AU2007202546B2 - IGF antagonist peptides - Google Patents

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant: GENENTECH, INC. Invention Title: IGP ANTAGONIST PEPTIDES The following statement is a full description of this invention, including the best method for performing it known to us: - la IGF ANTAGONIST PEPTIDES Background of the Invention 5 Field of the Invention This invention is directed to peptides that antagonize insulin-like growth factor (IGF), in particular, IGF-I. These peptides are useful in treating disorders caused or mediated by IGFs, such as cancer. The entire disclosure in the complete specification of our Australian Patent Application No. 10 2002248609 is by this cross-reference incorporated into the present specification. Description of Related Disclosures All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the 15 accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. There is a large body of literature on the actions and activities of IGFs (IGF-1, IGF-2, and IGF 20 variants). Human IGF- I is a 7649-dalton polypeptide with a pl of 8.4 (Rinderknecht and Humbel, Proc. Natl. Acad. Sci. USA, 73: 2365 (1976); Rinderknecht and Humbel, J. Biol. Chem., 253: 2769 (1978)) belonging to a family of somatomedins with insulin-like and mitogenic biological activities that modulate the action of growth hormone (GH) (Van Wyk et al., Recent Prog. Horm. Res., 30: 259 (1974); Binoux, Ann. Endocrinol., 41: 157 (1980); Clemmons and Van Wyk, Handbook Exp. Pharmacol., 57: 161 (1981); 25 Baxter, Adv. Clin. Chem., 25: 49(1986); U.S. Pat. No. 4,988,675; WO 91/03253; WO 93/23071). IGFs are structurally similar to insulin, and have been implicated in a variety of cellular functions and disease processes. Thus, IGF has been suggested as a therapeutic tool in a variety of diseases and injuries (for review, see Lowe, Scientific American (March/April 1996), p. 62). The IGF system is also composed of membrane-bound receptors for IGF-l, IGF-2, and insulin. 30 The Type I IGF receptor (IGF-IR) is closely related to the insulin receptor in structure and shares some of its signaling pathways (Jones and Clermons, Endocr. Rev., 16: 3-34 (1995)). The IGF-2 receptor is a clearance receptor that appears not to transmit an intracellular signal (Jones and Clemmons, supra). Since IGF-l and IGF-2 bind to IGF-IR with a much higher affinity than to the insulin receptor, it is most likely that most of the effects of IGF-l and IGF-2 are mediated by IGF-1R (Humbel, Eur. J Biochem. 35 190:445-462 (1990); Ballard et al., "Does IGF-1 ever act through the insulin receptor?", in Baxter et al. (Eds.), The Insulin-Like Growth Factors and Their Regulatory Proteins, (Amsterdam: Elsevier, 1994), pp 131-138). The crystal structure of the first three domains of IGF-I R has been determined (Garrett et al., Nature, 394, 395-399 (1998)). N;\Melbourne\Cases\Patent.\50000-50999\P50620.AU.1\Specis\P50620.AU.1 Specification 2007-6-1.doc 1/06/07 - lb IGF- I R is a key factor in normal cell growth and development (Daughaday and Rotwein, Endocrine Rev., 10:68-91 (1989)). Increasing evidence suggests, however, that IGF-IR signaling also plays a critical role in growth of tumor cells, cell transformation, and tumorigenesis (Baserga, Cancer Res, 55:249-252 (1995); for a review, see Khandwala et al., Endocr. Rev., 2 1: 215-244 (2000)). Key 5 examples include loss of metastatic phenotype of murine carcinoma cells by treatment with antisense RNA to the IGF-IR (Long et al., Cancer Res., 55:1006-1009 (1995)) and the in vitro inhibition of human melanoma cell motility (Stracke et al., J Biol. Chem., 264:21554-21559 (1989)) and of human breast cancer cell growth by the addition of IGF-IR antibodies (Rohlik et al., Biochem. Biophys. Res. Commun., 149:276- 281 (1987)). 10 The IGFs are potent breast cancer cell mitogens based on the observation that IGF-I enhanced breast cancer cell proliferation in vitro (Cullen et al., Cancer Res., 50:48-53 (1990)). Breast cancers express IGF-2 and IGF-IR, providing all the required effectors for an autocrine-loop-based proliferation paradigm N:\Melbourne\Cases\Patent\50000-50999\P50620.AU.l\Specis\P50620.AU.1 Specification 2007-6-1.doc 1/06/07 (Quinn et al., J Biol. Chem., 2L.:l 1477-11483 (1996); Steller et al., Cancer Res., 56:1761-1765 (1996)). Because breast cancer is a common malignancy affecting approximately one in every eight women and is a leading cause of death from cancer in North American women (LeRoith et al., Ann. Int. Med., 122:54-59 ( 1995)), new rational therapies are required for intervention. IGF-l can suppress apoptosis, and therefore 5 cells lacking IGF-lRs or having compromised IGF-IR signaling pathways may give rise to tumor cells that selectively die via apoptosis (Long et al., Cancer Res,, 5:1006-1009 (1995)). Furthermore, it has recently become evident that alterations in IGF signaling in the context of other disease states, such as diabetes, may be responsible for exacerbating the complications of retinopathy (Smith et al., Science, 276:1706-1709 (1997)) and nephropathy (Horney et al., Am. J Physiol. 274: F1045-Fl053 (1998)). 10 - The IGF binding proteins (IGFBPs) are a family of at least six proteins (Jones and Clemmons, supra; Bach and Rechler, Diabetes Reviews, 3 38-61 (1995)), that modulate access of the IGFs to the IGF I R. They also regulate the concentrations of IGF-I and IGF-2 in the circulation and at the level of the tissue IGF- I R (Clemmons et al., Anal. NY Acad. Sci. USA, 692:10-21 (1993)). The IGFBPs bind IGF-I and IGF 2 with varying affinities and specificities (Jones and Clemmons, supra; Bach and Rechler, supra). For 15 example, IGFBP-3 binds IGF- I and IGF-2 with a similar affinity, whereas IGFBP-2 and IGFBP-6 bind IGF 2 with a much higher affinity than they bind IGF-I (Bach and Rechler, supra; Oh et al., Endocrinology, 132, 1337-1344 (1993)). In most cases, addition of exogenous IGFBP blunts the effects of IGF-l. For example, the growth stimulating effect of estradiol on the MCF-7 human breast cancer cells is associated with decreased IGFBP-3 20 mRNA and protein accumulation, while the anti-estrogen ICI 182780 causes growth inhibition and increased IGFBP-3 mRNA and protein levels (Huynh et al., J Biol. Chem., 22]:1016-1021 (1996); Oh et al., Prop. Growth Factor Res., 6:503-512 (1995)). It has also been reported that the in vitro inhibition of breast cancer cell proliferation by retinoic acid may involve altered IGFBP secretion by tumor cells or decreased circulating IGF-l levels in vivo (LeRoith er al., Ann. Int. Med., 122:54-59 (1995); Oh et al., (1995), supra). 25 Contrary to this finding, treatment of MCF-7 cells with the anti-estrogen tamoxifen decreases IGF-IR signaling in a manner that is unrelated to decreased IGFBP production (Lee et al., J Endocrinol., 152:39 (1997)). Additional support for the general anti-proliferative effects of the IGFBPs is the striking finding that IGFBP-3 is a target gene of the tumor suppressor, p53 (Buckbinder et al., Nature, 377:646-649 (1995)). This suggests that the suppressor activity of p 5 3 is, in part, mediated by IGFBP-3 production and the 30 consequential blockade of IGF action (Buckbinder et al., supra). These results indicate that the IGFBPs can block cell proliferation by modulating paracrine/autocrine processes regulated by IGF-l/IGF-2. A corollary to these observations is the finding that prostate-specific antigen (PSA) is an IGFBP-3-protease, which upon activation, increases the sensitivity of tumor cells to the actions of IGF-l/IGF-2 due to the proteolytic inactivation of IGFBP-3 (Cohen et al., J. Endocr., 142:407-415 (1994)). The IGFBPs complex with IGF 35 ]/IGF-2 and interfere with the access of IGF- I/IGF-2 to IGF-lRs (Clemmons et al., Anal. NY Acad. Sci. USA, 692:10-21 (1993)). IGFBP-1, -2 and -3 inhibit cell growth following addition to cells in vitro (Lee et al. , J Endocrinol., J52:39 (1997); Feyen et al., J Biol. Chem., 266:19469-19474 (1991)). Further, IGFBP- I (McGuire et al., J NatI. Cancer Inst., 84:1335-1341(1992); Figueroa et al., J Cell Physiol., 15:229-236 (1993)), IGFBP-3 (Oh et al. (1995), supra; Pratt and Pollak, Biophys. Res. Commun., 198:292-297 (1994)) 40 and IGFBP-2 have all been shown to inhibit IGF- I or estrogen-induced breast cancer cell proliferation at nanomolar concentrations in vitro. These findings support the idea that the IGFBPs are potent antagonists of 2 IGF action. There is also evidence for a direct effect of IGFBP-3 on cells through its own cell surface receptor, independent of IGF interactions (Oh et al., J Biol. Chem., 268:14964-14971 (1993); Valentinis et al., Mol. Endocrinol., 9:361-367 (1995)). Taken together, these findings underscore the importance of IGF and IGF-IR as targets for therapeutic use. 5 Unlike most other growth factors, the IGFs are present in high concentrations in the circulation, but only a small fraction of the IGFs is not protein bound. For example, it is generally known that in humans or rodents, less than 1% of the IGFs in blood is in a "free" or unbound form (Juul et al., Clin. Endocrinol., 44: 515-523 (1996); Hizuka et al., Growth Regulation, 1: 5 1-55 (1991); Hasegawa et al., J. Clin. Endocrinol. Metab., 80: 3284-3286 (1995)). The overwhelming majority of the IGFs in blood circulate as part of a non 10 covalently associated ternary complex composed of IGF-1 or IGF-2, IGFBP-3, and a large protein termed the acid-labile subunit (ALS). This complex is composed of equimolar amounts of each of the three components. The ternary complex of an IGF, IGFBP-3, and ALS has a molecular weight of approximately 150,000 daltons, and it has been suggested that the function of this complex in the circulation may be to serve as a reservoir and buffer for IGF-1 and IGF-2, preventing rapid changes in free IGF-l or IGF-2. 15 Maintaining normal levels of IGF-1 signaling are important for proper cellular function, since both down-and up-regulation of IGF-1-related pathways have been implicated in several human diseases. The rate of cell proliferation is positively correlated with risk of transformation of certain epithelial cell types (Cohen and ElI wein, Science, 249: 1007 (1990); Cohen and Ellwein, Cancer Research, 51:6493 (1991)). Relatively high plasma IGF- I and low IGF binding protein-3 levels are associated with greater risk of breast cancer in 20 pre-menopausal women, prostate cancer in men, colorectal cancer in men and women, and lung cancer in men and women; additional in vitro and in vivo studies reflecting a link between IGF and cancer are found in "Insulin-Like Growth Factors and Cancer", Cytokine Bulletin, R&D Systems (Fall 2000 edition), pages 2-3. IGFs have mitogenic and anti-apoptotic influences on normal and transformed prostate epithelial cells (Hsing et al., Cancer Research, 5: 5146 (1996); Culig et al., Cancer Research, 54: 5474 (1994); Cohen et al., 25 Hormone and Metabolic Research, 26: 81 (1994); Iwamura et al., Prostate, 22: 243 (1993); Cohen et al., I Clin. Endocrin. & Metabol., 73: 401 (1991); Rajah et al., J. Biol. Chem., 272: 12181 (1997)). Most circulating IGF-I originates in the liver, but IGF bioactivity in tissues is related not only to levels of circulating IGFs and IGFBPs, but also to local production of IGFs, IGFBPs, and IGFBP proteases (Jones and Clemmons, Endocrine Reviews, 16: 3 (1995)), Person-to-person variability in levels of circulating IGF-1 and 30 IGFBP-3 (the major circulating IGFBP (Jones and Clemmons, supra)) is considerable (Juul et al., J. Clin. Endocrinol. & Metabol., 78: 744 (1994); Juul et al., J. Clin. Endocrinol. & Metabol., 80: 2534 (1995)), and heterogeneity in serum IGF-1 level appears to reflect heterogeneity in tissue IGF bioactivity. Markers relating to IGF-axis components can be used as a risk marker for prostate cancer, as PSA is likewise used (WO 99/3801 1). Further, it has been found that reduced IGF-I concentrations in serum correlate with 35 improved clinical scores in acromegaly patients (Trainer et al., New England J. Med., 342: 1171-1177 (2000)). There has been much work identifying the regions on IGF- I and IGF-2 that bind to the IGFBPs (Bayne et al., J. Biol. Chem., 265: 15648-15652 (1990); Dubaquie and Lowman, Biochemistry, : 6386 6396 (1999); and U.S. Pat. Nos. 5,077,276; 5,164,370; and 5,470,828). For example, it has been discovered 40 that the N-terminal region of IGF-1 and IGF-2 is critical for binding to the IGFBPs (U.S. Pat. Nos. 5,077,276; 3 5,164,370; and 5,470,828). Thus, the natural IGF-I variant, designated des (l-3) IGF-l, binds poorly to IGFBPs. A similar amount of research has been devoted to identifying the regions on IGF-I and IGF-2 that bind to IGF-lR (Bayne et al.,supra; Oh etal., Endocrinology (1993), supra). It was found that the tyrosine 5 residues in IGF- I at positions 24, 31, and 60 are crucial to the binding of IGF- I to IGF-I R (Bayne et al., supra). Mutant IGF-I molecules where one or more of these tyrosine residues are substituted showed progressively reduced binding to IGF- I R. Bayne et al., supra, also investigated whether such mutants of IGF-l could bind to IGF-I R and to the IGFBPs. They found that quite different residues on IGF-I and IGF-2 are used to bind to the IGFBPs from those used to bind to IGF-IR. It is therefore possible to produce IGF 10 variants that show reduced binding to the IGFBPs, but, because they bind well to IGF-IR, show maintained activity in in vitro activity assays. Also reported was an IGF variant that binds to IGFBPs but not to IGF receptors and therefore shows reduced activity in in vitro activity assays (Bar et al., Endocrinology, 127: 3243-3245 (1990)). In this variant, designated (1-27,gly , 38-70)-hIGF- 1, residues 28-37 of the C region of human IGF- I are replaced 15 by a four-residue glycine bridge. Other truncated IGF-1 variants are disclosed. For example, in the patent literature, WO 96/33216 describes a truncated variant having residues 1-69 of authentic IGF-l. EP 742,228 discloses two-chain IGF-l superagonists, which are derivatives of the naturally occurring, single-chain IGF- I having an abbreviated C region. The IGF-I analogs are of the formula: BC",A 20 wherein B is the B region of IGF-l or a functional analog thereof, C is the C region of IGF-l or a functional analog thereof, n is the number of amino acids in the C region and is from about 6 to about 12, and A is the A region of IGF-I or a functional analog thereof. Additionally, Cascieri et al., Biochemistry, 21: 3229-3233 (1988) discloses four mutants of IGF- 1, three of which have reduced affinity to IGF- I R. These mutants are: (Phe ,Phe24 25 )IGF- I (which is 24 25 equipotent to human IGF-I in its affinity to the Types I and 2 IGF and insulin receptors), (Leu )IGF-l and (Ser 24)IGF- I (which have a lower affinity than IGF- I to the human placental IGF- I R, the placental insulin receptor, and the IGF-I R of rat and mouse cells), and desoctapeptide (Leu 24)IGF-l (in which the loss of aromaticity at position 24 is combined with the deletion of the carboxyl-terminal D region of hIGF-1, which has lower affinity than (Leu 24)IGF-I for the IGF-IR and higher affinity for the insulin receptor). These four 30 mutants have normal affinities for human serum binding proteins. Bayne et al., J. Biol. Chem., 263: 6233-6239 (1988) discloses four structural analogs of human IGF I: a B-chain mutant in which the first 16 amino acids of IGF-I were replaced with the first 17 amino acids of the B-chain of insulin, (GIn 3,Ala 4)IGF-1, (Tyr ,Leu 16)IGF-1, and (GIn 3,Ala 4Tyr ,Leu 6)IGF-l. These studies identify some of the regions of IGF-l that are responsible for maintaining high-affinity binding with 35 the serum binding protein and the Type 2 IGF receptor. In another study, Bayne et al., J. Biol. Chem., 264: 11004-11008 (1988) discloses three structural analogs of IGF-1: (1-62)IGF-1, which lacks the carboxyl-terminal 8-amino-acid D region of IGF-l; (1 27,Gly ,38-70)IGF- 1, in which residues 28-37 of the C region of IGF- I are replaced by a four-residue glycine bridge; and (1-27,Gly ,38-62)IGF- 1, with a C region glycine replacement and a D region deletion. 4 Peterkofsky et al., Endocrinology, 128: 1769-1779 (1991) discloses data using the Gly 4 mutant of Bayne et al., supra (vol. 264). Cascieri el al., J. Biol. Chem., 2: 2199-2202 (1989) discloses three IGF-1 analogs in which specific residues in the A region of IGF-1 are replaced with the corresponding residues in the A chain of 5 insulin. The analogs are: (lie ,Glu 45,Gln 46,Thr 4,Ser 50,le ,SerS3 55,Gln )IGF.1, an A-chain mutant in which residue 41 is changed from threonine to isoleucine and residues 42-56 of the A region are replaced; (Thr 49,Ser 50,e )IGF-1; and (Tyr 55,Gln 56)IGF-1. Clemmons et al., J. Biol. Chem., 265: 12210-12216 (1990) discloses use of IGF-1 analogs that have 10 reduced binding affinity for either IGF-1 R or binding proteins to study the ligand specificity of IGFBP-1 and the role of IGFBP-1 in modulating the biological activity of IGF-1. WO 94/04569 discloses a specific binding molecule, other than a natural IGFBP, that is capable of binding to IGF-I and can enhance the biological activity of IGF-1. The direction of research into IGF variants has mostly been to make IGF variants that do not bind to 15 the IGFBPs, but show maintained binding to the IGF receptor. The idea behind the study of such molecules is that the major actions of the IGFBPs are proposed to be an inhibition of the activity of the IGFs. Chief among these variants is the natural molecule, des(1-3)IGF-1, which shows selectively reduced affinity for some of the IGF binding proteins, yet a maintained affinity for the IGF receptor (U.S. Pat. Nos. 5,077,276; 5,164,370; 5,470,828). 20 Peptides that bind to IGFBP-1, block IGF-I binding to this binding protein, and thereby release "free-IGF" activity from mixtures of IGF- I and IGFBP- I have been recently described (Lowman et al., Biochemistry, 32: 8870-8878 (1998); WO 98/45427 published October 15, 1998; Lowman et al., International Pediatric Nephrology Association, Fifth Symposium on Growth and Development in Children with Chronic Renal Failure (New York, March 13, 1999)). 25 Exploitation of the interaction between IGF and IGFBP in screening, preventing, or treating disease has been limited, however, because of a lack of specific antagonists. To date, only one publication is known to exist that describes the application of an IGF-l/ IGF- 2 antagonist as a potential therapeutic adjunct in the treatment of cancer (Pietrzkowski et al., Cancer Res., 52: 6447-6451 (1992)). In that report, a peptide corresponding to the D-region of IGF- I was synthesized for use as an IGF-1/2 antagonist. This peptide 30 exhibited questionable inhibitory activity against IGF-l. The basis for the observed inhibition is unclear as the D-region does not play a significant role in IGF- I R binding but rather, in IGF-I binding to the insulin receptor (Cooke et al., Biochem., 30:5484-5491 (1991); Bayne et al., J Biol. Chem., 264:11004-11008 (1988); Yee et al., Cell Growth and Different., 5:73-77 (1994)). IGF antagonists whose mechanism of action is via blockade of interactions at the IGF-IR interface may also significantly alter insulin action at the insulin 35 receptor, a disadvantage of such antagonists. Recently, certain IGF-l antagonists have been described by WO 00/23469, which discloses the portions of IGFBP and IGF peptides that account for IGF-IGFBP binding, i.e., an isolated IGF binding domain of an IGFBP or modification thereof that binds IGF with at least about the same binding affinity as the full-length IGFBP. The patent publication also discloses an IGF antagonist that reduces binding of IGF to 40 an IGF receptor, and/or binds to a binding domain of IGFBP. Disclosed uses of such antagonists and 5 fragments are in treating a subject having cancer and preventing cancer in a subject, treating a subject with a diabetic complication exacerbated by IGF and preventing diabetic complications exacerbated by IGF, or treating a subject with an ischemic injury or preventing an ischemic injury in a subject. Additionally, EP 639981 discloses pharmaceutical compositions comprising short peptides that 5 function as IGF- I receptor antagonists. The peptides used in the pharmaceutical compositions consist of less than 25 amino acids, comprise at least a portion of the C or D region from IGF-1, and inhibit IGF-l-induced autophosphorylation of IGF-1 receptors. Methods of inhibiting cell proliferation and of treating individuals suspected of suffering from or susceptible to diseases associated with undesirable cell proliferation such as cancer, restenosis and asthma are disclosed. 