AU714288B2 - Novel peptides - Google Patents

Description

I

S F Ref: 361351D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECFICATION FOR A STANDARD PATENT

ORIGINAL

4.4 4444 4..

44 4 4* 4.

*4 4 4 **44 Name and Address of Applicant: Actual Inventor(s): Address for Service: Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey 07065 UNITED STATES OF AMERICA Deborah Defeo-Jones, Dong-Mel Feng, Victor M Garsky, Raymond E Jones, Allen I 01lff Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Novel Peptides Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 Novel Peptides Background of the Invention In 1994 cancer of the prostate gland is expected to be diagnosed in 200 000 men in the US. and 38 000 American males will die from this disease (Garnick, M.B. (1994). The Dilemmas of Prostate Cancer. Scientific American, April: 72-81).

Thus, prostate cancer is the most frequently diagnosed malignancy (other than that of the skin) in US. men and the second leading cause of cancer-related deaths (behind lung cancer) in that group.

Prostate specific Antigen (PSA) is a single chain 33kDa glycoprotein that is produced almost exclusively by the human prostate epithelium and occurs at levels of 0.5 to 2.0mg/mL in human seminal fluid (Nadji, Taber, Castro, et al.

(1981) Cancer 48:1229; Papsidero, Kuriyama, Wang, et al. (1981). JNCI 66:37; Qui, Young, Bihartz, et al. (1990), J. Urol. 144:1550; Wang, Valenzuela, Murphy, et al. (1979). Invest. Urol. 17:159).

15 The single carbohydrate unit is attached at asparagine residue number 45 and accounts for 2 to 3kDa of the total molecular mass. PSA is a protease with chymotrypsin-like specificity (Christensson, Laurell, Lilja, H. (1990). Eur. J.

Biochem. 194:755-763). It has been shown that PSA is mainly responsible for dissolution of the gel structure formed at ejaculation by proteolysis of the major 20 proteins in the sperm entrapping gel, Semenogelin I and Semenogelin II, and fibronectin (Lilja, H. (1985). J. Clin. Invest. 76:1899; Lilja, Oldbring, Rannevik, et al. (1987). J. Clin. Invest. 80:281; McGee, Herr, J.C. (1988). Biol.

Reprod. 39:499). The PSA mediated proteolysis of the gel-forming proteins generates several soluble Semenogelin I and Semenogelin II fragments and soluble fibronectin fragments with liquefaction of the ejaculate and release of progressively motile spermatozoa (Lilja, Laurell, C.B. (1984). Scand. J. Clin. Lab. Invest.

44:447; McGee, Herr, J.C. (1987). Biol. Reprod. 37:431). Furthermore, PSA may proteolytically degrade IGFBP-3 (insulin-like growth factor binding protein 3) allowing IGF to stimulate specifically the growth of PSA secreting cells (Cohen et al., (1992) J. Clin. Endo. Meta. 75:1046-1053).

PSA complexed to al-antichymotrypsin is the predominant molecular form of serum PSA and may account for up to 95% of the detected serum PSA (Christensson, Bjork, Nilsson, et al. (1993). J. Urol. 150:100-105; Lilja, H., Christensson, Dahlen, U. (1991). Clin. Chem. 37:1618-1625; Stenman, U.H., Leinoven, Alfthan, et al. (1991). Cancer Res. 51:222-226). The prostatic tissue (normal, benign hyperplastic, or malignant tissue) is implicated to predominantly release the mature, enzymatically active form of PSA, as this form is required for complex formation with al-antichymotrypsin (Mast, Enghild, J.J., Pizzo, et al. (1991). Biochemistry 30:1723-1730; Perlmutter, Glover, Libc/03531.doc Rivetna, et al. (1990). Proc. Natl. Acad. Sci. USA 87:3753-3757).

Therefore, in the microenvironment of prostatic PSA secreting cells the PSA is believed to be processed and secreted in its mature enzymatically active form not complexed to any inhibitory molecule. PSA also forms stable complexes with a2macroglobulin, but as this results in encapsulation of PSA and complete loss of the PSA epitopes, the in vivo significance of this complex formation is unclear. A free, noncomplexed form of PSA constitutes a minor fraction of the serum PSA (Christensson, Bjork, Nilsson, etal. (1993). J. Urol. 150:100-105; Lilja, H., Christensson, Dahlen, U. (1991). Clin. Chem. 37:1618-1625). The size of this form of serum PSA is similar to that of PSA in seminal fluid (Lilja, Christensson, Dahlen, U. (1991). Clin. Chem. 37:1618-1625) but it is yet unknown as to whether the free form of serum PSA may be a zymogen; an internally cleaved, inactive form of mature PSA; or PSA manifesting enzyme activity. However, it seems unlikely that the free form of serum PSA manifests enzyme activity, since 15 there is considerable (100 to 1000 fold) molar excess of both unreacted alantichymotrypsin and (2-macroglobulin in serum as compared with the detected serum levels of the free 33kDa form of PSA (Christensson, Bjork, Nilsson, etal. (1993). J. Urol. 150:100-105; Lilja, Christensson, Dahlen, U. (1991).

Clin. Chem. 37:1618-1625).

20 Serum measurements of PSA are useful for monitoring the treatment of adenocarcinoma of the prostate (Duffy, M.S. (1989). Ann. Clin. Biochem. 26:379- 387; Brawer, M.K. and Lange, P.H. (1989). Urol. Suppl. 5:11-16; Hara, M. and Kimura, H. (1989). J. Lab. Clin. Med. 113:541-548), although above normal serum concentrations of PSA have also been reported in benign prostatic hyperplasia and subsequent to surgical trauma of the prostate (Lilja, Christensson, Dahlen, U. (1991). Clin. Chem. 37:1618-1625). Prostate metastases are also known to secrete immunologically reactive PSA since serum PSA is detectable at high levels in prostatectomised patients showing widespread metatstatic prostate cancer (Ford, Butcher, Masters, et al. (1985). Brit. J. Urology 57:50-55).

Therefore, a cytotoxic compound that could be activated by the proteolytic activity of PSA should be prostate cell specific as well as specific for PSA secreting prostate metastases.

Accordingly, it is the object of this invention to provide novel oligopeptides which selectively are enzymatically cleaved by active free prostate specific antigen

(PSA).

It is also the object of this invention to provide a quantitative assay for enzymatically active PSA which incorporates those novel oligopeptides.

It is further the object of this invention to provide a novel anti-cancer composition useful for the treatment of prostate cancer which comprises those novel oligopeptides in conjugation with a cytotoxic agent.

Libc/03531.doc Another object of this invention is to provide a method of treating prostate cancer which comprises administration of novel anti-cancer composition.

Summary of the Invention The several points of cleavage where semenogelin I is selectively proteolytically cleaved by free PSA have been identified. Oligopeptides which comprise the amino acid sequences that are recognised and proteolytically cleaved by free prostate specific antigen (PSA) are described. Such oligopeptides are useful in assays which can determine the free PSA protease activity in vitro and in vivo.

Furthermore, such oligopeptides may be incorporated into therapeutic agents which comprise conjugates of such oligopeptides and known cytotoxic agents and which are useful in the treatment of prostatic cancer.

Brief Description of the Figures FIGURE 1: Primary Amino Acid Sequence of Semenogelin I: The primary S amino acid sequence of Semenogelin I is shown. (SEQ.ID.NO.: 1) The PSA 15 proteolytic cleavage sites are shown (numbered in order of the relative affinity of a site towards PSA hydrolysis) and the protein fragments are numbered sequentially starting at the amino terminus.

FIGURE 2: Cleavage Affinity of Synthetic Oligopeptides: A nested set of synthetic oligopeptides was prepared and the oligopeptides were digested with enzymatically active free PSA for various times. The results are shown in Table 2 (Figure All of the oligopeptides were tested as trifluoroacetate salts.

FIGURES 3, 3A and 3B: Cleavage Affinity of Synthetic Oligopeptides: Synthetic oligopeptides were prepared and the oligopeptides were digested with enzymatically active free PSA for four hours. The percentage of the oligopeptide that is cleaved in this period of time is listed. The results are shown in Table 4 (Figures 3 and 3A). Table 4a (Figure 3B) shows the amount of time (in minutes) required for 50% cleavage of the noted oligopeptides with enzymatically active free PSA. If no salt is indicated for an oligopeptide, the free base was tested.

FIGURE 4: Cytotoxicity Data of Non-cleavable Oligopeptide-Doxorubicin Conjugates: The data of the figure shows comparative cytotoxicity of doxorubicin and a conjugate of doxorubicin covalently bound to an oligopeptide (Compound 12d) that does not contain the free PSA proteolytic cleavage site. The EC 50 for doxorubicin is 0.3pM, while the acetylated oligopeptide modified doxorubicin has an

EC

50 that has been reduced by greater than 300 fold. This conjugate had no HPLC detectable contamination with unmodified doxorubicin. The oligopeptide alone had no detectable cell killing activity.

FIGURES 5 and 5A: Cleavage Affinity of Oligopeptides in Conjugation with Doxorubicin by Free PSA In vitro: Oligopeptides-doxorubicin conjugates were prepared and the conjugates were digested with enzymatically active free PSA for Libc/03531.doc four hours. The percentage conjugate that is enzymatically cleaved in the oligopeptide in this period of time is listed. The results are shown in Table 5 (Figure Table 5a (Figure 5A) shows the amount of time (in minutes) required for 50% cleavage of the noted oligopeptide-cytotoxic agent conjugates with enzymatically active free PSA. If no salt is indicated for the conjugate, the free conjugate was tested.

FIGURE 6: Cleavage Affinity of Oligopeptides in Conjugation with Doxorubicin in Cell Conditioned Media: Oligopeptides-doxorubicin conjugates were reacted for four hours with cell culture media that had been conditioned by exposure to LNCaP cells (which are known to secrete free PSA) or DuPRO cell (which do not secrete free PSA). The percentage conjugate that is enzymatically to cleaved in the oligopeptide in this period of time is listed. The results are shown in Table 6 (Figure 6).

FIGURES 7 and 7A: Cytotoxicity Data of Cleavable Oligopeptide-Doxorubicin Conjugates: The data in Table 7 (Figures 7 and 7A) shows cytotoxicity (as EC 50 of conjugates of doxorubicin covalently bound to an oligopeptide that contain a free PSA proteolytic cleavage site against a cancer cell line that is known to secrete free PSA. Also shown for selected conjugates is the cytotoxicity of the conjugate against a cell line (DuPRO) which does not secrete free PSA. If no salt is indicated for the conjugate, the free conjugate was tested.

Detailed Description of the Invention The present invention relates to oligopeptides, not including Semenogelin I and II, Fibronectin or IGFBP-3, each of which oligopeptides comprises a sequence of amino acids that is recognised and S 2 selectively proteolytically cleaved by free prostate specific antigen or pharmaceutically Sacceptable salts thereof. Such oligopeptides include oligomers that comprise an amino acid sequence selected from: a) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: 13), b) LyslleSerTyrGlnlSer (SEQ.ID.NO.: 14), 25 c) GlyGluAsnGlyValGInLysAspValSerGinXaaSerlleTyrlSerGInlThrGIU (SEQ.ID.NO.: d) GlyLysGlylleSerSerGInTyrlSerAsnThrGluGluArgLeu (SEQ.ID.NO.: 2), e) AsnLyslleSerTyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerTyrGlnlSer (SEQ.ID.NO.: 128), g) SerTyrGlnlSerSer (SEQ.ID.NO.: 129); 30 h) LysTyrGlnlSerSer (SEQ.ID.NO.: 140); i) hArgTyrGlnlerSSer (SEQ.ID.NO.: 141); j) hArgChaGlnlSerSer (SEQ.ID.NO.: 185); and k) TyrGlnlSerSer (SEQ.ID.NO.: 186); wherein hArg is homoarginine, Cha is cyclohexylalanine and Xaa is any natural amino acid.

[R:\LIBAAJ00001 .doc:NJC In an embodiment of the instant invention, the oligopeptides include oligomers that comprise an amino acid sequence that is selected from: a) AsnLyslleSerTyrGlnlSerSer (SEQ.ID.NO.: 16), b) AsnLyslleSerTyrGlnlSerAla (SEQ.ID.NO.: 130), c) AsnLyslleSerTyrGlnlSerSerSer (SEQ. ID.NO.: 17), d) AlaAsnLyslleSerTyrGlnlSerSerSer (SEQ.ID.NO.: 18), e) LyslleSerTyrGlnlSerSerSerThrGlu (SEQ. ID.NO.: 19), f) GlyGluAsnGlyValGInLysAspVaSerGInArgSerIeTyrSerGflThrGu (SEQ. ID.NO.: 4), g) GlyGluAsnGlyVaIGInLysAspValSerGlflSerSerleTYrISerGIlThrGu (SEQ. ID.NO.: h) AlaAsn LyslIleSerTyrTyrlSer (SEQ.ID.NO.: 131), i) AlaAsnLysAlaSerTyrGlnlSer (SEQ.JD.NO.: 132), j) SerlyrGlnISerSerThr (SEQ. ID.NO.: 133), k) SerlyrGiniSerSerSer (SEQ. ID.NO.: 134), 1) LysTyrGInISerSerSer (SEQ.ID.NO.: 142), 15 mn) hArgTyrGlnlSerSerSer (SEQ.ID.NO.: 143), and n) SerTyrGlnlSerSerLeu (SEQ.ID.NO.: 135); or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of the instant invention, the oligopeptides include oligomers that comprise an amino acid sequence that is selected from: 20 a) AsnLyslleSerTyrGlnlSerSerSerThr (SEQ.ID.NO.: b) AlaAsnLyslIeSerTyrGInISerA~a (SEQ.ID.NO.: 136), c) AsnLyslleSerTyrGlnlSerSerSerThrGlu (SEQ.ID.NO.:3), AlaAsn Lysll eSerTyrGlInl SerSerSerTh rG lu (SEQ. ID.NO.: 11), GlyGluAsnGlyVaIGInLysAspVaISerGnArgSerIeTyrISerGIlThrGU (SEQ. ID.NO.: 4), f) AlaAsn LyslIleSerTyrTyrlSerSer (SEQ.ID.NO.: 137), g) AlaAsn Lys IleSerTyrTyrlSerAla (SEQ.ID.NO.: 138), h) AIaAsnLysAlaSerTyrGInISerAIa (SEQ. ID.NO.: 139), i) AlaSerTyrGlnISerSerLeu (SEQ.ID.NO.: 94); or the pharmaceutically acceptable salts thereof.

In a further embodiment of the instant invention, the oligopeptides include oligomers that comprise an amino acid sequence that is selected from: a) GlIyArg LysAiaAsn LyslI IeSerlyrGl nlSerSerSerTh rGIuGIuArgArg Leu HisTyrG IyGlIuAsnGly (SEQ.ID.NO.: 6).

The phrase "oligomers that comprise an amino acid sequence" as used hereinabove, and elsewhere in the Detailed Description of the Invention, describes oligomers of from about 6 to about 100 amino acids residues which include in their amino acid sequence the specific amino acid sequence described and which are therefore proteolytically cleaved within the amino acid sequence described by free PSA. Thus, for example, the following oligomer: GIn LeuAspAsn LyslIleSerTyrGl nlISerSerSerTh rH isGlfnSerSer (SEQ. ID.NO.: Libc1O3531 .doc comprises the amino acid sequence: AsnLyslleSerTyrGlnlSerSerSerThr (SEQ. ID.NO.: and would therefore come within the instant invention. It is understood that such oligomers do not include semenogelin I and semenogelin 1I.

