phe Val 1 5 10 15 239 16 PRT Artificial Sequence isolated from phage display libraries 239 Gln His Arg Gln His His Asn Val Ile Tyr Ser Ala Val Cys Val Ala 1 5 10 15 240 16 PRT Artificial Sequence isolated from phage display libraries 240 Gln Met Asp Thr Ile Asp Asp Met Thr Trp Thr Gly Asp Asp Asp Cys 1 5 10 15 241 16 PRT Artificial Sequence isolated from phage display libraries 241 Arg Gly Pro Tyr Ile Trp Trp Leu Glu Glu Gln Ser Arg Thr Trp Glu 1 5 10 15 242 16 PRT Artificial Sequence isolated from phage display libraries 242 Arg Arg Arg Asn Lys Leu Ala Arg Thr Leu Val Tyr Arg Arg Arg Val 1 5 10 15 243 16 PRT Artificial Sequence isolated from phage display libraries 243 Arg Arg Arg Pro Lys Pro Gly Pro His Ile Ile Phe Thr Ala Ile Asn 1 5 10 15 244 16 PRT Artificial Sequence isolated from phage display libraries 244 Arg Arg Tyr Ala Thr Trp Ser Val Ala Ser Ile Gln Glu Cys Pro Arg 1 5 10 15 245 16 PRT Artificial Sequence isolated from phage display libraries 245 Arg Tyr Pro Tyr Asp Met Asp Trp Asp Trp His His Gln Glu Arg Asp 1 5 10 15 246 16 PRT Artificial Sequence isolated from phage display libraries 246 Ser Phe Phe Phe Trp Asp Thr Phe Gly Glu Ser Asn Lys Phe Phe Met 1 5 10 15 247 16 PRT Artificial Sequence isolated from phage display libraries 247 Ser Phe Met Phe Asn Asp Ser Ile Asp Asp Asp Asp Asp Val Ser Glu 1 5 10 15 248 16 PRT Artificial Sequence isolated from phage display libraries 248 Ser Pro Gln Ala Arg Ser His Glu Asp Gln Val Met Gln Trp Trp Ile 1 5 10 15 249 16 PRT Artificial Sequence isolated from phage display libraries 249 Thr Phe Asp Asp Ala Met Leu Glu Trp Ser Leu Val Glu Trp Asp Ile 1 5 10 15 250 16 PRT Artificial Sequence isolated from phage display libraries 250 Thr Gly Gln Ser Ser Met Val Asn His Met Val Ser Glu Asn Gly Gly 1 5 10 15 251 16 PRT Artificial Sequence isolated from phage display libraries 251 Thr Met Gln Asp Phe Ser Ser Asp Glu Phe Tyr Thr Trp Thr Trp Asp 1 5 10 15 252 16 PRT Artificial Sequence isolated from phage display libraries 252 Val Phe Gly Phe Ser Cys Phe Glu Lys Asp Lys Arg Phe Asp Glu Leu 1 5 10 15 253 16 PRT Artificial Sequence isolated from phage display libraries 253 Val Leu Gly Trp Lys Ser Trp Lys Ile Tyr Trp Ala Trp Leu Val Glu 1 5 10