10 Generation of specific IGF-I antagonists has been restricted, at least in part, because of difficulties in studying the structure of IGF and IGFBP. Due to the inability to obtain crystals of IGF-I suitable for diffraction studies, for example, an extrapolation of IGF-1 structure based on the crystal structure of porcine insulin was the most important structural road map for IGF-l available (Blundell et al. , Proc. Nati. Acad. Sci. USA , 75:180- 184 (1978)). See also Blundell et al., Fed, Proc., 42: 2592 (1983), which discloses 15 tertiary structures, receptor binding, and antigenicity of IGFs. Based on studies of chemically modified and mutated IGF-1, a number of common residues between IGF- I and insulin have been identified as being part of the IGF-IR-insulin receptor contact site, in particular the aromatic residues at positions 23-25. Using NMR and restrained molecular dynamics, the solution structure of IGF-1 was recently reported (Cooke el al., supra). The resulting minimized structure was shown to better fit the experimental findings on modified IGF 20 1, as well as the extrapolations made from the structure-activity studies of insulin. Further, De Wolf er al., Protein Sci., 5: 2193 (1996) discloses the solution structure of a mini-IGF-1. Sato et al., Int. J. Pept., 41: 433 (1993) discloses the three-dimensional structure of IGF- 1 determined by 1 H-NMR and distance geometry. Torres et al., J Mol Biol., 248: 385 (1995) discloses the solution structure of human IGF-2 and its relationship to receptor and binding protein interactions. Laajoki et al., J. Biol, Chem., 275: 10009 (2000) discloses the 25 solution structure and backbone dynamics of long-[Arg(3)]IGF-l. Peptide sequences capable of binding to insulin and/or insulin-like growth factor receptors with either agonist or antagonist activity and identified from various peptide libraries are described in WO 01/72771 published October 4, 2001. There is a continuing need in the art for a molecule that acts as an IGF antagonist to control the 30 levels of circulating IGF as well as receptor response, for therapeutic or diagnostic purposes. Summary of the Invention Accordingly, the invention is as claimed. In one aspect the invention provides a peptide of family I comprising the sequence: (Xaa)I(Xaa)2Cys(Xaa)3(Xaa)4SerVal(Xaa)5AlaLeu(Xaa) 6 (Xaa) 7 CysMet(Xaa)s (SEQ ID NO: 1) where (Xaa),, (Xaa)2, and (Xaa)7 are any amino acid, (Xaa)3 is Phe, Leu, or Tyr, (Xaa)4 is 35 Glu, Asp, Ala, Gly, Thr, or Scr, (Xaa)s is Glu, Asp, Ala, or Gly, (Xaa)6 is Arg or Lys, and (Xaa)8 is Tyr or Arg. (Xaa)4 is Glu, Ala, Gly, Thr, or Ser, (Xaa)s is Glu, Ala, or Gly, and (Xaa)8 is Tyr. The preferred peptides of the above sequence are such that (Xaa) 4 is Glu, Ala or Thr, (Xaa)5 is Ala or Gly, and (Xaa) 8 is Tyr. More preferred are the peptides wherein (Xaa) 4 is Glu or Ala, (Xaa)5 is Ala or Gly, and (Xaa) 8 is Tyr. Still more preferred are the peptides comprising the sequence RNCFESVAALRRCMYG (SEQ ID NO:2), 6 -7 MDCLASVEALKWCMYG (SEQ ID NO:3), or FECLTSVEALRGCMYG (SEQ ID NO:4). Most preferred are peptides that comprise SEQ ID NO:2 or 3. In another aspect, the invention provides a peptide of family 2 comprising the sequence: (Xaa),(Xaa) 2 Cys (Xaa) 3 (Xaa) 4 Asp(Xaa)5(Xaa) 6 Gly(Xaa)7(Xaa)sTyrCysTrp(Xaa) 9 (SEQ ID NO:5), where 5 (Xaa),, (Xaa) 4 , and (Xaa) 8 are any amino acid, (Xaa) 2 is Arg, Lys, Gly, Ser, or Thr, (Xaa) 3 is Ala or Val, (Xaa) 5 is Ala or Leu, (Xaa) 6 is Ala, Gly, or Leu, (Xaa) 7 is Phe, Tyr, Trp, or Gly, and (Xaa) is Glu, Asp, Ala, or Gly. The preferred peptides herein are such that (Xaa) 2 is Gly, Ser, Arg, or Thr, and (Xaa) is Glu, Ala, or Asp. More preferred are peptides wherein (Xaa) 2 is Gly or Arg, (Xaa) 5 is Leu, (Xaa) 6 is Ala or Gly, (Xaa) 7 is Phe, and (Xaa) is Ala. The most preferred of this family of peptides are those that 10 comprise the sequence LGCASDLAGFWYCWAG (SEQ ID NO:6) or WRCVDDLGGFQYCWAG (SEQ ID NO:7). Preferably, all the amino acids in these two families of peptides are L-amino acids. Also preferred is that these families of peptides comprise a glycine residue after (Xaa) 8 for family I above or after (Xaa), for family 2 above. 15 The invention also provides conjugates comprising the peptide conjugated with a cytotoxic agent or polyethylene glycol. The cytotoxic agent here may be one that is active in killing cells once internalized. Uses of these peptides include all uses that antagonize at least one biological activity of exogenous or endogenous IGFs. They can be used in treating, inhibiting, or preventing conditions in which an IGF 20 antagonist such as IGFBP-3 or antibodies to IGF-l is useful, as described below. The invention also provides a composition comprising one of the peptides described above in a carrier. Preferably, this composition is sterile and the carrier is a pharmaceutically acceptable carrier. Also preferred is the composition further comprising an angiogenic agent or chemotherapeutic agent, and also one that is suitable for injection or inhalation. A kit is also provided comprising a container 25 containing the composition and instructions directing the user to utilize the composition. In another aspect, the invention provides a method for treating a mammal having a disorder involving an IGF-l-mediated event comprising administering to the mammal an effective amount of any of the peptides or compositions described above. More specifically, the invention provides a method of treating a mammal suffering from, or predisposed to, a disease or disorder involving an IGF-l-mediated 30 event, comprising administering to the mammal a therapeutically effective amount of a peptide as disclosed herein, or of a composition comprising the peptide and a pharmaceutically acceptable carrier. Preferably, this method further comprises administering to the mammal an effective amount of another agent that treats said disorder. This agent may be a growth inhibitory agent, an angiostatic agent, or a cytotoxic agent, or a chemotherapeutic agent or an antibody. In another preferred aspect, the mammal is 35 human. In a further preferred embodiment, before the administration step of the above method, the concentration of IGF-I in a body sample from the mammal is measured, wherein an elevated 17621292 (GHMatters) 1B/09109 - 7a concentration of IGF-I above a reference range for IGF-I indicates an increased risk for the disorder. The body sample is preferably selected from the group consisting of tumor tissue, blood, plasma, serum, mammary fluid, and seminal fluid. In another preferred embodiment, the IGF-1 is total IGF-l, free IGF I or complexed IGF-l, and the disorder is cancer, a diabetic complication exacerbated by IGF-l, 5 preferably diabetic retinopathy or diabetic nephropathy, acromegaly, age-related macular degeneration, ischemic injury, or a trauma. 17621292 (GHMalters) 18/09/09 If the disorder is cancer, preferably it comprises a tumor that expresses an insulin-like growth factor receptor. Further, the cancer is preferably breast cancer, prostate cancer, colorectal cancer, or lung cancer, more preferably breast or prostate cancer. If the disorder is prostate cancer the process preferably comprises, before the administration step, measuring the concentration of PSA in a body sample from the mammal, 5 wherein an elevated concentration of PSA above a reference range for PSA indicates an increased risk for prostate cancer. Alternatively, if the disorder is prostate cancer, the method preferably comprises, before the administration step, measuring the concentration of IGF-I in a body sample from the mammal, measuring the concentration of IGFBP-3 in a body sample from the mammal and conducting a multivariate adjustment of the IGF-l concentration relative to the IGFBP-3 concentration to provide an adjusted IGF-I level, wherein 10 the adjusted IGF-I level above a reference range for adjusted IGF-I indicates an increased risk for prostate cancer. Still alternatively, if the disorder is prostate cancer, the method preferably comprises, before the administration step, measuring the concentration of IGF-1 in a body sample from the mammal, measuring the concentration of IGFBP-3 in a body sample from the mammal, measuring the concentration of PSA in a body sample from the mammal, and conducting a multivariate adjustment of the IGF-t concentration relative to the 15 IGFBP-3 concentration and PSA concentration to provide an adjusted IGF/IGFBP/PSA value, wherein an adjusted IGF/IGFBP/PSA value above a reference range for adjusted IGF/IGFBP/PSA indicates an increased risk for severe prostate cancer. The present invention further provides various dosage forms of any of the peptides of the present invention, including but not limited to, those suitable for parenteral, oral, rectal and pulmonary administration 20 of a peptide. In preferred aspects herein a therapeutic dosage form is provided suitable for inhalation and the invention provides for the therapeutic treatment of diseases or disorders involving an IGF-mediated or associated process or event via pulmonary administration of a peptide of the invention. More particularly, the invention is directed to pulmonary administration of the peptides herein by inhalation. Thus, the present invention provides an aerosol formulation comprising an amount of a peptide of the invention, effective to 25 block or prevent an IGF-mediated or associated process or event and a dispersant. In one embodiment, any one of the above peptides can be provided in a liquid aerosol formulation. Alternatively, the peptide can be provided as a dry powder aerosol formulation. Therefore, according to the present invention, formulations are provided that provide an effective non-invasive alternative to other parenteral routes of administration of the peptides herein for the treatment of IGF-mediated or associated events. 30 Isolated nucleic acid encoding one of the above peptides herein is also provided, and may be used for in vivo or ex vivo gene therapy. Brief Description of the Drawings Figure I shows the three-dimensional minimized mean structure of the peptide IGF-FI-I in solution calculated using restraints derived from NMR data. The backbone fold is depicted as a ribbon, and all side-chains' 35 heavy atoms are shown; several side-chains are labeled. Description of the Preferred Embodiments A. Definitions As used herein, "mammal" for purposes of treatment refers to any animal classified as a mammal, 40 including humans, domestic, and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, 8 sheep, pigs, cows, etc. The preferred mammal herein is a human. The term "non-adult" refers to mammals that are from perinatal age (such as low-birth-weight infants) up to the age of puberty, the latter being those that have not yet reached full growth potential. As used herein, "IGF" refers to native insulin-like growth factor-I and native insulin-like growth 5 factor-2 as well as natural variants thereof such as brain IGF, otherwise known as des(1-3)IGF-l. As used herein, "IGF-1" refers to insulin-like growth factor-I from any species, including bovine, ovine, porcine, equine, and human, preferably human, and, if referring to exogenous administration, from any source, whether natural, synthetic, or recombinant. Human native-sequence, mature IGF-l, more preferably without a N-terminal methionine is prepared, e.g., by the process described in EP 230,869 published August 10 5, 1987; EP 128,733 published December 19, 1984; or EP 288,451 published October 26, 1988. More preferably, this native-sequence IGF-l is recombinantly produced and is available from Genentech, Inc., South San Francisco, CA for clinical investigations. As used herein, "IGF-2" refers to insulin-like growth factor-2 from any species, including bovine, ovine, porcine, equine, and human, preferably human, and, if referring to exogenous administration, from any 15 source, whether natural, synthetic, or recombinant. It may be prepared by the method described in, e.g., EP 128,733, supra. An "IGFBP" or an "1GF binding protein" refers to a protein or polypeptide normally associated with or bound or complexed to IGF-1 or IGF-2, whether or not it is circulatory (i.e., in serum or tissue). Such binding proteins do not include receptors. This definition includes IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, 20 IGFBP-5, IGFBP-6, Mac 25 (IGFBP-7), and prostacyclin-stimulating factor (PSF) or endothelial cell-specific molecule (ESM- I), as well as other proteins with high homology to IGFBPs. Mac 25 is described, for example, in Swisshclm et al., Proc. Nati. Acad. Sci. USA, 92: 4472-4476 (1995) and Oh et al., ]. Biol, Chem., 271: 30322-30325 (1996). PSF is described in Yamauchi et al., Biochemical Journal, 303: 591-598 (1994). ESM-1 is described in Lassalle et al., J. Biol. Chem., 271: 20458-20464 (1996). For other identified 25 IGFBPs, see, e.g., EP 375,438 published 27 June 1990; EP 369,943 published 23 May 1990; WO 89/09268 published 5 October 1989; Wood et al., Molecular Endocrinology, 2: 1176-1185 (1988); Brinkman et al., The EMBO J., 7: 2417-2423 (1988); Lee et al., Mol. Endocrinol., 2: 404-411 (1988); Brewer et al., BBRC, 152: 1289-1297 (1988); EP 294,021 published 7 December 1988; Baxter et al., BBRC, 147: 408-415 (1987); Leung et al., Nature, 330: 537-543 (1987); Martin et al., J. Biol. Chem., 261: 8754-8760 (1986); Baxter et 30 al., Comp, Biochem. Physiol., 91B: 229-235 (1988); WO 89/08667 published 21 September 1989; WO 89/09792 published 19 October 1989; and Binkert et al., EMBO J., 8: 2497-2502 (1989). The term "body sample" refers to a biological specimen from a mammal, preferably from a human, including issues, cells, and body fluid. Examples include tumor tissue, tumor cells, serum, plasma, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, mammary fluid, whole blood, urine, 35 spinal fluid, saliva, sputum, tears, perspiration, mucus, tissue culture medium, tissue extracts, and cellular extracts. Preferably, the body sample is tumor tissue, blood, plasma, serum, mammary fluid, or seminal fluid. As used herein, "human IGF receptor" refers to any receptor for an IGF found in humans and includes the Type I and Type 2 IGF receptors in humans to which both human IGF- I and IGF-2 bind, such as the placental IGF- I R, etc. 40 The term "amino acid" within the scope of the present invention is used in its broadest sense and is meant to include the naturally- occurring L a-amino acids or residues. The commonly used one- and three 9 letter abbreviations for naturally-occurring amino acids are used herein (Lehninger, Biochemistry, 2d ed., pp. 71-92, (Worth Publishers: New York, 1975). The term includes D-amino acids as well as chemically modified amino acids such as amino acid analogs, naturally- occurring amino acids that are not usually incorporated into proteins such as norleucine, and chemically-synthesized compounds having properties 5 known in the art to be characteristic of an amino acid. For example, analogs or mimetics of phenylalanine or proline, which allow the same conformational restriction of the peptide compounds as natural Phe or Pro, are included within the definition of amino acid. Such analogs and mimetics are referred to herein as "functional equivalents" of an amino acid. Other examples of amino acids are listed by Roberts and Vellaccio, The Peptides: Analysis, Synthesis, Biology, Eds. Gross and Meiehofer, Vol. 5, p. 341 (Academic Press, Inc.: N.Y. 10 1983). The term "conservative" amino acid substitution as used herein to refer to amino acid substitutions that substitute functionally-equivalent amino acids. Conservative amino acid changes result in silent changes in the amino acid sequence of the resulting peptide. For example, one or more amino acids of a similar polarity act as functional equivalents and result in a silent alteration within the amino acid sequence of the 15 peptide. The largest sets of conservative amino acid substitutions include: (1) hydrophobic: His, Trp, Tyr, Phe, Met, Leu, Ile, Val, Ala; (2) neutral hydrophilic: Cys, Ser, Thr; (3) polar: Ser, Thr, Asn, Gin; (4) acidic/negatively charged: Asp, Glu; 20 (5) charged: Asp, Glu, Arg, Lys, His; (6) basic/positively charged: Arg, Lys, His; (7) basic: Asn, Gin, His, Lys, Arg; (8) residues that influence chain orientation: Gly, Pro; and (9) aromatic: Trp, Tyr, Phe, His. 25 In addition, "structurally-similar" amino acids can substitute conservatively for some of the specific amino acids. Groups of structurally-similar amino acids include: (Ile, Leu, and Val); (Phe and Tyr); (Lys and Arg); (Gin and Asn); (Asp and Glu); and (Gly and Ala). In this regard, it is understood that amino acids are substituted on the basis of side-chain bulk, charge, and/or hydrophobicity. Amino acid residues are classified into four major groups: 30 Acidic: The residue has a negative charge due to loss of an H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous solution. Basic: The residue has a positive charge due to association with an H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a 35 peptide in which it is contained when the peptide is in aqueous medium at physiological pH. Neutral/non-polar: The residues are not charged at physiological pH and the residue is repelled by aqueous solution so as to seek the inner positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. These residues are also designated "hydrophobic residues." Neutral/polar: The residues are not charged at physiological pH, but the residue is attracted by 40 aqueous solution so as to seek the outer positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium. 10 "Amino acid" residues can be further classified as cyclic or non-cyclic, and aromatic or non aromatic with respect to their side-chain groups, these designations being commonplace to the skilled artisan. The table below shows the types of conservative substitutions that can be made. Original Residue Exemplary Conservative Substitution Preferred Conservative Substitution 5 Ala Val, Leu, Ile Val Arg Lys, Gin, Asn Lys Asn Gin, His, Lys, Arg Gin Asp Glu Glu 10 Cys Ser Ser Gin Asn Asn Glu Asp Asp Gly Pro Pro His Asn, Gin, Lys, Arg Arg 15 Ile Leu, Val, Met, Ala, Phe Lcu Leu Ile, Val, Met, Ala, Phe Ile Lys Arg, Gin, Asn Arg Met Leu, Phe, Ile Leu Phe Leu, Val, Ile, Ala Leu 20 Pro Gly Gly Ser Thr Thr Thr Ser Ser Trp Tyr Tyr Tyr Trp, Phe, Thr, Ser Phe 25 Val Ile, Leu, Met, Phe, Ala Leu Peptides synthesized by the standard solid-phase synthesis techniques described herein, for example, are not limited to amino acids encoded by genes for substitutions involving the amino acids. Commonly encountered amino acids that are not encoded by the genetic code include, for example, those described in WO 90/01940 and in the table below, as well as, for example, 2-amino adipic acid (Aad) for Glu and Asp; 2 30 aminopimelic acid (Apm) for Glu and Asp; 2-aminobutyric (Abu) acid for Met, Leu, and other aliphatic amino acids; 2-aminoheptanoic acid (Ahe) for Met, Leu, and other aliphatic amino acids; 2-aminoisobutyric acid (Aib) for Gly; cyclohexylalanine (Cha) for Val, Leu and Ile; homoarginine (Har) for Arg and Lys; 2,3 diaminopropionic acid (Dpr) for Lys, Arg, and His; N-ethylglycine (EtGly) for Gly, Pro, and Ala; N ethylglycine (EtGly) for Gly, Pro, and Ala; N-ethylasparagine (EtAsn) for Asn, and Gin; hydroxylysine (Hyl) 35 for Lys; allohydroxylysine (AHyl) for Lys; 3-(and 4-)hydroxyproline (3Hyp, 4Hyp) for Pro, Ser, and Thr; allo-isoleucine (Alle) for lIe, Leu, and Val; p-amidinophenylalanine for Ala; N-methylglycine (MeGly, sarcosine) for Gly, Pro, and Ala; N-methylisoleucine (Melle) for Ile; norvaline (Nva) for Met and other aliphatic amino acids; norleucine (Nie) for Met and other aliphatic amino acids; ornithine (Orn) for Lys, Arg and His; citrulline (Cit) and methionine sulfoxide (MSO) for Thr, Asn, and Gin; and N-methylphenylalanine 40 (MePhe), trimethylphenylalanine, halo-(F-, Cl-, Br-, or I-)phenylalanine, or trifluorylphenylalanine for Phe. I I Abbreviations used in the specification Compound Abbreviation Acetyl Ac Alanine Ala 5 3-(2-Thiazolyl)-L-alanine Tza Arginine Arg Asparagine Asn Aspartic acid Asp t-Butyloxycarbonyl Boc 10 Benzotriazol- I -yloxy-tris-(dimethyl amino)phosphonium-hexafluorophosphate Bop P-Alanine PAla P-Valine p Val 15 P-(2-Pyridyl)-alanine Pal(2) P-(3-Pyridyl)-alanine Pal(3) p-(4-Pyridyl)-alanine Pal(4) P-(3-N-Methylpyridinium)-alanine PalMe(3) t-Butyl tBu, But 20 t-Butyloxycarbonyl Boc Caffeic acid Caff Cysteine Cys Cyclohexylalanine Cha Cyclohexylglycine Chg 25 3,5-Dinitrotyrosine Tyr(3,5-No 2 ) 3,5-Diiodotyrosine Tyr(3,5-1) 3,5-Dibromotyrosine Tyr(3,5-Br) 9-Fluorenylmethyloxy-carbonyl Fmoc Glutamine Gln 30 Glutamic acid Glu y-Carboxyglutamic acid Gla