It is also understood that the instant invention includes oligomers wherein the N-terminus amino acid or the C-terminus amino acid, or both terminus amino acids are modified. Such modifications include, but are not limited to, acylation of the amine group at the N-terminus and formation of an amide to replace the carboxylic acid at the C-terminus. Addition of such moieties may be performed during solidphase synthesis of the oligomer; thus, attachment of the C-terminus amino acid to a solid phase resin may be through an amine which results in an amide moiety upon acidic cleavage of the oligomer from the resin. Thus the following compounds are considered "oligomers that comprise an amino acid sequence" as used hereinabove and are meant to be illustrative and are not limiting: 15 AlaAsn LyslIleSerTyrG InlISerSerSefhrGlu-amnide (SEQ. ID.NO.: 11) Ac-AlaAsn LyslIleSerTyrGlnlISerSerSerTh rLeu (SEQ.ID.NO.: Ac-AaAsn Lys IIeSerTyrG In ISerSerSerTh rGu-amlide (SEQ. ID.NO.: 11) Ac-AlaAsn Lys I eSerTyrGI nlSerSerSerTh rLeu-alhide (SEQ. ID.NO.: Ac-AlaAsnLysIleSerTyrGInISerAlaSerThrGIu-amide (SEQ. ID.NO.: 73) 20 Ac-AlaAsn Lys IIeSerTyrGIn ISerSerLysThrGIlU-amide (SEQ.ID.NO.: 74) *Ac-AlaAsn LyslIleSerlyrGlIfllSerSerTh rGlIu-arn ide (SEQ.ID.NO.: Ac-AlaAsnLysIleSerTyrGInISerSerGIflThrGIU-amide (SEQ.ID.NO.: 78) *Ac-AlaAsn Lys IIeSerTyrG In ISerAl aLys~hrGI U-amide (SEQ.ID.NO. :79) *Ac-AlaAsn LyslIIeSerTyrGInISerTh rGlu-amide (SEQ. ID.NO.: 81) Ac-AlaAsnLysSerlyrGlnlSerSerThrGu-amide (SEQ.ID.NO.: 82) Ac-AlaAsnLysAlaSerTyrGInISerAlaSerThrGIU-amide (SEQ.ID.NO.: 84) Ac-AlaAsnGluIleSerTyrGlnISerAlaSerThrGIu-amide (SEQ. ID.NO.: Ac-Asn LyslIleSerTyrGl nlSerSer-amide (SEQ. ID.NO.: 16) Ac-LyslleSerTyrGlnlSerSer-amide (SEQ.ID.NO.: 86) Ac-SerTyrGInISerSerThrGIu-amide (SEQ.ID.NO.: 87) Ac-AlaSerTyrGlnlSerSerlhrGlu-amide (SEQ.ID.NO.: 89) Ac-AlaAsn LyslIleSerTyrTyrl SerSerSerlhrGlu-amide (SEQ. ID. NO.: 92) Ac-AlaAsnLyslleSerTyrTyrlSerAlaSerThrGlU-amide (SEQ.ID.NO 93) Ac-AlaSerTyrGlnlSerSerLeu-amide (SEQ.ID.NO.: 94) Ac-AlaAsnSerTyrGlnlSerSerSerThrGlu-amide (SEQ.ID.NO.: Ac-AlaSerTyrGInISerSerSerThrGlu-amide (SEQ.I D. NO.: 96) Ac-SerTyrGlnlSerSerSerThrGlu-amide (SEQ. ID.NO.: 97) Ac-AlaAsnLysAlaSerTyrGInISerAlaSerCys-amlide (SEQ. ID.NO.: 98) Ac-hArg(Cha)GInISerNie-Acid (SEQ.ID.NO.: 147) Ac-hArghlyrGlnlSerSerNe-Acid (SEQ.ID.NO.: 148) Libc(O353l .doc 7 Ac-hArgh(Cha)GlnlSerSerNle-Acid (SEQ. ID.NO.: 149) Ac-AlaAspLysAlaSerTyrGlnlSerSer-Cha-NHNH2 (SEQ. ID.NO.: 150) Ac-hArgTyrGln ISerSerPro-Acid (SEQ. ID.NO.: 151) Ac-hArgTyrGlnlSerSerHis-Acid (SEQ. ID.NO.: 152) Ac-hArgTyrGlnlSerAsn-Acid (SEQ.ID.NO.: 153) Ac-hArgTyrGlnlSerSerSerNle-Acid (SEQ. ID. NO.: 154) Ac-(Amf)TyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 155) H2NCO-hArgTyrGlnlSerSerSerLeu-Acid (SEQ.ID.NO.: 156) Ac-AlaAspLysAlaLysTyrGInISerSer(Cha)-NHNH2 (SEQ.ID.NO.: 157) lo Ac-(DPL)TyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 158) Ac-(imidazole)LysTyrGlnlSerSerLeu-Acid (SEQ. ID.NO.: 159) Ac-AlaAspLysAla(hArg)TyrGlnlSerSerLeu-Acid (SEQ. ID.NO.: 160) Ac-(p-NH 2 -Cha)TyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 161) Ac(imidazolyl)LysTyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 162) Ac-hArg(Cha)GInISerSerSerNle-Acid (SEQ. ID.NO.: 163) Ac-hArgTyrGlnlSerSerSerhArg-Acid (SEQ. ID.NO.: 164) Ac-hArgTyrGlnlSerSerSer(MeLeu) (SEQ. ID.NO.: 188) Ac-hArgTyrGlnlSerSerSer(Ethylester-Leu) (SEQ. ID.NO.: 156) Ac-AlaAspLysAla(imidazoleLys)TyrGlnlSerSerNle-Acid (SEQ. ID. NO.: 165) Ac-hArg(3-Iodo-Tyr)GInISerSerSerNle-Acid (SEQ.ID.NO.: 166) Ac-hArg (Me 2 PO3-Tyr) GinlSerSerSerN le-Acid (SEQ.ID.NO.: 167) Ac-hArgTyrGlnlSerSerAsp-Acid (SEQ. ID. NO.: 168) Ac-hArg(O-Me-Iyr)GInISerSerSerN le-Acid (SEQ. ID. NO.: 169) '*.*Ac-AlaAspLysAlaLysTyrGlnlSerSerNle-Acid (SEQ. ID. NO.: 170) Ac-hArg(Cha)GlnlSerSerSer(ethylester-Leu) (SEQ. ID.NO.: 171) **.,Ac-(imidazolyl)Lys(Cha)GInISerSerSerNle-Acid (SEQ. ID.NO.: 172) Ac-hArg(Cha)GlnlSerSerSer-Acid (SEQ. ID.NO.: 173) Ac-hArg(Cha)GlnlSerSerNle-Acid (SEQ.ID.NO.: 174) Ac-hArg(Cha)GlnISerProNle-Acid (SEQ. ID.NO.: 175) and Ac-hArg(m-fluoro-Iyr)GlnlSerSerSerNe-Acid (SEQ. ID. NO.: 176), and the pharmaceutically acceptable salts.

A person of ordinary skill in the peptide chemistry art would readily appreciate that certain amino acids in a biologically active oligopeptide may be replaced by other homologous, isosteric and/or isoelectronic amino acids wherein the biological activity of the original oligopeptide has been conserved in the modified oligopeptide.

Certain unnatural and modified natural amino acids may also be utilised to replace the corresponding natural amino acid in the oligopeptides of the instant invention.

Thus, for example, tyrosine may be replaced by 3-iodotyrosine, 2-methyltyrosine, 3fluorotyrosine, 3-methyltyrosine and the like. Further for example, lysine may be Libc03531 .doc

S

55..

S 5 9 *4*5 S S *5 S 5* S

S

8 replaced with N'-(2-imidazolyl)lysine and the like. The following list of amino acid replacements is meant to be illustrative and is not limiting: Original Amino Acid Replacement Amino Acid(s) Ala Gly Arg Lys, Ornithine Asn Gln Asp Glu Glu Asp Gln Asn Gly Ala Ile Val, Leu, Met, NMe Leu Ilie, Val, Met, NMe Lys Arg, Ornithine Met Leu, Ilie, Nle, Val Ornithine Lys, Arg Phe Tyr, Trp Ser Thr Thr Ser Trp Phe, Tyr Tyr Phe, Trp a Val Leu, Ilie, Met, NMe Thus, for example, the following oligopeptides may be synthesised by techniques well known to persons of ordinary skill in the art and would be expected 5 to be proteolytically cleaved by free PSA: AsnArglleSerTyrGlnlSer (SEQ.ID.NO.: 21) AsnLysValSerTyrGlnlSer (SEQ. ID.NO.: 22) AsnLysMetSerTyr GlnlSerSer(SEQ. IDNO.: 23) AsnLysLeuSerTyrGln ISerSer (SEQ.ID.NO.: 24) AsnLyslleThrTyrGlnlSerSerSer (SEQ. ID.NO.: AsnLyslleSerPheGlnlSerSerSer (SEQ. ID.NO.: 26) Asn Lys lleSerTrpGlnlSerSerSerThr (SEQ.ID.NO.: 21) AsnLyslleSerlyrAsnlSerSerSerThr (SEQ. ID.NO.: 28) AsnLyslleSerTyrGlnlThrSerSerThr (SEQ. ID.NO.: 29) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: GlnLyslleSerTyrGlnlSerSer (SEQ.ID.NO.: 31) AsnArg lleThrTyrGlnlSerSerSer (SEQ. ID.NO.: 32) AsnArg lleSerPheGlnlSerSerSerlhr (SEQ. ID.NO.: 33) AsnArglleSerTrpGlnlSerSerSerThr (SEQ.ID.NO.: AsnArglIleSerTyrGlnITh rSerSerThr (SEQ. ID.NO.: 36) AsnLyslleThrTyrGln lThrSerSerThr (SEQ.ID.NO.: 37) AsnLysLeuSerlyrGlnlThrSerSerThr (SEQ. ID.NO.: 38) GlnLysLeuSerTyrGlnlSerSerSerThr (SEQ. ID.NO.: 39) AsnArgLeuSerTyrGlnlThrSerSerThr (SEQ. ID.NO.: LjbcI353l .doc 9 AsnLysValSerPheGlnlSerSerSerThr (SEQ. ID.NO.: 41) AsnArgValSerTrpGlnlSerSerSerThr (SEQ. ID.NO.: 42) GlnLysValSerTyrGlnlSerSerSerThr (SEQ.ID.NO.: 43) GlnLyslleSerTyrGlnlThrSerSerThr (SEQ. ID.NO.: 34) AsnLysleSerTyrGlnlSerSerSerThr (SEQ. ID.NO.: 44); or the pharmaceutically acceptable salts thereof.

Similarly, the following oligopeptides may be synthesised by techniques well known to persons of ordinary skill in the art and would be expected to be proteolytically cleaved by free PSA: GlyGluGInGlyVaIGlnLysAspValSerGlnSerSerIIeyrISerG~nThrGlu (SEQ. ID.NO.: GlyGluAsnGlyLeuGlnLysAspValSerG~nSerSerIeTyrlSerGInhrGlu (SEQ. ID.NO.: 47), GiyGluAsnGlyValAsnLysAspValSerGlnSerSerleTyrSerGnThrGlu (SEQ.ID.NO.: 48), G~yGluAsnGlyVaIGlnArgAspVaISerGlnArgSerlleTyrISerGnThrG~u (SEQ. ID.NO.: 49), GlyGluAsnGlyVaIGInLysAspVaISerGInLysSerIleTyrISerGnThrGlu (SEQ.iD.NO.: GlyGluAsnGlyVaIGInLysAspLeuSerGInThrSerIeTyrISerGInThrGlu (SEQ. ID.NO.: 51), GlyGluAsnGlyVaiGInLysAspValSerGInSerSerIIePhelSerGnThrGlu (SEQ. ID.NO.: 52), GlyGluAsnGlyValGInLysAspMetSerGlnSerSerIIe~yrlIhrGnThrGlu (SEQ. ID.NO.: 53), GlyGluAsnGlyVaIGInLysAspValSerGlnArgSerIeTyrlThrGln~hrGlu (SEQ. ID.NO.: 54), GIyGl uAsn GlyVa Gin LysAspVaISerGlInSerSerl leTyrI SerGl nSerG Iu (SEQ.ID. NO.: 20 GlyGluAsnGlyVaIGInLysAspVaISerGInArgSerIeTyrISerAsnThrGlu (SEQ.ID.NO.: 56), G l*s i l e e r rI e n h u l g e (SQ*.N 5 .~*Gly~ys~lalleSerSerGlnTyrlSerAsnThrGluGluArgLeu (SEQ. ID.NO.: 57), G*.slleh~r~~rie~nh~ul~ge (SQ*.O:6) Gly~rgGlylleSer~erGlnTyrlSerAsnThrGluGluArgLeu (SEQ.ID.NO.: 59), GlyLysGlylle~hrSer~lnTyrSerAsnThrGuGluArgLeu (SEQ. ID.NO.: GAlyLysGlylleSer~hrGInTyrlSerAsnThrGluGluArgLeu (SEQ. ID.NO.: 61), (SEQ. ID.NO.: 62), AlaLysGlylleSerSerGnTyr~erAsnThrGluGluArgLeu (SEQ. ID. NO.: 63), GlyLysGlylleSerSerGln~helSerAsnlhrGluGluArgLeu (SEQ. IDNO.: 64),an (SEQ. ID. NO.: 6) and the like.

The inclusion of the symbol within an amino acid sequence indicates the point within that sequence where the oligopeptide is proteolytically cleaved by free

PSA.

The compounds of the present invention may have asymmetric centres and occur as racemnates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.

Unless otherwise specified, named amino acids are understood to have the natural stereo configuration LibcI3531.doc The following abbreviations are utilised in the specification and figures to denote the indicated amino acids and moieties: hR or hArg: homoarginine hY or hTyr: homotyrosine s Cha: cyclohexylalanine Amf: 4-aminomethylphenylalanine DPL: 2-(4,6-dimethylpyrimidinyl)lysine (imidazolyl)K: N'-(2-imidazolyl)lysine Me 2

PO

3 O-dimethylphosphotyrosine O-Me-Y: O-methyltyrosine TIC: tetrahydro-3-isoquinoline carboxylic acid MeL: 2-keto-3-amino-5-methylhexane DAP: 1,3-diaminopropane TFA: trifluoroacetic acid AA: acetic acid The invention also concerns a method for assaying proteolytic free PSA activity in a composition. This is an important aspect of the invention in that such an assay system provides one with the ability to measure quantitatively the amount of free PSA present in certain physiological fluids and tissues. Such an assay will also 20 provide not only the ability to follow isolation and purification of free PSA, but also is S. a basis for a screening assay for inhibitors of the proteolytic activity of free PSA.

The assay method generally includes simply determining the ability of a composition suspected of containing enzymatically active free PSA to proteolytically cleave the oligopeptide.

Typically, the assay protocol is carried out using one of the oligopeptides described hereinabove. However, one may find a particular benefit in construction of an assay wherein the oligopeptide containing the cleavage site is labelled so that one can measure the appearance of such a label, for example, a radioactive label, in both the uncleaved oligopeptide and the portion of the oligopeptide remaining after cleavage which contains the label.