15 254 16 PRT Artificial Sequence isolated from phage display libraries 254 Trp Leu Trp Thr Trp Gln Glu Thr Ala Glu His Pro Ile Trp Asn Ser 1 5 10 15 255 16 PRT Artificial Sequence isolated from phage display libraries 255 Trp Met Trp Gln Ile Cys Pro Cys Met Met His Trp Val Leu Asn Trp 1 5 10 15 256 16 PRT Artificial Sequence isolated from phage display libraries 256 Trp Asn Cys Asp Tyr Glu Thr Gly Ala Gly Trp Arg Cys Ser Glu Ala 1 5 10 15 257 16 PRT Artificial Sequence isolated from phage display libraries 257 Trp Asn Phe Tyr Phe Val Ala Phe Ile Ala Leu Pro Met Glu Phe Val 1 5 10 15 258 16 PRT Artificial Sequence isolated from phage display libraries 258 Trp Trp Phe Arg Phe Lys Arg Arg Arg Arg Trp Met Lys Ser Val Arg 1 5 10 15 259 16 PRT Artificial Sequence isolated from phage display libraries 259 Tyr Asp Met Met Met Asp Met Leu Lys Asn Asp Asp Lys Gly Phe Phe 1 5 10 15 260 16 PRT Artificial Sequence isolated from phage display libraries 260 Tyr Arg Met Ala Asp Arg Asp Val His Arg Trp Asp Lys Glu Tyr Glu 1 5 10 15 261 16 PRT Artificial Sequence isolated from phage display libraries 261 Tyr Arg Asn Met Glu Arg Ser Asn Met Ala Glu Thr Asn Ile Leu Ala 1 5 10 15 262 16 PRT Artificial Sequence isolated from phage display libraries 262 Tyr Tyr Phe Thr Glu Trp Ser Glu Asp Thr Ser Gly Gly Ser Ser Gly 1 5 10 15 263 13 PRT Artificial Sequence isolated from phage display libraries 263 Ala Lys Ile Leu Tyr Tyr Tyr Asp Met Gln Trp His Ile 1 5 10 264 13 PRT Artificial Sequence isolated from phage display libraries 264 Ala Pro Phe Leu Val Trp Tyr Ala Ser Thr Ser Asp Thr 1 5 10 265 13 PRT Artificial Sequence isolated from phage display libraries 265 Ala Val Ser Thr Ala Leu Tyr Asn Thr Trp Gln Val Leu 1 5 10 266 13 PRT Artificial Sequence isolated from phage display libraries 266 Cys Ala His Pro Pro Pro Tyr Lys Glu Asn Tyr Leu Tyr 1 5 10 267 13 PRT Artificial Sequence isolated from phage display libraries 267 Cys Cys Trp Thr Glu Ala Tyr Asp Ala His Pro Trp Arg 1 5 10 268 13 PRT Artificial Sequence isolated from phage display libraries 268 Cys Lys Phe Phe Phe His Tyr His Ile Gly Phe Ala Thr 1 5 10 269 13 PRT Artificial Sequence isolated from phage display libraries 269 Cys Val Trp Cys Ser Glu Tyr Phe Arg Glu Asp Pro Pro 1 5 10 270 13 PRT Artificial Sequence isolated from phage display libraries 270 Cys Tyr Thr Ser Lys Tyr Tyr Arg Glu Lys Tyr Glu Leu 1 5 10 271 13 PRT Artificial Sequence isolated from phage display libraries 271 Asp Thr Ile Trp Trp Trp Tyr Met Trp Cys Trp His Tyr 1 5 10 272 13 PRT Artificial Sequence isolated from phage display libraries 272 Glu His Gly Pro Phe Val Asp Ser Glu Tyr Pro Gln Pro 1 5 10 273 13 PRT Artificial Sequence isolated from phage display libraries 273 Phe Ala Asp Asn Leu Gly Tyr Val Gly Ser Asp Val Ile 1 5 10 274 13 PRT Artificial Sequence isolated from phage display libraries 274 Phe Ala Pro Met Lys Ser Tyr Gly Val Ser Leu Pro Pro 1 5 10 275 13 PRT Artificial Sequence isolated from phage display libraries 275 Phe Glu Leu Ala Thr Gly Tyr Val Pro Ala Leu Leu Lys 1 5 10 276 13 PRT Artificial Sequence isolated from phage display libraries 276 Phe Phe Phe Ser Met Ser Tyr Phe Phe Phe Arg Ala Ala 1 5 10 277 13 PRT Artificial Sequence isolated from phage display libraries 277 Phe Phe Gly Phe Asp Val Tyr Asp Met Ser Asn Ala Leu 1 5 10 278 13 PRT Artificial Sequence isolated from phage display libraries 278 Phe Phe His Phe Cys Phe Tyr Thr Cys Met Phe His Leu 1 5 10 279 13 PRT Artificial Sequence isolated from phage display libraries 279 Phe Phe Leu Ser Pro Phe Tyr Phe Phe Asn Glu Phe Phe 1 5 10 280 13 PRT Artificial Sequence isolated from phage display libraries 280 Phe Phe Met Ala Ser Ser Tyr Ser Tyr Pro Val Ala Gly 1 5 10 281 13 PRT Artificial Sequence isolated from phage display libraries 281 Phe Phe Pro Ser Ser Trp Tyr Ser His Leu Gly Val Leu 1 5 10 282 13 PRT Artificial Sequence isolated from phage display libraries 282 Phe Phe Val Leu Phe Leu Tyr Leu Trp Leu Gly Val Ser 1 5 10 283 13 PRT Artificial Sequence isolated from phage display libraries 283 Phe Gly Cys Glu Leu Pro Tyr Ser Gly Val Cys Ser Val 1 5 10 284 13 PRT Artificial Sequence isolated from phage display libraries 284 Phe Gly Ser Asp Val Phe Tyr Leu Arg Ser Ala Pro His 1 5 10 285 13 PRT Artificial Sequence isolated from phage display libraries 285 Phe His Glu Ala Pro Val Tyr Glu Thr Ser Glu Pro Pro 1 5 10 286 13 PRT Artificial Sequence isolated from phage display libraries 286 Phe Leu Gly Phe Gln Asp Tyr Lys Ser Ala Ala Met Met 1 5 10 287 13 PRT Artificial Sequence isolated from phage display libraries 287 Phe Leu Leu Thr Gly Glu Tyr Val Asp Val Val Ala Ala 1 5 10 288 13 PRT Artificial Sequence isolated from phage display libraries 288 Phe Leu Ser Phe Ala Asn Tyr Glu Asp Glu Leu Leu Arg 1 5 10 289 13 PRT Artificial Sequence isolated from phage display libraries 289 Phe Met Phe Ile Phe Phe Tyr Pro Val Phe Cys Phe Gln 1 5 10 290 13 PRT Artificial Sequence isolated from phage display libraries 290 Phe Arg Phe Phe Asn His Tyr Arg Tyr Pro Ser Gly Gln 1 5 10 291 13 PRT Artificial Sequence isolated from phage display libraries 291 Phe Arg Met Asp Phe Asp Tyr Leu Tyr Pro Ser Leu Pro 1 5 10 292 13 PRT Artificial Sequence isolated from phage display libraries 292 Phe Arg Tyr Phe Tyr Phe Tyr Ser His Gly Phe Lys Phe 1 5 10 293 13 PRT Artificial Sequence isolated from phage display libraries 293 Phe Ser Ala Leu Pro Thr Tyr Glu Val Asn Ser Tyr Lys 1 5 10 294 13 PRT Artificial Sequence isolated from phage display libraries 294 Phe Ser Asp Ser Ser Phe Tyr Ser Asp Leu Ser Val Val 1 5 10 295 13 PRT Artificial Sequence isolated from phage display libraries 295 Phe Ser Ser Val Asp Ser Tyr Ser Gly Pro Arg Pro Asp 1 5 10 296 13 PRT Artificial Sequence isolated from phage display libraries 296 Phe Ser Tyr Ser Val Ser Tyr Ala His Pro Glu Gly Leu 1 5 10 297 13 PRT Artificial Sequence isolated from phage display libraries 297 Phe Val Gly Phe Phe Leu Tyr Leu Thr Leu Leu Leu Pro 1 5 10 298 13 PRT Artificial Sequence isolated from phage display libraries 298 Gly Glu Asn Phe Cys Pro Tyr Ser Phe Phe Gly Cys Gly 1 5 10 299 13 PRT Artificial Sequence isolated from phage display libraries 299 Gly Phe Ala Trp Ser Ser Tyr Leu Gly Thr Thr Val His 1 5 10 300 13 PRT Artificial Sequence isolated from phage display libraries 300 Gly Phe Pro Phe Ile Phe Tyr Val Val Asp Trp Met Arg 1 5 10 301 13 PRT Artificial Sequence isolated from phage display libraries 301 Gly Phe Ser Glu Phe Leu Tyr Asp Leu Glu Val Gly Ile 1 5 10 302 13 PRT Artificial Sequence isolated from phage display libraries 302 Gly Phe Val Ala Tyr Asn Tyr Asp Lys Tyr Ser Gly Ala 1 5 10 303 13 PRT Artificial Sequence isolated from phage display libraries 303 Gly Val Ser Gln Phe Leu Tyr Asp Trp Val Lys Gly Gly 1 5 10 304 13 PRT Artificial Sequence isolated from phage display libraries 304 Gly Tyr Asn Ile Tyr Trp Tyr Ile Asn Asn Val Glu Tyr 1 5 10 305 13 PRT Artificial Sequence isolated from phage display libraries 305 His Tyr Lys Tyr Asn Val Tyr Cys Lys Tyr Asn Gly Tyr 1 5 10 306 13 PRT Artificial Sequence isolated from phage display libraries 306 Ile Phe Leu Pro Trp His Tyr Asp Gly Tyr Thr Phe Ala 1 5 10 307 13 PRT Artificial Sequence isolated from phage display