G lycine Gly Histidine His Homoarginine hArg 35 3-Hydroxyproline Hyp Isoleucine lie Leucine Leu tert-Leucine Tie Lysine Lys 40 Mercapto-P,P-cyclopentamethylene-propionic acid Mpp 12 Mercaptoacetic acid Mpa Mercaptopropionic acid Mpr Methionine Met l-Naphthylalanine Nal(I) 5 2-Naphthylalanine Nal(2) Nicotinic acid Nic Nipecotic acid Npa N-methyl nicotinic acid NicMe Norarginine nArg 10 Norleucine Nle Norvaline Nva Ornithine Orn Ornithine-derived dimethylamidinium Orn(N-C3H7N) Phenylalanine Phe 15 p-Guanidinophenylalanine Phe(Gua) p-Aminophenylalanine Phe(NH 2 ) p-Chlorophenylalanine Phe(Cl) p-Flurophenylalanine Phe(F) p-Nitrophenylalanine Phe(N0 2 ) 20 p-Hydroxyphenylglycine Pgl(OH) p-Toluenesulfonyl Tos m-Amidinophenylalanine mAph p-Amidinophenylalanine pAph Phenylglycine Pgl 25 Phenylmalonic acid Pma Proline Pro 4-Quinolinecarboxy 4-Qca Sarcosine Sar Serine Ser 30 Threonine Thr Tryptophan Trp Tyrosine Tyr 3-iodotyrosine Tyr(3-l) 0-Methyl tyrosine Tyr(Mc) 35 Valine Val *Amino acids of D configuration are denoted by D-prefix using three-letter code (e.g., D-Ala, D-Cys, D-Asp, D-Trp). "Peptides" include molecules having at least two amino acids and include polypeptides having at least about 60 amino acids. Preferably, the peptides have about 10 to about 60 amino acids, more preferably 13 about 10-25, and most preferably about 12-25 amino acids. The definition includes linear and cyclic peptides, peptide derivatives, their salts, or optical isomers. As used herein, an "amide bond-forming substituent contained in an amino acid side-chain", a "side chain amide bond-forming substituent", and their grammatical variants, are defined to include (1) any 5 carboxy substituent contained in the side-chain ("R" group) of an amino acid wherein the carboxy substituent is capable of forming an amide linkage with an amino group contained in another molecule, i.e., the carboxy substituent reacts with an amino group contained in another molecule to form an amide linkage; and (2) any amino substituent contained in the side-chain ("R" group) of an amino acid wherein the amino substituent is capable of forming an amide linkage with a carboxy group contained in another molecule, i.e., the amino 10 substituent reacts with a carboxy group contained in another molecule to form an amide linkage. As used herein, "differentially-removable" protecting or protective groups are defined as any pair of protective groups capable of protecting a first amide bond-forming substituent and a second amide bond forming substituent, wherein it is possible to deprotect the first amide bond-forming substituent protected with one member of the pair under conditions which do not deprotect the second amide bond-forming 15 substituent protected with the other member of the pair. Differentially-removable protecting groups are also referred to herein as "orthogonal" protecting groups, and the differentially-removable protection conferred by such protective groups is referred to herein as "orthogonal" protection. As used herein, the term "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those 20 prone to having the disorder or diagnosed with the disorder or those in which the disorder is to be prevented. Consecutive treatment or administration refers to treatment on at least a daily basis without interruption in treatment by one or more days. Intermittent treatment or administration, or treatment or administration in an intermittent fashion, refers to treatment that is not consecutive, but rather cyclic in nature. The treatment regime herein can be either consecutive or intermittent. Subjects for whom the preventive measures are 25 appropriate include those with one or more known risk factors for the disorder, such as cancer. As used herein, the term "pulmonary administration" refers to administration of a formulation of the invention through the lungs by inhalation. As used herein, the term "inhalation" refers to intake of air to the alveoli. In specific examples, intake can occur by self-administration of a formulation of the invention while inhaling through a nebulizer or other acrosol-delivery device, or by administration via a respirator, e.g., to a 30 patient on a respirator. The term "inhalation" used with respect to a formulation of the invention is synonymous with "pulmonary administration." As used herein, the term "parenteral" refers to introduction of a peptide of the invention into the body by other than the intestines, and in particular, intravenous (i.v.), intraarterial (i.a.), intraperitoneal (i.p.), intramuscular (i.m.), intraventricular, and subcutaneous (s.c.) routes. 35 As used herein, the term "aerosol" refers to suspension in the air. In particular, aerosol refers to the formation of particles or particulates in a formulation of the invention and its suspension in the air. According to the present invention, an aerosol formulation is a formulation comprising a peptide of the present invention that is suitable for aerosolization, i.e., formation of particles or particulates and suspension in the air, for inhalation or pulmonary administration. 40 As used herein, the term "dispersant" refers to an agent that assists aerosolization of the peptide or absorption of the protein in lung tissue, or both. Preferably, the dispersant is pharmaceutically acceptable. 14 As used herein, the modifier "pharmaceutically-acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. A "disorder" is any condition caused, mediated, or exacerbated by, or associated with, an IGF, 5 preferably IGF-1, that would benefit from treatment with the peptides herein. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question. Non-limiting examples of disorders to be treated herein include diseases associated with undesirable cell proliferation, such as benign tumors, cancer, restenosis, and asthma; acromegaly; inflammatory, angiogenic, or immunological disorders; an ischemic injury such as a stroke, myocardial 10 ischemia, or ischemic injury to the kidneys; diabetic complications such as diabetic retinopathies or neuropathics; eye-related diseases; or neuronal, glial, astrocytal, hypothalamic or other glandular, macrophagal, epithelial, stromal, or blastocoelic disorders. Eye-related disorders include age-related macular degeneration; ophthalmic surgery such as cataract extraction, corneal transplantation, glaucoma filtration surgery, and keratoplasty; surgery to correct refraction, i.e., a radial keratotomy, also in sclera macular holes 15 and degeneration; retinal tears; vitreoretinopathy; cataract disorders of the cornea such as the sequelae of radial keratotomy; dry eye; viral conjunctivitis; ulcerative conjunctivitis; optical wounds such as corneal epithelial wounds; Sjogren's syndrome; macular and retinal edema; vision-limited scarring; and retinal ischemia. Preferably, such disorders are cancer, a diabetic complication, an ischemic injury, acromegaly, restenosis, an eye-related disorder, or asthma. The efficacy of the treatment can be evidenced by a reduction 20 in clinical manifestations or symptoms, including, for example, decreased cell proliferation or growth, improved renal clearance, improved vision, or a reduction in the amount of IGF available for binding to the IGF receptor. The term "effective amount" refers to an amount of a peptide effective to treat a disease or disorder in a mammal. In the case of cancer, the effective amount of the peptide may reduce the number of cancer 25 cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the disorder. To the extent the peptide may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy in vivo can, for example, be measured by assessing the time to 30 disease progression (TTP) and/or determining the response rates (RR). The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, 35 adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck 40 cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade 15 immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Preferably, the cancer 5 comprises a tumQr that expresses an IGF receptor, more preferably breast cancer, lung cancer, colorectal cancer, or prostate cancer, and most preferably breast or prostate cancer. An "another agent that treats the disorder" is any agent other than the peptides herein that in effective amounts will treat the disorder in question. This includes a growth inhibitory agent, an angiostatic agent, or a cytotoxic agent. Preferably, the agent is a chemotherapeutic agent or antibody, preferably a 10 growth-inhibitory antibody, an antibody that induces cell death, or an antibody that induces apoptosis. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g. At 2 t , 131 125 90 186 188 153 .212 32 I , I , Y , Re , Re , Sm , Bi , P and radioactive isotopes of Lu), chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal 15 origin, including fragments and/or variants thereof. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXANTM cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylcnemelamine, 20 trietylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin I and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as 25 chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustinc, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustinc, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin yI and calicheamicin 0 (see, e.g., Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including 30 dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCINT doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and 35 deoxydoxorubicin), cpirubicin, esorubicin, idarubicin, inarcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, strepbozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine 40 analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, 16 enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium 5 acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK@ polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A 10 and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL0 paclitaxel (Bristol Myers Squibb Oncology, Princeton, NJ) and TAXOTERE Vdoxetaxel (Rh6ne-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR' m gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; 15 mitoxantrone; vincristine; NAVELBINE vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone 20 action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEXI" tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LYI 17018, onapristone, and FARESTONTM toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASEm megestrol acetate, AROMASINTm exemestane, 25 formestane, fadrozole, RIVISORTM vorozole, FEMARATM letrozole, and ARIMIDEXm anastrozole; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a l,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC-alpha, Raf, and H-Ras; ribozymes such as a VEGF expression inhibitor (e.g., ANGIOZYME@ 30 ribozyme) and a HER2 expression inhibitor; vaccines such as gene therapy vaccines, for example, ALLOVECTINTI vaccine, LEUVECTINTM vaccine, and VAXIDTI vaccine; PROLEUKINT" rIL-2; LURTOTECANTM topoisomerase I inhibitor; ABARELIXTM rGnRH; and pharmaceutically acceptable salts, acids or derivatives of any of the above. A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits 35 growth of a cell in vitro and/or in vivo. Thus, the growth inhibitory agent may be one that significantly reduces the percentage of cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G I arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), TAXOL@ paclitaxel, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that 40 arrest G I also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, 17 prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al. (WB Saunders: Philadelphia, 1995), especially p. 13. 5 Examples of "growth inhibitory" anti-HER2 antibodies are those which bind to HER2 and inhibit the growth of cancer cells overexpressing HER2. Preferred growth inhibitory anti-HER2 antibodies inhibit growth of SKBR3 breast tumor cells in cell culture by greater than 20%, and preferably greater than 50% (e.g., from about 50% to about 100%) at an antibody concentration of about 0.5 to 30 pg/ml, where the growth inhibition is determined six days after exposure of the SKBR3 cells to the antibody (see U.S. Patent 10 No. 5,677,171 issued October 14, 1997). An antibody which "induces cell death" is one which causes a viable cell to become nonviable. The cell is generally one which expresses the antigen to which the antibody binds, especially where the cell overexpresses the antigen. Preferably, the cell is a cancer cell, e.g., a breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic or bladder cell. In vitro, the cell may be a SKBR3, 15 BT474, Calu 3, MDA-MB-453, MDA-MB-361 or SKOV3 cell. Cell death in vitro may be determined in the absence of complement and immune effector cells to distinguish cell death induced by antibody dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Thus, the assay for cell death may be performed using heat inactivated serum (i.e. in the absence of complement) and in the absence of immune effector cells. To determine whether the antibody is able to induce cell death, loss of membrane 20 integrity as evaluated by uptake of propidium iodide (PI), trypan blue (see Moore et al. Cytotechnology, 17:1-11 (1995)) or 7AAD can be assessed relative to untreated cells. An antibody that "induces apoptosis" is one which induces programmed cell death as determined by binding of annexin V, fragmentation of DNA, cell shrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies). The cell is one which 25 expresses the antigen to which the antibody binds and may be one which overexpresses the antigen. The cell may be a tumor cell, e.g., a breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic or bladder cell. In vitro, the cell may be a SKBR3, BT474, Calu 3 cell, MDA-MB-453, MDA-MB-361 or SKOV3 cell. Various methods are available for evaluating the cellular events associated with apoptosis. For example, phosphatidyl serine (PS) translocation can be measured by annexin binding; 30 DNA fragmentation can be evaluated through DNA laddering as disclosed in the example herein; and nuclear/chromatin condensation along with DNA fragmentation can be evaluated by any increase in hypodiploid cells. Preferably, the antibody which induces apoptosis is one which results in about 2 to 50 fold, preferably about 5 to 50 fold, and most preferably about 10 to 50 fold, induction of annexin binding relative to untreated cell in an annexin binding assay using cells expressing the antigen to which the antibody 35 binds. Examples of antibodies that induce apoptosis include the anti-HER2 monoclonal antibodies 7F3 (ATCC HB-12216), and 7C2 (ATCC HB 12215), including humanized and/or affinity matured variants thereof; the anti-DR5 antibodies 3F 1.39.7 (ATCC HB- 12456); 3H3.14.5 (ATCC HB- 12534); 3D5. 1.10 (ATCC HB- 1-2536); and 3H3.14.5 (ATCC HB- 12534), including humanized and/or affinity matured variants 40 thereof; the human anti-DR5 receptor antibodies 16E2 and 20E6, including affinity matured variants thereof (W098/51793, expressly incorporated herein by reference); the anti-DR4 antibodies 4E7.24.3 (ATCC HB 18 - 19 12454); 4H6.17.8 (ATCC HB-12455); 1H5.25.9 (ATCC HB-12695); 4G7.18.8 (ATCC PTA-99); and 5G1 1. 17.1 (ATCC HB-12694), including humanized and/or affinity matured variants thereof. In order to screen for antibodies which bind to an epitope on an antigen bound by an antibody of interest, a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, eds. 5 Harlow and Lane (New York: Cold Spring Harbor Laboratory, 1988) can be performed. The word "label" when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the polypeptide. The label may be itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable. 10 B. Modes for Carrying Out the Invention The present invention relates to various peptides having the function of antagonizing IGF-l. Specifically, one family of such peptides (family 1) comprises the sequence: (Xaa),(Xaa) 2 Cys (Xaa) 3 (Xaa) 4 SerVal(Xaa)sAlaLeu(Xaa) 6 (Xaa),CysMet (Xaa)g (SEQ ID NO: 1) where (Xaa),. (Xaa) 2 , and (Xaa) 7 are any amino acid, (Xaa) 3 is Phe, Leu, or Tyr, (Xaa) 4 is Glu, Asp, Ala, Gly, 15 Thr, or Ser, (Xaa) 5 is Glu, Asp, Ala, or Gly, (Xaa) 6 is Arg or Lys, and (Xaa)s is Tyr or Arg. (Xaa) 4 is Glu, Ala, Gly, Thr, or Ser, (Xaa) 5 is Glu, Ala, or Gly, and (Xaa)g is Tyr. The preferred peptides of the above sequence are such that (Xaa) 4 is Glu, Ala or Thr, (Xaa) 5 is Ala or Gly, and (Xaa) 8 is Tyr. More preferred are the peptides wherein (Xaa) 4 is Glu or Ala, (Xaa)5 is Ala or Gly, and (Xaa) 8 is Tyr. Still more preferred are the peptides comprising the sequence RNCFESVAALRRCMYG (SEQ ID NO:2), 20 MDCLASVEALKWCMYG (SEQ ID NO:3), or FECLTSVEALRGCMYG (SEQ ID NO:4). Most preferred are peptides that comprise SEQ ID NO:2 or 3. The second family of such peptides (family 2) comprises the sequence: (X aa),(Xaa) 2 Cys(Xaa) 3 (Xaa) 4 Asp(Xaa) 5 (Xaa) 6 Gly(Xaa) 7 (Xaa) 8 TyrCysTrp(Xaa), (SEQ ID NO:5), where (Xaa),,(Xaa) 4 , and (Xaa)B are any amino acid, (Xaa) 2 is Arg, Lys, Gly, Ser, or Thr, (Xaa) 3 is Ala or Val, 25 (Xaa)5 is Ala or Leu, (Xaa) 6 is Ala, Gly, or Leu, (Xaa) 7 is Phe, Tyr, Trp, or Gly, and (Xaa), is Glu, Asp, Ala, or Gly. The preferred peptides herein are such that (Xaa) 2 is Gly, Ser, Arg, or Thr, and (Xaa), is Glu, Ala, or Asp. More preferred are peptides wherein (Xaa) 2 is Gly or Arg, (Xaa)s is Leu, (Xaa) 6 is Ala or Gly, (Xaa) 7 is Phe, and (Xaa) 9 is Ala. The most preferred of this family of peptides are those that comprise the sequence LGCASDLAGFWYCWAG (SEQ ID NO:6) or WRCVDDLGGFQYCWAG 30 (SEQ ID NO:7). Preferably, all the amino acids in these two families of peptides are L-amino acids. Also preferred is that these families of peptides comprise a glycine residue after (Xaa)g for family I above or after (Xaa), for family 2 above. Production of Peptides 35 The peptides of this invention can be made by chemical synthesis or by employing recombinant technology. These methods are known in the art. Chemical synthesis, especially solid-phase synthesis, is preferred for short (e.g., less than 50 residues) peptides or those containing unnatural or unusual amino 17621292 (GHMatters) 1809/09 - 19a acids such as D-Tyr, ornithine, amino-adipic acid, and the like. Recombinant procedures are preferred for longer 17621292 (GHMatters) 18109/09 polypeptides. When recombinant procedures are selected, a synthetic gene may be constructed de novo or a natural gene may be mutated by, for example, cassette mutagenesis. A useful method for identification of certain residues or regions of the peptides herein suitable for amino acid substitution other than those described herein is called alanine-scanning mutagenesis as described 5 by Cunningham and Wells, Science, 244:1081-1085 (1989). Here a residue or group of target residues are identified (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) and replaced by a neutral or negatively-charged amino acid to affect the interaction of the amino acids with the surrounding aqueous environment in or outside the cell. Those domains demonstrating functional sensitivity to the substitution then are refined by introducing further or other variations at or for the sites of substitution. Thus, while the 10 site for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to optimize the performance of a mutation at a given site, Ala-scanning or random mutagenesis may be conducted at the target codon or region and the expressed compound screened for the optimal combination of desired activity. Phage display of protein or peptide libraries offers another methodology for the selection of 15 compounds with improved affinity, altered specificity, or improved stability (Smith, Curr. Opin. Biotechnol., 2:668-673 (1991)). High affinity proteins, displayed in a monovalent fashion as fusions with the M13 gene III coat protein (Clackson et al., Trends Biotechnol. 12:173-183 (1994)), can be identified by cloning and sequencing the corresponding DNA packaged in the phagemid particles after a number of rounds of binding selection. 