The instant invention further relates to a method for identifying compounds (hereinafter referred to as candidate compounds) that will inhibit the proteolytic activity of free PSA. It is contemplated that this screening technique will prove useful in the general identification of any candidate compound that will serve such as an inhibitory purpose, whether or not the candidate compound is proteinaceous or peptidyl in structure.

Thus, the present invention is also directed to a method for determining the ability of a test substance to inhibit the proteolytic activity of free PSA, the method which comprises: Libc/03531.doc reacting a substrate, wherein the substrate comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, with free prostate specific antigen in the presence of a test substance; and detecting whether the substrate has been cleaved, in which the ability of the test substance to inhibit proteolytic activity of prostate specific antigen is indicated by a decrease in the cleavage of the substrate as compared to the cleavage of the substrate in the absence of the test substance.

The candidate screening assay is quite simple to set up and perform, and is related in many ways to the assay discussed above for determining proteolytic activity. Thus, after obtaining a relatively purified preparation of free PSA, one will desire to simply admix a test substance with the proteolytic preparation, preferably under conditions which would allow the PSA to perform its cleavage function but for inclusion of a inhibitory substance. Thus, for example, one will typically desire to 15 include within the admixture an amount of a known oligopeptide having a PSA specific cleavage site, such as those oligopeptides described hereinabove. In this fashion, one can measure the ability of the test substance to reduce cleavage of the oligopeptide relatively in the presence of the test substance.

Accordingly, one will desire to measure or otherwise determine the activity of 20 the free PSA in the absence of the added test substance relative to the activity in the presence of the test substance in order to assess the relative inhibitory capability of the test substance.

The instant invention also relates to novel anti-cancer compositions useful for the treatment of prostate cancer. Such compositions comprise the oligopeptides of the instant invention covalently bonded directly, or through a chemical linker, to a cytotoxic agent. Such a combination of an oligopeptide and cytotoxic agent may be termed a conjugate. Ideally, the cytotoxic activity of the cytotoxic agent is greatly reduced or absent when the oligopeptide containing the PSA proteolytic cleavage site is bonded directly, or through a chemical linker, to the cytotoxic agent and is intact. Also ideally, the cytotoxic activity of the cytotoxic agent increases significantly or returns to the activity of the unmodified cytotoxic agent upon proteolytic cleavage of the attached oligopeptide at the cleavage site. While it is not necessary for practicing this aspect of the invention, a preferred embodiment of this aspect of the invention is a conjugate wherein the oligopeptide, and the chemical linker if present, are detached from the cytotoxic agent by the proteolytic activity of the free PSA and any other native proteolytic enzymes present in the tissue proximity, thereby releasing unmodified cytotoxic agent into the physiological environment at the place of proteolytic cleavage. Pharmaceutically acceptable salts of the conjugates are also included.

Libc/03531.doc 12 It is understood that the oligopeptide of the instant invention that is conjugated to the cytotoxic agent, whether through a direct covalent bond or through a chemical linker, does not need to be the oligopeptide that has the greatest recognition by free PSA and is most readily proteolytically cleaved by free PSA.

Thus, the oligopeptide that is selected for incorporation in such an anti-cancer composition will be chosen both for its selective, proteolytic cleavage by free PSA and for the cytotoxic activity of the cytotoxic agent-proteolytic residue conjugate (or, in what is felt to be an ideal situation, the unmodified cytotoxic agent) which results from such a cleavage.

Because the conjugates of the invention can be used for modifying a given biological response, cytotoxic agent is not to be construed as limited to classical chemical therapeutic agents. For example, the cytotoxic agent may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumour necrosis factor, a-interferon, p-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 interleukin-2 interleukin-6 granulocyte macrophage colony stimulating factor granulocyte colony stimulating factor or 20 other growth factors.

The preferred cytotoxic agents include, in general, alkylating agents, antiproliferative agents, tubulin binding agents and the like.

S.Preferred classes of cytotoxic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the pteridine family of drugs, diynenes, the podophyllotoxins and the .taxanes. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, podophyllotoxin, or podophyllotoxin derivatives such as etoposide or etoposide phosphate, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, taxol and the like. Other useful cytotoxic agents include estramustine, cisplatin and cyclophosphamide. One skilled in the art may make chemical modifications to the desired cytotoxic agent in order to make reactions of that compound more convenient for purposes of preparing conjugates of the invention.

A highly preferred group of cytotoxic agents for the present invention include drugs of the following formulae: Libc/03531.doc The methotrexate group of formula(l): in which R1 2 is amino or hydroxy; R 7 is hydrogen or methyl; R 8 is hydrogen, fluoro, chloro, bromo or iodo; R9 is hydroxy or a moiety which completes a salt of the carboxylic acid; The mitomycin group of formula

V.

V. p p p..

p.

p p p.

*pV.

p 0* p 0p p p pp. p p p.

10 in which R10 is hydrogen or methyl; The bleomycin group of formula (3) (3) in which R 1 1 is hydroxy, amino, Cl-C 3 alkylamino, di(Cl-C 3 alkyl)amino, C 4

-C

6 polymethylene amino, H UtH 3 or

H

NI NH 2 H NH LibcIO353l .doc Meiphalan of formula C1 a. *a a a a a.

a. a.

a.

a a.

a a a.

a. a a.

a a *4~a a a .a a a 6-mercaptopurine of formula

S

A cytosine arabinoside of formula

NH

2 0

OH

HO OH (6) The podophyllotoxins of formula(7):

R

1 4 HO 0 OH 0 (7) in which R 13 is hydrogen or methyl; R 14 is methyl or thienyl; or a phosphate salt thereof; Libc/0353l .doc The ymnca alkaloid group of drugs of formula

R

1 6. B 17 (8) in which R 15 is H, OH 3 or CHO; when R 17 and R 1 8 are taken singly; R 18 is H, and one of R 16 and R 17 is ethyl and the other is H or OH; when R 17 and R 1 8 are taken together with the carbons to which they are attached, they form an oxirane ring in which case R 16 is ethyl; R 19 is hydrogen, (C 1

-C

3 alkyl)-CO, or chioro substituted (Cl- 03 alkyl)-CO; Difl uoron ucleos ides of formula

OH

F e F OH (9) *0 0 0 so 0 0 060 in which R 21 is a base of one of the formulae: 0 0 R 23

HR

22 H IN> ON *N H2N:%N I O'in which R 22 is hydrogen, methyl, bromo, fluoro,

R

24 is hydrogen, bromo, chioro or iodo; or, The anthracyclines antibiotics of formula

NH

2

NN

is -OH or-NH 2 I I or chloro or iodo; R 23 wherein R, is -OH 3

-CH

2 OH, -CH 2 0C0(CH 2 3

CH

3 or -CH 2 0C0CH(C 2

H

5 2 R3 is -OCH 3 OH or R 4 is -NH 2

-NHCOCF

3 4-morpholinyl, 3-cyano-4-morpholinyl, 1piperidinyl, 4-methoxy-1 -piperid inyl, benzylamine, d ibenzylamine, Libc[O353l .doc 16 cyanomethylamine, or 1-cyano-2-methoxyethyl amine; R 5 is -OH -OTHP or-H; and

R

6 is -OH or -H provided that R 6 is not -OH when R 5 is -OH or -OTHP.

Estramustine (11) (11) Cyclophosphamide (12)

CI

N 0

O

C l a (12) The most highly preferred drugs are the anthracycline antibiotic agents of Formula described previously. One skilled in the art understands that this structural formula includes compounds which are drugs, or are derivatives of drugs, which have acquired in the art different generic or trivial names. Table 1, which follows, represents a number of anthracycline drugs and their generic or trivial names and which are especially preferred for use in the present invention.

Compound Ra Rb Re Rs R6 daunorubicuna CH 3

OCH

3

NH

2 OH H doxorubicinb CH 2 OH OCH 3

NH

2 OH H detorubicin CH 2 0COCH(OC 2

H

5 2

OCH

3

NH

2 OH H carminomycin CH 3 OH NH 2 OH H idarubicin CH 3 H NH 2 OH H epirubucin CH 2 OH OCH 3

NH

2 OH OH esorubicin CH 2 OH OCH 3

NH

2 H H THP CH 2 0H OCH 3

NH

2 OTHP H AD-32 CH 2

OCO(CH

2 3

CH

3

OCH

3

NHCOCF

3 OH H a"danomycin" is an alternative name for daunorubicin b"adriamycin" is an alternative name for doxorubicin Libc/03531.doc 17 Of the compounds shown in Table 1, the most highly preferred cytotoxic agents are doxorubicin, vinblastine and desacetylvinblastine. Doxorubicin (also referred to herein as "DOX") is that anthracycline of Formula (10) in which R 1 is

CH

2 0H, R 3 is -OCH 3

R

4 is -NH 2

R

5 is -OH, and R 6 is -H.

The oligopeptides, peptide subunits and peptide derivatives (also termed "peptides") of the present invention can be synthesised from their constituent amino acids by conventional peptide synthesis techniques, preferably by solid-phase technology. The peptides are then purified by reverse-phase high performance liquid chromatography (HPLC).

Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965; Bodansky et al., "Peptide Synthesis", Interscience Publishers, 1966; McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973; Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, and 15 Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by •reference.

The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as 20 formed, eg., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

The conjugates of the instant invention which comprise the oligopeptide containing the PSA cleavage site and a cytotoxic agent may similarly be synthesised by techniques well known in the medicinal chemistry art. For example, a free amine moiety on the cytotoxic agent may be covalently attached to the oligopeptide at the carboxyl terminus such that an amide bond is formed. Similarly, an amide bond may be formed by covalently coupling an amine moiety of the oligopeptide and a carboxyl moiety of the cytotoxic agent. For these purposes a reagent such as 2-(1H-benzotriazol-1-yl)-1,3,3-tetramethyluronium hexafluorophosphate (known as HBTU) and 1-hyroxybenzotriazole hydrate (known as HOBT), dicyclohexyl-carbodiimide (DCC), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide (EDC), diphenylphosphorylazide (DPPA), benzotriazol-1-yl-oxy-tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) and the like, used in combination or singularly, may be utilised.

Libc/03531.doc Furthermore, the instant conjugate may be formed by a non-peptidyl bond between the PSA cleavage site and a cytotoxic agent. For example, the cytotoxic agent may be covalently attached to the carboxyl terminus of the oligopeptide via a hydroxyl moiety on the cytotoxic agent, thereby forming an ester linkage. For this purpose a reagent such as a combination of HBTU and HOBT, a combination of BOP and imidazole, a combination of DCC and DMAP, and the like may be utilised.

The carboxylic acid may also be activated by forming the nitrophenyl ester or the like and reacted in the presence of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene.

The instant conjugate may also be formed by attachment of the oligopeptide to the cytotoxic agent via a linker unit. Such linker units include, for example, a biscarbonyl alkyl diradical whereby an amine moiety on the cytotoxic agent is connected with the linker unit to form an amide bond and the amino terminus of the oligopeptide is connected with the other end of the linker unit also forming an amide bond. Conversely, a diaminoalkyl diradical linker unit, whereby a carbonyl moiety on 15 the cyctotoxic agent is covalently attached to one of the amines of the linker unit while the other amine of the linker unit is covalently attached to the C terminus of the oligopeptide, may also be useful. Other such linker units which are stable to the physiological environment when not in the presence of free PSA, but are cleavable upon the cleavage of the PSA proteolytic cleavage site, are also envisioned.

20 Furthermore, linker units may be utilised that, upon cleavage of the PSA proteolytic cleavage site, remain attached to the cytotoxic agent but do not significantly decrease the cytotoxic activity of such a post-cleavage cytotoxic agent derivative when compared with an unmodified cytotoxic agent.

One skilled in the art understands that in the synthesis of compounds of the invention, one may need to protect or block various reactive functionalities on the starting compounds and intermediates while a desired reaction is carried out on other portions of the molecule. After the desired reactions are complete, or at any desired time, normally such protecting groups will be removed by, for example, hydrolytic or hydrogenolytic means. Such protection and deprotection steps are conventional in organic chemistry. One skilled in the art is referred to Protective Groups in Organic Chemistry, McOmie, ed., Plenum Press, NY, NY (1973); and, Protective Groups in Organic Synthesis, Greene, ed., John Wiley Sons, NY, NY (1981) for the teaching of protective groups which may be useful in the preparation of compounds of the present invention.

By way of example only, useful amino-protecting groups may include, for example, C 1

-C

10 alkanoyl groups such as formyl, acetyl, dichloroacetyl, propionyl, hexanoyl, 3,3-diethylhexanoyl, y-chlorobutryl, and the like; C 1 -Clo alkoxycarbonyl and C 5

-C

15 aryloxycarbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, 4-nitrobenzyloxycarbonyl, fluorenylmethyloxycarbonyl and cinnamoyloxycarbonyl; halo-(C 1 -C1o)-alkoxycarbonyl such as 2,2,2- Libc/03531.doc 19 trichloroethoxycarbonyl; and C1-C15 arylalkyl and alkenyl group such as benzyl, phenethyl, allyl, trityl, and the like. Other commonly used amino-protecting groups are those in the form of enamines prepared with 5-keto-esters such as methyl or ethyl acetoacetate.

Useful carboxy-protecting groups may include, for example, C1-C10 alkyl groups such as methyl, tert-butyl, decyl; halo-C 1 -Clo alkyl such as 2,2,2trichloroethyl, and 2-iodoethyl; C5-C15 arylalkyl such as benzyl, 4-methoxybenzyl, 4nitrobenzyl, triphenylmethyl, diphenylmethyl; C1-Co10 alkanoyloxymethyl such as acetoxymethyl, propionoxymethyl and the like; and groups such as phenacyl, 4halophenacyl, allyl, dimethylallyl, tri-(C1-C3 alkyl)silyl, such as trimethylsilyl, toluenesulfonylethyl, P-p-nitrophenyl-thioethyl, 2,4,6-trimethylbenzyl, methylthioethyl, phthalimidomethyl, 2,4-dinitrophenylsulfenyl, 2-nitrobenzhydryl and related groups.

Similarly, useful hydroxy protecting groups may include, for example, the 15 formyl group, the chloroacetyl group, the benzyl group, the benzhydryl group, the trityl group, the 4-nitrobenzyl group, the trimethylsilyl group, the phenacyl group, the tert-butyl group, the methoxymethyl group, the tetrahydropyranyl group, and the like.

With respect to the preferred embodiment of an oligopeptide combined with 20 the anthracycline antibiotic doxorubicin, the following Reaction Schemes illustrate the synthesis of the conjugates of the instant invention.

Reaction Scheme I 0 OH 0 0 OH 0 OH OH Q Q**OH Q "OH 0 0 OH 0 7O 0 OH O O O

H

3 C NH 2

H

3 NH-oligOpeptide OH OH C-terminus '-1 O OH O O-oligopeptide QOO Q'OH C-terminus HC'O 0 OH 0 HHaC

H

3 C

NH

2

OH

Libc0353 .doc Reaction Scheme 11 0 OH 0 OH NH 2 O o -'OH

O

HC' 0 OH 0 0

H

3 C T NH-protect

OH

C-terminus 0 OH NH-oigopeptide

OH

O o

H

3 C' 0 OH 0 0

H

3 C T N H 2

OH

S

a. S a

S

Reaction Scheme III 0 OH 0

OH

O o HC' 0 OH 0 0

H

3 0 T

'NIH

2

OH

OH 0 0

H

3 C NH

OH

lopeptide OH 0

H

3 C

NIH

2

OH

Libc/0353l .doc Reaction Scheme IV H C-terminus i N-oligopeptide

H

2

N

OH 0 0

OH

H

3 C

NH

2

OH

Reaction Scheme V Br 2 CCl 4 HS C-terminus

H

2 N-oligopeptide 0

H

H

3 O O OH O H

H

3 C- NH 2

OH

Reaction Scheme VI illustrates preparation of conjugates of the oligopeptides of the instant invention and the vinca alkaloid cytotoxic agent vinblastine.