libraries 307 Ile Phe Ser Phe Leu Ser Tyr Val Pro Val Asp Lys Val 1 5 10 308 13 PRT Artificial Sequence isolated from phage display libraries 308 Ile Tyr Ala Ala Leu Tyr Tyr Arg Phe Pro Thr Met Asp 1 5 10 309 13 PRT Artificial Sequence isolated from phage display libraries 309 Lys Phe Phe Phe Trp Phe Tyr Ile Asn Phe Val Met Met 1 5 10 310 13 PRT Artificial Sequence isolated from phage display libraries 310 Leu Asp Pro Leu Val Pro Tyr Leu Tyr Glu Asn Leu Phe 1 5 10 311 13 PRT Artificial Sequence isolated from phage display libraries 311 Leu Phe Asp Ala Tyr Trp Tyr Ser Asp Thr Ala Met Ser 1 5 10 312 13 PRT Artificial Sequence isolated from phage display libraries 312 Leu Leu Phe Phe Asp Asp Tyr Phe Lys Ser Ala Gly Arg 1 5 10 313 13 PRT Artificial Sequence isolated from phage display libraries 313 Leu Asn Phe Met Ile Phe Tyr Leu Ser Leu Asn Pro Trp 1 5 10 314 13 PRT Artificial Sequence isolated from phage display libraries 314 Leu Pro His Leu Ile Gln Tyr Arg Val Leu Leu Val Ser 1 5 10 315 13 PRT Artificial Sequence isolated from phage display libraries 315 Leu Pro Ser Gln Phe Gly Tyr Gly Ser Val Pro Thr Asp 1 5 10 316 13 PRT Artificial Sequence isolated from phage display libraries 316 Leu Pro Ser Gln Phe Gly Tyr Gly Ser Val Pro Thr Asp 1 5 10 317 13 PRT Artificial Sequence isolated from phage display libraries 317 Leu Ser Phe Ser Asp Phe Tyr Phe Ser Glu Gly Ser Glu 1 5 10 318 13 PRT Artificial Sequence isolated from phage display libraries 318 Leu Thr Asn Ser Gly Val Tyr Asp Gly Thr Pro Leu Pro 1 5 10 319 13 PRT Artificial Sequence isolated from phage display libraries 319 Leu Val Leu Leu Ile Leu Tyr Leu Phe Leu Ser Trp Pro 1 5 10 320 13 PRT Artificial Sequence isolated from phage display libraries 320 Leu Val Leu Leu Leu Phe Tyr Phe Leu Met Leu Ser Pro 1 5 10 321 13 PRT Artificial Sequence isolated from phage display libraries 321 Leu Tyr Leu Phe Tyr Pro Tyr Pro Asn Tyr Tyr Met Val 1 5 10 322 13 PRT Artificial Sequence isolated from phage display libraries 322 Asn Phe Ser Ser Ser Phe Tyr Ser Leu Val Ser Glu Gly 1 5 10 323 13 PRT Artificial Sequence isolated from phage display libraries 323 Asn Trp Tyr Ala Glu Tyr Tyr Tyr Val Tyr Asp Lys Gly 1 5 10 324 13 PRT Artificial Sequence isolated from phage display libraries 324 Asn Tyr Phe Ser Ala Met Tyr Tyr Asp Gly Trp Met Ser 1 5 10 325 13 PRT Artificial Sequence isolated from phage display libraries 325 Pro Ala Ser Leu Glu Leu Tyr Glu Asn Leu Val Ala Gly 1 5 10 326 13 PRT Artificial Sequence isolated from phage display libraries 326 Pro Cys Trp Tyr Arg Tyr Tyr His Glu Phe Trp Ile Trp 1 5 10 327 13 PRT Artificial Sequence isolated from phage display libraries 327 Pro Leu Tyr Tyr Glu Ser Tyr Arg Met Arg Thr Tyr Gln 1 5 10 328 13 PRT Artificial Sequence isolated from phage display libraries 328 Gln Tyr Ala Ser Tyr Met Tyr Tyr Cys Phe Pro Lys Tyr 1 5 10 329 13 PRT Artificial Sequence isolated from phage display libraries 329 Arg Ala Trp Trp Trp Trp Tyr Leu Asp Met Tyr Trp Thr 1 5 10 330 13 PRT Artificial Sequence isolated from phage display libraries 330 Arg Ala Tyr Asn Tyr Tyr Tyr Tyr Val Met Tyr Ala Cys 1 5 10 331 13 PRT Artificial Sequence isolated from phage display libraries 331 Arg Trp Ile Trp Trp Pro Tyr Val Asn Met Ile Trp Thr 1 5 10 332 13 PRT Artificial Sequence isolated from phage display libraries 332 Ser Asp Phe Leu Ser Pro Tyr Leu Ala Tyr Glu Arg Ser 1 5 10 333 13 PRT Artificial Sequence isolated from phage display libraries 333 Ser Phe Asp Val Arg Ser Tyr Val Leu Ala Gly Thr Glu 1 5 10 334 13 PRT Artificial Sequence isolated from phage display libraries 334 Ser Leu Phe Leu Asp Asp Tyr Ala Leu Gly Pro Arg Val 1 5 10 335 13 PRT Artificial Sequence isolated from phage display libraries 335 Ser Ser Val Leu Gly Phe Tyr Asp Pro Val Glu Val Ser 1 5 10 336 13 PRT Artificial Sequence isolated from phage display libraries 336 Ser Val Ala Phe Tyr Asp Tyr Leu Pro Thr Asp Leu Pro 1 5 10 337 13 PRT Artificial Sequence isolated from phage display libraries 337 Ser Val Leu Asp Phe Asn Tyr Gly His Asp Val Asn Val 1 5 10 338 13 PRT Artificial Sequence isolated from phage display libraries 338 Ser Val Ser Asp Phe Leu Tyr Arg Ser Ile Tyr Ser Leu 1 5 10 339 13 PRT Artificial Sequence isolated from phage display libraries 339 Ser Val Ser Asp Phe Leu Tyr Arg Ser Ile Tyr Ser Leu 1 5 10 340 13 PRT Artificial Sequence isolated from phage display libraries 340 Ser Val Ser Asp Phe Leu Tyr Arg Ser Ile Tyr Ser Leu 1 5 10 341 13 PRT Artificial Sequence isolated from phage display libraries 341 Ser Trp Ser Trp Trp Arg Tyr Gly Pro Gln Asn Thr Val 1 5 10 342 13 PRT Artificial Sequence isolated from phage display libraries 342 Ser Tyr Gly Phe Pro Ile Tyr Asp Ala Leu Leu Glu Gln 1 5 10 343 13 PRT Artificial Sequence isolated from phage display libraries 343 Val Phe Asp Val Gly Leu Tyr Trp His Ala Ala Pro Pro 1 5 10 344 13 PRT Artificial Sequence isolated from phage display libraries 344 Val Gly Phe Trp Val Asp Tyr Asp Asn Ser Ser Val Met 1 5 10 345 13 PRT Artificial Sequence isolated from phage display libraries 345 Val Leu Asp Leu Pro Tyr Tyr Trp Pro Val Lys Tyr Thr 1 5 10 346 13 PRT Artificial Sequence isolated from phage display libraries 346 Val Leu Leu Ala Asp Ser Tyr Gln Arg Asp Glu His Met 1 5 10 347 13 PRT Artificial Sequence isolated from phage display libraries 347 Val Leu Leu Phe Asp Asp Tyr Gly Tyr Ala Glu Ser Ala 1 5 10 348 13 PRT Artificial Sequence isolated from phage display libraries 348 Val Ser Ala Ser Gly Met Tyr Asp Gly Val Asp Leu Met 1 5 10 349 13 PRT Artificial Sequence isolated from phage display libraries 349 Val Ser Leu Leu Phe Ser Tyr Ser Pro Ala Gly Tyr Asp 1 5 10 350 13 PRT Artificial Sequence isolated from phage display libraries 350 Val Ser Ser Glu Trp Thr Tyr Gly Ala Val Ala Asp Leu 1 5 10 351 13 PRT Artificial Sequence isolated from phage display libraries 351 Val Ser Val Leu Ser Asp Tyr Ser Ile Lys Ala Leu Leu 1 5 10 352 13 PRT Artificial Sequence isolated from phage display libraries 352 Trp Ala Asp Met Tyr Tyr Tyr Tyr Asp Trp Tyr Thr Met 1 5 10 353 13 PRT Artificial Sequence isolated from phage display libraries 353 Trp Asp Trp Trp Gln Phe Tyr Glu Lys Met Trp Leu Phe 1 5 10 354 13 PRT Artificial Sequence isolated from phage display libraries 354 Trp Asn Trp Trp Gly Val Tyr Leu Gly Ile Cys Trp Leu 1 5 10 355 13 PRT Artificial Sequence isolated from phage display libraries 355 Trp Trp Gln Thr Trp Trp Tyr Arg Thr Tyr Trp Glu Ile 1 5 10 356 13 PRT Artificial Sequence isolated from phage display libraries 356 Tyr Ala Gly Val Tyr Ser Tyr Phe Thr Gly Ser Thr Leu 1 5 10 357 13 PRT Artificial Sequence isolated from phage display libraries 357 Tyr Cys Gln Tyr Arg Glu Tyr Tyr Thr Met Tyr Val Cys 1 5 10 358 13 PRT Artificial Sequence isolated from phage display libraries 358 Tyr Phe Val Glu Thr Tyr Tyr Asn Arg Tyr His Val Ser 1 5 10 359 13 PRT Artificial Sequence isolated from phage display libraries 359 Tyr Leu Ser Leu His Ala Tyr Glu Ser Phe Gly Gly Ser 1 5 10 360 13 PRT Artificial Sequence isolated from phage display libraries 360 Tyr Arg Tyr Gln Met Ser Tyr Tyr Ala Tyr Gln Tyr His 1 5 10 361 13 PRT Artificial Sequence isolated from phage display libraries 361 Tyr Ser Met Tyr Pro Ile Tyr Asn Lys Cys Ser Gln His 1 5