20 Other peptides include the fusion to the N- or C-terminus of the peptides described herein of immunogenic polypeptides, e.g., bacterial polypeptides such as beta-lactamase or an enzyme encoded by E. coli Trp locus or yeast protein, and C-terminal fusion with proteins having a long half-life such as immunoglobulin constant region or other immunoglobulin regions, albumin, or ferritin as described in WO 89/02922 published 6 April 1989. Further, free functional groups on the side-chains of the amino acid 25 residues can also be modified by amidation, acylation, or other substitution, which can, for example, change the solubility of the peptides without affecting their activity. Set forth below are exemplary general recombinant procedures. From a purified IGF and its amino acid sequence, for example, an IGF antagonist that is a peptidyl mutant of an IGF may be produced using recombinant DNA techniques. These techniques contemplate, in 30 simplified form, taking the gene, either natural or synthetic, encoding the peptide; inserting it into an appropriate vector; inserting the vector into an appropriate host cell; culturing the host cell to cause expression of the gene; and recovering or isolating the peptide produced thereby. Preferably, the recovered peptide is then purified to a suitable degree. Somewhat more particularly, the DNA sequence encoding a peptidyl IGF antagonist is cloned and 35 manipulated so that it may be expressed in a convenient host. DNA encoding parent polypeptides can be obtained from a genomic library, from cDNA derived from mRNA from cells expressing the peptide, or by synthetically constructing the DNA sequence (Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed.) (Cold Spring Harbor Laboratory: N.Y., 1989)). The parent DNA is then inserted into an appropriate plasmid or vector that is used to transform a 40 host cell. In general, plasmid vectors containing replication and control sequences derived from species compatible with the host cell are used in connection with those hosts. The vector ordinarily carries a 20 replication site, as well as sequences encoding proteins or peptides that are capable of providing phenotypic selection in transformed cells. For example, E. coli may be transformed using pBR322, a plasmid derived from an E. coli species (Mandel et al., J. Mol. Biol. 53: 154 (1970)). Plasmid pBR322 contains genes for ampicillin and tetracycline 5 resistance, and thus provides easy means for selection. Other vectors include different features such as different promoters, which are often important in expression. For example, plasmids pKK223-3, pDR720, and pPL-lambda represent expression vectors with the tac, irp, or PL promoters that are currently available (Pharmacia Biotechnology). One preferred vector is pB0475. This vector contains origins of replication for phage and E. coli 10 that allow it to be shuttled between such hosts, thereby facilitating both mutagenesis and expression (Cunningham et al., Science, 243: 1330-1336 (1989); U.S. Pat. No. 5,580,723). Other preferred vectors are pRIT5 and pRIT2T (Pharmacia Biotechnology). These vectors contain appropriate promoters followed by the Z domain of protein A, allowing genes inserted into the vectors to be expressed as fusion proteins. Other preferred vectors can be constructed using standard techniques by combining the relevant 15 traits of the vectors described above. Relevant traits include the promoter, the ribosome binding site, the decorsin or ornatin gene or gene fusion (the Z domain of protein A and decorsin or ornatin and its linker), the antibiotic resistance markers, and the appropriate origins of replication. The host cell may he prokaryotic or eukaryotic. Prokaryotes are preferred for cloning and expressing DNA sequences to produce parent IGF-I polypeptide, segment-substituted peptides, residue 20 substituted peptides, and peptide variants. For example, E. coli K12 strain 294 (ATCC No. 31446) may be used as well as E. coli B, E. coli X1776 (ATCC No. 31537), and E. coli c600 and c600hf1, E. coli W31 10 (F-, gamma-, prototrophic/ATCC No. 27325), bacilli such as Bacillus subtilis, and other enterobacteriaceae such as Salmonella typhimurium or Serratia marcesans, and various Pseudomonas species. The preferred prokaryote is E. coli W3 110 (ATCC 27325). When expressed by prokaryotes the peptides typically contain 25 an N-terminal methionine or a formyl methionine and are not glycosylated. In the case of fusion proteins, the N-terminal methionine or formyl methionine resides on the amino terminus of the fusion protein or the signal sequence of the fusion protein. These examples are, of course, intended to be illustrative rather than limiting. In addition to prokaryotes, eukaryotic organisms, such as yeast cultures, or cells derived from multicellular organisms may be used. In principle, any such cell culture is workable. However, interest has 30 been greatest in vertebrate cells, and propagation of vertebrate cells in culture (tissue culture) has become a reproducible procedure. Tissue Culture, Academic Press, Kruse and Patterson, editors (1973). Examples of such useful host cell lines are VERO and HeLa cells, Chinese Hamster Ovary (CHO) cell lines, W 138, 293, BHK, COS-7 and MDCK cell lines. A variation on the above procedures contemplates the use of gene fusions, wherein the gene 35 encoding the desired peptide is associated, in the vector, with a gene encoding another protein or a fragment of another protein. This results in the desired peptide being produced by the host cell as a fusion with another protein or peptide. The "other" protein or peptide is often a protein or peptide that can be secreted by the cell, making it possible to isolate and purify the desired peptide from the culture medium and eliminating the necessity of destroying the host cells that arises when the desired peptide remains inside the cell. 21 Alternatively, the fusion protein can be expressed intracellularly. It is useful to use fusion proteins that are highly expressed. The use of gene fusions, though not essential, can facilitate the expression of heterologous peptides in E. coli as well as the subsequent purification of those gene products. Harris, in Genetic Engineerine, 5 Williamson, R., Ed. (Academic Press, London, Vol. 4, 1983), p. 127; Ljungquist et al., Eur. 1. Biochem., 186: 557-561 (1989) and Ljungquist et al., Eur. I. Biochem., 186: 563-569 (1989). Protein A fusions are often used because the binding of protein A, or more specifically the Z domain of protein A, to IgG provides an 'affinity handle" for the purification of the fused protein. See Nilsson et al., Protein Engineering, 1: 107-113 (1987). It has also been shown that many heterologous proteins are degraded when expressed directly in E. 10 coli, but are stable when expressed as fusion proteins. Marston, Biochem J., 240: 1 (1986). After expression and secretion, for example, from E. coli, the fusion protein is cleaved to yield free peptide, which can be purified from the reaction mix. The cleavage may be accomplished using chemicals, such as cyanogen bromide, which cleaves at a methionine, or hydroxylamine, which cleaves between an Asn and Gly residue. Using standard recombinant DNA methodology, the nucleotide base pairs encoding these 15 amino acids may be inserted just prior to the 5'end of the gene encoding the desired peptide. Alternatively, one can employ proteolytic cleavage of fusion protein (Carter, in Protein Purification: From Molecular Mechanisms to Large-Scale Processes, Ladisch et al., eds. (American Chemical Society Symposium Series No. 427, 1990), Ch 13, pages 181-193; Varadarajan et al., Proc. Nati. Acad. Sci. USA, 82: 5681-5684 (1985); Castellanos-Serra et al., FEBS Letters, 378: 171-176 (1996); Nilsson et al., J. Biotechnol., 20 48: 241-250 (1996)). Proteases such as Factor Xa, thrombin, subtilisin, or trypsin, or its mutants, and a number of others have been successfully used to cleave fusion proteins. Trypsin is preferred because peptide-Z-domain fusions are found to be readily cleaved by this protease. Detailed procedures for employing trypsin as protease are found in Smith, Methods in Mol. Biol., 32: 289-196 (1994). Typically, a peptide linker that is 25 amenable to cleavage by the protease used is inserted between the "other" protein (e.g., the Z domain of protein A) and the desired peptide. Using recombinant DNA methodology, the nucleotide base pairs encoding the linker are inserted between the genes or gene fragments coding for the other proteins. Proteolytic cleavage of the partially- purified fusion protein containing the correct linker can then be carried out on either the native fusion protein, or the reduced or denatured fusion protein. 30 The peptide may or may not be properly folded when expressed as a fusion protein. Also, the specific peptide linker containing the cleavage site may or may not be accessible to the protease. These factors determine whether the fusion protein must be denatured and refolded, and if so, whether these procedures are employed before or after cleavage. When denaturing and refolding are needed, typically the peptide is treated with a chaotrope, such as 35 guanidine HCI, and is then treated with a redox buffer, containing, for example, reduced and oxidized dithiothreitol or glutathione at the appropriate ratios, pH, and temperature, such that the peptide is refolded to its native structure. As well as by recombinant methods, peptides of the invention can be conveniently prepared using solid phase peptide synthesis (Merrifield, J. Am. Chem. Soc., 85: 2149 (1964); Houghten, Proc. NatI. Acad. 40 Sci. USA, 2: 5132 (1985)), although other equivalent chemical syntheses known in the art are employable. Solid-phase synthesis is initiated from the C-terminus of the peptide by coupling a protected a-amino acid to 22 a suitable resin. Such a starting material can be prepared by attaching an a-amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a BHA resin or MBHA resin. The preparation of the hydroxymethyl resin is described by Bodansky et al., Chem. Ind. (London), 38: 1597-1598 (1966). Chloromethylated resins are commercially available from BioRad 5 Laboratories, Richmond, CA and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart et al., Solid Phase Peptide Synthesis (Freeman & Co., San Francisco 1969), Chapter 1, pp. 1-6. BHA and MBHA resin supports are commercially available and are generally used only when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus. The amino acids are coupled to the peptide chain using techniques well known in the art for the 10 formation of peptide bonds. One method involves converting the amino acid to a derivative that will render the carboxyl group more susceptible to reaction with the free N-terminal amino group of the peptide fragment. For example, the amino acid can be converted to a mixed anhydride by reaction of a protected amino acid with ethylchloroformate, phenyl chloroformate, sec-butyl chloroformate, isobutyl chloroformate, pivaloyl chloride or like acid chlorides. Alternatively, the amino acid can be converted to an active ester such 15 as a 2,4,5-trichlorophenyl ester, a pentachlorophenyl ester, a pentafluorophenyl ester, a p-nitrophenyl ester, a N-hydroxysuccinimide ester, or an ester formed from l-hydroxybenzotriazole. Another coupling method involves use of a suitable coupling agent such as N,N' dicyclohexylcarbodiimide or N,N'-diisopropyl-carbodiimide. Other appropriate coupling agents, apparent to those skilled in the art, are disclosed in E. Gross & J. Meienhofer, The Peptides: Analysis, Structure, Biology, 20 Vol. 1: Major Methods of Peptide Bond Formation (Academic Press: New York, 1979). It should be recognized that the a-amino group of each amino acid employed in the peptide synthesis must be protected during the coupling reaction to prevent side reactions involving their active a amino function. It should also be recognized that certain amino acids contain reactive side-chain functional groups (e.g., sulfhydryl, amino, carboxyl, and hydroxyl) and that such functional groups must also be 25 protected with suitable protecting groups to prevent a chemical reaction from occurring at that site during both the initial and subsequent coupling steps. Suitable protecting groups, known in the art, are described in Gross and Meienhofer, The Peptides: Analysis, Structure, Biology, Vol.3: "Protection of Functional Groups in Peptide Synthesis" (Academic Press: New York, 1981). In the selection of a particular side-chain protecting group to be used in synthesizing the peptides, 30 the following general rules are followed. An a-amino protecting group (a) must render the a-amino function inert under the conditions employed in the coupling reaction, (b) must be readily removable after the coupling reaction under conditions that will not remove side-chain protecting groups and will not alter the structure of the peptide fragment, and (c) must eliminate the possibility of racemization upon activation immediately prior to coupling. A side-chain protecting group (a) must render the side-chain functional group 35 inert under the conditions employed in the coupling reaction, (b) must be stable under the conditions employed in removing the a-amino protecting group, and (c) must be readily removable upon completion of the desired amino acid peptide under reaction conditions that will not alter the structure of the peptide chain. It will be apparent to those skilled in the art that the protecting groups known to be useful for peptide synthesis will vary in reactivity with the agents employed for their removal. For example, certain 40 protecting groups such as triphenylmethyl and 2-(p-biphenylyl)isopropyloxycarbonyl are very labile and can 23 be cleaved under mild acid conditions. Other protecting groups, such as t-butyloxycarbonyl (BOC), t amyloxycarbonyl. adamantyl-oxycarbonyl, and p-methoxybenzyloxycarbonyl, are less labile and require moderately strong acids, such as trifluoroacetic, hydrochloric, or boron trifluoride in acetic acid, for their removal. Still other protecting groups, such as benzyloxycarbonyl (CBZ or Z), halobenzyloxycarbonyl, p 5 nitrobenzyloxycarbonyl cycloalkyloxycarbonyl, and isopropyloxycarbonyl, are even less labile and require stronger acids, such as hydrogen fluoride, hydrogen bromide, or boron trifluoroacetate in trifluoroacetic acid, for their removal. Among the classes of useful amino acid protecting groups are included: (1) for an a-amino group, (a) aromatic urethane-type protecting groups, such as fluorenylmethyloxycarbonyl (FMOC) CBZ, and substituted CBZ, such as, e.g., p-chlorobenzyloxycarbonyl, 10 p-6-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl, o chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2,6-dichlorobenzyloxycarbonyl, and the like; (b) aliphatic urethane-type protecting groups, such as BOC, t-amyloxycarbonyl, isopropyloxycarbonyl, 2-(p biphenylyl)-isopropyloxycarbonyl, allyloxycarbonyl and the like; (c) cycloalkyl urethane-type protecting groups, such as cyclopentyloxycarbonyl, adamantyloxycarbonyl, and cyclohexyloxycarbonyl; and d) 15 allyloxycarbonyl. The preferred a-amino protecting groups are BOC or FMOC. (2) for the side chain amino group present in Lys, protection may be by any of the groups mentioned above in (1) such as BOC, p-chlorobenzyloxycarbonyl, etc. (3) for the guanidino group of Arg, protection may be by nitro, tosyl, CBZ, adamantyloxycarbonyl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,3,6-trimethyl-4-methoxyphenylsulfonyl, 20 or BOC. (4) for the hydroxyl group of Ser, Thr, or Tyr, protection may be, for example, by Cl-C4 alkyl, such as t-butyl; benzyl (BZL); or substituted BZL, such as p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, and 2,6-dichlorobenzyl. (5) for the carboxyl group of Asp or Glu, protection may be, for example, by esterification 25 using groups such as BZL, t-butyl, cyclohexyl, cyclopentyl, and the like. (6) for the imidazole nitrogen of His, the tosyl moiety is suitably employed. (7) for the phenolic hydroxyl group of Tyr, a protecting group such as tetrahydropyranyl, tert-butyl, trityl, BZL, chlorobenzyl, 4-bromobenzyl, or 2,6-dichlorobenzyl is suitably employed. The preferred protecting group is 2,6-dichlorobenzyl. 30 (8) for the side-chain amino group of Asn or Oln, xanthyl (Xan) is preferably employed. (9) for Met, the amino acid is preferably left unprotected. (10) for the thio group of Cys, p-methoxybenzyl is typically employed. The C-terminal amino acid, e.g., Lys, is protected at the N-amino position by an appropriately selected protecting group, in the case of Lys, BOC. The BOC-Lys-OH can be first coupled to the 35 benzyhydrylamine or chloromethylated resin according to the procedure set forth in Horiki et al., Chemistry Letters, 165-168 (1978) or using isopropylcarbodiimide at about 25*C for 2 hours with stirring. Following the coupling of the BOC-protected amino acid to the resin support, the a-amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone. The deprotection is carried out at a temperature between about O'C and room temperature. Other standard cleaving reagents, such as HCI in 40 dioxane, and conditions for removal of specific a-amino protecting groups are described in the literature. 24 After removal of the a-amino protecting group, the remaining a-amino and side-chain protected amino acids are coupled stepwise within the desired order. As an alternative to adding each amino acid separately in the synthesis, some may be coupled to one another prior to addition to the solid-phase synthesizer. The selection of an appropriate coupling reagent is within the skill of the art. Particularly 5 suitable as a coupling reagent is N,N'-dicyclohexyl carbodiimide or diisopropylcarbodiimide. Each protected amino acid or amino acid sequence is introduced into the solid-phase reactor in excess, and the coupling is suitably carried out in a medium of dimethylformamide (DMF) or CH 2 C1 2 or mixtures thereof. If incomplete coupling occurs, the coupling procedure is repeated before removal of the N amino protecting group prior to the coupling of the next amino acid. The success of the coupling reaction at 10 each stage of the synthesis may be monitored. A preferred method of monitoring the synthesis is by the ninhydrin reaction, as described by Kaiser et aL, Anal. Biochem, 34: 595 (1970). The coupling reactions can be performed automatically using well-known methods, for example, a BIOSEARCH 95006' peptide synthesizer. Upon completion of the desired peptide sequence, the protected peptide must be cleaved from the 15 resin support, and all protecting groups must be removed. The cleavage reaction and removal of the protecting groups is suitably accomplished simultaneously or stepwise. When the resin support is a chloro methylated polystyrene resin, the bond anchoring the peptide to the resin is an ester linkage formed between the free carboxyl group of the C-terminal residue and one of the many chloromethyl groups present on the resin matrix. It will be appreciated that the anchoring bond can be cleaved by reagents that are known to be 20 capable of breaking an ester linkage and of penetrating the resin matrix. One especially convenient method is by treatment with liquid anhydrous hydrogen fluoride. This reagent not only will cleave the peptide from the resin but also will remove all protecting groups. Hence, use of this reagent will directly afford the fully deprotected peptide. When the chloromethylated resin is used, hydrogen fluoride treatment results in the formation of the free peptide acids. When the benzhydrylamine 25 resin is used, hydrogen fluoride treatment results directly in the free peptide amines. Reaction with hydrogen fluoride in the presence of anisolc and dimethylsulfide at O'C for one hour will simultaneously remove the side-chain protecting groups and release the peptide from the resin. When it is desired to cleave the peptide without removing protecting groups, the protected peptide resin can undergo methanolysis to yield the protected peptide in which the C-terminal carboxyl group is 30 methylated. The methyl ester is then hydrolyzed under mild alkaline conditions to give the free C-terminal carboxyl group. The protecting groups on the peptide chain then are removed by treatment with a strong acid, such as liquid hydrogen fluoride. A particularly useful technique for methanolysis is that of Moore et al., Peptides, Proc. Fifth Amer, Pept. Symp., M. Goodman and J. Meienhofer, Eds., (John Wiley, N.Y., 1977), p. 518-521, in which the protected peptide-resin is treated with methanol and potassium cyanide in the 35 presence of crown ether. Another method for cleaving the protected peptide from the resin when the chloromethylated resin is employed is by ammonolysis or by treatment with hydrazine. If desired, the resulting C-terminal amide or hydrazide can be hydrolyzed to the free C-terminal carboxyl moiety, and the protecting groups can be removed conventionally. 