Attachment of the N-terminus of the oligopeptide to vinblastine is illustrated (S.P.

Kandukuri etal. J. Med. Chem. 28:1079-1088 (1985)).

Reaction Scheme VII illustrates preparation of conjugates of the oligopeptides of the instant invention and the vinca alkaloid cytotoxic agent vinblastine wherein the attachment of vinblastine is at the C-terminus of the oligopeptide. The use of the 1,3-diaminopropane linker is illustrative only; other spacer units between the carbonyl of vinblastine and the C-terminus of the oligopeptide are also envisioned.

Furthermore, Scheme VII illustrates a synthesis of conjugates wherein the C-4position hydroxy moiety is reacetylated following the addition of the linker unit.

Applicants have discovered that the desacetyl vinblastine conjugate is also Libc/03531 .doc 22 efficacious and may be prepared by eliminating the steps shown in Reaction Scheme VII of protecting the primary amine of the linker and reacting the intermediate with acetic anhydride, followed by deprotection of the amine.

Conjugation of the oligopeptide at other positions and functional groups of vinblastine may be readily accomplished by one of ordinary skill in the art and is also expected to provide compounds useful in the treatment of prostate cancer.

It is also understood that conjugates may be prepared wherein the N-terminus of the oligopeptide of the instant invention is covalently attached to one cytotoxic agent, such as vinblastine, while the C-terminus is simultaneously attached to another cytotoxic agent, which is the same or different cytotoxic agent, such as doxorubicin. Reaction Scheme VIII illustrates the synthesis of such a polycytotoxic agent conjugate. Such a polycytotoxic conjugate may offer advantages over a conjugate containing only one cytotoxic agent.

Reaction Scheme VI

H

3 C H 3

C

HO

HO

H

CH

3 CH3

N

CH

3

CH

N 0 N

OOH

OH CHOH O N-H O OH H N SN C Ni 0 I 3 C N C C 3

N

2

H

4 reflux, MeOH

H

3

NH

S 15

H

HONO

H

3 C 3

C

HO

HO

HO

*CH

3 N C H 3 HC3

H

3 N 0 0C N N CH3 N H 3 0

O

OH CH 3 C-terminus N-H O.ON O OH

H

3 O oliopeptide--NH2 1 oigopeptid-R C-terminus 2. Ac 2 O, pyridine H 3 N 3 wherein R is -NH 2 -O-alkyl and the like.

Libc/03531.doc Reaction Scheme VII 1. HNCHCHCHNH, 2. BOO-Cl 1. AC 2 O, pyridine 2. sq. HCI N-terminus R'-oligopepbde a. a a a a.

a. a a a a a a a 5wherein R' is acetyl, alkyl, hydrogen or the like.

Reaction Scheme ViII

HOC

H

0

OH

Q N-H O 0 N~N VJ-terminus 1. oligopeptide-OH 2. Ac 2 O, pyidine or 1. oligopeptide-OCH 3 2.LOH 3. Ac 2 O, pyridine Idoxowubicin Libc/0353l .doc The oligopeptide-cytotoxic agent conjugate of the instant invention wherein the cytotoxic agent is the preferred cytotoxic agent doxorubicin may be described by the general formula I below: 0 OH 0

OH

Q.OH

H

3 C 0 0 OH 0 0 H3C/OH 3

C

OH XL-Oligopeptide-R wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen; XL is absent or is an amino acid selected from: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl)alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline, i) 10 norleucine, and j) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; R is hydrogen or-(C=O)Ri; and R 1 is C1-C 6 -alkyl or aryl, or the pharmaceutically acceptable salt .*thereof.

In a preferred embodiment of the oligopeptide-cytotoxic agent conjugate:oligopeptide is an oligomer that comprises an amino acid sequence 15 selected from: a) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: 13), b) LysleSerTyrGlnlSer (SEQ.ID.NO.: 14), c) GlyGluAsnGlyValGlnLysAspValSerGnXaaSerlIeTyrlSerGlnThrGlu (SEQ.ID.NO.: d) GlyLysGlylleSerSerGInTyrlSerAsnThrGluGluArgLeu (SEQ.ID.NO.: 2), 20 e) AsnLyslleSerTyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerTyrGlnlSer (SEQ.ID.NO.: 128), g) SerTyrGinlSerSer (SEQ.ID.NO.: 129), h) LysTyrGlnlSerSer (SEQ.ID.NO.: 140); i) hArgTyrGlnlSerSer (SEQ.ID.NO.: 141); j) hArgChaGlnlSerSer (SEQ.ID.NO.: 185); and k) TyrGlnlSerSer (SEQ.ID.NO.: 186); wherein Xaa is any natural amino acid; XL is absent or is an amino acid selected from: a) leucine, b) isoleucine, c) norleucine, and d) valine; and R is acetyl, pivaloyl or benzoyl, or the pharmaceutically acceptable salt thereof.

The following compounds are specific examples of the oligopeptide-cytotoxic agent conjugate of the instant invention: Libc/03531 .doc O OH 0

OH

Oo OH H3CO1 0 OH 0 0

H

3 C

N

OH

X

wherein X is: AsnLysileSerTyrGnSer- (SEQ. ID.NO.: 13), AsnLyslieSerTyrGnSerSer- (SEQ. ID.NO.: 16), AsnLysileSerTyrGnSerSerSer- (SEQ. ID.NO. :17) AsnLysileSerTyrGnSerSerSerThr- (SEQ.ID.NO. AsnLysileSerTyrGnSerSerSerlhrGlu- (SEQ. ID.NO.: 3), :AlaAsnLysileSerTyrGlnSerSerSerThrGlu- (SEQ.ID.NO. 11), N-terminus Ac AlaAsnLysileSerTyrGnSerSerSerThr- (SEQ.ID.NO.: 117), AcAasa...e~r~ne~re~h~u(E.I.O:7) Ac AlaAsnLysileSerTyrGnSererSerThrLeU (SEQID.NO.: Ac AlaAsnLysAlaSerTyrGlnSerAlaSer~hLeu- (SEQ. 11), 15 Ac AlaAsnLysAlaSerTyrGlnSer~laSerLeU- (SEQ.ID.NO.: 119), is Ac AlaAsnLysAlaSerTyrGlnSerSer~Leu- (SEQ. IDNO.: 12), Ac Ala~yrsnySelSer~yr~Ler e- (SEQ.ID.NO.: 1 21).

SergTyrGlnSerSerSerLeu- (SEQ.ID.NO.: 14) Ac-LysTyrGnSerSerSerLeu- (SEQ.ID.NO.: 124), or (Compound 4) 2o Ac-LysyrGinSerSerfe- (SEQ.ID.NO.: 146).

N-terminus

H

2 N-AsnLysileSerTyrGlnSer-C(O)- (SEQ. ID.NO.: 13),

H

2 N-AsnLysileSerTyrGlnSerSer-C(O)- (SEQ.ID.NO.: 16),

H

2 N-AsnLysileSerTyrGlnSerSerSer-C(O)- (SEQ.[DlO. 17),

H

2 N-Asn LysileSerlyrGlnSerSerSerThr-C(O)- (SEQ. ID. NO.

H

2 N-AsnLysileSerlyrGlnSerSerSerThrGlu-C(O)- (SEQ. ID.NO.: 3),

H

2 N-AlaAsnLysileSerTyrGnSerSerSerlhrGlu-C(O)- (SEQ. ID.NO.: 11), AcHN-AlaAsnLysileSerTyrGlnSerSerSerThr-C(O)- (SEQ. ID.NO.: 117), AcHN-AlaAsnLyslleSerTyrGlnSerSerSerThrLeu-C(O) (SEQ.ID.NO.: AcHN-AlaAsnLysAlaSerTyrGlnSerAlaSerThrLeu-C(O)- (SEQ.ID.NO.: 118), AcHN-AlaAsnLysAlaSerTyrGInSerAlaSerLeJ-C(O)- (SEQ.ID.NO.: 119).

AcHN-AlaAsnLysAlaSerTyrGinSerSerSerLeu-C(O)- (SEQ. ID.NO.: 120), AcH N-AlaAsnLysAlaSerTyrGlnSerSerLeu-C(O)- (SEQ. ID.NO.: 121), AcHN-SerTyrGlnSerSerSerLeu-C(O)- (SEQ.ID.NO.: 144), LibcJO353l .doc 26 AcHN-hArgTyrGlnSerSerSerLeu-C(O)- (SEQ. ID.NO.: 145), AcHN-LysTyrGlnSerSerSerLeU-C(O)- (SEQ.ID.NO.: 124), or AcHN-LysTyrGlnSerSerNle-C(O)- (SEQ. ID.NO.: 146).

or the pharmaceutically acceptable salt thereof.

Further examples of conjugates of an oligopeptide and doxorubicin wherein the N-terminus of the oligopeptide is acylated and the C-terminus of the oligopeptide is attached to the doxorubicin at the 3'-amine are as follows: Ac-hArgTyrGln-SerSerPro-dox(3') (SEQ. ID. NO.: 151) Ac-hArgTyrGln-SerPro-dox(3') (SEQ. ID. NO.: 177) Ac-hArglyrGln-SerSerSerNle-dox(3') (SEQ. ID.NO.: 154) Ac-AmfTyrGln-SerSerSerNe-dox(3') (SEQ. ID. NO.: 155)

H

2 NCO-hArgTyrGln-SerSerSerLeu-dox(3') (SEQ. lD.NO.: 156) Ac-LysTyrGln-SerSerNle-dox(3') (SEQ. ID. NO.: 146) Ac-LysTyrGln-SerLysNle-dox(3') (SEQ.ID.NO.: 178) 15 Ac(cis-p-NH 2 Cha)TyrGlnSerSerNledox(3') (SEQ.ID.NO.: 161) Ac-AaAspLysAla(hArg)TyrGIfl-SerSerLeu-dox(3') (SEQ. ID.NO.: 160) Ac-hArgTyrGln-SerAsn-dox(3') (SEQ. ID. NO.: 153) Ac-hArgTyrGln-SerSerHis-dox(3') (SEQ.ID.NO.: 152) Ac-(imidazolyl)LysTyrGln-SerSerLeu-dox(3') (SEQ. ID. NO.: 159) 20 Ac-(imidazolyI)LysTyrGlnSerSerSerNle-dox(3') (SEQ. ID. NO.: 162) Ac-hArg(Cha)Gln-SerSerSerNle-dox(3') (SEQ.ID.NO.: 163) Ac-hArg(Me 2

PO

3 Tyr)Gln-SerSerSerNe-dox( 3 (SEQ. ID. NO.: 167) Ac-hArgTyrGln-SerSerSerhArg-dox(3') (SEQ. ID. NO.: 164) 40..Ac-hArg(3-Iodo-Tyr)Gln-SerSerSerNie-dox(3') (SEQ. ID. NO.: 166) Ac-hArg(O-Me-Tyr)Gln-SerSerSerNle-dox( 3 (SEQ. ID.NO.: 169) Ac-hArg(p-NH 2 -Phe)Gl-SerSerSerNe-dox(3') (SEQ.ID.NO.: 179) Ac-hArg(Cha)Gln-SerSerNle-dox(3') (SEQ. ID.NO.: 174) Ac-hArg(Cha)Gin-SerProNle-dox(3') (SEQ.ID.NO.: 175) Ac(i mid azolyl) Lys(Ch a) Gln SerSerSerN le-dox(3') (SEQ.ID.NO.: 172) Ac-hArg (7-HO-TIC)Gln-SerSerSerNe-dox(3') (SEQ. ID.NO.: 180) Ac-hArg(3-Hluoro)TyrGlnSerSerSerNle-dox(3') (SEQ. ID.NO.: 176) Ac-(ornithine)TyrGIn-SerSerSerNe-dox(3') (SEQ.ID.NO.: 181) Ac-LysAlaAlaSerSerSerLeu-dox(3') (SEQ. ID. NO.: 183) Ac-hArgh(Cha)Gln-SerSerNle-dox(3') (SEQ. ID. NO.: 149) Ac-AlaArgLysAlaSerTyrGIl-SerLeu-dox(3') (SEQ. ID. NO.: 193) and Ac-(Orn)TyrGIn-SerSerSerLeu-dox(3') (SEQ. ID. NO.: 194) or the pharmaceutically acceptable salt thereof.

The oligopeptide-cytotoxic agent conjugate of the instant invention wherein the cytotoxic agent is the preferred cytotoxic agent vinbiastine or desacetylvinblastine may be described by the general formula I below: Libe/O353l .doc

CH

3 '3 wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen; XL is absent or is an amino acid selected from: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl)alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline, i) norleucine, and j) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; or XL is -NH-

(CH

2 )n-NH- R is hydrogen or R 1 is C 1

-C

6 -alkyl or aryl; R 19 is hydrogen or acetyl; and n is 1,2,3,4 or 5, or the pharmaceutically acceptable salt thereof.

10 The following compounds are specific examples of the oligopeptidedesacetylvinblastine conjugate of the instant invention:

H

3

C

HO

,,H

CH

3

CH

3 N O N

O

N-H (SEQ.ID.NO.: 183)

H

0 N OH H* I Ca 3 NH-NleSerSerSerGInTyrLs-Ac CH3 3 H N-terminu Compound 14

H

3

C

HO

N

OCH

3

C

H

3

OOH

0OH N-H (SEQ.ID.NO.: 184) I ;C LeuAsnLysAlaSerTyrG i nSerSerSerLeu-NH 2

CH

3 3 N-terminus Compound or the pharmaceutically acceptable salt thereof.

The following compound is a specific example of the polycytotoxic agent conjugates of the instant invention: Libc/03531.doc

H

3

C

HO

rN

OCH

3 N iCH 3 0

OH

NO /OH3OH C-terminus N H N (SEQ.ID.NO.: 184) 0 0| g LeuAsnLysAlaTyrGSerTyrGnSerSerLeu CH3 OH

H

3 C

H

0

H

3 CO O OH

O

QQWOH

0OH 0 OH 0 (Compound or the pharmaceutically acceptable salt thereof.

It is well known in the art, and understood in the instant invention, that peptidyl 5 therapeutic agents such as the instant oligopeptide-cytotoxic agent conjugates preferably have the terminal amino moiety of any oligopeptide substituent protected with a suitable protecting group, such as acetyl, benzoyl, pivaloyl and the like. Such protection of the terminal amino group reduces or eliminates the enzymatic degradation of such peptidyl therapeutic agents by the action of exogenous amino peptidases which are present in the blood plasma of warm blooded animals.