10 362 13 PRT Artificial Sequence isolated from phage display libraries 362 Tyr Trp Ile Tyr Asn Asn Tyr Thr Tyr Tyr Tyr Cys Gly 1 5 10 363 13 PRT Artificial Sequence isolated from phage display libraries 363 Tyr Trp Trp Glu Gln Trp Tyr Ser Trp Trp Ile Glu His 1 5 10 364 13 PRT Artificial Sequence isolated from phage display libraries 364 Tyr Tyr Arg Asp Ala Ser Tyr Thr Tyr Pro Tyr Met Tyr 1 5 10 365 13 PRT Artificial Sequence isolated from phage display libraries 365 Tyr Tyr Tyr Ile Pro Val Tyr Ser Ala Gln Cys Tyr Thr 1 5 10 366 13 PRT Artificial Sequence isolated from phage display libraries 366 Ala Cys Pro Trp Pro Ile Pro Pro Trp Pro Leu Arg Val 1 5 10 367 13 PRT Artificial Sequence isolated from phage display libraries 367 Ala Arg Arg Trp Pro Leu Pro Arg Arg Asp Gln Phe Ser 1 5 10 368 13 PRT Artificial Sequence isolated from phage display libraries 368 Cys Arg Arg Ile Gln Gln Pro Cys Val Phe Arg Arg His 1 5 10 369 13 PRT Artificial Sequence isolated from phage display libraries 369 Asp Glu Pro Pro Cys Ala Pro Glu Cys Asn Gly Asp Gly 1 5 10 370 13 PRT Artificial Sequence isolated from phage display libraries 370 Asp Phe Gln Phe Pro Lys Pro Ala Phe Cys Ser Thr Cys 1 5 10 371 13 PRT Artificial Sequence isolated from phage display libraries 371 Glu Leu Tyr Phe Phe Phe Pro Cys Gly Ser Phe Cys Gln 1 5 10 372 13 PRT Artificial Sequence isolated from phage display libraries 372 Phe Phe Gly Phe Asn His Pro Phe Leu Phe Ser Cys Trp 1 5 10 373 13 PRT Artificial Sequence isolated from phage display libraries 373 Phe Phe Gln Ser Ile Gln Pro Ile Phe Ala Arg Ser Met 1 5 10 374 13 PRT Artificial Sequence isolated from phage display libraries 374 Phe Phe Trp Val Lys Asp Pro Ser Pro Cys Phe Asp His 1 5 10 375 13 PRT Artificial Sequence isolated from phage display libraries 375 Phe Gly Lys Phe Phe Asp Pro Leu Arg Arg Ala Lys Asp 1 5 10 376 13 PRT Artificial Sequence isolated from phage display libraries 376 Phe Lys Gly Glu Phe Trp Pro Ala Phe Gly Val Gln Val 1 5 10 377 13 PRT Artificial Sequence isolated from phage display libraries 377 Phe Lys Leu His Trp Phe Pro Thr Cys Pro Phe Ile Gln 1 5 10 378 13 PRT Artificial Sequence isolated from phage display libraries 378 Phe Leu Ser Phe Val Phe Pro Ala Ser Ala Trp Gly Gly 1 5 10 379 13 PRT Artificial Sequence isolated from phage display libraries 379 Phe Met Asp Ile Trp Ser Pro Trp His Leu Leu Gly Thr 1 5 10 380 13 PRT Artificial Sequence isolated from phage display libraries 380 Phe Asn Pro Pro Glu Pro Pro Cys Pro Glu Phe Ser Lys 1 5 10 381 13 PRT Artificial Sequence isolated from phage display libraries 381 Phe Gln Phe Phe Asp Pro Pro Ser Phe Phe Gly Phe Lys 1 5 10 382 13 PRT Artificial Sequence isolated from phage display libraries 382 Phe Gln Phe Ser Phe Gln Pro Asp Gly Val Glu Arg Arg 1 5 10 383 13 PRT Artificial Sequence isolated from phage display libraries 383 Phe Gln Asn Cys Phe Trp Pro Ile Phe Glu Ala Met Glu 1 5 10 384 13 PRT Artificial Sequence isolated from phage display libraries 384 Phe Ser Phe Phe Ala Asp Pro Ile Glu Leu Glu Trp Asp 1 5 10 385 12 PRT Artificial Sequence isolated from phage display libraries 385 Phe Ser Ser Leu Phe Phe Pro His Trp Ala Gln Leu 1 5 10 386 13 PRT Artificial Sequence isolated from phage display libraries 386 Phe Tyr Met Pro Phe Gly Pro Thr Trp Trp Gln His Val 1 5 10 387 13 PRT Artificial Sequence isolated from phage display libraries 387 Phe Tyr Tyr Phe Gly Phe Pro Gln Cys Leu Ile Leu Phe 1 5 10 388 13 PRT Artificial Sequence isolated from phage display libraries 388 Gly Phe Glu Glu Phe Gln Pro Val Asp Phe Ile Ile Arg 1 5 10 389 13 PRT Artificial Sequence isolated from phage display libraries 389 Gly Leu Thr Arg Phe Phe Pro Val Ser Phe Ser Phe Phe 1 5 10 390 13 PRT Artificial Sequence isolated from phage display libraries 390 His Ala Arg Pro Pro Cys Pro Phe Val Asn Glu Lys Pro 1 5 10 391 13 PRT Artificial Sequence isolated from phage display libraries 391 His Glu Phe Met Trp Phe Pro Val His Trp Glu Phe His 1 5 10 392 13 PRT Artificial Sequence isolated from phage display libraries 392 His Arg Asn Pro Arg Arg Pro Gln Ile Glu Gly Val Arg 1 5 10 393 13 PRT Artificial Sequence isolated from phage display libraries 393 Ile Ser Gly His Cys Phe Pro Cys Ile Glu Val Ser Asp 1 5 10 394 13 PRT Artificial Sequence isolated from phage display libraries 394 Lys Phe Gln Asp Phe Met Pro Gln Met Phe His Gly Ile 1 5 10 395 13 PRT Artificial Sequence isolated from phage display libraries 395 Leu Phe Phe Met Pro Phe Pro Phe Phe Phe Phe Pro Tyr 1 5 10 396 13 PRT Artificial Sequence isolated from phage display libraries 396 Leu Phe Ser Trp Phe Leu Pro Thr Asp Asn Tyr Pro Val 1 5 10 397 13 PRT Artificial Sequence isolated from phage display libraries 397 Leu Val Cys Ile Arg Arg Pro Arg Arg Arg Cys Phe Cys 1 5 10 398 13 PRT Artificial Sequence isolated from phage display libraries 398 Met Pro Arg Arg Glu Arg Pro Leu Trp Met Leu Thr Arg 1 5 10 399 13 PRT Artificial Sequence isolated from phage display libraries 399 Met Arg Arg His Arg Ala Pro Arg Ser Gln Cys Met Glu 1 5 10 400 13 PRT Artificial Sequence isolated from phage display libraries 400 Asn Phe Phe Gly Pro Ile Pro Met Asn Phe Ala Phe Thr 1 5 10 401 13 PRT Artificial Sequence isolated from phage display libraries 401 Asn Phe Phe Ser Ile Asp Pro Phe Cys Gln Ala Ile Tyr 1 5 10 402 13 PRT Artificial Sequence isolated from phage display libraries 402 Asn Asn Gly Ala Arg Arg Pro Tyr Val Ala Ser Asn Pro 1 5 10 403 13 PRT Artificial Sequence isolated from phage display libraries 403 Asn Arg Arg Arg Tyr Arg Pro Arg Phe Tyr Arg Arg Cys 1 5 10 404 13 PRT Artificial Sequence isolated from phage display libraries 404 Pro Phe Phe Trp Met Phe Pro Ile Cys Phe Pro Pro Asn 1 5 10 405 13 PRT Artificial Sequence isolated from phage display libraries 405 Pro Phe Gly Leu Phe Pro Pro Gln Val Tyr Tyr Phe Leu 1 5 10 406 13 PRT Artificial Sequence isolated from phage display libraries 406 Pro Gly Ala Ala Pro Pro Pro Cys Asn Asn Ser Asp Asn 1 5 10 407 13 PRT Artificial Sequence isolated from phage display libraries 407 Pro Pro Cys Pro Trp Arg Pro Ser Ala Thr His Leu Pro 1 5 10 408 13 PRT Artificial Sequence isolated from phage display libraries 408 Pro Pro Lys Phe Leu Ala Pro His Thr Ser Ala Met Leu 1 5 10 409 13 PRT Artificial Sequence isolated from phage display libraries 409 Pro Pro Arg Val Ala Phe Pro Ile Arg Gln Arg Arg Val 1 5 10 410 13 PRT Artificial Sequence isolated from phage display libraries 410 Pro Thr Arg Pro Asn Gly Pro Glu Ser Glu Asp Leu Phe 1 5 10 411 13 PRT Artificial Sequence isolated from phage display libraries 411 Gln Cys Pro Asp Pro Ser Pro Ser Lys Cys Pro Phe Gly 1 5 10 412 13 PRT Artificial Sequence isolated from phage display libraries 412 Gln Arg Arg Ala Pro Arg Pro Ser Glu His Arg Arg Glu 1 5 10 413 13 PRT Artificial Sequence isolated from phage display libraries 413 Arg Ala Arg Arg Ala Gly Pro Leu Gly Asp Arg Lys Leu 1 5 10 414 13 PRT Artificial Sequence isolated from phage display libraries 414 Arg Glu Gly Arg Thr Arg Pro Arg Tyr Pro Arg Trp Phe 1 5 10 415 13 PRT Artificial Sequence isolated from phage display libraries 415 Arg Glu Pro Asn Pro Pro Pro Leu Gln Ser Pro Met Ser 1 5 10 416 13 PRT Artificial Sequence isolated from phage display libraries 416 Arg Gly Phe Gln Phe Gly Pro Ser Thr Phe Glu Tyr Phe 1 5 