25 It will also be recognized that (he protecting group present on the N-terminal a-amino group may be removed preferentially either before or after the protected peptide is cleaved from the support. Purification of the polypeptides of the invention is typically achieved using conventional procedures such as preparative high-pressure liquid chromatography (HPLC) (including reversed-phase HPLC) or other 5 known chromatographic techniques such as gel permeation, ion exchange, partition chromatography, affinity chromatography (including monoclonal antibody columns), or countercurrent distribution. The peptides of this invention may be stabilized by polymerization. This may be accomplished by crosslinking monomer chains with polyfunctional crosslinking agents, either directly or indirectly, through multi-functional polymers. Ordinarily, two substantially identical polypeptides are crosslinked at their C- or 10 N-termini using a bifunctional crosslinking agent. The agent is used to crosslink the terminal amino and/or carboxyl groups. Generally, both terminal carboxyl groups or both terminal amino groups are crosslinked to one another, although by selection of the appropriate crosslinking agent the a-amino group of one polypeptide is crosslinked to the terminal carboxyl group of the other polypeptide. Preferably, the polypeptides are substituted at their C-termini with cysteine. Under conditions well known in the an a 15 disulfide bond can be formed between the terminal cysteines, thereby crosslinking the polypeptide chains. For example, disulfide bridges are conveniently formed by metal-catalyzed oxidation of the free cysteines or by nucleophilic substitution of a suitably modified cysteine residue. Selection of the crosslinking agent will depend upon the identities of the reactive side-chains of the amino acids present in the polypeptides. For example, disulfide crosslinking would not be preferred if cysteine was present in the polypeptide at additional 20 sites other than the C-terminus. Also within the scope hereof are peptides crosslinked with methylene bridges. Suitable crosslinking sites on the peptides, aside from the N-terminal amino and C-terminal carboxyl groups, include epsilon amino groups found on lysine residues, as well as amino, imino, carboxyl, sulfhydryl and hydroxyl groups located on the side-chains of internal residues of the peptides or residues introduced into 25 flanking sequences. Crosslinking through externally added crosslinking agents is suitably achieved, e.g., using any of a number of reagents familiar to those skilled in the art, for example, via carbodiimide treatment of the polypeptide. Other examples of suitable multi-functional (ordinarily bifunctional) crosslinking agents are found in the literature. The peptides of this invention also may be conformationally stabilized by cyclization. The peptides 30 ordinarily are cyclized by covalently bonding the N- and C-terminal domains of one peptide to the corresponding domain of another peptide of this invention so as to form cyclo-oligomers containing two or more iterated peptide sequences, each internal peptide having substantially the same sequence. Further, cyclized peptides (whether cyclo-oligomers or cyclo-monomers) are crosslinked to form 1-3 cyclic structures having from 2 to 6 peptides comprised therein. The peptides preferably are not covalently bonded through a 35 amino and main-chain carboxyl groups (head to tail), but rather are crosslinked through the side-chains of residues located in the N- and C-terminal domains. The linking sites thus generally will be between the side chains of the residues. Many suitable methods per se are known for preparing mono-or poly-cyclized peptides as contemplated herein. Lys/Asp cyclization has been accomplished using Na-Boc-amino acids on solid-phase 26 support with Fmoc/ 9 -fluorenylmethyl (OFm) side-chain protection for Lys/Asp; the process is completed by piperidine treatment followed by cyclization. GIu and Lys side-chains also have been crosslinked in preparing cyclic or bicyclic peptides: the peptide is synthesized by solid-phase chemistry on a p-methylbenzhydrylamine resin. The peptide is cleaved 5 from the resin and deprotected. The cyclic peptide is formed using diphenylphosphorylazide in diluted methylformamide. For an alternative procedure, see Schiller et at., Peptide Protein Res., 25: 171-177 (1985). See also U.S. Pat. No. 4,547,489. Disulfide crosslinked or cyclized peptides are generated by conventional methods. The method of Pelton et al. (J. Med. Chem., 29: 2370-2375 (1986)) is suitable, except that a greater proportion of cyclo 10 oligomers are produced by conducting the reaction in more concentrated solutions than the dilute reaction mixture described by Pelton et al., supra, for the production of cyclo-monomers. The same chemistry is useful for synthesis of dimers or cyclo-oligomers or cyclo-monomers. Also useful are thiomethylene bridges. Lebl and Hruby, Tetrahedron Letters, 25: 2067-2068 (1984). See also Cody et al., J. Med. Chem., 28: 583 (1985). 15 The desired cyclic or polymeric peptides are purified by gel filtration followed by reversed-phase HPLC or other conventional procedures. The peptides are sterile filtered and formulated into conventional pharmacologically acceptable vehicles. The starting materials required for the processes described herein are known in the literature or can be prepared using known methods and known starting materials. 20 If in the peptides being created carbon atoms bonded to four non-identical substituents are asymmetric, then the compounds may exist as diastereoisomers, enantiomers, or mixtures thereof. The syntheses described above may employ racemates, enantiomers, or diastercomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods. Likewise, enantiomeric product mixtures may be separated using the same 25 techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present, may be in one of two configurations (R or S), and both are within the scope of the present invention. The peptides described in this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Examples of such salts include ammonium, metal salts like sodium, potassium, calcium, and magnesium; salts with 30 organic bases like dicyclohexylamine, N-methyl-D-glucamine and the like; and salts with amino acids like arginine or lysine. Salts with inorganic and organic acids may be likewise prepared, for example, using hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, methanesulfonic, malic, maleic, fumaric acid, and the like. Non-toxic and physiologically-compatible salts are particularly useful, although other less desirable salts may have use in the processes of isolation and purification. 35 A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. Examples include reaction of the free acid or free base form of the peptide with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble; or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion-exchange resin to 40 form the desired salt or one salt form of the product may be converted to another using the same general process. 27 Use of Peptides The peptides herein may be useful in diagnostic assays, e.g., for detecting expression of IGF- I in specific cells, tissues, or serum. For diagnostic applications, the peptide typically will be labeled with a detectable moiety. 5 Numerous labels are available which can be generally grouped into the following categories: (a) Radioisotopes, such as 35 14C, I, 3H, and 1I. The peptide can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes I and 2, Coligen et al., ed. (Wiley-Interscience: New York, 1991), for example, and radioactivity can be measured using scintillation counting. 10 (b) Fluorescent labels such as rare earth chelates (europium chelates) or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin and Texas Red are available. The fluorescent labels can be conjugated to the peptide using the techniques disclosed in Current Protocols in Immunologic, supra, for example. Fluorescence can be quantified using a fluorimeter. (c) Various enzyme-substrate labels are available and U.S. Patent No. 4,275,149 provides a 15 review of some of these. The enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques. For example, the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically. Alternatively, the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above. The chemiluminescent substrate becomes electronically excited by a chemical reaction and 20 may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor. Examples of enzymatic labels include luciferases (e.g-, firefly luciferase and bacterial luciferase; U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish pcroxidase (HRPO), alkaline phosphatase, P-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6 25 phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Techniques for conjugating enzymes to antibodies are described in O'Sullivan et al., Methods for the Preparation of Enzyme-Antibody Conjugates for use in Enzyme Immunoassay, in Methods in Enzym. (ed J. Langone & H. Van Vunakis), , 73:147-166 (Academic Press, New York, 1981). Examples of enzyme-substrate combinations include, for example: 30 (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g.,orthophenylene diamine (OPD) or 3,3,5,5'tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para-nitrophenyl phosphate as chromogenic substrate; and (iii) D-D-galactosidase (S-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl--D 35 galactosidase) or fluorogenic substrate 4-methylumbelliferyl-$-D-galactosidase. Numerous other enzyme-substrate combinations are available to those skilled in the art. For a general review of these, see U.S. Patent Nos. 4,275,149 and 4,318,980. Sometimes, the label is indirectly conjugated with the peptide. The skilled artisan will be aware of various techniques for achieving this. For example, the peptide can be conjugated with biotin and any of the 40 three broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds 28 selectively to avidin and thus, the label can be conjugated with the peptide in this indirect manner. Alternatively, to achieve indirect conjugation of the label with the peptide, the peptide is conjugated with a small hapten (e.g., digoxin) and one of the different types of labels mentioned above is conjugated with an anti-hapten peptide (e.g., anti-digoxin antibody). Thus, indirect conjugation of the label with the peptide can 5 be achieved. In another embodiment of the invention, the peptide need not be labeled, and the presence thereof can be detected using a labeled antibody that binds to the peptide. The peptide of the present invention may be employed in any known assay method, such as competitive binding assays, direct and indirect sandwich assays, and immunoprecipitation assays. Zola, 10 Monoclonal Antibodies: A Manual of Techniques, pp.1 4 7-158 (CRC Press, Inc. 1987). The peptide may also be used for in vivo diagnostic assays. Generally, the peptide is labeled with a radionuclide (such as In, 9Tc, 1C, I, 1I, 3H, 32P or 35S) so that the antigen or cells expressing it can be localized using immunoscintiography. The peptides of this invention are shown to bind to IGF- I and inhibit IGFBP-3 and IGFBP-1 15 binding to IGF- 1. It is contemplated that the peptide of the present invention may be used to treat a mammal, e.g. a patient suffering from, or predisposed to, a disease or disorder who could benefit from administration of the peptide. It is known to those skilled in the art that there are many disorders caused by IGFs. These disorders are set forth above. If the disorder is cancer comprising a tumor with an IGF receptor, the efficacy of the treatment can 20 he evidenced by a reduction in clinical manifestations or symptoms, including, for example, the size of a tumor or reductions in the amount of IGF available for binding to an IGF receptor of the tumor. Examples of these protocols are well known in the art. For example, the peptide can be administered to subjects having an IGF-dependent tumor, and tumor size could be monitored using imaging techniques, such as MRI, mammography, or ultrasound depending on the type of tumor. Imaging could be performed, for example, 25 twice monthly. Serum levels of IGF and IGFBP could also be measured from serum samples from the subject at regular intervals. For example, levels of plasma IGF- I and IGF-2 in treated subjects can be monitored with radioimmunoassay, using an antibody specific for IGF and preferably for the IGFBP binding domain on IGF. Plasma IGF levels could be measured with and without acid dissociation of IGFs and IGFBPs in order to assess the levels of bound and unbound IGF. Thus, by comparing the IGF levels with and without acid 30 dissociation, the amount of unbound IGF can be determined. Normal serum levels of IGF- I and IGF-2 after acid dissociation typically range from about 90 to 320 and 288-740 pig/L, respectively. Plasma levels of the IGF antagonist peptide herein can be assessed similarly using a high affinity monoclonal antibody specific for the IGF antagonist peptide. The peptides of this invention may be administered to the mammal by any suitable technique, 35 including oral, intraventricular, transdermal, extracorporeal, parenteral (e.g., intradermal, intramuscular, intraperitoneal, intravenous, intratracheal, or subcutaneous injection or infusion, or implant), nasal, pulmonary, vaginal, rectal, sublingual, or topical routes of administration, and can be formulated in dosage forms appropriate for each route of administration. The specific route of administration will depend, e.g., on the medical history of the patient, including any perceived or anticipated side effects using the peptide, the 40 type of peptide being administered, and the particular disorder to be corrected. Most preferably, the 29 administration is orally or by pulmonary administration or continuous infusion (using, e.g., slow-release devices or minipumps such as osmotic pumps or skin patches), or by injection (using, e.g., intravenous or subcutaneous means). A specific method for administering can be found in, e.g., US Pat. No. 6,124,259. The peptide to be used in the therapy will be formulated, dosed, and administered in a fashion 5 consistent with good medical practice, taking into account the particular mammal being treated, the clinical condition of the individual patient (especially the side effects of treatment with the peptide), the type and cause of disorder being treated, the type of particular peptide used, the site of delivery of the peptide, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the peptide to be administered for purposes herein are thus determined by such 10 considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder herein, resulting in bioavailability of the drug to the mammal and the desired effect. As a general proposition, the total pharmaceutically effective amount of the IGF-l antagonist peptide administered parenterally per dose will be in a range that can be measured by a dose-response curve. Depending on the type and severity of the disease, about 1 pg/kg to 1000 mg/kg of body weight 15 once per day of peptide is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage might range from about I pg/kg to 100 mg/kg or more, depending on the factors mentioned above, more preferably about 0.1 to 20 mg/kg of body weight, and, when administered subcutaneously or intramuscularly, about 0.1 to 10 mg/kg of body weight. Necessary modifications in this dosage range may be determined by one of ordinary skill in 20 the an using only routine experimentation given the teachings herein. See Remington's Pharmaceutical Sciences, 16th edition, Osol, ed. (Mack Publishing Co., Easton , PA, 1980). For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays. 25 The peptide is suitably administered by a sustained-release system. Suitable examples of sustained release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers, 22, 547-556 (1983)), poly(2-hydroxyethyl methacrylate) (Langer et al., J. Biomed. Mater. Res., 15: 167-277 (1981), and 30 Langer, Chem. Tech., 12: 98-105 (1982)), ethylene vinyl acetate (Langer et al., supra) or poly-D-(-)-3 hydroxybutyric acid (EP 133,988). Sustained-release compositions also include a liposomally-entrapped peptide. Liposomes containing the peptide are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. U.S.A., 82: 3688-3692 (1985); Hwang et al., Proc. Natil. Acad. Sci. U.S.A., 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appln. 83 35 118008; U.S. Pat. Nos. 4,485,D45 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (from or about 200 to 800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the most efficacious therapy. See also the microencapsulation technique of Langer, Nature, 392:5-10 (1998). The active ingredients may also be entrapped in microcapsule prepared, for example, by coacervation techniques or by interfacial 40 polymerization, for example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) 30 microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, supra. The formulations to be used for in vivo administration must be sterile. This is readily accomplished 5 by filtration through sterile filtration membranes. Peptides derivatized with polyethylene glycol (PEG) having a longer life can also be employed, based on, e.g., the conjugate technology described in WO 95/32003 published November 30, 1995. For parenteral administration, in one embodiment, the peptide herein is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), 10 with a pharmaceutically, or parenterally, acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides. Depending on the intended mode of administration, the peptides of the present invention can be in 15 pharmaceutical compositions in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the selected antagonist in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc. By 20 "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected antagonist without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical 25 grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. the peptide as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered 30 may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, supra. For oral administration, fine powders or granules may contain diluting, dispersing, and/or surface 35 active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state, or in a nonaqueous solution or suspension wherein suspending agents may be included, in tablets wherein bindeis and lubricants may be included, or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening, or emulsifying agents may be included. Tablets and granules are preferred oral administration forms, and these may be coated. 40 Parenteral administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or 31 suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system, such that a constant level of dosage is maintained. Generally, the formulations are prepared by contacting the peptide uniformly and intimately with 5 liquid carriers or finely-divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein. 10 The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; 15 hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counter-ions such as sodium; non-ionic surfactants such as polysorbates, poloxamers, or polyethylene glycol (PEG); and/or neutral salts, e.g., NaCl, KCI, MgC 2 , CaCI 2 , etc. 20 The peptide is typically formulated in such vehicles at a pH of from about 4.5 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the peptide. The final preparation may be a stable liquid or lyophilized solid. The peptide to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic 25 compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. The peptide ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-mL vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution of 30 peptide, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized peptide using bacteriostatic Water-for-Injection. A preferred route of administration of the present invention is in the aerosol or inhaled form. The peptides of the present invention, combined with a dispersing agent, or dispersant, can be administered in an aerosol formulation as a dry powder or in a solution or suspension with a diluent. 