The oligopeptide-cytotoxic agent conjugates of the invention are administered to the patient in the form of a pharmaceutical composition which comprises a conjugate of Formula and a pharmaceutically acceptable carrier, excipient or diluent therefor. As used, "pharmaceutically acceptable" refers to those agents which are useful in the treatment or diagnosis of a warm-blooded animal including, for example, a human, equine, porcine, bovine, murine, canine, feline, or other mammal, as well as an avian or other warm-blooded animal. The preferred mode of administration is parenterally, particularly by the intravenous, intramuscular, subcutaneous, intraperitoneal, or intralymphatic route. Such formulations can be prepared using carriers, diluents or excipients familiar to one skilled in the art. In this regard, See, eg. Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Company, edited by Osol et al. Such compositions may include proteins, such as serum proteins, for example, human serum albumin, buffers or buffering substances such as phosphates, other salts, or electrolytes, and the like. Suitable diluents may include, for example, sterile water, isotonic saline, dilute aqueous dextrose, a polyhydric alcohol or mixtures of such alcohols, for example, glycerin, propylene glycol, polyethylene glycol and the like. The compositions may contain Libc/03531.doc 29 preservatives such as phenethyl alcohol, methyl and propyl parabens, thimerosal, and the like. If desired, the composition can include about 0.05 to about .20 percent by weight of an antioxidant such as sodium metabisulfite or sodium bisulfite.

For intravenous administration, the composition preferably will be prepared so that the amount administered to the patient will be from about 0.01 to about 1g of the conjugate. Preferably, the amount administered will be in the range of about 0.2g to about 1g of the conjugate. The conjugates of the invention are effective over a wide dosage range depending on factors such as the disease state to be treated or the biological effect to be modified, the manner in which the conjugate is administered, the age, weight and condition of the patient as well as other factors to be determined by the treating physician. Thus, the amount administered to any given patient must be determined on an individual basis.

One skilled in the art will appreciate that although specific reagents and reaction conditions are outlined in the following examples, modification can be 15 made which are meant to be encompassed by the spirit and scope of the invention.

The following preparations and examples, therefore, are provided to further illustrate the invention, and are not limiting.

Example 1 Identification of the Semenogelin PSA Mediated Cleavage Site Liquefaction of the seminal gel parallels proteolytic fragmentation of semenogelin I [Lilja, Laurell, (1984) Scand. J. Clin. Lab. Inves. 44, 447- 452]. It is believed that the proteolytic fragmentation of semenogelin is mainly due to the proteolytic activity of prostate-specific antigen [Lilja, (1985) J. Clin. Invest.

76, 1899-1903]. Utilising the published sequence of semenogelin I [Lilja, H., Abrahamsson, Lundwall, (1989) J. of Biol. Chem. 264, 1894-1900] (Figure 1) we designed polymerase chain reaction primers to clone the semenogelin cDNA from a commercially avail able pro static cDNA library (Clone-tech, Palo Alto, CA.).

The purified semenogelin cDNA was placed into the bacterial expression vector pTAC [Linemeyer, Kelly, Minke, Gimenez-Gallego, DeSalvo, J.

and Thomas, (1987) Bio/Technology 5, 960-965]. The semenogelin cDNA was designed so that a tubulin epitope was placed at the carboxyl end of semenogelin protein.. The bacterially expressed semenogelin protein was purified on an anti-tubulin antibody column. The purified semenogelin I protein was mixed with commercially prepared prostate-specific antigen (PSA) (York Biologicals International, Stony Brook, NY) in an 100 to 1 molar ratio (semenogelin I/PSA) in 12mM Tris pH8.0, 25mM NaCI, 0.5mM CaCI 2 and incubated for various times. The digest was fractionated by polyacrylamide gel electrophoresis and transferred by electrophoresis to ProBlott filter paper (Applied Biosystems, Inc., Foster City, CA.) in CAPS buffer [Matsudaira, (1987) J. Biol. Chem. 252, 10035-10038]. The Libc/03531.doc ProBlott filter paper was stained with coomassie blue to identify the novel PSA generated semenogelin I protein fragments. The novel fragments were cut out of the filter with a scalpel and submitted for sequence determination. After the proteolytic fragments were identified by variable time digestion, a 10 minute digestion reaction was performed. The affinity of PSA for the 5 potential cleavage sites in semenogelin I was determined to be as follows: site 349/350 site 375/376 site 289/290 site 315/316 site 159/160. The relative affinities were derived from the coomassie blue staining intensity of each PSA generated peptide fragment. These intensities had approximate ratios of 3:1 :0.6:0.3.

Example 2 Preparation of Oligopeptides which Comprise the PSA Mediated Cleavage Site Oligopeptides were prepared by solid-phase synthesis, using a double coupling protocol for the introduction of amino acids on the Applied Biosystems model 430A automated peptide synthesiser. Deprotection and removal of the 15 oligopeptide from the resin support were achieved by treatment with liquid hydrofluoric acid. The oligopeptides were purified by preparative high pressure liquid chromatography on reverse phase C18 silica columns using an aqueous 0.1% trifluoroacetic acid/acetonitrile gradient. Identity and homogeneity of the oligopeptides were confirmed by amino acid composition analysis, high pressure liquid chromatography, and fast atom bombardment mass spectral analysis. The oligopeptides that were prepared by this method are shown in Figure 2.

Example 3 Assessment of the Recognition of Oligopeptides by Free PSA The oligopeptides prepared as described in Example 2 were individually 25 dissolved in PSA digestion buffer (12mM tris(hydroxymethyl)-aminomethane NaCI, 0.5mM CaCI 2 and the solution added to PSA at a molar ration of 100 to 1. The reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1% (volume/volume). The quenched reaction was analysed by HPLC on a reversed-phase C18 column using an aqueous 0.1% TFA/acetonitrile gradient. The results of the assessment are shown in Figure 2.

Other oligopeptides prepared as described in Example 2 were tested in the same assay wherein the reaction was quenched at 4h. Those results of the assessment are shown in Figure 3. The removal of an asparagine residue from the amino terminus of the oligopeptide results in a significant loss of PSA mediated peptide hydrolysis, while the presence of a glutamic acid residue at the carboxyl end of the peptide appears not to be essential to recognition by PSA.

Libc/03531.doc 31 Example 4 Preparation of Non-cleavable Oligopeptide-Doxorubicin Conjugates The derivatives of doxorubicin shown in Table 3 were prepared using the following general reaction: To a mixture of doxorubicin (Sigma) and the corresponding peptide (prepared by solid phase synthesis or commercially available (Sigma)) in DMSO was added HBTU and HOBT along with diisopropylethylamine and the reaction mixture was stirred overnight. The crude reaction mixture was purified directly by preparative HPLC on a reversed-phase C- 18 column using a 0.1% trifluoroacetic acid (TFA) in acetonitrile/0.1% TFA in water gradient.

Table 3 0 OH 0

OOH

Q'OH

.O O o H

*H

3 O 0 OH 0

C

SH

3 C ~HCH a a Compound R MS (parent ion) 12a H-Ala- 615 12b N-Ac-Ala- 657 12c N-Ac-Ala-Ala-Ala- 799.5 12d N-Ac-Ala-Gly-Pro-Thr-Gly-Ala-Ser- Ala- 1199 (SEQ.ID.NO.: 12) Example In vitro Assay of Cytotoxicity of Peptidyl Derivatives of Doxorubicin The cytotoxicities of the non-cleaveable oligopeptide-doxorubicin conjugates, prepared as described in Example 4, against a line of cells which is known to be killed by unmodified doxorubicin were assessed with an Alamar Blue assay.

Specifically, cell cultures of LNCaP prostate tumour cells, which are a human metastatic prostate adenocarcinoma isolated from a needle biopsy of a lymph node (LNCaP.FGC: American Type Culture Collection, ATCC CRL 1740), or DuPRO cells in 96 well plates were diluted with medium containing various concentrations of a given conjugate (final plate well volume of 200piL). The cells were incubated for 3 days at 37 0 C and then 20iL of Alamar Blue was added to the assay well. The cells were further incubated and the assay plates were read on a EL-310 ELISA reader at the dual wavelengths of 570 and 600nm at 4 and 7 hours after addition of Alamar Blue. Relative percentage viability at the various concentration of conjugate tested was then calculated versus control (no conjugate) cultures. Cytotoxicities of Libc/03531.doc 32 unmodified doxorubicin and unmodified oligopeptide were also assessed. Figure 3 shows the cytotoxicity data for a representative compound (Compound 12d).

Example 6 Assessment of Enzymatically Active PSA from LNCaP Cells Enzymatic activity was demonstrated by incubating LNCaP serum free media (concentrated approximately 200 fold) with recombinant Sememogelin I protein.

Approximately 0.5[ig of immunologically reactive PSA in concentrated conditioned media [determined by HYBRIDTECH (Tandem®) elisa] was mixed with approximately 3pg of recombinant Semenogelin I and incubated for 4h at 37°C. At the end of the incubation, the digest mixture was analysed by Western blot procedures. The results show that purified PSA from semen and PSA from LNCaP conditioned media generate identical proteolytic maps of the recombinant Semenogelin I protein. Thus, LNCap cells produce enzymatically active PSA.

LNCaP are tumourigenic in nude mice and produce detectable levels of circulating 15 PSA.

Example 7 Preparation of Cleavable Oligopeptide-Doxorubicin Conjugates The derivatives of doxorubicin wherein an oligopeptide which is proteolytically cleaved by free PSA is covalently attached to the amine of the sugar moiety of the 20 doxorubicin were prepared using the following general reaction: To a mixture of doxorubicin (Sigma) and the corresponding peptide (prepared by solid phase synthesis as described in Example 2) in DMSO was added HBTU and HOBT along with diisopropylethylamine and the reaction mixture stirred overnight. The crude reaction mixture was purified directly by preparative HPLC on a reversed-phase C- 25 18 column using a 0.1% trifluoroacetic acid (TFA) in acetonitrile/0.1% TFA in water gradient. When reactive amine moieties were present on the peptide, such a functionality was typically protected as the fluorenylmethyloxycarbonyl adduct, which was removed by treatment with a secondary amine, such as piperidine and the like, subsequent to conjugation with doxirubicin. The instant conjugates have a structure of the general formula 0 OH O 0 0 OH 0 3 -H OH

H

O' peptide-N/ Ac Libc/03531.doc

I

33 and may be represented by the phrase "Ac-peptide-DOX Conjugates which were prepared by the above general method or by the synthetic route described in Example 8, but utilising the appropriate starting amino acid residues which are readily available commercially or by synthetic techniques well known in the art, are listed in Tables 5, 5a and 7 in Figures 5, 5A and 7.

Example 8 Ac-Lys-Tyr-GIn-Ser-Ser-Ser-Leu-Dox.Acetate Step A: Ac-Lys(Fmoc)-Gln-Ser(Bzl)-Ser(Bzl)-Ser(Bzl)-Leu-PAM Resin Starting with 0.5mmol (0.67g) Boc-Leu-PAM resin, the protected peptide was synthesised on a 430A ABI peptide synthesiser. The protocol used a 4 fold excess (2mmol) of each of the following protected amino acids: Boc-Ser(OBzl), Boc-GIn, Boc-Tyr(BrZ), Boc-Lys(Fmoc). Coupling was achieved using DCC and HOBT activation in methyl-2-pyrrolidinone. Acetic acid was used for the introduction of the N terminal acetyl group. Removal of the Boc group was performed using 50% TFA 15 in methylene chloride and the TFA salt neutralised with diisopropylethylamine. At the completion of the synthesis, the peptide resin was dried to yield 1.3g of Step B: Ac-Lys(Fmoc)-Tyr-Gln-Ser-Ser-Ser-Leu-OH The protected peptide resin 1.3g, was treated with HF (20mL) for 2h at 0°C in the presence of anisole (2mL). After evaporation of the HF, the residue was washed with ether, filtered and extracted with DMF. The DMF filtrate (75mL) was S" concentrated to dryness and triturated with H 2 0. The insoluble product was filtered and dried (0.46g).

Step C: Ac-Lys(Fmoc)-Tyr-GIn-Ser-Ser-Ser-Leu-Dox (3) The above prepared intermediate 0.46g, (0.43mmol) was dissolved in DMF (15mL) and doxorubicin hydrochloride, 125mg (0.215mmol), added followed by 60pL of triethylamine (0.430mmol). The stirred solution was cooled and 92pL of diphenylphosphoryl azide (0.43mmol) added. After 5 minutes, an additional 92pL of DPPA was added and the pH adjusted to -7.5 (pH paper) with TEA. After 1 hour, an additional 92 L of DPPA was added, pH adjusted to and the reaction stirred at 0 0 -5 0 C overnight. After 18 hours, the reaction (found to be complete by analytical HPLC) was concentrated to an oil Step D: Ac-Lys-GIn-Tyr-Ser-Ser-Ser-Leu-Dox The above product was dissolved in DMF (20mL), cooled and of piperidine added. The solution was concentrated to dryness and purified by preparative HPLC. Buffer A 15% acetic acid-H20; B 15% acetic acid-methanol.

The crude product was dissolved in 300mL of 10% B/90% A buffer, filtered and purified on a C-18 reverse phase HPLC radial compression column (Waters, Delta- Pak 15pm, 300A). A step gradient of 10% B to 60% B was used at a flow rate of Libc/03531.doc (uv 260nm). Homogeneous product fractions were pooled, concentrated and freeze-dried from H 2 0 to yield 125mg of purified product Example 9 Deacetylvinblastinyl-Leu-Asn-Lys-Ala-Ser-Try-GIn-Ser-Ser-Ser-Leu-NH2.Acetate (SEQ.ID.NO. 184) Step A: NH 2 -Leu-Asn-Lys(Fmoc)-Ala-Ser-Tyr-GIn-Ser-Ser-Ser-Leu-Amide (6) Starting with 0.5mmol of p-methylbenzhydrylamine resin (MBHA), the protected peptide, NH 2 -Leu-Asn-Lys(Fmoc)-Ala-Ser(OBzl)-Tyr(BrZ)-Gln-Ser(OBzl)- Ser(OBzl)-Ser(OBzl)-Leu-MBHA, intermediate was synthesised on a 430A ABI peptide synthesiser. The protocol used a 4 fold excess (2mmol) of each of the following protected amino acids: Boc-Leu, Boc-Asn, Boc-Lys (Fmoc), Boc-Ala, Boc- Ser(OBzl), Boc-Tyr(BrZ), Boc-GIn. Coupling was achieved using DCC and HOBT activation in N-methyl-2-pyrrolidinone (NMP).

Removal of the Boc group was performed using 50% TFA in methylene 15 chloride and the TFA salt neutralised with diisopropylethylamine. The dried protected peptide resin (1.80g) was treated with HF (20mL) for 2h at 0°C in the presence of anisole (2mL). After evaporation, the residue was extracted with DMF.

The DMF filtrate (75mL) was concentrated to dryness, dissolved in a 1:1 mixture of acetonitrile-H 2 0 and freeze-dried to give 750mg of crude product. A portion 20 (200mg) was purified by preparative HPLC on a C-18 reverse phase support (Waters, p-Bondapak). Buffer A 15% acetic acid-H 2 0; B 15% acetic acidmethanol. For the purification, the crude product was suspended in 400mL of B/90% A buffer, filtered and the filtrate loaded onto the column. A step gradient of 10% B to 55% B was used at a flow rate of 75mL/min. Homogeneous product fractions were pooled, concentrated and freeze-dried from H 2 0 to yield Step B: Deacetylvinblastin Monohydrazide (7) 1g of vinblastine sulfate was converted to the amine form by extraction in methylene chloride and saturated sodium bicarbonate. The methylene chloride layer was washed with H 2 0, dried over anhydrous MgSO 4 and concentrated to dryness. The vinblastine was then dissolved in anhydrous ethanol (20mL) and anhydrous hydrazine added (20mL). The solution was heated (60 0 C) under an N 2 atmosphere for 17h. The reaction was concentrated to an oil, dissolved in methylene chloride, extracted with H 2 0 and dried over MgSO 4 After evaporation compound was isolated. [Ref: K.S.P. Bhushana Rao et al., J. Med. Chem.