10 417 13 PRT Artificial Sequence isolated from phage display libraries 417 Arg Gly Pro Arg Arg Thr Pro Thr Ile His Arg Pro Trp 1 5 10 418 13 PRT Artificial Sequence isolated from phage display libraries 418 Arg His Phe His Val Arg Pro Val Asn Trp Trp Ser Lys 1 5 10 419 13 PRT Artificial Sequence isolated from phage display libraries 419 Arg Ile Asn Arg Ser Arg Pro Ile Met Trp Gln Arg Thr 1 5 10 420 13 PRT Artificial Sequence isolated from phage display libraries 420 Arg Asn Asp Arg Val Arg Pro Trp Lys Val Lys His Gln 1 5 10 421 13 PRT Artificial Sequence isolated from phage display libraries 421 Arg Asn Met Arg Tyr Arg Pro Gln Tyr Ala Asp Leu Cys 1 5 10 422 13 PRT Artificial Sequence isolated from phage display libraries 422 Arg Asn Asn Arg Pro Lys Pro Thr Gln Ser His Arg Val 1 5 10 423 13 PRT Artificial Sequence isolated from phage display libraries 423 Arg Arg His Arg Trp Trp Pro Gln Glu Phe Ser Arg His 1 5 10 424 13 PRT Artificial Sequence isolated from phage display libraries 424 Arg Arg Arg Leu Phe Thr Pro Asn Ser Arg Ala Arg His 1 5 10 425 13 PRT Artificial Sequence isolated from phage display libraries 425 Arg Arg Ser Arg Phe Val Pro Glu Tyr Leu Phe Arg Pro 1 5 10 426 13 PRT Artificial Sequence isolated from phage display libraries 426 Arg Trp His Pro Arg Tyr Pro Val Met Lys Lys Asn Ser 1 5 10 427 13 PRT Artificial Sequence isolated from phage display libraries 427 Arg Trp Ile Pro Arg Pro Pro Arg Arg Ala Cys Arg Arg 1 5 10 428 13 PRT Artificial Sequence isolated from phage display libraries 428 Ser Phe Trp Pro Phe Cys Pro Thr Thr Trp Ala Asn Tyr 1 5 10 429 13 PRT Artificial Sequence isolated from phage display libraries 429 Ser Ile Phe Gln Phe Asn Pro Phe Pro Glu Gly Phe Phe 1 5 10 430 13 PRT Artificial Sequence isolated from phage display libraries 430 Ser Leu Phe Phe Met Pro Pro Glu Arg Leu Asp His Arg 1 5 10 431 13 PRT Artificial Sequence isolated from phage display libraries 431 Ser Asn Arg His Arg Arg Pro Arg Arg Arg Trp Arg Met 1 5 10 432 13 PRT Artificial Sequence isolated from phage display libraries 432 Thr Phe Phe Thr Asn Lys Pro Phe Ser Tyr His Phe Glu 1 5 10 433 13 PRT Artificial Sequence isolated from phage display libraries 433 Thr Thr Pro Val Gln Pro Pro Gly Glu Val Ser Gln Val 1 5 10 434 13 PRT Artificial Sequence isolated from phage display libraries 434 Thr Tyr Asn Ser Phe Phe Pro Phe Arg His Phe Ala Glu 1 5 10 435 13 PRT Artificial Sequence isolated from phage display libraries 435 Val Lys Ile Arg Arg Arg Pro Arg Arg Met Arg Leu Met 1 5 10 436 13 PRT Artificial Sequence isolated from phage display libraries 436 Trp Lys His Pro Pro Arg Pro Tyr Cys Trp Lys Pro Leu 1 5 10 437 13 PRT Artificial Sequence isolated from phage display libraries 437 Tyr Ile Tyr Thr Val Tyr Pro Arg Asn Ser Ser Trp Phe 1 5 10 438 13 PRT Artificial Sequence isolated from phage display libraries 438 Tyr Gln Pro Trp Gly Pro Pro Pro Pro Pro Leu Val Leu 1 5 10 439 13 PRT Artificial Sequence isolated from phage display libraries 439 Ala Arg Asp Tyr Asp Asn Asn Met Lys Tyr Tyr Leu Asp 1 5 10 440 13 PRT Artificial Sequence isolated from phage display libraries 440 Ala Arg Ile Asn Asn Lys Asn Val Ile Thr Phe Gln Pro 1 5 10 441 13 PRT Artificial Sequence isolated from phage display libraries 441 Ala Ser Arg Ser Ser Asp Asn Ile Ser Tyr Ser Ser Thr 1 5 10 442 13 PRT Artificial Sequence isolated from phage display libraries 442 Ala Ser Ser Asp Ala Gly Asn Tyr Glu Ile Ala Gly Pro 1 5 10 443 13 PRT Artificial Sequence isolated from phage display libraries 443 Ala Thr Asp Asp Glu Asn Asn Glu Met Asn Val Gly Met 1 5 10 444 13 PRT Artificial Sequence isolated from phage display libraries 444 Cys Ser Ser Phe Ser Leu Asn Trp Ser Leu Ser Lys Ser 1 5 10 445 13 PRT Artificial Sequence isolated from phage display libraries 445 Asp Cys Asp His Leu Phe Asn Met Glu Gln Thr Leu Arg 1 5 10 446 13 PRT Artificial Sequence isolated from phage display libraries 446 Asp Cys Val Ser Ser Asn Asn His Asp Ile Thr Arg Gly 1 5 10 447 13 PRT Artificial Sequence isolated from phage display libraries 447 Asp Asp Glu Arg Val Ile Asn Ser Asp Tyr Ser Glu Tyr 1 5 10 448 13 PRT Artificial Sequence isolated from phage display libraries 448 Asp Asp Lys Asn Glu Asp Asn Asp Ile Pro Lys Thr Pro 1 5 10 449 13 PRT Artificial Sequence isolated from phage display libraries 449 Asp Asp Thr Asn Asp Met Asn Asn Ser Glu Glu Lys Phe 1 5 10 450 13 PRT Artificial Sequence isolated from phage display libraries 450 Asp Asp Val Gln Asp Asp Asn Asp Gln Pro Tyr Asn Thr 1 5 10 451 13 PRT Artificial Sequence isolated from phage display libraries 451 Asp Lys Gly Asn Asp Gln Asn Asn Ser Pro Leu Trp Ala 1 5 10 452 13 PRT Artificial Sequence isolated from phage display libraries 452 Asp Leu Val Cys Asn Asn Asn Cys Arg Asn Leu Phe Asn 1 5 10 453 13 PRT Artificial Sequence isolated from phage display libraries 453 Asp Asn His Asp Lys Phe Asn Gln Ala Ile Gln Asp Trp 1 5 10 454 13 PRT Artificial Sequence isolated from phage display libraries 454 Asp Arg Cys Asn Gly Asp Asn Trp Cys Asn Gln Gly Asp 1 5 10 455 13 PRT Artificial Sequence isolated from phage display libraries 455 Asp Ser Glu Tyr Leu Ser Asn Lys Ser Val Asn Asp Phe 1 5 10 456 13 PRT Artificial Sequence isolated from phage display libraries 456 Asp Thr Met Thr Asp Asn Asn Gln Gly Asp Asp Gln Trp 1 5 10 457 13 PRT Artificial Sequence isolated from phage display libraries 457 Glu Lys Asn Trp Asn Tyr Asn Pro Val Met Leu Ala Asn 1 5 10 458 13 PRT Artificial Sequence isolated from phage display libraries 458 Phe Phe Ser Phe Leu Pro Asn Ser Asp Arg Phe Gln Trp 1 5 10 459 13 PRT Artificial Sequence isolated from phage display libraries 459 Phe Phe Ser Tyr Trp Ser Asn Phe Asp Ala Ser Trp His 1 5 10 460 13 PRT Artificial Sequence isolated from phage display libraries 460 Phe His Ile Asp Asp Asp Asn Asp Phe Asp Thr Thr Ser 1 5 10 461 13 PRT Artificial Sequence isolated from phage display libraries 461 Phe Asn Asn Phe Asn Asp Asn Glu His Asn Val Asn Lys 1 5 10 462 13 PRT Artificial Sequence isolated from phage display libraries 462 Phe Tyr Asn Ile Val Asn Asn Ile Phe Ile Cys Cys Ile 1 5 10 463 13 PRT Artificial Sequence isolated from phage display libraries 463 Phe Tyr Trp Asp Arg Leu Asn Val Gly Trp Gly Leu Leu 1 5 10 464 13 PRT Artificial Sequence isolated from phage display libraries 464 Gly Asp Asn His Asn His Asn Thr Asn Thr Ile Glu Pro 1 5 10 465 13 PRT Artificial Sequence isolated from phage display libraries 465 His Ala Asp Gln Asp Asp Asn Cys Arg Gly Lys Asp Asp 1 5 10 466 13 PRT Artificial Sequence isolated from phage display libraries 466 His Asp Trp Asp Asp Trp Asn Ile Glu Ala Glu Asp Gly 1 5 10 467 13 PRT Artificial Sequence isolated from phage display libraries 467 His Gly Ser Ser Asp Thr Asn Gly Gln Ile Leu Phe Glu 1 5 10 468 13 PRT Artificial Sequence isolated from phage display libraries 468 His Asn Trp Asn His Asn Asn Asn Leu Ile Asp Arg Phe 1 5 10 469 13 PRT Artificial Sequence isolated from phage display libraries 469 Ile Cys Asp Asp Asp Asn Asn Met His Leu Tyr Glu Pro 1 5 10 470 13 PRT Artificial Sequence isolated from phage display libraries 470 Ile Asp Asp Ser His Leu Asn Asp Gln Cys Arg Asp Asp 1 5 10 471 13 PRT Artificial Sequence isolated from phage display libraries 471 Ile Asn Cys Asn Asn Asn Asn Ser Leu Asn Asn Asn Asn 1