35 Suitable dispersing agents are well known in the art, and include but are not limited to surfactants and the like. For example, surfactants that are generally used in the art to reduce surface-induced aggregation of the peptide caused by atomization of the solution forming the liquid aerosol may be used. Non-limiting examples are surfactants such as polyoxyethylene fatty acid esters and alcohols and polyoxyethylene sorbitan fatty acid esters. Amounts of surfactants used will vary, being generally within the range of about 0.00 1 and 40 4% by weight of the formulation. In a specific aspect, the surfactant is polyoxyethylene sorbitan monooleate or sorbitan trioleate. Suitable surfactants are well known in the art, and can be selected on the basis of 32 desired properties, depending on the specific formulation, concentration of the peptide, diluent (in a liquid formulation), or form of powder (in a dry powder formulation), etc. Moreover, depending on the choice of the peptide, the desired therapeutic effect, the quality of the lung tissue (e.g., diseased or healthy lungs), and numerous other factors, the liquid or dry formulations can 5 comprise additional components, as discussed further below. The liquid aerosol formulations generally contain the peptide and a dispersing agent in a physiologically-acceptable diluent. The dry powder aerosol formulations of the present invention consist of a finely divided solid form of the peptide and a dispersing agent. With either the liquid or dry powder aerosol formulation, the formulation must be aerosolized. That is, it must be broken down into liquid or solid 10 particles to ensure that the aerosolized dose actually reaches the alveoli. In general, the mass median dynamic diameter will be about 5 micrometers or less in order to ensure that the drug particles reach the lung alveoli (Wearley, Crit. Rev. in Ther. Drug Carrier Systems, 8: 333 (199 1)). Aerosol particles are the liquid or solid particles suitable for pulmonary administration, i.e., that will reach the alveoli. Other considerations such as construction of the delivery device, additional components in the formulation, and particle 15 characteristics are important. These aspects of pulmonary administration of a drug are well known in the art, and manipulation of formulations, aerosolization means, and construction of a delivery device require at most routine experimentation by one of ordinary skill in the art. With regard to construction of the delivery device, any form of aerosolization known in the art, including but not limited to nebulization, atomization, or pump aerosolization of a liquid formulation, and 20 aerosolization of a dry powder formulation, can be used in the practice of the invention. Adelivery device that is uniquely designed for administration of solid formulations is envisioned. Often, the aerosolization of a liquid or a dry powder formulation will require a propellent. The propellent may be any propellant generally used in the art. Specific nonlimiting examples of such useful propellants include a chloroflourocarbon, a hydrofluorocarbon, a hydochlorofluorocarbon, or a hydrocarbon, including trifluoromethane, 25 dichlorodifluoromethane, dichlorotetrafluoroethanol, and l, l, l,2-tetrafluoroethane, or combinations thereof. In a preferred aspect of the invention, the device for aerosolization is a metered dose inhaler. A metered dose inhaler provides a specific dosage when administered, rather than a variable dose depending on administration. Such a metered dose inhaler can be used with either a liquid or a dry powder aerosol formulation. Metered dose inhalers are well known in the art. 30 Once the peptide reaches the lung, a number of formulation-dependent factors affect the drug absorption. It will be appreciated that in treating a disease or disorder that requires circulatory levels of the peptide, such factors as aerosol particle size, aerosol particle shape, the presence or absence of infection, lung disease, or emboli may affect the absorption of the peptides. For each of the formulations described herein, certain lubricators, absorption enhancers, protein stabilizers or suspending agents may be appropriate. The 35 choice of these additional agents will vary depending on the goal. It will be appreciated that in instances where local delivery of the peptides is desired or sought, such variables as absorption enhancement will be less critical. The liquid aerosol formulations of the present invention will typically be used with a nebulizer. The nebulizer can be either compressed air driven or ultrasonic. Any nebulizer known in the art can be used in 40 conjunction with the present invention such as but not limited to the: ULTRAVENTM nebulizer (Mallinckrodt, Inc., St. Louis, MO) or the ACORN IIT' nebulizer (Marquest Medical Products, Englewood 33 CO). Other nebulizers useful in conjunction with the present invention are described in U.S. Patent Nos. 4,624,25 1; 3,703,173; 3,561,444; and 4,635,627. The liquid aerosol formulation may include a carrier. The carrier is a macromolecule that is soluble in the circulatory system and that is physiologically acceptable where physiological acceptance means that 5 those of skill in the art would accept injection of said carrier into a patient as part of a therapeutic regime. The carrier preferably is relatively stable in the circulatory system with an acceptable plasma half life for clearance. Such macromolecules include but are not limited to soya lecithin, oleic acid, and sorbitan trioleate, with sorbitan trioleate preferred. The liquid aerosol formulations herein may also include other agents useful for protein stabilization 10 or for the regulation of osmotic pressure. Examples of the agents include but are not limited to salts, such as sodium chloride or potassium chloride, and carbohydrates, such as glucose, galactose or mannose, and the like. It is also contemplated that the present pharmaceutical formulation will be used as a dry powder inhaler formulation comprising a finely divided powder form of the peptide and a dispersant. The form of the 15 peptide will generally be a lyophilized powder. Lyophilized forms of peptides can be obtained through standard techniques. In another embodiment, the dry powder formulation will comprise a finely divided dry powder containing one or more peptides of the present invention, a dispersing agent and also a bulking agent. Bulking agents useful in conjunction with the present formulation include such agents as lactose, sorbitol, 20 sucrose, or mannitol, in amounts that facilitate the dispersal of the powder from the device. The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Hence, the present application contemplates combining the peptide with one or more other therapeutic agent(s), which depend on the particular indication being treated. While the agent may be an 25 endocrine agent such as a GH, a GHRP, a GHRH, a GH secretagogue, an IGFBP, ALS, a GH complexed with a GHBP, it is preferably a cytotoxic agent, especially for treating cancer. For instance, the peptide may be co-administered with another peptide (or multivalent antibodies), a monovalent or bivalent antibody (or antibodies), chemotherapeutic agent(s) (including cocktails of chemotherapeutic agents), other cytotoxic agent(s), anti-angiogenic agent(s), cytokines, and/or growth inhibitory agent(s). Where the peptide induces 30 apoptosis, it may be particularly desirable to combine the peptide with one or more other therapeutic agent(s) that also induce apoptosis. For instance, the peptide may be combined with pro-apoptotic antibodies (e.g., bivalent or multivalent antibodies) directed against B-cell surface antigens (e.g., RITUXAN , ZEVALIN® or BEXXARG anti-CD20 antibodies) and/or with (I) pro-apoptotic antibodies (e.g., bivalent or multivalent antibodies directed against a receptor in the TNF receptor superfamily, such as anti-DR4 or anti-DR5 35 antibodies) or (2) cytokines in the TNF family of cytokines (e.g., Apo2L). Likewise, the peptide may be administered along with anti-ErbB antibodies (e.g., HERCEPTIN® anti-HER2 antibody) alone or combined with (1) and/or (2). Alternatively, or additionally, the patient may receive combined radiation therapy (e.g., external beam irradiation or therapy with a radioactive labeled agent, such as an antibody), ovarian ablation, chemical or surgical, or high-dose chemotherapy along with bone marrow transplantation or peripheral-blood 40 stem-cell rescue or transplantation. Such combined therapies noted above include combined administration 34 (where the two or more agents are included in the same or separate formulations), and separate administration, in which case, administration of the peptide can occur prior to, and/or following, administration of the adjunct therapy or therapies. The effective amount of such other agents depends on the amount of peptide present in the formulation, the type of disorder or treatment, and other factors discussed 5 above. These are generally used in the same dosages and with administration routes as used hereinbefore or about from I to 99% of the heretofore employed dosages. Optionally, before the peptide is administered to the mammal, the levels of various markers are measured to determine disease state. Hence, assays can be used for measuring IGF levels, particularly IGF- I levels as a measure of predicting, diagnosing, and monitoring a disorder such as cancer. A strong consistent 10 positive association between IGF-l and breast or prostate cancer risk has been observed, especially with adjustment for IGFBP-3. See WO 99/38011. High levels of IGF-l are predictive of increased risk for prostate cancers, whereas IGFBP has a protective effect. Additionally, the IGF or IGF/IGFBP assay can be combined with a test for prostate-specific antigen (PSA) for improved ability to predict patient prognosis and monitor treatment. The method involves measuring the concentration of IGF or IGFBP-3 and/or PSA in a 15 body sample from a mammal, wherein changes in the concentration of such components as compared to normal reference values indicate an increased risk for prostate cancer. In one embodiment, before treatment the concentration of IGF- I is measured in a body sample from the mammal, wherein an elevated concentration of IGF- I above a reference range for IGF-l indicates an increased risk for prostate cancer. 20 In another embodiment, the method involves measuring the concentration of IGF-I and IGFBP in a specimen from an individual, wherein increased IGF-1 and decreased IGFBP, as compared to a normal reference range value, indicates an increased risk for prostate cancer. In yet another embodiment, the method involves measuring the IGF/PSA status of an individual. High IGF and PSA levels and/or low IGFBP levels are indicative of individuals at risk for severe prostate 25 cancer or who have prostate cancer with a poor prognosis. A multivariate adjustment of the IGF- I concentration relative to the IGFBP-3 concentration provides an adjusted IGF-I level that can be compared to an adjusted normal reference range value. An algorithm can be designed, by those skilled in the art of statistical analyses, which will allow the user to quickly calculate an adjusted IGF level or IGF status for use in making predictions or monitoring prostate 30 disease. With additional patient data, generated similarly to the manner described herein, it will be possible to more accurately define normal reference range values for IGF status parameters. The algorithm and normal reference values can be used to generate a device that will allow the end user to input IGF, IGFBP, and quickly and easily determine the IGF status or risk index of an individual. Similarly, it is possible to provide a device that indicates the IGF/PSA status of an individual. 35 The IGF status is reflected in the levels of IGF and IGFBP. For example, a high IGF status is reflected by high levels of IGF and stimulators of IGF activity and low levels of inhibitors of IGF activity such as IGFBP. The IGF status of an individual is now known to vary--either up or down--in certain conditions involving the prostate, including but not limited to prostate adenocarcinoma and benign prostatic hyperplasia. The IGF/PSA status is a combination of IGF status and PSA levels. Individuals with high 40 IGF/PSA status are at risk for developing severe prostate cancer. High IGF and PSA levels and low IGFBP levels reflect a high IGF/PSA status. 35 "Prostate disease" includes diseases or disorders associated with pathologic conditions of the prostate, including but not limited to, prostate cancer or benign prostatic hyperplasia. The method here is preferably used to determine the risk of an individual developing prostate cancer. The body sample collected from the mammal may be taken by any method, including venipuncture 5 or capillary puncture, or biopsy, and the specimen collected into an appropriate container for receiving the specimen. Alternative, the specimen may be placed onto filter paper. The IGF and IGFBP and/or PSA can be measured by techniques well known to those skilled in the art, including immunoassays such as enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), fluorescence polarization immunoassay (FPIA), fluorescence immunoassay (FIA), and 10 radioimmunoassay (RIA). The assays described in, for example, U.S. Pat. Nos. 5,935,775; 6,066,464; and 5,747,273; Zapp et al., J. Clin. Invest., 68: 1321-1330 (1981); and EP 700,994) are particularly suitable herein. Further, the concentrations of the IGF, IGFBP, and/or PSA may, for example, be measured by test kits supplied by Diagnostic Systems Laboratories, Inc., Webster, TX. In a preferred embodiment, total IGF-l can be measured. In some cases, it may be advantageous to measure total, bound, and/or free IGF-l. For 15 example, suitable highly specific and simple non-competitive ELISAs for reliable determination of IGF-I (Khosravi et al., Clin. Chem., _42: 1147-54 (1996)), IGFBP-3 (Khosravi et al., Clin. Chem., S6:234 (1996)), and IGFBP-I (Khosravi et al., Clin. Chem., S6:171 (1996)) have been described. The high-affinity antibodies incorporated in these immunoassays have been selected for lack of cross-reactivity or interference by the closely related peptides or binding protein. 20 Men in the highest quartile of circulating IGF-l have a relative risk of prostate cancer of 4.32 (95 percent confidence interval 1.76-10.6) compared to men in the lowest quartile. There was a significant linear trend such that a 100 ng/ml increase in IGF-I level was associated with a doubling of risk (p=0.001). Furthermore, this association is evident among men with normal as well as elevated baseline PSA levels. These results indicate that circulating IGF-1 is a predictor of prostate cancer risk. 25 In addition, the invention contemplates using gene therapy for treating a mammal, using nucleic acid encoding the IGF antagonist peptide. Generally, gene therapy is used to increase (or overexpress) IGF levels in the mammal. Nucleic acids that encode the IGF antagonist peptide can be used for this purpose. Once the amino acid sequence is known, one can generate several nucleic acid molecules using the degeneracy of the genetic code, and select which to use for gene therapy. 30 There are two major approaches to getting the nucleic acid (optionally contained in a vector) into the patient's cells for purposes of gene therapy: in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly into the patient, usually at the site where the IGF antagonist peptide is required. For ex vivo treatment, the patient's cells are removed, the nucleic acid is introduced into these isolated cells and the modified cells are administered to the patient either directly or, for example, encapsulated within porous 35 membranes which are implanted into the patient. See, e.g., U.S. Patent Nos. 4,892,538 and 5,283,187. There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate 40 precipitation method, etc. A commonly used vector for ex vivo delivery of the gene is a retrovirus. 36 The currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE, and DC-Chol, for example). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, 5 such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins that bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake. Such proteins include, e.g., capsid proteins or fragments-thereof tropic for a particular cell type, antibodies for proteins that undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life. 10 The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem., 262: 4429-4432 (1987) and Wagner et al., Proc. NatI. Acad. Sci. USA, 87: 3410-3414 (1990). For review of the currently known gene marking and gene therapy protocols, see Anderson et al., Science, 256: 808-813 (1992). See also WO 93/25673 and the references cited therein. Articles of Manufacture 15 In another embodiment of the invention, an article of manufacture or kit containing materials useful for the treatment of the disorders described above is provided. The article of manufacture comprises a container and instructions, such as a label or package or product insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc., preferably a vial. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition with at 20 least the peptide herein and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The instructions direct the user how to utilize the composition for treating the condition of choice, such as cancer. The kit may optionally include a second container with a composition comprising a further active agent as set forth above, such as a cytotoxic agent. Alternatively, or additionally, the article of manufacture may further comprise a 25 second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. The invention will be more fully understood by reference to the following examples. They should 30 not, however, be construed as limiting the scope of the invention. The disclosures of all literature and patent citations mentioned herein are expressly incorporated by reference. EXAMPLES Data on a model compound (an IGF- I mutant with amino acid changes at residues 24 and 31 35 (Y24L,Y3 IA), also designated (Leu, 24 Ala 31 )hIGF- or IGF-M) for predicting behavior of the peptides herein in vitro and in vivo is also disclosed in WO 98/45427, supra. WO 98/45427 also discloses how to dose an IGF antagonist for use in humans. From the doses of IGF-1 used and the concentrations of IGFBP, IGF-1 and IGF-2 demonstrated, it is simple to calculate how much of an IGF antagonist should be given to decrease levels of active endogenous IGF. The molecular size relative to IGF- I, the affinity of the IGF antagonist for 40 the IGF-I, and its bioavailability would be other variables taken into account to arrive at doses that decreased active IGF in a human. 37 EXAMPLE I Experimental Procedure 5 Construction of polyvalent naive peptide libraries Libraries were constructed using the method of Sidhu et al., Methods Enzymol., 328: 333-363 (2000) with a phagemid containing an IPTG-inducible Ptac promoter driving the expression of open reading frames encoding fusion proteins of the following form: the STII secretion signal (MKKNIAFLLASMFVFSIATNAYA; SEQ ID NO:8), followed by a random peptide (i.e., a member of the 10 naive peptide library), followed by a linker (GGGSGGG; SEQ ID NO:9), followed by the M13 gene-8 major coat protein (AEGDDPAKAAFNSLQASATEYIGYAWAMVVVIVGATIGIKLFKKFTSKAS; SEQ ID NO:10). Twenty-two different peptide libraries were constructed as shown in Table 1. Phage displaying the naive libraries were purified by precipitation with PEG/NaC as described in Sidhu et al., supra, and stored frozen at -70*C. 15 Isolation of IGF-I binding peptides from naive peptide-phage libraries IGF-l was obtained in house as described in U.S. Pat. No. 5,342,763. Immunosorbant plates (Nunc Maxisorp) were coated with 5 pg/mI of IGF- I in 50 mM sodium carbonate buffer (pH 9.6) for one hour at room temperature, followed by blocking for I hr with 0.2% BSA in phosphate-buffered saline (PBS). The plates were washed four times with PBS, 0.05% TWEENO-20 20 detergent. Phage from 26 naive peptide-P8 libraries (Table 1) were pooled. To select peptide-phage that bound specifically to IGF-l, the library pool was added to the above-described IGF-l-coated plate. In the first round of selection, 4.8 mL of phage solution (about 1013 phage/mL) was added to 48 coated wells (100 pl/well). After two hours incubation with shaking, the plate was washed 12 times with PBS, 0.05% 25 TWEEN -20 detergent to remove unbound phage. Bound phage were then eluted with 0.2M glycine, pH 2.0 for 5 minutes (100 pl/well), and the phage eluant was neutralized by adding 1/6 volume of l.OM Tris, pH8.0. The eluted phage were amplified by propagation in E. coli XLI-blue cells with M13-VCS helper phage (Stratagene), and the amplified phage pool was cycled through additional rounds of binding selection. In total, four rounds of binding selection were performed. The procedure for round 3 was identical to that for 30 round I, while rounds 2 and 4 differed only in the use of 0.2% Casein in place of BSA in both the blocking solution and the phage cocktail. From each round, individual peptide-displaying phage were isolated and analyzed for binding to IGF-I in a phage ELISA by capturing the peptide-phage with IGF-I immobilized on a plate, and detecting bound phage (see below). As a control for non-specific binding, the phage were also analyzed in a phage 35 ELISA that used plates coated with BSA. Phage that exhibited strong signals in the phage ELISA with IGF-1 immobilized on plates, but not with the control ELISA, were subjected to DNA sequence analysis. The results from sequencing of positive phage clones are seen in Table 2a. Second-generation affinin' maturation of IGF-I binding peptides The IGF- I binding peptides from the CX9C class shown in Table 2a could be grouped into two 40 distinct families based on sequence homology. Based on the sequence conservation in the two families, four second-generation libraries were designed in which highly conserved residues were held constant, moderately 38 conserved residues were represented by degenerate codons that provided partial randomization, and unconserved residues were represented by a codon (NNK) that encoded all twenty natural amino acids (Table 2b). The peptide phage libraries were displayed on the N-terminus of human growth hormone (hGH) fused to P3 of the phage coat to ensure monovalency (Table 2b). 