(1985), 28:1079.] Step C: Deacetylvinblastine Acid Azide Deacetylvinblastine monohydrazide (48mg, 0.0624mmol) was dissolved in DMF (3mL), cooled (-15 0 C) and acidified to -2.5 (pH paper) with HCI/dioxane.

Isoamylnitrite (10pL) was added followed by an additional 10pL after 10 min. HPLC Libc/03531 .doc analysis indicated complete conversion of the hydrazide to azide after 5 min. The azide was maintained in solution at -15°C until ready for use.

Step D: Deacetylvinblastinyl-Leu-Asn-Lys-Ala-Ser-Try-Gln-Ser-Ser-Ser-Leu-NH2.Acetate The oligopeptide product from Step A, 32mg (0.0225mmol), was dissolved in DMF (lmL) and cooled To this solution was added a 1.5mL DMF solution (0.031mmol) of desacetylvinblastine acid azide The pH was adjusted to (pH paper) with triethylamine and the reaction stirred at -5°C and 0°C for 18h. To the reaction was added H 2 0 (2mL) and the solution evaporated to dryness.

The intermediate was dissolved in DMF (4mL), cooled and 2mL of piperidine added. The solution was concentrated to dryness and purified by preparative HPLC as described in Step A. The homogeneous fractions were pooled, concentrated and freeze-dried from H 2 0 to yield Example Deacetylvinblastinyl-Leu-Asn-Lys-Ala-Ser-Try-Gn-Ser-Ser-Ser-Leu-Dox.Acetate Step A: Deacetylvinblastinyl-Leu-Asn-Lys(Fmoc)-Ala-Ser-Trv-Gn-Ser-Ser-Ser-Leu- Dox.Acetate (9) The oligopeptide product prepared as described in Example 9, Step A, (166mg, 0.125mmol), was dissolved in DMSO (3mL) and cooled to -150C. To this 20 solution was added a DMF solution (0.125mmol) of desacetylvinblastine acid azide prepared as described in Example 9, Step C. The pH was adjusted to -7.5 (pH paper) with triethylamine and the reaction stirred at -15 C for 90 mins.

After stirring 18 hours at 0-5°C, the reaction was concentrated to dryness and the crude residue was dissolved in DMF (10mL) and filtered. Doxorubicin hydrochloride, 62mg (0.106mmol), was added to the filtrate followed by 30tL of triethylamine. The stirred solution was cooled and 27 iL of diphenylphosphoryl azide (DPPA, 0.134mmol) added. After 5 minutes, an additional 27L of DPPA was added and the pH adjusted to -7.5 (pH paper) with TEA. After 1 hour, an additional 27 1 iL of DPPA was added, pH adjusted to and the reaction stirred at 0°-5°C overnight. After 18 hours, the reaction (found to be complete by analytical HPLC) was concentrated to an oil Step B: Deacetylvinblastinyl-Leu-Asn-Lys-Ala-Ser-Try-GIn-Ser-Ser-Ser-Leu-Dox.Acetate The above intermediate product was dissolved in DMF (20mL), cooled and 10mL of piperidine added. The solution was concentrated to dryness and purified by preparative HPLC. Buffer A 15% acetic acid-H 2 0; B 15% acetic acidmethanol. The crude product was dissolved in 300mL of 10% B/90% A buffer, filtered and purified on a C-18 reverse phase HPLC radial compression column (Waters, [-Bondapak). A step gradient of 10% B to 60% B was used at a flow rate Libc/03531.doc of 75mL/min (uv 260nm). Semi-pure product was further purified on C-18 (Waters, Prep Pak) using Buffer A 0.13M pH3.0 triethylammonium phosphate and Buffer B acetonitrile. A step gradient of 10% B to 40% B was used at a flow rate of 75mL/min. (uv 214nm). Pure product fractions were pooled, diluted with H 2 0 and desalted by applying the product onto the same column and eluting the product as the acetate salt with 90% acetonitrile/10%

H

2 0 acetic acid). The product fractions were concentrated and freeze dried from H 2 0 to yield the purified product Example 11 Ac-Lys-Tyr-Gln-Ser-Ser-Ser-Nle-NH-(CH2)3NH-deacetylvinblastine amide (14) Step A: Deacetylvinblastine-3-aminopropyl amide (111 To a cooled (-15oC) a DMF solution (3mL, 0.0624mmol) of deacetylvinblastine acid azide (synthesis described in Example 9, Step C) was added 120ipL of 1,3diaminopropane in DMF (2mL). The reaction was stirred at -10°C for 1h, filtered and 15 concentrated to dryness to yield (11).

Step B: Deacetylvinblastine-3-aminopropylamide-norleucine amide (12) To a DMF solution (lmL) of Boc-NIe (22mg, 0.095mmol) was added 318L of a 1M solution of HOBT (in NMP) followed by 280iL of a 1M solution of DCC (in NMP). After 30 min., intermediate (11) (0.0624mmol) was added in a 3.5mL DMF.

20 The pH of the reaction was adjusted -7.5 with diisopropylethylamine. After stirring for 18h the reaction was concentrated to an oil and the Boc protecting group removed by treating the oil with a 1:1 solution of TFA: CH 2

CI

2 (20mL). After 5 min.

the reaction was concentrated to dryness. Purification was achieved by preparative HPLC on a C-18 reverse phase support (Waters, Delta Pak). Buffer A 0.1% TFA- H20; B= 0.1% TFA-CH3CN. The crude product was loaded in 100% A buffer (100mL) and a step gradient of 100% A to 30% A was used at a flow rate of Homogeneous product fractions were pooled and freeze-dried to yield (12).

Step C: Ac-Lys(Fmoc)-Tyr-Gln-Ser-Ser-Ser-Nle-OH (13) The above intermediate was prepared as described in Example 9, Step A for the preparation of Ac-Lys(Fmoc)-Tyr-Gln-Ser-Ser-Ser-Leu-OH.

Step D: Ac-Lys-Tyr-Gin-Ser-Ser-Ser-NIe-NH-CH2)3NH-deacetylvinblastine amide (14) The oligopeptide product (70mg, 0.065mmol) in DMF (1mL) was combined with (41mg, 0.05mmol) of (12) in DMF (4mL). The solution was cooled and 171L of diphenylphosphoryl azide (0.08mmol) added. After 5 min. an additional 17[pL of DPPA was added and the pH adjusted to -7.5 (pH paper) with triethylamine. After 2h additional 35mg, was added in DMF (0.5mL) and 17p1L of DPPA. The pH was maintained at -7.5 with TEA and after 3h an additional of (13) was added in DMF (0.5mL). The reaction was stirred at 0-5°C. After 18h, the Libc/03531.doc 37 reaction was concentrated to dryness, redissolved in DMF (9mL), cooled and 3mL of piperidine added. The solution was concentrated to dryness and purified by preparative HPLC. Buffer A 0.1% TFA-H 2 0; B= 0.1% TFA-CH 3 CN. The crude product was dissolved in 30% acetic acid H 2 0 (100mL) and purified on a C-18 reverse phase HPLC radial compression column (Waters, Delta Pak). A step gradient of 100% A to 70% A was used at a flow rate of 75mL/min. Semi-pure product fractions were pooled and freeze-dried. Purification to homogeneity was achieved by repurification on a C-4 support (Waters, Delta Pak) as described above. Product fractions were pooled and freeze dried to yield pure (14).

Example 12 Assessment of the Recognition of Oligopeptide-Doxorubicin Conjugates by Free PSA The conjugates prepared as described in Examples 7-9 were individually dissolved in PSA digestion buffer (12mM tris(hydroxymethyl)-aminomethane 25mM NaCI, 0.5mM CaCI2) and the solution added to PSA at a molar ration of 100 15 to 1. The reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1% (volume/volume). The quenched reaction i* was analysed by HPLC on a reversed-phase C-18 column using an aqueous 0.1%TFA/acetonitrile gradient. The results of the assessment are shown in Tables and 5a of Figure Example 13 Assessment of the Cleavage of Oligopeptide-Doxorubicin Conjugates in Cell .Conditioned Media: Cell conditioned serum-free a-MEM media (phenol red minus) was collected 3 days after the addition of the media to either LNCaP or Dupro (prepared as 25 described in J. Urology, 146:915-919 (1991)) cell lines. The media was concentrated 20 fold using an Amicon® CentriprepTM concentrator with a 10 000 molecular weight cutoff. The LNCaP conditioned media contained free PSA protein at, on average, approximately 100ng/mL concentration as determined by the Tandem®-EPSA immunodetection kit (Hybritech®). There was no detectable free PSA in the Dupro cell conditioned media.

100ptL portions of concentrated conditioned media was mixed with 35 ig of a oligopeptide-doxorubicin conjugate prepared as described in Example 7 and the mixture was incubated at 37°C for 0, 4 and 24 hour time points. The reactions were stopped by the addition of ZnCI 2 (to a 0.01M final concentration and analysed by HPLC on a reversed-phase C-18 column using an aqueous 0.1 %TFAlacetonitrile gradient to determine the percentage of peptide-cytotoxic agent conjugate that had been digested. The results of the assessment are shown in Table 6 of Figure 6.

Libc/03531.doc Example 14 In vitro Assay of Cytotoxicity of Peptidyl Derivatives of Doxorubicin: The cytotoxicities of the cleaveable oligopeptide-doxorubicin conjugates, prepared as described in Example 7, against a line of cells which is known to be killed by unmodified doxorubicin was assessed with an Alamar Blue assay as described in Example 5. Specifically, cell cultures of LNCap prostate tumour cells or DuPRO cells in 96 well plates was diluted with medium containing various concentrations of a given conjugate (final plate well volume of 200pL). The cells were incubated for 3 days at 37 0 C, 20ptL of Alamar Blue is added to the assay well.

The cells were further incubated and the assay plates were read on a EL-310 ELISA reader at the dual wavelengths of 570 and 600nm at 4 and 7 hours after addition of Alamar Blue. Relative percentage viability at the various concentration of conjugate tested was then calculated versus control (no conjugate) cultures.

Cytotoxicities of the conjugates were also compared to the cytotoxicity of 15 unmodified doxorubicin and unmodified oligopeptide assessed in the same assay.

Results of this assay are shown in Table 7 of Figure 7.

Example

C.

In vivo Efficacy of Peptidyl -Cytotoxic Agent Conjugates LNCaP.FGC or DuPRO-1 cells are trypsinised, resuspended in the growth S' 20 medium and centrifuged for 6 min at 200xg. The cells are resuspended in serumfree a-MEM and counted. The appropriate volume of this solution containing the desired number of cells is then transferred to a conical centrifuge tube, centrifuged as before and resuspended in the appropriate volume of a cold 1:1 mixture of a- MEM-Matrigel. The suspension is kept on ice until the animals are inoculated.

Harlan Sprague Dawley male nude mice (10-12 weeks old) are restrained without anaesthesia and are inoculated with 0.5mL of cell suspension on the left flank by subcutaneous injection using a 22G needle. Mice are either given approximately 5x10 5 DuPRO cells or 1.5x10 7 LNCaP.FGC cells.

Following inoculation with the tumour cells the mice are treated under one of two protocols: Protocol A: One day after cell inoculation the animals are dosed with a 0.1volume of test conjugate, doxorubicin or vehicle control (sterile water).

Dosages of the conjugate and doxorubicin are initially the maximum non-lethal amount, but may be subsequently titrated lower. Identical doses are administered at 24 hour intervals for 5 days. After 10 days, blood samples are removed from the mice and the serum level of PSA is determined. Similar serum PSA levels are determined at 5-10 day intervals. At the end of 5.5 weeks the mice are sacrificed and weights of any tumours present are measured and serum PSA again Libc/03531 doc 39 determined. The animals' weights are determined at the beginning and end of the assay.

Protocol B: Ten days after cell inoculation, blood samples are removed from the animals and serum levels of PSA are determined. Animals are then grouped according to their PSA serum levels. At 14-15 days after cell inoculation, the animals are dosed with a 0.1-0.5mL volume of test conjugate, doxorubicin or vehicle control (sterile water). Dosages of the conjugate and doxorubicin are initially the maximum non-lethal amount, but may be subsequently titrated lower. Identical doses are administered at 24 hour intervals for 5 days. Serum PSA levels are determined at 5-10 day intervals. At the end of 5.5 weeks the mice are sacrificed, weights of any tumours present are measured and serum PSA again determined.

The animals' weights are determined at the beginning and end of the assay.

Sequence Listing INFORMATION FOR SEQ ID NO: 1: SEQUENCE CHARACTERISTICS: LENGTH: 462 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear 20 (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Met Lys Pro Asn lie lie Phe Val Leu Ser Gin Ala Ala Ser Glu Phe Pro Met Gly Gin Lys 25 Gin Phe Pro His 40 Lvs Gin Gin Thr Gly Leu Leu Leu lie Gly Ser Lys Gly Gin Lys Gly Gin Ser Lys Gly Ser Leu Arg His Tyr Glu Leu Ser GIv Gin Lvs Gly Glu Phe Ser lie Gin 55 Tyr Thr Tyr His Gin Gin Tyr Asp Ser Val Asp Ala Asn Asp 75 Leu Asn Ala Leu His 90 Ser Gin Gin Leu Leu His Lvs Asp Gin Ser Arg Thr Thr Lys Ser Arg His Leu Glv GIv Gin 100 His Gly Arg Asp 115 His His Lys 105 Asp Lys Ser Lys 120 GIv Lvs Ala His His Asn Lys 110 Glv 130 Asp Gin 145 135 Asn Ser Pro Ser Gin Gly His Phe His Arg Gly Thr Gin 140 Lys Gly lie Ser 155 Ara Val Val lie Asn Pro Ser Gin Ser Gin Tyr Ser 160 Glv Gly 150 Libc/03531.doc Asn Thr Glu Glu Arg Leu Trp Val His Gly Leu Ser Lys Glu Gin Thr 165 170 175 Ser Val Ser Gly Ala Gin Lys Gly Arg Lys Gin Gly Gly Ser Gin Ser 180 185 190 Ser Tyr Val Leu Gin Thr Glu Glu Leu Val Ala Asn Lys Gin Gin Arg 195 200 205 Glu Thr Lys Asn Ser His Gin Asn Lys Gly His Tyr Gin Asn Val Val 210 215 220 Glu Val Arg Glu Glu His Ser Ser Lys Val Gin Thr Ser Leu Cys Pro 225 230 235 240 Ala His Gin Asp Lys Leu Gin His Gly Ser Lys Asp lie Phe Ser Thr 245 250 255 Gin Asp Glu Leu Leu Val Tyr Asn Lys Asn Gin His Gin Thr Lys Asn 260 265 270 Leu Asn Gin Asp Gin Gin His Gly Arg Lys Ala Asn Lys lie Ser Tyr 275 280 285 Gin Ser Ser Ser Thr Glu Glu Arg Arg Leu His Tyr Gly Glu Asn Gly 290 295 300 SVal Gin Lys Asp Val Ser Gin Ser Ser lie Tyr Ser Gin Thr Glu Glu 305 310 315 320 Lys Ala Gin Gly Lys Ser Gin Lys Gin lie Thr lie Pro Ser Gin Glu 325 330 335 Gin Glu His Ser Gin Lys Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser 340 345 350 Thr Glu Glu Arg Arg Leu His Tyr Gly Glu Asn Gly Val Gin Lys Asp 355 360 365 Val Ser Gin Arg Ser lie Tyr Ser Gin Thr Glu Lys Leu Val Ala Gly 370 375 380 Lys Ser Gin lie Gin Ala Pro Asn Pro Lys Gin Glu Pro Trp His Gly 385 390 395 400 Glu Asn Ala Lys Gly Glu Ser Gly Gin Ser Thr Asn Arg Glu Gin Asp 405 410 415 Leu Leu Ser His Glu Gin Lys Gly Arg His Gin His Gly Ser His Gly 420 425 430 Gly Leu Asp lie Val lie lie Glu Gin Glu Asp Asp Ser Asp Arg His 435 440 445 Leu Ala Gin His Leu Asn Asn Asp Arg Asn Pro Leu Phe Thr 450 455 460 INFORMATION FOR SEQ ID NO: 2: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal Libc/03531.doc 41 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Gly Lys Gly lie Ser Ser Gin Tyr Ser Asn Thr Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 3: SEQUENCE