5 10 472 13 PRT Artificial Sequence isolated from phage display libraries 472 Ile Asn Asn Val Val Tyr Asn Leu His Asp Arg Asn Asn 1 5 10 473 13 PRT Artificial Sequence isolated from phage display libraries 473 Ile Ser Asn Cys Asn Ile Asn Asn Gly Asn Asn Asp Ser 1 5 10 474 13 PRT Artificial Sequence isolated from phage display libraries 474 Ile Ser Asn Arg Gln Ser Asn Thr Ser Asn Gly Met Ser 1 5 10 475 13 PRT Artificial Sequence isolated from phage display libraries 475 Lys Phe Ser Ser Leu His Asn Ile Ser Gly Pro Lys Ser 1 5 10 476 13 PRT Artificial Sequence isolated from phage display libraries 476 Lys Asn Leu Asn Gln Asn Asn Asn Asn His Phe Asn Asn 1 5 10 477 13 PRT Artificial Sequence isolated from phage display libraries 477 Lys Asn Arg Val Asn Lys Asn Thr Asn Val His Cys Phe 1 5 10 478 13 PRT Artificial Sequence isolated from phage display libraries 478 Leu Ser Asn Leu Asn Tyr Asn Pro Asn His His Asp Met 1 5 10 479 13 PRT Artificial Sequence isolated from phage display libraries 479 Met Arg Ser Ser Ser Phe Asn Phe Gly Ser Phe Asp Gln 1 5 10 480 13 PRT Artificial Sequence isolated from phage display libraries 480 Met Ser Asn Ser Ser Ser Asn Ser Ser Ser Ser Ser Gly 1 5 10 481 13 PRT Artificial Sequence isolated from phage display libraries 481 Met Tyr Ser Asn Tyr Tyr Asn Phe Leu Gln Lys Ser Trp 1 5 10 482 13 PRT Artificial Sequence isolated from phage display libraries 482 Asn Asp Arg Asn Asp His Asn Gln His Arg Tyr Asp His 1 5 10 483 13 PRT Artificial Sequence isolated from phage display libraries 483 Asn Glu Met Trp Asn Asn Asn Asn Val Met Asn His His 1 5 10 484 13 PRT Artificial Sequence isolated from phage display libraries 484 Asn Glu Asn Glu Asn Asp Asn Asn Met Asn Met Glu Ile 1 5 10 485 13 PRT Artificial Sequence isolated from phage display libraries 485 Asn Asn Asn Ser Asn His Asn Asp Pro Thr Asn Ala Glu 1 5 10 486 13 PRT Artificial Sequence isolated from phage display libraries 486 Asn Asn Val Leu Asn His Asn Cys Asn Met Phe Leu Asn 1 5 10 487 13 PRT Artificial Sequence isolated from phage display libraries 487 Asn Pro Thr Lys Asn Arg Asn Thr His Leu Gly Gly Arg 1 5 10 488 13 PRT Artificial Sequence isolated from phage display libraries 488 Asn Arg Glu Val Lys Asn Asn Arg Gln Lys Val Phe Lys 1 5 10 489 13 PRT Artificial Sequence isolated from phage display libraries 489 Asn Arg Asn Asn His Phe Asn Asn Glu Tyr Glu Trp Asn 1 5 10 490 13 PRT Artificial Sequence isolated from phage display libraries 490 Asn Thr Asp Leu Asn Asn Asn Gln Thr Val Ser Asn Arg 1 5 10 491 13 PRT Artificial Sequence isolated from phage display libraries 491 Pro Asp Asp Ala Pro His Asn Tyr Cys Thr Asp Pro Leu 1 5 10 492 13 PRT Artificial Sequence isolated from phage display libraries 492 Pro Lys Asp Asp Arg Asn Asn Thr Val Ala Ser Cys Glu 1 5 10 493 13 PRT Artificial Sequence isolated from phage display libraries 493 Pro Val Asn Tyr Ala Asn Asn Pro Glu Arg Val Gly His 1 5 10 494 13 PRT Artificial Sequence isolated from phage display libraries 494 Pro Tyr Asn Gly Ser Asn Asn Asn Asn Ala Thr Val Pro 1 5 10 495 13 PRT Artificial Sequence isolated from phage display libraries 495 Gln Asn Ser Gln His Asn Asn His His Cys Val Leu Gly 1 5 10 496 13 PRT Artificial Sequence isolated from phage display libraries 496 Arg Ser Ser Ser Ser Gly Asn Ser Ser His His His Met 1 5 10 497 13 PRT Artificial Sequence isolated from phage display libraries 497 Ser Glu Ser Asn Ser Asn Asn Pro Gly His Asn Leu Pro 1 5 10 498 13 PRT Artificial Sequence isolated from phage display libraries 498 Ser Phe Leu Asn Asn Cys Asn His Asn Lys Leu Met Ser 1 5 10 499 13 PRT Artificial Sequence isolated from phage display libraries 499 Ser Ile Phe Asn Ser Ser Asn His Thr His Gln Ser Met 1 5 10 500 13 PRT Artificial Sequence isolated from phage display libraries 500 Ser Asn Met Asp Ser Ser Asn Ala Pro Gln Ser Trp Val 1 5 10 501 13 PRT Artificial Sequence isolated from phage display libraries 501 Ser Asn Ser Trp Asn Asn Asn Glu Asp Lys His Ile Leu 1 5 10 502 13 PRT Artificial Sequence isolated from phage display libraries 502 Ser Arg Ser Gly Trp Ser Asn Tyr Phe Cys Ser Arg Gln 1 5 10 503 13 PRT Artificial Sequence isolated from phage display libraries 503 Ser Ser Met Leu His Asn Asn Pro Trp Ser Lys Trp Ser 1 5 10 504 13 PRT Artificial Sequence isolated from phage display libraries 504 Ser Ser Asn Gln Val Ile Asn Thr Phe Glu Asp Leu Gln 1 5 10 505 13 PRT Artificial Sequence isolated from phage display libraries 505 Ser Ser Gln Ser Met Pro Asn Gly Ser Gly Lys Glu Thr 1 5 10 506 13 PRT Artificial Sequence isolated from phage display libraries 506 Ser Val Ser Cys Ser Cys Asn Thr Ser Arg Gly Cys Ser 1 5 10 507 13 PRT Artificial Sequence isolated from phage display libraries 507 Ser Val Ser Ser Lys Ser Asn Glu Ile Ser Phe Cys Thr 1 5 10 508 13 PRT Artificial Sequence isolated from phage display libraries 508 Thr Asp Ser Gly Ser Ser Asn Ser Ala Lys Ala Ile Cys 1 5 10 509 13 PRT Artificial Sequence isolated from phage display libraries 509 Thr Asn Trp Cys Ser Ser Asn Val Gly Ser Asn Thr Ser 1 5 10 510 13 PRT Artificial Sequence isolated from phage display libraries 510 Thr Ser Ser Trp Ser Phe Asn Gly Thr Asn Gly Ser Ala 1 5 10 511 13 PRT Artificial Sequence isolated from phage display libraries 511 Val Ala Asp Ser Phe Asp Asn Ala Asn Tyr Thr Leu Asp 1 5 10 512 13 PRT Artificial Sequence isolated from phage display libraries 512 Val Asp Asp Gln Tyr Asp Asn Trp Asp Ile Arg Asp Cys 1 5 10 513 13 PRT Artificial Sequence isolated from phage display libraries 513 Tyr Asn Gly Asn Tyr His Asn His Gly Leu Asn Ile Arg 1 5 10 514 13 PRT Artificial Sequence isolated from phage display libraries 514 Cys Phe Val Leu Asn Cys His Leu Val Leu Asp Arg Pro 1 5 10 515 13 PRT Artificial Sequence isolated from phage display libraries 515 Cys Arg Arg Pro Phe Glu His Ala Leu Phe Tyr Ala Ser 1 5 10 516 13 PRT Artificial Sequence