5 Phage from the libraries were pooled and cycled through four rounds of binding selections as described above. Rounds I and 3 used immobilized IGF-I as the capture target to select phage that bound specifically to IGF-l; 0.2% BSA was used in the blocking buffer and the phage cocktail. Rounds 2 and 4 used anti-hGH monoclonal antibody 3F6.B1.4B1 (Jin et al., J. Mol. Biol., 226: 851-865 (1992)) as the capture target to select for phage that still displayed hGH and thus select against clones in which the hGH 10 gene had been deleted; 0.2% Casein was used in the blocking buffer and the phage cocktail. Finally, a fifth round of selection was conducted in which the harvested phage pool was incubated with 1.0 nM biotinylated IGF-l (bio-IGF) in PBS with 0.2% BSA for 2 hours. The phage and bio-IGF solution was added to streptavidin-linked magnetic beads, previously blocked with BSA and washed as above. After half an hour, the magnetic beads were washed 12 times with PBS, 0.05% TWEEN*-20 15 detergent to remove unbound phage. The remaining phage was eluted with 1.0 M HCI and neutralized by adding 1/6 volume of I .0 M Tris buffer, pH 8.0. Individual phage clones from round 5 were isolated and analyzed in phage ELISAs. Specifically binding phage clones were identified as those which bound to both IGF-1 and anti-hGH but not to BSA. These positive clones were subjected to DNA sequence analysis and the results are shown in Table 3. 20 Phage ELISA E. coli XLI-Blue harboring phagemids were grown overnight at 37 0 C in 2YT, 50 pg/mL carbenicillin, 10 pg/mL tetracycline and M13-VCS helper phage (1010 phage/mL). Phage were harvested from the culture supernatant by precipitation twice with PEG/NaCI and resuspended in phosphate-buffered saline, 0.2% BSA, 0.1 % TWEEN -20 detergent (BSA blocking buffer). Phage concentrations were 25 determined spectrophotometrically (X 268 = 1.2 x 108 M-lcm- 1 ). MAXISORPm immunoplates (96-well) were coated with capture target protein for 2 hours at room temperature (100 pL at 5 pg/mL in 50 mM carbonate buffer, pH 9.6). The plates were then blocked for I h with 0.2% BSA in phosphate-buffered saline (PBS) and washed eight times with PBS, 0.05% TWEEN 0 -20 detergent. Phage particles were serially diluted into BSA blocking buffer and 100 pL were transferred to 30 coated wells. After I h, plates were washed eight times with PBS, 0.05% TWEEN -20 detergent, incubated with 100 pL of 1:3000 horse radish peroxidase/anti-M13 antibody conjugate in BSA blocking buffer for 30 min, and then washed eight times with PBS, 0.05% TWEEN -20 detergent and two times with PBS. Plates were developed using a tetramethylbenzidine substrate (TMB, Kirkegaard and Perry, Gaithersburg, MD), stopped with 1.0 M H 3

PO

4 , and read spectrophotometrically at 450 nm. 35 Affinity measurement by monova lent phage ELISA A modified phage ELISA was used to estimate the binding affinities of selected second- generation IGF-l binding peptides displayed in a'monovalent format as described in Sidhu et al., supra, and in Clackson et a., supra. Phage ELISAs were carried out as described above, using plates coated with IGF- 1. Peptide 39 displaying phage were serially diluted and binding was measured to determine a phage concentration giving <50% of the ELISA signal at saturation. A fixed, subsaturating concentration of peptide-phage was mixed with serial dilutions of IGF-I and incubated for 1.0 hr and then transferred to assay plates coated with IGF-l. After 30- min incubation, the 5 plates were washed and developed as described above. The binding affinities of the peptides for IGF-1 were determined as IC50 values where the IC50 value is defined as the concentration of IGF- I that blocked 50% of the peptide-phage binding to the immobilized IGF- 1. The results are shown in Table 4. Peptide synthesis Peptides were synthesized by either manual or automated (Milligen 9050) solid-phase synthesis at 10 0.2 mM on PEG-polystyrene resin (Bodansky and Bodansky, in The Practice of Peptide Synthesis (Springer Verlag, New York, 1984)) utilizing Fmoc chemistry. Purification was as described in Dubaquid and Lowman, Biochemistry, 38: 6386-6396 (1999)) Synthesized peptides are shown in Table 5. Peptide inhibition of phage IGF-J binding to IGF binding proteins For inhibition of IGFBP-I and IGFBP3, E. coli cells (XLI-Blue, Stratagene) freshly transformed 15 with the phage vector pIGF-g3 displaying human IGF- 1 as described in Dubaquid and Lowman, supra, was grown overnight in 5ml of 2YT medium (Sambrook et al., Molecular Cloning. A Laboratory Handbook (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989)). The IGF-l displaying phage was tiered against IGF bpl and bp3 for a 500-1000x dilution for preincubation with serial dilutions the synthesized peptides and binding protein standards for 45 minutes. Immunosorbant plates were coated with 20 IGF binding proteins and blocked with 0.5% TWEEN*-20 detergent and PBS and washed as above. The samples were added to the plates for 20 minutes, washed and detected as above. The experimental IC50 values are in Table 5. Cell-based insulin KIRA assay of IGF- I binding peptide activity A kinase receptor activation assay (KIRA) (Sadick et al., J. Pharm. Biomed. Anal., 19, 883-891 25 (1999)) for measuring phosphorylation of human insulin receptor (hIR) was developed using Chinese hamster ovary cells transfected with the hIR. (TRY-IR 5.3) Cells were grown overnight in 96-well plates with medium (PS/20) at 37*C. Supernatants were decanted and stimulation media (PS/20 and 0.5% BSA) containing either peptide samples (peptides incubated with 25nm IGF-I for Ihr), experimental controls (IGF Bpl incubated with IGF-I for I hr), and 25nm rhlGF-l standards were added. After fifteen minute 30 stimulation at 37*C, stimulation solutions were removed and cells were lysed with a buffer containing 50mM HEPES, 150 mM NaCl, 0.5% Triton-X- 10" octylphenyl ethylene oxide condensate, I mM AEBSF, aprotinin and 0.05 mM leupeptin, and 2 mM sodium orthovanadate. Lysates were frozen at -70*C for ELISA. Immunosorbant plates were coated with 2 pg/mI insulin receptor Ab-2 (clone 83-7) in PBS at pH 7.0 overnight at 4*C. The plate was blocked and washed as above. Cell lysates containing transfected hIR were 35 incubated on the capture ELISA plates for 2 hrs. After removing unbound receptor by washing, biotinylated anti-phosphotyrosine 4G10 (Upstate Biologicals Inc.) was added to detect activated receptor. After 2 hrs, the plates were developed with streptavidin conjugated to HRP and TMB substrate as above. The results are shown in Table 5. 40 Displacement of lGF-1 on MCF-7 cells MCF7 (ATCC-HTB, Bethesda, MD), a breast carcinoma cell line that expresses IGF receptors as well as insulin receptors (Grupe et al., J. Biol. Chem., 270, 22085-22088 (1995)) was used to detect inhibition of 1I IGF- I to receptors on cells by synthesized peptides. Cell were passaged weekly in media 5 containing a 50/50 mix of high-glucose DMEM/ Ham's F12, with 10% fetal bovine serum and 10 mM HEPES pH 7.2. Cells were plated and grown overnight maintained at 37"C and 5% CO 2 . For IGF-1 iodination, 50 pg of IGF- I was diluted into 200 pL of PBS and added to a tube coated with 100 pg of IODOGEN I ,3,4,6-tetrachloro-3a-6p-diphenylglycouril) (Pierce Chemical Co.), incubated with I mCi of 125 I-Nal (10 pt) at room temperature for 10-15 minutes. Synthesized peptides and binding protein controls 10 were preincubated with 2nm I IGF-I for 40 minutes at 37*C. The samples were added to cells for 30 minutes. The cells were washed with media and lysed with IN NaOH. Fifteen-minute counts were taken and the results are shown in Table 5 Cell-Based IGF-I KIRA assay A KIRA for measuring the activation of the human type I IGF- I receptor was performed using 15 human MCF-7 cells (as described above). Cells were grown overnight in 96-well plates with medium (50:50 F12/DMEM, Gibco). Supernatants were decanted, and stimulation media (50:50 F12IDMEM with 25mM HEPES and 2.0% BSA) containing either controls (2nM IGF-I preincubated with IGF Bp I or Bp3) or experimental samples (Peptides preincubated for 30min. with 2nm IGF- 1) were added. After 15-minute stimulation the cells were lysed, and added to the polyclonal anti-IGF-IR (3B7 Santa Cruz Biotech) coated 20 overnight on immunosorbant plates. The detection ELISA was performed as above. The results are seen in Table 5. Results: Table 1. Naive phage library design and diversity (where X is any amino acid and any number following X is a multplier Library Design (P8 display) SEQ ID NO: Diversity (x 101) I X8 11 2.6 2 X20 12 1.2 3 C-X6-C-X6-CC-X3-C-X6-C 13 1.6 4 CC-X3-C-X6-C 14 1.7 5 CC-X5-C-X4-C-X4-CC 15 1.6 6 C-X-C-X7-C-X3-C-X6 16 1.5 7 X4-C-X2-GP-X4-C-X4 17 2.0 8 C-X2-GP-X4-C 18 2.5 9 X7-C-X4-C-X7 19 2.5 10 X7-C-X5-C-X6 20 1.4 I1 X6-C-X6-C-X6 21 2.5 12 X6-C-X7-C-X5 22 2.1 13 X5-C-X8-C-X5 23 1.9 14 X5-C-X9-C-X4 24 2.0 15 X4-C-XIO-C-X4 25 2.5 16 X2-C-X4-C-X2 26 2.1 17 X2-C-X5-C-X2 27 2.2 18 X2-C-X6-C-X2 28 1.5 19 X2-C-X7-C-X2 29 2.1 20 X2-C-X8-C-X2 30 2.1 21 X2-C-X9-C-X2 31 2.2 22 X2-C-XIO-C-X2 32 2.4 41 Tctle2a Ndvephcgspepcsenos SEQ SCAFFOLD I D NOG X20 ASQT PWP Y S I L FGEWWNAGF 33 E AGAE S R GWL QAR CGE L L GV 3 4 HWDWT GGYWW I GR E PWK E AA 3 5 R L NAE X L R MGWGY MVWHW L S 3 6 CX6C GAQAW L CE QR E EWCGQML GT 3 7 Y DWVE ACQKWP V L CMDS T MY 3 8 CX7C GI R E E L CDKGL HK MCF R E VR 3 9 CE C GK VS S R GC E K L CW L VS Y M 4 0 CX8C D AMDCVVGP EWR K CF L E G 4 1 SGT ACRWGPSW L L CS L AGS P 4 2 GEGP E CD L RQWGNL CGHWE T 43 L S S E E CWE AL KWQGCL MS E R 44 S F CE F NDWWP T CL V 45 CX9C GVE T CY S DAMNT QY CW T T E L 46 E VAR CVVDAGGTWY CWAE MA 4 7 GE S T CV T D L E R VE Y CWDE K S 4 8 HPDK CF ADVR AL QE CME S VR 4 9 R E VK CMK D L SGH E Y CWAE P R 50 S T Y SC I R DMGWAVY CWE T T L 51 VE E K CY E S I T AL R H CMQAMQ 5 2 VE S E CL L S L P N L R R CMMDR L 5 3 VK DE CL MS VE AL K NCMGL VS 5 4 VMDQCF E S Y AE MR K CML DGS 5 5 I DCL DS VE AL KQCMY 56 I E CWQDL QGT R L CWE 57 GAS T T CL E K Y R E R QWCK E L T 58 GE AAE CAY DS L GMAY CY AK E 59 Q I P AGCY E S VQS L L E CVQS A 60 T AGI E CAY DK H L DQY CWWK E 61 42 0 CY4 0w u 1 <~ <- <~ z 00 0yv 0 > u- Z < -u ~< UZ< > F 0 u o U 0> <> < V) < V)F Uz < .0 V 1 ZW < o U0 U UU (N U U U u F- F- F U*U 0 < V 0 cy( > x 2 > 43 Table 3. Sequences from second generation library sorting Family I SEQ ID NO: R N C F E S V A A L R R C M Y 62 F G C Y E S V A A L R T C M Y 63 Y H C F E S V D A L R R C M K 64 L E C F K S V E A L K T C M A 65 R D C F D S V E A L R X C M Y 66 L D C F T S V E A L R W C M R 67 A E C F G S V E A L K G C M H 68 R D C F V S V E A L R H C M Y 69 H D C F A S V E A L R R C M Y 70 S D C F G S V E A L K M C M Y 71 S D C F E S V E A L R A C M Y 72 M E C H G S V E A L K I C M X 73 D E C L T S V E A L R Y C M A 74 G D C L G S V E A L K M C M D 75 N D C L D S V E A L R F C M S 76 A D C L D S V E A L R R C M R 77 F E C L T S V E A L R G C M Y 78 R D C L A S V E A L R S C M Y 79 M D C L A S V E A L K W C M Y 80 L E C Y T S V E A L K W C M R 81 M D C Y S S V E A L R Y C M R 82 L T C L D S V G A L R R C M R 83 H P C L E S V G A L K A C M Y 84 N S C L E S V H A L R E C M L 85 A G C L D S V K A L K R C M I 86 Y T C F E S V P A L R P C M R 87 Y T C F E S V P A L R P C M R 88 S H C F D S V R A L R H C M R 89 T S C F E S V R A L R A C M R 90 N A C L E S V R A L K A C M S 91 L T C L D S V R A L K E F M L 92 S K C L D S V S A L R R C M Q 93 R G C Y E S V T A L R H C M Y 94 Family II W R C A Q D A G G W T Y C W A 95 F R C A G D A G G R S Y C W D 96 V R C A Y D A G G S R Y C W E 97 A R C A R D A G G F Y Y C W A 98 I R C V Q D A G G V R Y C W D 99 V R C V A D A G G F L Y C W A 100 W R C V T D A G G R P Y C W A 101 A S C V A D A G G G G Y C W D 102 V D C V W D A H G W G Y C W A 103 V T C A A D A L G F L Y C W E 104 L R C T E D A S G R V Y C W D 105 G G C A S D L A G F R Y C W E 106 L G C A S D L A G F W Y C W A 107 Y R C A T D L A G F S Y C W A 108 K G C V S D L F G A G Y C W D 109 V R C A W D L G G R A Y C W A 110 L R C A E D L G G Y F Y C W A 111 W R C V D D L G G F Q Y C W A 112 44 V K C A R D L S G F V Y C W A 113 G G C T G D S A G P G Y C W E 114 R R C V S D S G G R T Y C W A 115 L K C A L D T F G G L Y C W A 116 R K C A S D V G G V T Y C W D 117 M S C A R D V R G V R Y C W A 118 G A C M T D V R G R E Y C W D 119 F R C A W E L G W L Y V L G L 120 45 r~ ~ - - -- - m 0 "to 0 00 0 - - 0 CO000000 0 ~x x x xx x w ~ ~ 8~~ 8n r-0r v.r0U 7 0DC lC p0 C D0 0)v0 0 U -v 000 d.00 00 0a)0D o C oooOi r. oo4 6 0 0 0 00('~~ o o:) w ,c- r-0N \J -Z r- m c 0 .0 w U) O) ~0 000000 0 00 JOOO 0 - MM <<<<<<<<000003:a00000000 w w w < o -w<U> a )w< < UI -J > U- LL -J LL -J < << < < < < > 00 ZO 0 WOO 0 m 4 0 m~ w m FI- mI m m m M U- MI M) W L 0 0> >> -J U. < 3 > <J> < > - - - - - -~~~~~ "- ",JC ~ %J(JCJ( C J C' ~JC C'j C\' UL LL U. LL U- LL U- LL U. U U. LL U. U. LL LL LL LL U. U. U. U. 46 Table 5 Synthetic IGF-l binding Peptide Phage BPI BP3 Insulin IGF-1 MCF-7 Comp Comp KIRA KIRA binding (M) (PM) (pM) (PM) (I'M) Fl-P DECLMSVEALKNCMGG NT - - 183 400 (SEQ ID NO:121) Fl-I RNCFESVAALRRCMYG .08x 10-7M 1.4 2.93 5.48 84.9 5.12 (SEQ ID NO:2) I F1-2 MDCLASVEALKWCMYG 1.47x107M 15.5 9.20 32.6 20 15.3 (SEQ ID NO:3) FI-3 FECLTSVEALRGCMYG 2.86x10'M 11.65 12.84 66.1 102 45.7 (SEQ ID NO:4) F2-P ARCVVDAGGTWYCWAG NT - - 300 NT (SEQ ID NO:122) F2-1 LGCASDLAGFWYCWAG 5.54x104M - - 40.41 NT (SEQ ID NO:5) F2-2 WRCVDDLGGFQYCWAG 3.19XI0'7M - - 93.6 130 (SEQ ID NO:6) EXAMPLE 2 Structure Determination of IGF-F1-1 by NMR I H NMR data were collected on peptide IGF-FI-1 either in pure H 2 0 solution (30*C, pH 5.1 and 5.0 millimolar concentration) or in H 2 0 containing 6% (v/v) d 6 - DMSO (40*C, pH 5.2 and at a concentration of 6.7 millimolar). In addition to one-dimensional spectra, two-dimensional double-quantum-filtered correlation spectroscopy (2QF-COSY), total correlation spectra (TOCSY), and rotating-frame Overhauser effect spectra (ROESY) were collected. The experiments were recorded as described by Cavanagh et al. in Protein NMR Spectroscopy, Principles and Practice (Academic Press, San Diego; ISBN 0-12-164490-1, 1995), except that pulsed-field gradients were used for coherence selection in the 2QF-COSY (van Zij] et al., J. Magn. Reson., _ I 3A: 265-270 (1995)) and excitation sculpting was used to suppress the water resonance in the TOCSY and ROESY experiments (Hwang and Shaka, J. Magn. Reson., IJ_ 2A: 275-279 (1995)). After lyophilization and dissolution of the peptide in 2

H

2 0, a 2D ROESY spectrum (Cavanagh et al., supra) and a COSY spectrum with a 35" mixing pulse (Cavanagh et al, supra) were acquired. Complete I H resonance assignments were obtained from these data by standard methods (WUthrich, in NMR of proteins and nucleic acids (John Wiley & Sons, New York; ISBN 0-471-82893-9, 1986) and are listed in Table 6. Evidence of a well defined three-dimensional structure for IGF-F1- I was obtained from the following: (1) Scalar coupling constants between amide and alpha protons (obtained from the 2QF-COSY spectrum) are distinct from the averaged values observed in unstructured peptides. The values less than 6.0 Hz for Glu5, Ser6, Ala8, AIa9, Leul0, ArgI 1, Arg12, and Cysl3 are indicative of a helical conformation for these residues. The value of8.3 Hz observed for Phe4 is indicative of an extended conformation for this residue. (2) Scalar coupling constants were also measured between alpha and beta protons in the COSY-35 spectrum. These data indicate that the side chains of Cys3, Phe4, Ser6 and Cys13 have fixed chi-l angles; i.e., these side chains do not sample the range of chi-l rotamers that are populated in unstructured peptides. (3) Peaks in the ROESY spectra indicate that there are many proton-proton contacts (< 5 A) between residues that are not adjacent in the primary sequence. These can only occur if the peptide folds up into a well 47 defined structure. Contacts between residues at position i and i+3 in the primary sequence are prevalent between Val6 and Arg 12, consistent with the presence of a helix in this region. Many contacts are observed between the aromatic side chain of Phe4 and the methyl groups of Val7, Lcu 10, and Metl4, indicating the presence of a hydrophobic patch along one face of the helix. The NMR data were used to derive restraints that could be used to determine a three-dimensional model of the IGF-FI-1 structure. Dihedral angle restraints were derived from the amide-alpha and alpha-beta scalar coupling constants via an appropriate Karplus relationship (Karplus, J. Phys. Chem,, 30: 11-15 (1959)). Distance restraints were introduced between protons that exhibited a through-space interaction in the ROESY spectrum; the size of the upper bound, and corrections to the upper bound because of peak overlap or resonance degeneracy were as described by Skelton et al., Biochemistry, 33: 13581-92 (1994). These restraints were used to generate a family of structures using the program DGII (Havel, Prog. Biophys. Mol. Biol., 56: 43-78 (1991)), which were subsequently refined by restrained molecular dynamics with the program Discover (MSI, San Diego) using the AMBER all-atom force field (Weiner et al., J, Comput. Chem., 7: 230-252 (1986)). 