CHARACTERISTICS:

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NO

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CHARACTERISTICS:

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LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: Gin Lys Val Ser Tyr Gin Ser Ser Ser Thr 1 5 INFORMATION FOR SEQ ID NO: 44: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids S 15 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO 20 (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr 1 5 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Gly Glu Gin Gly Val Gin Lys Asp Val Ser Gin Ser Ser Ile Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 46: Libc/03531.doc SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: Gly Lys Gly lie Ser Ser Gin Tyr Ser Asn Thr Asp Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 47: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid 15 STRANDEDNESS: single .i TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO 20 FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47: Gly Glu Asn Gly Leu Gin Lys Asp Val Ser Gin Ser Ser lie Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 48: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: Gly Glu Asn Gly Val Asn Lys Asp Val Ser Gin Ser Ser lie Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 49: Libc/03531.doc 56 SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49: Gly Glu Asn Gly Val Gin Arg Asp Val Ser Gin Arg Ser lie Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID No SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid 15 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Gly Glu Asn Gly Val Gin Lys Asp Val Ser Gin Lys Ser lie Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 51: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: Gly Glu Asn Gly Val Gin Lys Asp Leu Ser Gin Thr Ser lie Tyr Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 52: Libc/03531.doc 57 SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: Gly Glu Asn Gly Val Gin Lys Asp Val Ser Gin Ser Ser lie Phe Ser 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: 53: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid 15 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53: Gly Glu Asn Gly Val Gin Lys Asp Met Ser Gin Ser Ser lie Tyr Thr 1 5 10 SGin Thr Glu INFORMATION FOR SEQ ID NO: 54: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: Gly Glu Asn Gly Val Gin Lys Asp Val Ser Gin Arg Ser lie Tyr Thr 1 5 10 Gin Thr Glu INFORMATION FOR SEQ ID NO: Libc/03531.doc 9 a.

9 9* 9. 9 a.

9 *9 a SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Glu Asn Gly Val Gin Lys Asp Val Ser Gin Ser Ser Glu INFORMATION FOR SEQ ID NO: 56: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56: Glu Asn Gly Val Gin Lys Asp Val Ser Gin Arg 10 Thr Glu INFORMATION FOR SEQ ID NO: 57: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: Lys Ala lie Ser Ser Gin Tyr Ser Asn Thr Glu 10 INFORMATION FOR SEQ ID NO: 58: Ser lie Ser lie Tyr Glu Arg Leu Libc/03531.doc SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: Lys Gly lie Ser Ser Gin Tyr Ser Asn Ser Glu Glu Arg *4 9.

0r *c 0

S.

*9 S S *r S 00 .0 S 0 0SO* INFORMATION FOR SEQ ID NO: 59: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID No: 59: Arg Gly lie Ser Ser Gin Tyr Ser Asn Thr Glu 10 Glu Arg Leu INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Lys Gly lie Thr Ser Gin Tyr Ser Asn Thr Glu Glu Arg Leu 10 INFORMATION FOR SEQ ID NO: 61: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids Libc/03531 .doc TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: Gly Lys Gly lie Ser Thr Gin Tyr Ser Asn Thr Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 62: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear 15 (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62: Gly Lys Gly lie Ser Ser Asn Tyr Ser Asn Thr Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 63: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63: Ala Lys Gly lie Ser Ser Gin Tyr Ser Asn Thr Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 64: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single Libc/03531.doc TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64: Gly Lys Gly lie Ser Ser Gin Phe Ser Asn Thr Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: SEQUENCE

CHARACTERISTICS:

LENGTH: 15 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO 15 (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Gly Lys Gly lie Ser Ser Gin Tyr Thr Asn Ser Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 66: SEQUENCE CHARACTERISTICS: LENGTH: 15 amino acids TYPE: amino acid S. STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66: Gly Lys Gly lie Ser Ser Gin Tyr Ser Asn Ser Glu Glu Arg Leu 1 5 10 INFORMATION FOR SEQ ID NO: 67 SEQUENCE CHARACTERISTICS: LENGTH: 25 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide Libc/03531.doc (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: Ser Gin Lys Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr Glu Glu 1 5 10 Arg Arg Leu His Tyr Gly Glu Asn Gly INFORMATION FOR SEQ ID NO: 68: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal i' (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: lie Ser Tyr Gin Ser Ser Ser Thr S.9 1 INFORMATION FOR SEQ ID NO: 69: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69: Ala Asn Lys lie Ser Tyr Gin Ser Ser 1 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide Libc/03531.doc (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr Leu 1 5 INFORMATION FOR SEQ ID NO: 71: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal 15 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71: Ala Asn Gly lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 72: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid 20 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72: Ala Asn Pro lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 73: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO Libc/03531.doc FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73: Ala Asn Lys lie Ser Tyr Gin Ser Ala Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 74: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74: Ala Asn Lys lie Ser Tyr Gin Ser Ser Lys Thr Glu 1 5 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ala Asn Lys lie Ser Tyr Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 76: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: Libc/03531.doc NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /label= d-serine /note= "unnatural configuration of the amino acid" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76: Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 77: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO 15 FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 4 OTHER INFORMATION: /label= d-isoleucine /note= "unnatural amino acid stereochemical configuration" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77: Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 78: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78: Ala Asn Lys lie Ser Tyr Gin Ser Ser Gin Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 79: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids Libc/03531.doc TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79: Ala Asn Lys lie Ser Tyr Gin Ser Ala Lys Thr Glu 1 5 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear 15 (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 3 OTHER INFORMATION: /label= d-lysine /note= "unnatural amino acid stereochemical configuration" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ala Asn Lys lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 81: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81: Ala Asn Lys lie Ser Tyr Gin Ser Thr Glu 1 5 Libc/03531.doc INFORMATION FOR SEQ ID NO: 82: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82: Ala Asn Lys Ser Tyr Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 83: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids 15 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal SEQUENCE DESCRIPTION: SEQ ID NO: 83: Ala Asn Lys lie Tyr Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 84: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84: Ala Asn Lys Ala Ser Tyr Gin Ser Ala Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: Libc/03531.doc LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ala Asn Glu lie Ser Tyr Gin Ser Ala Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 86: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single 15 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO a(iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: Lys lie Ser Tyr Gin Ser Ser 1 INFORMATION FOR SEQ ID NO: 87: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87: Ser Tyr Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 88: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid Libc/03531.doc STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88: Ser Tyr Gin Ser Ser Thr Leu 1 INFORMATION FOR SEQ ID NO: 89: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 15 (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal SEQUENCE DESCRIPTION: SEQ ID NO: 89: Ala Ser Tyr Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Glu lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 91: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear Libc/03531.doc (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91: Ala Asn Glu lie Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 92: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO 15 FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92: Ala Asn Lys lie Ser Tyr Tyr Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 93: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93: Ala Asn Lys lie Ser Tyr Tyr Ser Ala Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 94: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO Libc/03531.doc (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94: Ala Ser Tyr Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ala Asn Ser Tyr Gin Ser Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 96: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid .o STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide o. (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96: Ala Ser Tyr Gin Ser Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 97: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal Libc/03531.doc 72 (xii) SEQUENCE DESCRIPTION: SEQ ID NO:97: Ser Tyr Gin Ser Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 98: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98: Ala Asn Lys Ala Ser Tyr Gin Ser Ala Ser Thr Cys 1 5 INFORMATION FOR SEQ ID NO: 99: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99: Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 100: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100: Libc/03531.doc Tyr Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 101: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101: Ser Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 102: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acid TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102: Ala Asn Lys lie Ser Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO:103: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 3 OTHER INFORMATION: /label= unnatural /note= "ornithine" Libc/03531 .doc 74 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103: Ala Asn Xaa lie Ser Tyr Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 1 0 4: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE 1YPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 15 OTHER INFORMATION: /label= unnatural /note= "3,4-dichlorophenalanine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104: Ser Xaa Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 105: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /label= unnatural /note= "(3-pyridinyl)alanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105: Ser Xaa Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 106: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid Libc/03531.doc STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106: Ser Lys Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO:107: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 15 (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107: Ser Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:108: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /label= unnatural /note= "epsilon aminocaproic acid" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 1 0 9: SEQUENCE CHARACTERISTICS: Libc/03531.doc LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 4 OTHER INFORMATION: /label= unnatural /note= "N-methylisoleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109: Ala Asn Lys Xaa Ser Tyr Gin Ser Ser Thr Glu 1 5 INFORMATION FOR SEQ ID NO: 110: 1 SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110: Ser Tyr Gin Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO: 111: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: Tyr Gin Ser Ser Thr Glu 1 Libc/03531.doc 77 INFORMATION FOR SEQ ID NO:112: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal SEQUENCE DESCRIPTION: SEQ ID NO:112: Ser Tyr Lys Ser Ser Thr Glu 1 INFORMATION FOR SEQ ID NO:113: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids 15 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113: Ser Tyr Tyr Ser Ser Thr Glu S1 INFORMATION FOR SEQ ID NO: 114: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114: Ser Tyr Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 115: SEQUENCE CHARACTERISTICS: Libc/03531.doc *0

B

0B B

B

B.

B B

B

.1 *0

B

B.

B B 000 LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115: Ser Tyr Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 116: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /label= unnatural /note= "2,3-diaminopropionic acid" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116: Xaa Tyr Gin Ser Ser Ser Leu 1 (2) INFORMATION FOR SEQ ID NO:117: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117: Asn Lys lie Ser Tyr Gin Ser Ser Ser Libc/03531.doc 79 INFORMATION FOR SEQ ID NO:118: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118: Ala Asn Lys Ala Ser Tyr Gin Ser Ala S. eg 0* S S *0 *5 *5

S

*5

S

5 *0 S 1 (2)

(A)

15 (B)

(C)

(D)

Ala 1 (2)

(A)

(B)

(C)

(D)

5 INFORMATION FOR SEQ ID NO: 119: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119: Asn Lys Ala Ser Tyr Gin Ser 5 INFORMATION FOR SEQ ID NO: 120: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120: Asn Lys Ala Ser Tyr Gin Ser Ser Ser Ala SE 1( Ser Thr Leu er Leu INFORMATION FOR SEQ ID NO:121: SEQUENCE CHARACTERISTICS: Libcl03531 .doc LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121: Ala Asn Lys Ala Ser Tyr Gin Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO:122: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single 15 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /label= d-leucine /note= "unnatural amino acid stereochemical configuration" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122: Ser Tyr Gin Ser Ser Thr Leu 1 INFORMATION FOR SEQ ID NO:123: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123: Libc/03531.doc Ala Asn Lys Ala Ser Tyr Ala Ser Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO:124: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124: :Lys Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO :125: o SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO 20 (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125: Ser Tyr Gin Ser Ser Lys Leu 1 INFORMATION FOR SEQ ID NO: 126: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 Libc/03531.doc 82 OTHER INFORMATION: /label= d-leucine /note= "unnatural amino acid stereochemical configuration" (xii) SEQUENCE DESCRIPTION: SEQ ID NO:126: Ser Tyr Gin Ser Ser Lys Leu 1 INFORMATION FOR SEQ ID NO:127: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear: (ii) MOLECULE TYPE: peptide X (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127: Asn Lys lie Ser Tyr Tyr Ser 1

S.

S.

*5S

S

S.

S

S 15 (2) Asn 1 (2) INFORMATION FOR SEQ ID NO:128: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128: Lys Ala Ser Tyr Gin Ser INFORMATION FOR SEQ ID NO:129: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal Libc/03531.doc 83 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129: Tyr Gin Ser Ser INFORMATION FOR SEQ ID NO: 130: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ Asn Lys lie Ser Tyr Gin Ser 0*

S

a.

5* a a ID NO:130: Ala INFORMATION FOR SEQ ID NO: 131 SEQUENCE CHARACTERISTICS: 15 LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 20 (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131: Ala Asn Lys lie Ser Tyr Tyr Ser 1 INFORMATION FOR SEQ ID NO: 132: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132: Libc/03531.doc Ala Asn Lys Ala Tyr Gin INFORMATION FOR SEQ ID NO: 133: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ Ser Tyr Gin Ser Ser ID NO:133: Thr 0 00 0 000 00 0**0 0** 0* 0 0* INFORMATION FOR SEQ ID NO:134: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134: Tyr Gin Ser Ser Ser INFORMATION FOR SEQ ID NO:135: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135: Tyr Gin Ser Ser Leu Libc/03531.doc INFORMATION FOR SEQ ID NO:136: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136: Ala Asn Lys lie Ser Tyr Gin Ser Ala 1 INFORMATION FOR SEQ ID NO: 137: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids 15 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137: Ala Asn Lys lie Ser Tyr Tyr Ser Ser 1 INFORMATION FOR SEQ ID NO: 138: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138: Ala Asn Lys lie Ser Tyr Tyr Ser Ala 1 INFORMATION FOR SEQ ID NO:139: SEQUENCE CHARACTERISTICS: Libc/03531.doc LENGTH: 9 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139: Ala Asn Lys Ala Ser Tyr Gin Ser Ala 1 INFORMATION FOR SEQ ID NO:140: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single 15 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140: Lys Tyr Gin Ser Ser 1 INFORMATION FOR SEQ ID NO: 141: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /label= homoarginine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141: Xaa Tyr Gin Ser Ser 1 Libc/03531.doc 87 INFORMATION FOR SEQ ID NO:142: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142: Lys Tyr Gin Ser Ser Ser 1 INFORMATION FOR SEQ ID NO: 143: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids 15 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /label= homoarginine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143: Xaa Tyr Gin Ser Ser Ser 1 INFORMATION FOR SEQ ID NO: 144: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal Libc/03531.doc 88 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144: Ser Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:145: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Peptide LOCATION: I *i 15 OTHER INFORMATION: /label= homoarginine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:146: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME,'KEY: Peptide LOCATION: 7 OTHER INFORMATION: /label= norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146: Lys Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:147: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid Libc/03531.doc 89 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine* (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "nol-leucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147: Xaa Xaa Gin Ser Leu 1 INFORMATION FOR SEQ ID NO:148: *9*9 SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine9 (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "homotyrosine" (ix) FEATURE: NAME,'KEY: Peptide LOCATION: 6 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148: Xaa Xaa Gin Ser Ser Leu 1 Libc/03531.doc a.

a a.