isolated from phage display libraries 516 Asp Ser Trp Leu Leu Ser His Ser Arg Ser Lys Ser Met 1 5 10 517 13 PRT Artificial Sequence isolated from phage display libraries 517 Asp Ser Trp Trp Thr Gln His Ser Gln Ala His Ser Asp 1 5 10 518 13 PRT Artificial Sequence isolated from phage display libraries 518 Asp Thr Asn Met Leu Asn His Gly Met Tyr Gly His Cys 1 5 10 519 13 PRT Artificial Sequence isolated from phage display libraries 519 Glu Asn Ile Asn Ala Ser His Cys Leu Ser Thr Val Asp 1 5 10 520 13 PRT Artificial Sequence isolated from phage display libraries 520 Phe Phe Ser Tyr Ser Gly His Leu Val Gln Lys Val Trp 1 5 10 521 13 PRT Artificial Sequence isolated from phage display libraries 521 Phe Met Phe Ala Val Trp His Asp Gly His Ile Lys Asn 1 5 10 522 13 PRT Artificial Sequence isolated from phage display libraries 522 Phe Met Ser Gln His Phe His Asn Pro Met Met Ile Arg 1 5 10 523 13 PRT Artificial Sequence isolated from phage display libraries 523 Phe Val Phe Tyr Ile Met His Tyr Cys Gly His Phe Met 1 5 10 524 13 PRT Artificial Sequence isolated from phage display libraries 524 His Phe Lys Asp Asp Asp His Met Met Leu Tyr Gly Pro 1 5 10 525 13 PRT Artificial Sequence isolated from phage display libraries 525 His Thr Gln His Arg Leu His Val Gly Gln Ser Ser Ser 1 5 10 526 13 PRT Artificial Sequence isolated from phage display libraries 526 Ile Ser Asn Ser Trp Tyr His Trp Ser Trp Glu Met Trp 1 5 10 527 13 PRT Artificial Sequence isolated from phage display libraries 527 Leu Cys Phe Tyr Glu Tyr His Phe Met Gln Cys Ala Met 1 5 10 528 13 PRT Artificial Sequence isolated from phage display libraries 528 Leu Gly Leu Ser Asp Ser His Tyr Glu Cys Ser Phe Arg 1 5 10 529 13 PRT Artificial Sequence isolated from phage display libraries 529 Leu Arg Ser Thr Ser Phe His Phe Arg Cys Ala Lys Cys 1 5 10 530 13 PRT Artificial Sequence isolated from phage display libraries 530 Leu Ser Val Phe Ser His His Lys Trp Val Tyr Thr Ser 1 5 10 531 13 PRT Artificial Sequence isolated from phage display libraries 531 Met Ala Met His His Met His His Met Ala Asn Asn Leu 1 5 10 532 13 PRT Artificial Sequence isolated from phage display libraries 532 Met Ser Ser Phe Asp Val His Arg Ser His Thr Asn Ser 1 5 10 533 13 PRT Artificial Sequence isolated from phage display libraries 533 Pro Gly Ser Leu Ser Glu His Ile Tyr Gln Ala Trp Ser 1 5 10 534 13 PRT Artificial Sequence isolated from phage display libraries 534 Pro Ser Ser Ala Ser Met His Ile Ala Ser Ser Cys Ile 1 5 10 535 13 PRT Artificial Sequence isolated from phage display libraries 535 Gln Tyr Trp Trp Ile Trp His Lys Ser Asp Ser Gly Ser 1 5 10 536 13 PRT Artificial Sequence isolated from phage display libraries 536 Ser Gly Gln Ser Asn Ser His His Asp Lys Thr Ile Cys 1 5 10 537 13 PRT Artificial Sequence isolated from phage display libraries 537 Ser Gly Gln Ser Val Phe His His Phe Phe Pro Asn Asp 1 5 10 538 13 PRT Artificial Sequence isolated from phage display libraries 538 Ser His Val Ser Leu Tyr His Ala Ser Thr Asp Ser Asp 1 5 10 539 13 PRT Artificial Sequence isolated from phage display libraries 539 Ser Met Ser Ser Ser Lys His Met Asp Met Asp Cys Phe 1 5 10 540 13 PRT Artificial Sequence isolated from phage display libraries 540 Ser Ser Cys Leu Pro Ser His Val Arg Ser Asp Thr Lys 1 5 10 541 13 PRT Artificial Sequence isolated from phage display libraries 541 Ser Ser Gly Met Ser Glu His Thr Pro Leu Cys Ser Glu 1 5 10 542 13 PRT Artificial Sequence isolated from phage display libraries 542 Ser Ser Pro Ser Phe Pro His Met Trp Ser Glu Asp Glu 1 5 10 543 13 PRT Artificial Sequence isolated from phage display libraries 543 Val His Ser Glu Ser Trp His Ser Tyr Ser Ile His Ala 1 5 10 544 13 PRT Artificial Sequence isolated from phage display libraries 544 Val Asn Asn Ala Met Gly His Met Gly Met Met Trp Cys 1 5 10 545 13 PRT Artificial Sequence isolated from phage display libraries 545 Val Ser Cys Ser Ser Arg His Tyr Ser Ile Ser Trp Ser 1 5 10 546 13 PRT Artificial Sequence isolated from phage display libraries 546 Trp Thr Trp Lys Arg Gln His His Arg Ser Ser Leu Tyr 1 5 10 547 13 PRT Artificial Sequence isolated from phage display libraries 547 Tyr Ile Ser Phe Phe Glu His Gly Gln Ile Val Asp Ser 1 5 10 548 19 PRT Artificial Sequence isolated from phage display libraries 548 Ser Cys Leu Val Phe Met Arg Pro Tyr Phe Leu Leu Val Phe Leu Met 1 5 10 15 Cys Trp Ser 549 19 PRT Artificial Sequence isolated from phage display libraries 549 Ser Cys Thr Phe Gly Phe Pro Cys Val Met Ser Leu Val Asn His Val 1 5 10 15 Pro Ser Ser 550 19 PRT Artificial Sequence isolated from phage display libraries 550 Ser Cys Leu Tyr Cys Leu Asn Tyr Ala Asn Phe Ser Asp Pro Met Thr 1 5 10 15 Met Phe Ser 551 13 PRT Artificial Sequence isolated from phage display libraries 551 Gly Phe Ala Trp Ser Ser Tyr Leu Gly Thr Thr Val His 1 5 10 552 13 PRT Artificial Sequence isolated from phage display libraries 552 Leu Phe Gly Pro Ile Glu Tyr Thr Gln Phe Leu Ala Asn 1 5 10 553 13 PRT Artificial Sequence isolated from phage display libraries 553 Phe Phe Ser Phe Phe Phe Pro Ala Ser Ala Trp Gly Ser 1 5 10 554 20 PRT Artificial Sequence isolated from phage display libraries 554 Phe Phe Ser Phe Phe Phe Pro Ala Ser Ala Trp Gly Ser Ser Gly Ser 1 5 10 15 Ser Arg Gly Asp 20 555 12 PRT Artificial Sequence isolated from phage display libraries 555 Leu Leu Ser Leu Leu Leu Pro Gly Ser Ser Gly Lys 1 5 10 556 12 PRT Artificial Sequence isolated from phage display libraries 556 Ile Ile Ser Ile Ile Ile Pro Gly Ser Ser Gly Lys 1 5 10 557 12 PRT Artificial Sequence isolated from phage display libraries 557 Phe Trp Ser Phe Trp Phe Pro Gly Ser Ser Gly Lys 1 5 10 558 32 PRT Artificial Sequence isolated from phage display libraries 558 Ser Cys Ser Asp Cys Leu Lys Ser Val Asp Phe Ile Pro Ser Ser Leu 1 5 10 15 Ala Ser Ser Ser Ser Gly Arg Gly Asp Ser Pro Gly Arg Gly Asp Ser 20 25 30