81 inter-proton distance restraints (45 between non-sequential residues) and 18 dihedral angle restraints (14 $ and 4 Xl) were used in the final calculation. The resulting structures converged to a single global fold (mean root-mean-squared deviation from the mean structure of 0.46±0.16 A and 1.5 1±0.14 A for backbone or all heavy atoms, respectively, of residues 3-13). The best 20 structures (least violation of the input restraints) agreed with the input data very well (no distance restraint violations greater than 0.13 A and no dihedral angle violations greater than 2.0*), and had good covalent geometry as judged by the program PROCHECK (Laskowski et al., J. Appl. Cryst., 26: 283-291). Mean coordinates were generated for IGF-FI-I from the ensemble of 20 structure; energy minimization of these coordinates under the influence of the experimental restraints produced the minimized mean structure depicted in Figure 1. The atomic coordinates of the minimized mean are listed in Table 7. According to the Kabsch and Sander secondary structure algorithm within PROCHECK (supra), IGF-FI-l contains a type I reverse turn at residues Cys3-Phe4 and an alpha helix from Val7 to Cysl3; Ser6 and Met 14 are extensions of the main helix. Hydrogen-bond interactions consistent with these designations are observed in most of the structures within the ensemble. Residues Arg], Asn2, Tyr15, and Gly16 are not well defined by the NMR restraints and may be more flexible in solution than the other residues. There are extensive hydrophobic contacts between the side-chains of Phe4, Val7, LeulO, and Metl4. These residues also pack on top of the disulfide bond (residues Cys3 and Cys13). The non-bonded interactions along this face of the helix likely help to stabilize the folded conformation of the peptide. IGF-FI-I was selected from a peptide library displayed on phage. Although selection was based only on the ability of the peptide to bind to IGF-1, the sequence identified also folds up into a stable, compact structure. Highly structured peptides containing a C-terminal helix have been observed in a number of other phage-derived peptide selection experiments (Dennis et al., Nature, 404: 465-470 (2000); Lowman et al., Biochemistry, 3: 8870-8878 (1998)). In these examples the conformation observed for the peptide in solution is similar to that present when bound to the target protein. Selection of a peptide that has a stable fold in solution that does not change significantly on binding to its target provides an energetic benefit to binding since the association will not lead to a loss of conformational entropy. In these two examples, hydrophobic residues on one face of the peptide helix provide important contacts for binding to the target protein. On the basis of these prior findings, it is hypothesized, without being limited to any one theory, that 48 the hydrophobic patch of residues on the front surface depicted in Figure 1 (Phe4, Val7, Leul0, Met14) likely represents the surface that IGF-FI-I uses to bind to or interact with IGF-l. Thus, the structure of IGF-F1 contains information about the particular arrangement of atoms that is necessary for binding to IGF-1. Table 6 Chemical shifts and coupling constant data for IGF-F1-l a Res HN Ha H Other J ha-H 3HN-Hct I Arg - 4.02 1.89* y=1.63*; &=3.18*; * * 2 Asn - 4.80 2.84, 2.76 8-7.57, 6.95 7.6, 6.5 3 Cys 8.52 4.37 2.92, 2.68 4.5, 10.0 6.2 4 Phe 7.98 4.65 3.28,2.92 &7.23, E=7.33, C=7.28 4.5, 11.0 8.3 5 Glu 7.82 4.18 2.03* y= 2.28* * * 5.6 6 Ser 7.73 4.57 4.09,4.00 4.5, 3.0 5.9 7 Val 8.43 3.96 2.14 y=l.06, 0.99 8.0 6.2 8 Ala 8.12 4.13 1.40 - 5.4 9 Ala 7.97 4.13 1.45 5.1 10 Leu 7.87 4.19 1.80, 1.75 y=1.62, 8=0.91, 0.85 * * 5.1 11 Arg 8.13 4.12 1.92, 1.87 y=1.77, 1.64, &=3.19* -4.7 12 Arg 7.96 4.26 1.90, 1.84 y=1.79, 1.64, =3.19* - 6.1 13 Cys 8.22 4.47 3.35,3.08 11.0,3.5 6.0 14 Met 8.17 4.29 1.85* pr2.49, 2.37, E=2.10 - 6.6 15 Tyr 8.03 4.65 3.16, 2.94 8=7.16, E=6.83 5.5, 10.5 7.9 16Gly 8.07 3.95, 3.87 1 1 - I - _ Data obtained from H 2 0 solution containing 6% (v/v) d6-DMSO at 40*C and pH 5.1. Stereospecifically assigned prochiral groups are indicated by bold typeface; underlined resonances indicate the proR stereochemistry. * indicates degenerate methylene (methyl) resonances. Table 7 Atomic coordinates of the minimized mean structure of IGF-FI -l REMARK 4 1IGF COMPLIES WITH FORMAT V. 2.0, 31-JAN-2001 ATOM 1 N ARG 1 9.068 4.862 -21.485 1.00 0.00 N1+ ATOM 2 CA ARG 1 8.948 5.526 -20.172 1.00 0.00 C ATOM 3 C ARG 1 7.528 6.018 -19.856 1.00 0.00 C ATOM 4 0 ARG 1 7.310 6.619 -18.805 1.00 0.00 0 ATOM 5 CB ARG 1 10.010 6.628 -20.005 1.00 0.00 C ATOM 6 CG ARG 1 10.080 7.674 -21.132 1.00 0.00 C ATOM 7 CD ARG 1 8.816 8.524 -21.315 1.00 0.00 C ATOM 8 NE ARG 1 8.348 9.114 -20.052 1.00 0.00 N1+ ATOM 9 CZ ARG 1 8.892 10.172 -19.427 1.00 0.00 C ATOM 10 NH1 ARG 1 9.953 10.809 -19.942 1.00 0.00 N ATOM 11 NH2 ARG 1 8.364 10.593 -18.271 1.00 0.00 N 49 ATOM 12 1H ARG 1 8.848 5.519 -22.219 1.00 0.00 H ATOM 13 2H ARG 1 10.013 4.526 -21.606 1.00 0.00 H ATOM 14 3H ARG 1 8.428 4.081 -21.529 1.00 0.00 H ATOM 15 HA ARG 1 9.169 4.765 -19.422 1.00 0.00 H ATOM 16 1HB ARG 1 9.871 7.128 -19.046 1.00 0.00 H ATOM 17 2HB ARG 1 10.983 6.135 -19.972 1.00 0.00 H ATOM 18 1HG ARG 1 10.308 7.179 -22.076 1.00 0.00 H ATOM 19 2HG ARG 1 10.914 8.339 -20.904 1.00 0.00 H ATOM 20 1HD ARG 1 9.016 9.313 -22.041 1.00 0.00 H ATOM 21 2HD ARG 1 8.020 7.906 -21.727 1.00 0.00 H ATOM 22 HE ARG 1 7.549 8.667 -19.619 1.00 0.00 H ATOM 23 1HH1 ARG 1 10.354 11.603 -19.465 1.00 0.00 H ATOM 24 2HH1 ARG 1 10.356 10.496 -20.813 1.00 0.00 H ATOM 25 1HH2 ARG 1 7.552 10.124 -17.894 1.00 0.00 H ATOM 26 2HH2 ARG 1 8.756 11.385 -17.783 1.00 0.00 H ATOM 27 N ASN 2 6.559 5.760 -20.745 1.00 0.00 N ATOM 28 CA ASN 2 5.164 6.118 -20.525 1.00 0.00 C ATOM 29 C ASN 2 4.533 5.260 -19.427 1.00 0.00 C ATOM 30 0 ASN 2 3.607 5.721 -18.766 1.00 0.00 0 ATOM 31 CB ASN 2 4.368 5.991 -21.831 1.00 0.00 C ATOM 32 CG ASN 2 4.188 4.536 -22.261 1.00 0.00 C ATOM 33 OD1 ASN 2 5.063 3.972 -22.913 1.00 0.00 0 ATOM 34 ND2 ASN 2 3.065 3.920 -21.884 1.00 0.00 N ATOM 35 H ASN 2 6.779 5.264 -21.597 1.00 0.00 H ATOM 36 HA ASN 2 5.119 7.164 -20.219 1.00 0.00 H ATOM 37 1HB ASN 2 4.884 6.539 -22.621 1.00 0.00 H ATOM 38 2HB ASN 2 3.386 6.445 -21.691 1.00 0.00 H ATOM 39 1HD2 ASN 2 2.912 2.957 -22.147 1.00 0.00 H ATOM 40 2HD2 ASN 2 2.376 4.408 -21.323 1.00 0.00 H ATOM 41 N CYS 3 5.015 4.019 -19.260 1.00 0.00 N ATOM 42 CA CYS 3 4.420 2.986 -18.419 1.00 0.00 C ATOM 43 C CYS 3 3.982 3.500 -17.051 1.00 0.00 C ATOM 44 0 CYS 3 2.868 3.218 -16.624 1.00 0.00 0 ATOM 45 CB CYS 3 5.389 1.810 -18.264 1.00 0.00 C ATOM 46 SG CYS 3 5.740 0.927 -19.807 1.00 0.00 S ATOM 47 H CYS 3 5.786 3.732 -19.845 1.00 0.00 H ATOM 48 RA CYS 3 3.533 2.615 -18.932 1.00 0.00 H ATOM 49 1HB CYS 3 6.329 2.151 -17.829 1.00 0.00 H ATOM 50 2HB CYS 3 4.937 1.097 -17.575 1.00 0.00 H ATOM 51 N PHE 4 4.839 4.271 -16.376 1.00 0.00 N ATOM 52 CA PHE 4 4.620 4.668 -14.991 1.00 0.00 C ATOM 53 C PHE 4 3.808 5.963 -14.883 1.00 0.00 C ATOM 54 0 PHE 4 3.418 6.342 -13.781 1.00 0.00 0 ATOM 55 CB PHE 4 5.979 4.775 -14.291 1.00 0.00 C ATOM 56 CG PHE 4 6.802. 3.507 -14.430 1.00 0.00 C ATOM 57 CD1 PHE 4 6.472 2.370 -13.668 1.00 0.00 C ATOM 58 CD2 PHE 4 7.860 3.443 -15.357 1.00 0.00 C ATOM 59 CE1 PHE 4 7.157 1.160 -13.872 1.00 0.00 C ATOM 60 CE2 PHE 4 8.549 2.234 -15.557 1.00 0.00 C ATOM 61 CZ PHE 4 8.192 1.090 -14.821 1.00 0.00 C ATOM 62 H PHE 4 5.729 4.495 -16.796 1.00 0.00 H ATOM 63 HA PHE 4 4.058 3.890 -14.476 1.00 0.00 H ATOM 64 1HB PHE 4 6.529 5.618 -14.712 1.00 0.00 H ATOM 65 2HB PHE 4 5.817 4.977 -13.231 1.00 0.00 H ATOM 66 HD1 PHE 4 5.675 2.417 -12.941 1.00 0.00 H ATOM 67 HD2 PHE 4 8.131 4.312 -15.938 1.00 0.00 H ATOM 68 HE1 PHE 4 6.888 0.284 -13.301 1.00 0.00 H ATOM 69 HE2 PHE 4 9.351 2.182 -16.279 1.00 0.00 H ATOM 70 HZ PHE 4 8.717 0.159 -14.980 1.00 0.00 H ATOM 71 N GLU 5 3.517 6.612 -16.018 1.00 0.00 N ATOM 72 CA GLU 5 2.586 7.725 -16.118 1.00 0.00 C ATOM 73 C GLU 5 1.192 7.161 -16.410 1.00 0.00 C 50 ATOM 74 0 GLU 5 0.253 7.395 -15.652 1.00 0.00 0 ATOM 75 CB GLU 5 3.048 8.689 -17.220 1.00 0.00 C ATOM 76 CG GLU 5 4.445 9.252 -16.928 1.00 0.00 C ATOM 77 CD GLU 5 4.950 10.091 -18.096 1.00 0.00 C ATOM 78 OE1 GLU 5 5.644 9.505 -18.955 1.00 0.00 0 ATOM 79 OE2 GLU 5 4.644 11.303 -18.107 1.00 0.00 01 ATOM 80 H GLU 5 3.862 6.243 -16.894 1.00 0.00 H ATOM 81 HA GLU 5 2.556 8.277 -15.177 1.00 0.00 H ATOM 82 1HB GLU 5 3.068 8.176 -18.181 1.00 0.00 H ATOM 83 2HB GLU 5 2.340 9.517 -17.287 1.00 0.00 H ATOM 84 1HG GLU 5 5.155 8.440 -16.766 1.00 0.00 H ATOM 85 2HG GLU 5 4.407 9.865 -16.027 1.00 0.00 H ATOM 86 N SER 6 1.070 6.406 -17.510 1.00 0.00 N ATOM 87 CA SER 6 -0.159 5.760 -17.938 1.00 0.00 C ATOM 88 C SER 6 -0.348 4.451 -17.166 1.00 0.00 C ATOM 89 0 SER 6 0.164 3.409 -17.575 1.00 0.00 0 ATOM 90 CB SER 6 -0.111 5.533 -19.456 1.00 0.00 C ATOM 91 G SER 6 1.085 4.881 -19.830 1.00 0.00 0 ATOM 92 H SER 6 1.892 6.238 -18.076 1.00 0.00 H ATOM 93 HA SER 6 -1.008 6.416 -17.739 1.00 0.00 H ATOM 94 1HB SER 6 -0.966 4.929 -19.763 1.00 0.00 H ATOM 95 2HB SER 6 -0.156 6.494 -19.969 1.00 0.00 H ATOM 96 HG SER 6 1.246 4.174 -19.198 1.00 0.00 H ATOM 97 N VAL 7 -1.099 4.521 -16.059 1.00 0.00 N ATOM 98 CA VAL 7 -1.390 3.409 -15.156 1.00 0.00 C ATOM 99 C VAL 7 -1.852 2.163 -15.922 1.00 0.00 C ATOM 100 0 VAL 7 -1.406 1.058 -15.622 1.00 0.00 0 ATOM 101 CB VAL 7 -2.428 3.844 -14.104 1.00 0.00 C ATOM 102 CG1 VAL 7 -1.886 4.995 -13.243 1.00 0.00 C ATOM 103 CG2 VAL 7 -2.804 2.681 -13.174 1.00 0.00 C ATOM 104 H VAL 7 -1.468 5.426 -15.805 1.00 0.00 H ATOM 105 HA VAL 7 -0.470 3.161 -14.627 1.00 0.00 H ATOM 106 HB VAL 7 -3.334 4.185 -14.610 1.00 0.00 H ATOM 107 1HG1 VAL 7 -0.965 4.688 -12.747 1.00 0.00 H ATOM 108 2HG1 VAL 7 -1.687 5.877 -13.850 1.00 0.00 H ATOM 109 3HG1 VAL 7 -2.622 5.265 -12.485 1.00 0.00 H ATOM 110 1HG2 VAL 7 -3.480 3.035 -12.395 1.00 0.00 H ATOM 111 2HG2 VAL 7 -3.311 1.892 -13.729 1.00 0.00 H ATOM 112 3HG2 VAL 7 -1.907 2.272 -12.706 1.00 0.00 H ATOM 113 N ALA 8 -2.737 2.343 -16.910 1.00 0.00 N ATOM 114 CA ALA 8 -3.245 1.267 -17.752 1.00 0.00 C ATOM 115 C ALA 8 -2.110 0.454 -18.383 1.00 0.00 C ATOM 116 0 ALA 8 -2.138 -0.775 -18.339 1.00 0.00 0 ATOM 117 CB ALA 8 -4.159 1.854 -18.830 1.00 0.00 C ATOM 118 H ALA 8 -3.065 3.279 -17.099 1.00 0.00 H ATOM 119 HA ALA 8 -3.844 0.601 -17.129 1.00 0.00 H ATOM 120 1HB ALA 8 -4.562 1.050 -19.447 1.00 0.00 H ATOM 121 2HB ALA 8 -4.986 2.389 -18.361 1.00 0.00 H ATOM 122 3HB ALA 8 -3.600 2.544 -19.463 1.00 0.00 H ATOM 123 N ALA 9 -1.110 1.137 -18.956 1.00 0.00 N ATOM 124 CA ALA 9 0.041 0.493 -19.573 1.00 0.00 C ATOM 125 C ALA 9 0.921 -0.183 -18.521 1.00 0.00 C ATOM 126 0 ALA 9 1.383 -1.297 -18.755 1.00 0.00 0 ATOM 127 CB ALA 9 0.846 1.510 -20.383 1.00 0.00 C ATOM 128 H ALA 9 -1.117 2.146 -18.913 1.00 0.00 H ATOM 129 HA ALA 9 -0.321 -0.267 -20.268 1.00 0.00 H ATOM 130 1HB ALA 9 1.641 0.997 -20.925 1.00 0.00 H ATOM 131 2HB ALA 9 0.198 2.019 -21.097 1.00 0.00 H ATOM 132 3HB ALA 9 1.294 2.241 -19.714 1.00 0.00 H ATOM 133 N LEU 10 1.138 0.487 -17.377 1.00 0.00 N ATOM 134 CA LEU 10 1.939 0.017 -16.244 1.00 0.00 C ATOM 135 C LEU 10 1.692 -1.468 -15.959 1.00 0.00 C 51 ATOM 136 o LEU 10 2.636 -2.251 -15.870 1.00 0.00 0 ATOM 137 CB LEU 10 1.618 0.868 -15.001 1.00 0.00 C ATOM 138 CG LEU 10 2.813 1.119 -14.068 1.00 0.00 C ATOM 139 CD1 LEU 10 2.377 2.089 -12.963 1.00 0.00 C ATOM 140 CD2 LEU 10 3.346 -0.165 -13.427 1.00 0.00 C ATOM 141 H LEU 10 0.724 1.407 -17.290 1.00 0.00 H ATOM 142 HA LEU 10 2.986 0.165 -16.507 1.00 0.00 H ATOM 143 1HB LEU 10 1.267 1.843 -15.331 1.00 0.00 H ATOM 144 2HB LEU 10 0.812 0.410 -14.427 1.00 0.00 H ATOM 145 HG LEU 10 3.623 1.579 -14.634 1.00 0.00 H ATOM 146 1HD1 LEU 10 3.221 2.317 -12.311 1.00 0.00 H ATOM 147 2HD1 LEU 10 2.014 3.019 -13.402 1.00 0.00 H ATOM 148 3HD1 LEU 10 1.580 1.643 -12.368 1.00 0.00 H ATOM 149 1HD2 LEU 10 2.531 -0.720 -12.963 1.00 0.00 H ATOM 150 2HD2 LEU 10 4.088 0.082 -12.668 1.00 0.00 H ATOM 151 3HD2 LEU 10 3.828 -. 0.779 -14.184 1.00 0.00 H ATOM 152 N ARG 11 0.411 -1.838 -15.843 1.00 0.00 N ATOM 153 CA ARG 11 -0.061 -3.183 -15.534 1.00 0.00 C ATOM 154 C ARG 11 0.635 -4.232 -16.405 1.00 0.00 C ATOM 155 0 ARG 11 1.279 -5.138 -15.881 1.00 0.00 0 ATOM 156 CB ARG 11 -1.584 -3.244 -15.715 1.00 0.00 C ATOM 157 CG ARG 11 -2.312 -2.303 -14.745 1.00 0.00 C ATOM 158 CD ARG 11 -3.799 -2.197 -15.096 1.00 0.00 C ATOM 159 NE ARG 11 -4.441 -1.098 -14.363 1.00 0.00 N1+ ATOM 160 CZ ARG 11 -4.800 -1.128 -13.069 1.00 0.00 C ATOM 161 NH1 ARG 11 -4.608 -2.225 -12.323 1.00 0.00 N ATOM 162 NH2 ARG 11 -5.357 -0.043 -12.515 1.00 0.00 N ATOM 163 H ARG 11 -0.290 -1.121 -15.970 1.00 0.00 H ATOM 164 HA ARG 11 0.170 -3.395 -14.488 1.00 0.00 H ATOM 165 1HB ARG 11 -1.828 -2.967 -16.742 1.00 0.00 H ATOM 166 2HB ARG 11 -1.929 -4.264 -15.539 1.00 0.00 H ATOM 167 1HG ARG 11 -1.890 -1.303 -14.801 1.00 0.00 H ATOM 168 2HG ARG 11 -2.191 -2.670 -13.726 1.00 0.00 H ATOM 169 1HD ARG 11 -4.303 -3.144 -14.896 1.00 0.00 H ATOM 170 2HD ARG 11 -3.896 -1.977 -16.160 1.00 0.00 H ATOM 171 HE ARG 11 -4.603 -0.248 -14.884 1.00 0.00 H ATOM 172 2HH1 ARG 11 -4.184 -3.045 -12.731 1.00 0.00 H ATOM 173 1HH1 ARG 11 -4.882 -2.234 -11.351 1.00 0.00 H ATOM 174 1HH2 ARG 11 -5.631 -0.053 -11.543 1.00 0.00 H ATOM 175 2HH2 ARG 11 -5.505 0.789 -13.068 1.00 0.00 H ATOM 176 N ARG 12 0.521 -4.095 -17.732 1.00 0.00 N ATOM 177 CA ARG 12 1.150 -5.005 -18.679 1.00 0.00 C ATOM 178 C ARG 12 2.66B -4.836 -18.713 1.00 0.00 C ATOM 179 0 ARG 12 3.387 -5.828 -18.801 1.00 0.00 0 ATOM 180 CB ARG 12 0.576 -4.808 -20.086 1.00 0.00 C ATOM 181 CG ARG 12 -0.805 -5.459 -20.231 1.00 0.00 C ATOM 182 CD ARG 12 -1.215 -5.535 -21.705 1.00 0.00 C ATOM 183 NE ARG 12 -0.296 -6.395 -22.465 1.00 0.00 N1+ ATOM 184 CZ ARG 12 -0.331 -6.587 -23.792 1.00 0.00 C ATOM 185 NH1 ARG 12 -1.292 -6.032 -24.544 1.00 0.00 N ATOM 186 NH2 ARG 12 0.613 -7.344 -24.367 1.00 0.00 N ATOM 187 H ARG 12 0.007 -3.307 -18.101 1.00 0.00 H ATOM 188 HA ARG 12 0.942 -6.025 -18.370 1.00 0.00 H ATOM 189 1HB ARG 12 0.523 -3.747 -20.333 1.00 0.00 H ATOM 190 2HB ARG 12 1.262 -5.284 -20.783 1.00 0.00 H ATOM 191 1HG ARG 12 -0.778 -6.473 -19.832 1.00 0.00 H ATOM 192 2HG ARG 12 -1.541 -4.879 -19.673 1.00 0.00 H ATOM 193 1HD ARG 12 -2.223 -5.949 -21.769 1.00 0.00 H ATOM 194 2HD ARG 12 -1.216 -4.530 -22.129 1.00 0.00 H ATOM 195 HE ARG 12 0.445 -6.844 -21.942 1.00 0.00 H ATOM 196 2HH1 ARG 12 -2.004 -5.462 -24.111 1.00 0.00 H ATOM 197 1HH1 ARG 12 -1.307 -6.182 -25.542 1.00 0.00 H 52 ATOM 198 1HH2 ARG 12 1.348 -7.745 -23.800 1.00 0.00 H ATOM 199 2HH2 ARG 12 0.603 -7.503 -25.364 1.00 0.00 H ATOM 200 N CYS 13 3.142 -3.586 -18.683 1.00 0.00 N ATOM 201 CA CYS 13 4.531 -3.206 -18.914 1.00 0.00 C ATOM 202 C CYS 13 5.525 -3.948 -18.013 1.00 0.00 C ATOM 203 0 CYS 13 6.661 -4.171 -18.428 1.00 0.00 0 ATOM 204 CB CYS 13 4.649 -1.684 -18.783 1.00 0.00 C ATOM 205 SG CYS 13 6.253 -0.953 -19.202 1.00 0.00 S ATOM 206 H CYS 13 2.476 -2.833 -18.584 1.00 0.00 H ATOM 207 HA CYS 13 4.770 -3.463 -19.947 1.00 0.00 H ATOM 208 1HB CYS 13 3.918 -1.242 -19.461 1.00 0.00 H ATOM 209 2HB CYS 13 4.396 -1.389 -17.766 1.00 0.00 H ATOM 210 N MET 14 5.105 -4.380 -16.816 1.00 0.00 N ATOM 211 CA MET 14 5.942 -5.147 -15.894 1.00 0.00 C ATOM 212 C MET 14 6.053 -6.635 -16.274 1.00 0.00 C ATOM 213 0 MET 14 6.252 -7.476 -15.399 1.00 0.00 0 ATOM 214 CB MET 14 5.406 -4.976 -14.464 1.00 0.00 C ATOM 215 CG MET 14 5.447 -3.513 -14.009 1.00 0.00 C ATOM 216 SD MET 14 4.877 -3.219 -12.313 1.00 0.00 S ATOM 217 CE MET 14 3.147 -3.748 -12.439 1.00 0.00 C ATOM 218 H MET 14 4.157 -4.176 -16.530 1.00 0.00 H ATOM 219 HA MET 14 6.954 -4.744 -15.928 1.00 0.00 H ATOM 220 1HB MET 14 4.382 -5.349 -14.430 1.00 0.00 H ATOM 221 2HB MET 14 6.016 -5.556 -13.770 1.00 0.00 H ATOM 222 1HG MET 14 4.841 -2.904 -14.676 1.00 0.00 H ATOM 223 2HG MET 14 6.478 -3.163 -14.074 1.00 0.00 H ATOM 224 1HE MET 14 3.096 -4.826 -12.584 1.00 0.00 H ATOM 225 2HE MET 14 2.627 -3.490 -11.517 1.00 0.00 H ATOM 226 3HE MET 14 2.665 -3.245 -13.277 1.00 0.00 H ATOM 227 N TYR 15 5.966 -6.955 -17.571 1.00 0.00 N ATOM 228 CA TYR 15 6.208 -8.276 -18.144 1.00 0.00 C ATOM 229 C TYR 15 6.195 -8.190 -19.673 1.00 0.00 C ATOM 230 0 TYR 15 7.091 -8.715 -20.332 1.00 0.00 0 ATOM 231 CB TYR 15 5.219 -9.338 -17.628 1.00 0.00 C ATOM 232 CG TYR 15 3.737 -9.035 -17.779 1.00 0.00 C ATOM 233 CD1 TYR 15 3.054 -9.396 -18.956 1.00 0.00 C ATOM 234 CD2 TYR 15 3.028 -8.436 -16.720 1.00 0.00 C ATOM 235 CE1 TYR 15 1.667 -9.198 -19.058 1.00 0.00 C ATOM 236 CE2 TYR 15 1.635 -8.274 -16.808 1.00 0.00 C ATOM 237 CZ TYR 15 0.952 -8.664 -17.972 1.00 0.00 C ATOM 238 OH TYR 15 -0.402 -8.517 -18.047 1.00 0.00 0 ATOM 239 H TYR 15 5.831 -6.199 -18.224 1.00 0.00 H ATOM 240 HA TYR 15 7.209 -8.590 -17.845 1.00 0.00 H ATOM 241 1HB TYR 15 5.430 -10.269 -18.157 1.00 0.00 H ATOM 242 2HB TYR 15 5.422 -9.532 -16.576 1.00 0.00 H ATOM 243 HD1 TYR 15 3.587 -9.844 -19.782 1.00 0.00 H ATOM 244 HD2 TYR 15 3.541 -8.135 -15.819 1.00 0.00 H ATOM 245 HEl TYR 15 1.151 -9.477 -19.966 1.00 0.00 H ATOM 246 HE2 TYR 15 1.089 -7.854 -15.976 1.00 0.00 H ATOM 247 HH TYR 15 -0.771 -8.820 -18.879 1.00 0.00 H ATOM 248 N GLY 16 5.175 -7.530 -20.233 1.00 0.00 N ATOM 249 CA GLY 16 4.972 -7.394 -21.664 1.00 0.00 C ATOM 250 C GLY 16 3.630 -6.713 -21.920 1.00 0.00 C ATOM 251 0 GLY 16 2.619 -7.446 -21.996 1.00 0.00 0 ATOM 252 OXT GLY 16 3.636 -5.467 -22.024 1.00 0.00 01 ATOM 253 H GLY 16 4.476 -7.124 -19.626 1.00 0.00 H ATOM 254 IHA GLY 16 5.777 -6.795 -22.091 1.00 0.00 H ATOM 255 2HA GLY 16 4.974 -8.380 -22.131 1.00 0.00 H TER 53 The present invention has of necessity been discussed herein by reference to certain specific methods and materials. It is to be understood that the discussion of these specific methods and materials in no way constitutes any limitation on the scope of the present invention, which extends to any and all alternative materials and methods suitable for accomplishing the objectives of the present invention. 5 In the claims which follow and in the description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. 54 H:\veronica\keep\speci\2002248609.doc 11/03/05

Claims (14)

1. 2. A peptide according to claim 1, wherein the amino acids in the peptide are all L-amino acids.
2. 3. A peptide according to claim I or claim 2, further comprising a glycine residue after (Xaa),. 10 4. A peptide according to any one of claims I to 3, wherein (Xaa) 2 is Gly, Ser, Arg, or Thr, and (Xaa), is Glu, Ala, or Asp.
3. 5. A peptide according to any one of claims I to 4, wherein (Xaa) 2 is Gly or Arg, (Xaa) 5 is Leu, (Xaa) 6 is Ala or Gly, (Xaa) 7 is Phe, and (Xaa), is Ala.
4. 6. A peptide of any one of claims I to 5, which comprises the sequence 15 LGCASDLAGFWYCWAG (SEQ ID NO:6) or WRCVDDLGGFQYCWAG (SEQ ID NO:7).
5. 7. A peptide according to any one of claims I to 6, which is conjugated to a cytotoxic agent or polyethylene glycol.
6. 8. A composition comprising a peptide according to any one of claims I to 7 in a carrier.
7. 9. A composition according to claim 8, further comprising an angiogenic agent or 20 chemotherapeutic agent and/or suitable for injection or inhalation.
8. 10. A kit comprising a container containing a composition according to claim 8 or 9, and instructions directing the user to utilize the composition. I1. A method for treating a mammal having a disorder involving an insulin-like growth factor-I (IGF- 1)-mediated event, comprising administering to the mammal an effective amount of a 25 peptide according to any of claims I to 7.
9. 12. A method according to claim I I comprising a further administering step, wherein said further administering step comprises administering to the mammal an effective amount of another agent that treats said disorder, which other agent includes a growth inhibitory agent; an angiostatic agent; a cytotoxic agent; a chemotherapeutic agent; or an antibody. 3 0 13. A method according to claim I I or 12, wherein the mammal is human.
10. 14. A method according to any one of claims I I to 13, comprising, before the administration step, a further step comprising measuring the concentration of IGF- I in a body sample from the mammal, the body sample including tumor tissue; blood; plasma; serum; mammary fluid; or seminal fluid, wherein an elevated concentration of IGF-I above a reference range for IGF-l 35 indicates an increased risk for the disorder, and wherein the IGF-1 is total IGF-l, free IGF-l or complexed IGF-I.
11. 15. Use of an effective amount of a peptide of any one of claims I to 7 in the manufacture of a medicament for treating a mammal having a disorder involving an insulin-like growth factor-I (IGF-1)-mediated event. 1762129_2 (GHMattors) 18/09109 - 56 16. A method according to any one of claims I I to 14 or use according to claim 15, wherein the disorder is cancer, a diabetic complication exacerbated by IGF-I, acromegaly, age-related macular degeneration, ischemic injury, or a trauma.
12. 17. A method or use according to claim 16, wherein the cancer comprises cancer selected from the 5 group consisting of a tumour that expresses an insulin-like growth factor receptor; breast cancer; prostate cancer; colorectal cancer; and lung cancer.
13. 18. A method or use according to claim 16, wherein the diabetic complication is diabetic retinopathy or diabetic nephropathy.
14. 19. A method according to claim 16 or 17, wherein the disorder is prostate cancer, and comprises, 10 before the administration step, (a) measuring the concentration of prostate-specific antigen (PSA) in a body sample from the mammal, wherein an elevated concentration of PSA above a reference range for PSA indicates an increased risk for prostate cancer; (b) measuring the concentration of IGF-l in a body sample from the mammal, measuring the concentration of insulin-like growth factor binding protein-3 (IGFBP-3) in a body sample from the mammal and 15 conducting a multivariate adjustment of the IGF-I concentration relative to the IGFBP-3 concentration to provide an adjusted IGF-I level, wherein the adjusted IGF-I level above a reference range for adjusted IGF-l indicates an increased risk for prostate cancer; and (c) measuring the concentration of IGF-I in a body sample from the mammal, measuring the concentration of insulin-like growth factor binding protein-3 (IGFBP-3) in a body sample from 20 the mammal, measuring the concentration of prostate-specific antigen (PSA) in a body sample from the mammal, and conducting a multivariate adjustment of the IGF-l concentration relative to the IGFBP-3 concentration and PSA concentration to provide an adjusted IGF/IGFBP/PSA value, wherein an adjusted IGF/IGFBP/PSA value above a reference range for adjusted IGF/IGFBP/PSA indicates an increased risk for severe prostate cancer. 25 20. A peptide according to claim 1, a composition according to claim 8, a kit according to claim 10, a method according to claim 11, or a use according to claim 15, substantially as herein described with reference to any one of the examples and drawing. 17621292 (GHMatters) 18/09109