Claims

1-9. (canceled)

10. A medical device having an interfacial biomaterial coating on a portion of the surface thereof which inhibits formation of a biofilm thereon wherein the interfacial biomaterial comprises a plurality of moieties each moiety comprising: a) a binding module comprising a peptide of at least 3 amino acids to about 50 amino acids and having a binding affinity for the surface of the medical device to be coated of 1.times.10.sup.4M.sup.-1; b) an affector module selected from the group consisting of: 1) a peptide of at least 3 amino acids to about 50 amino acids that acts to inhibit formation of the biofilm adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 2) a peptide of at least 3 amino acids to about 50 amino acids having a binding affinity of 1.times.10.sup.4M.sup.-1 for a protein bound thereto that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 3) a peptide of at least 3 amino acids to about 50 amino acids having a binding affinity of 1.times.10.sup.4M.sup.-1 for a non-protein bound thereto that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 4) a non-peptide that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; c) a linker module that links the binding module to the affector module.

11. A device according to claim 10 wherein the medical device is a patient implant.

12. A device according to claim 10 wherein the medical device is a medical conduit.

13. A device according to claim 10 wherein the medical device is a storage device for biological materials.

14. An interfacial biomaterial for coating at least a portion of the surface of a selected medical device which comprises a plurality of moieties each moiety comprising: a) a binding module comprising a peptide of at least 3 amino acids to about 50 amino acids and having a binding affinity for the surface of the medical device to be coated of 1.times.10.sup.4M.sup.-1; b) an affector module selected from the group consisting of: 1) a peptide of at least 3 amino acids to about 50 amino acids that acts to inhibit formation of the biofilm adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 2) a peptide of at least 3 amino acids to about 50 amino acids having a binding affinity of 1.times.10.sup.4M.sup.-1 for a protein bound thereto that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 3) a peptide of at least 3 amino acids to about 50 amino acids having a binding affinity of 1.times.10.sup.4M.sup.-1 for a non-protein bound thereto that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; 4) a non-peptide that acts to inhibit formation of adhesion to the medical device by at least 5% compared to the surface of the medical device that is coated; c) a linker module that links the binding module to the affector module.

15. An interfacial biomaterial according to claim 14 wherein the affector module binds the biofilm inhibitor albumin.

16. An interfacial biomaterial according to claim 14 wherein the affector module inhibits biofilm formation by damaging cells capable of forming a biofilm.

17. An interfacial biomaterial according to claim 16 wherein the affector module is an anti-microbial or where the affector module binds an antimicrobial.

18. An interfacial biomaterial according to claim 14 wherein the affector module affects a regulatory mechanism of cells capable of forming a biofilm where the regulatory mechanism is involved in the cells establishment of or participation in biofilm formation.

19. An interfacial biomaterial according to claim 18 wherein the affector module is a quorum-sensing inhibitor.

20. An interfacial biomaterial according to claim 19 wherein the affector module is RIP.

21. An interfacial biomaterial according to claim 14 wherein the affector module is poly(ethylene glycol).