INFORMATION FOR SEQ ID NO: 149: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 15 OTHER INFORMATION: /product= "cyclohexylhomoalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 6 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149: Xaa Xaa Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:150: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "cyclohexylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150: Ala Asn Lys Ala Ser Tyr Gin Ser Ser Xaa 1 5 INFORMATION FOR SEQ ID NO:151: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid Libc/03531.doc STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151: Xaa Tyr Gin Ser Ser Pro 1 INFORMATION FOR SEQ ID NO:152: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear 15 (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152: Xaa Tyr Gin Ser Ser His 1 INFORMATION FOR SEQ ID NO:153: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153: Xaa Tyr Gin Ser Asn 1 INFORMATION FOR SEQ ID NO:154: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids Libc/03531.doc TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:155: 15 SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid S* STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "4-aminomethylphenylalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:156: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide Libc/03531.doc (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:157: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide 15 LOCATION: OTHER INFORMATION: /product= "cyclohexylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157: Ala Asn Lys Ala Lys Tyr Gin Ser Ser Xaa 1 5 INFORMATION FOR SEQ ID NO:158: t SEQUENCE CHARACTERISTICS: 20 LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "2(4,6-dimethylpyrimidine)lysine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:159: SEQUENCE CHARACTERISTICS: Libc/03531.doc LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "N'-(2-imidazolyl)lysine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159: Xaa Tyr Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 160: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid 15 STRANDEDNESS: single TOPOLOGY: linear o (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide 20 LOCATION: OTHER INFORMATION: /product= "homoarginine@ (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160: Ala Asn Lys Ala Xaa Tyr Gin Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO: 161: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "(4-aminocycloheayl)alanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 Libc/03531.doc OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:162: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "N'-(2-imidazolyl)lysine" (ix) FEATURE: 15 NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine@& (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:163: 20 SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 Libc/03531.doc OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:164: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: 15 NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164: Xaa Tyr Gin Ser Ser Ser Xaa 1 INFORMATION FOR SEQ ID NO:165: 20 SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "N'-(2-imidazolyl)lysine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165: Ala Asn Lys Ala Xaa Tyr Gin Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO: 166: Libc/03531.doc 97 SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "3-iodotyrosine" 15 (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166: Xaa Xaa Gin Ser Ser Ser Leu "1 S 20 INFORMATION FOR SEQ ID NO: 167: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "O-dimethylphosphotyrosine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" Libc/03531 doc 98 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 168: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168: Xaa Tyr Gin Ser Ser Asp 1 1 INFORMATION FOR SEQ ID NO: 169: 15 SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "O-methyltyrosine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:170: SEQUENCE CHARACTERISTICS: Libc/03531.doc 99 LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170: Ala Asn Lys Ala Lys Tyr Gin Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO:171: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid S 15 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:172: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 Libc/03531.doc OTHER INFORMATION: iproduct= "N'-(2-imidazolyl)lysine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (ix) FEATURE: 8 NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 173: SEQUENCE CHARACTERISTICS: S* LENGTH: 6 amino acids TYPE: amino acid S 15 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION:

I

OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= cyclohexylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173: Xaa Xaa Gin Ser Ser Ser 1 INFORMATION FOR SEQ ID NO:174: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I Libc/03531.doc 101 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 6 OTHER INFORMATION: /product= norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174: Xaa Xaa Gin Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 17 SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE .YPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 6 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175: Xaa Xaa Gin Ser Pro Leu 1 INFORMATION FOR SEQ ID NO:176: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear Libc/03531.doc (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "3-fluorotyrosine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176: Xaa Xaa Gin Ser Ser Ser Leu INFORMATION FOR SEQ ID NO: 177: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177: Xaa Tyr Gin Ser Pro 1 INFORMATION FOR SEQ ID NO:178: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 6 Libc/03531.doc OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178: Lys Tyr Gin Ser Lys Leu 1 INFORMATION FOR SEQ ID NO:179: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 S(D) OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: 15 NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "4-aminophenylalanine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFOREtTION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:180: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 Libc/03531.doc OTHER INFORMATION: /product= "7-HO-tetrahydroisoquinoline CO 2

H"

(ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180: Xaa Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOP SEQ ID NO:181: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= "ornithine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181: Xaa Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:182: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182: Lys Ala Ala Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:183: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single Libc/03531 .doc TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 7 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183: Lys Tyr Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:184: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 15 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184: Leu Asn Lys Ala Ser Tyr Gin Ser Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO:185: SEQUENCE rHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid 20 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 OTHER INFORMATION: /product= "homoarginine" (ix) FEATURE: NAME/KEY: Peptide LOCATION: 2 OTHER INFORMATION: /product= "cyclohexylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185: Xaa Xaa Gin Ser Ser 1 INFORMATION FOR SEQ ID NO: 186: SEQUENCE CHARACTERISTICS: LENGTH: 4 amino acids TYPE: amino acid Libc/03531.doc STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186: Tyr Gin Ser Ser 1 INFORMATION FOR SEQ ID NO: 187: SEQUENCE CHARACTERISTICS: LENGTH: 4 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: 1 S 15 OTHER INFORMATION: /product= "homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187: Xaa Tyr Gin Ser 1 INFORMATION FOR SEQ ID NO: 188: SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids 20 TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear fo (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide LOCATION: I OTHER INFORMATION: /product= homoarginine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188: Xaa Tyr Gin Ser Ser Ser 1 INFORMATION FOR SEQ ID NO:189: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid.

STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide Libc/03531.doc (ix) FEATURE: NAME/KEY: Peptide LOCATION: OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189: Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO:190: 0 SEQUENCE CHARACTERISTICS: LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide is LOCATION: 1 OTHER INFORMATION: /product= "7-HO-tetrahydro-3-isoquinoline CO 2

H"

(ix) FEATURE: NAME/KEY: Peptide LOCATION: 6 OTHER INFORMATION: /product= "norleucine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190: Xaa Gin Ser Ser Ser Leu 1 INFORMATION FOR SEQ ID NO: 191: t: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191: Ala Asn Lys Ala Ser Tyr Ala Ser Ser Ser Leu 1 5 INFORMATION FOR SEQ ID NO: 192: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear Libc/03531 .doc (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192: Ser Tyr Gin Ser Ser Lys Leu 1 INFORMATION FOR SEQ ID NO :193: SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193: Ala Asn Lys Ala Ser Tyr Gin Ser Leu 1 INFORMATION FOR SEQ ID NO:194: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid 15 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Peptide 20 LOCATION: I OTHER INFORMATION: /product= "ornithine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194: Xaa Tyr Gin Ser Ser Ser Leu 1 Libc/03531.doc

Claims (5)

1. An oligopeptide, not including Semenogelin I and II, Fibronectin or IGFBP-3, that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen or a pharmaceutically acceptable salt thereof.

2. The oligopeptide or pharmaceutically acceptable salt according to claim 1 wherein the sequence of amino acids is a) AsnLyslleSerlyrGlnlSer (SEQ ID.NO.: 13), b) LyslleSerTyrGlnlSer (SEQ.ID.NO.: 14), c) GlyGluAsnGlyValGlnLysAspValSerGnXaaSerlleTyrlSerGlnThrGlu (SEQ.ID.NO.: d) GlyLysGlylleSerSerGlnTyrlSerAsnlhrGluGluArgLeu (SEQ.ID.NO.: 2), e) AsnLyslleSerTyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerlyrGlnlSer (SEQ.ID.NO.: 128), g) SerlyrGlnlSerSer (SEQ.ID.NO.: 129); h) LysTyrGlnlSerSer (SEQ ID.NO.: 140); I) hArgTyrGlnlSerSer (SEQ.ID.NO.: 141); wherein hArg is homoarginine and Xaa is any natural amino acid.

3. The oligopeptide or pharmaceutically acceptable salt according to claim 2 wherein the sequence of amino acids is a) AsnLysleSerTyrGlnlSerSer (SEQ.IDNO.: 16), b) AsnLyslleSerlyrGlnlSerAla (SEQ.ID.NO.: 130), c) AsnLyslleSerlyrGlnlSerSerSer (SEQ.ID.NO.: 17), d) AaAsnLys!eSerTyrGlnlSerSerSer (SEQ.ID.NO.: 18), e) LyslleSerTyrGlnlSerSerSerlhrGlu (SEQ.ID.NO.: 19), f) GlyGluAsnGlyVaIGlnLysAspValSerGlnArgSerl eTyrSerGInIThrGlu (SEQ.ID.NO.: 4), g) GlyGluAsnGlyValGlnLysAspVaISerGInSerSerl eTyrlSerGInIThrGlu (SEQ.ID.NO.: h) AlaAsnLyslleSerTyrTyrlSer (SEQ.ID.NO.: 131), i) AlaAsnLysAlaSerTyrGlnlSer (SEQ.ID.NO.: 132), j) SerTyrGlnlSerSerThr (SEQ ID.NO.: 133), k) SerTyrGlnlSerSerSer (SEQ.IDNO.: 134), 3 o I) LyslyrGlnlSerSerSer (SEQ.ID.NO.: 142), m) hArgTyrGlnlSerSerSer (SEQ.ID.NO.: 143), or n) SerlyrGlnlSerSerLeu (SEQ ID.NO.: 135).

4. The oligopeptide or pharmaceutically acceptable salt according to claim 2 wherein the sequence of amino acids is a) AsnLyslleSerTyrGlnlSerSerSerThr (SEQ ID.NO.: [R:\LIBAA]00001 .doc:NJC I 09a b) AIaAsnLysIIeSerTyrGInISerAIa (SEQ. IDNO.: 136), c) AsnLyslleSerTyrGinlSerSerSerThrGlu (SEQIDNO.: 3), d) AlaAsnLyslleSerTyrGlnlSerSerSerThrGlu (SEQ IDNO.: 11), e) GIyGiuAsnGIyVaIGinLysAspVaISerGInArgSerlIeTyrIserGInIIhrGIu (SEQIDNo.: 4), f) AlaAsnLyslleSerlyrTyrlSerSer (SEQIDNO.: 137), V a a a S

55.5 S. S S S S 5555 S S ft 5 9 S SSSS S S 5545 555555 S S. S S S S 5 5. S S *5 S [R:\LIBAA]OO1 I.doc:NJC g) AlaAsn LyslIleSerTyrTyriSerAla (SEQ.ID.NO.: 138), h) AlaAsnLysAlaSerTyrGlnlSerAla (SEQ.ID.NO.: 139), or i) AlaSerTyrGlnlSerSerLeu (SEQ.iD.NO.: 94). The oligopeptide or pharmaceutically acceptable salt according to claim 2 wherein the amino acid sequence is a) GlyArg LysAlaAsn Lysl I eSerTyrGlnlISerSerSerlh rG uGuArgArg Leu HisTyrG lyGluAsnGly (SEQ.ID.NO.: 6). 6. The oligopeptide or pharmaceutically acceptable salt according to claim 1 which is selected from: AsnArglleSerTyrGinlSer (SEQ.ID.NO.: 21), AsnLysValSerTyrGlnlSer (SEQ. ID.NO.: 22), AsnLysMetSerTyrGlnlSerSer (SEQ. ID.NO.: 23), AsnLysLeuSerTyrGlnlSerSer (SEQ.ID.NO.: 24), AsnLyslleThrTyrGlnlSerSerSer (SEQ.iD.NO.: AsnLyslleSerPheGlnlSerSerSer (SEQ.ID.NO.: 26), Asn Lys lleSerTrpGlnlSerSerSerThr (SEQ. ID.NO.: 27), AsnLyslI eSerTyrAsn iSerSerSerThr (SEQ. ID. NO. :28), Asn LyslIleSerTyrGlnlIThrSerSerThr (SEQ. ID.NO. :29), Asn LyslIleSerTyrGlnlSer (SEQ.ID.NO.: 20 Gin Lysl leSerTyrGlnlSerSer (SEQ.ID.NO.: 31), A s*g l r y r l l e r e SQ**N .3 AsnArg lle~hr~yrGlnlSerSerSer~ (SEQ. ID.NO.:3), AsnArg IleSerrpGlnlSerSerSerThr (SEQ. IDNO. :33), AsnArglleSerTyrGlnl~rSerSerlhr (SEQ.ID.NO.: 36), Asn~rg Ile~erTyrGlnlThrSerSerlhr (SEQ.ID.NO.: 36), (SEQIDNO.: 3), AsnLysLeuSerTyrGlnl~rSerSerlhr (SEQ.ID.NO.: 38), Gln~rsLeuSerTyrGlnl~erSerSerThr (SEQ. ID.NO.: 39), Asn~yrgLuSer~hrGlnl~hrSerSerThr (SEQ.ID.NO.: Asn~rysVal SerrPhGlnlSerSerSerTh r (SEQ.ID.NO.: 41), A srValSerTyrGlnlSerSerSerlhr (SEQ. ID.NO.: 42), GlnLyslSerTyrGlnl~rSerSerThr (SEQ.ID.NO.: 4),o GlnLyslleSerTyrGlnl~hrSerSerThr (SEQ.ID.NO.: 44),o 7. The oligopeptide or pharmaceutically acceptable salt according to claim 1 which is AlaAsn LyslIleSerTyrGlnlSerSerSerTh rGlu-amide (SEQ.ID.NO.: 11) Ac-AlaAsn LyslIleSerTyrGlnlSerSerSerThrLeu (SEQ.ID.NO.: Ac-AlaAsn LyslIleSerTyrGln lSerSerSerThrGlu-amide (SEQ. ID.NO.: 11) Ac-AlaAsn Lys I IeSerTyrGlnlSerSerSerThrLeu-amide (SEQ. ID.NO Ac-AlaAsn LyslIleSerTyrGlnlSerAl aSerTh rGlu-amide (SEQ.ID.NO.: 73) Libc/0353l .doc ill Ac-AlaAsnLyslleSerTyrGlnlSerSerLysThrGlu-amide (SEQ.ID.NO.: 74) Ac-AlaAsn LyslIleSerTyrGl nlSerSerTh rGlu-amnide (SEQ. ID.NO.: Ac-AlaAsnLysleSerTyrGlnlSerSerGlnlhrGlu-amide (SEQ. ID.NO.: 78) Ac-AlaAsnLyslleSerTyrGlnlSerAlaLysThrGlu-amide (SEQ.ID.NO.: 79) Ac-Al aAsn LyslIleSerTyrGlnlISerTh rG lu-amnide (SEQ. ID.NO.: 81) Ac-AlaAsnLysSerTyrGlnlSerSerThrGlu-amide (SEQ.ID.NO.: 82) Ac-AlaAsnLysAlaSerTyrGlnlSerAlaSerThrGlu-amide (SEQ. ID.NO.: 84) Ac-AlaAsnGluIleSerTyrGlnlSerAaSer~hrGlu-amide (SEQ.ID.NO.: Ac-AsnLyslleSerTyrGlnlSerSer-amide (SEQ. ID.NO.: 16) Ac-LysleSerTyrGlniSerSer-amnide (SEQ. ID.NO.: 86) Ac-SerlyrGlnlSerSerThrGlu-amide (SEQ.ID.NO.: 87) Ac-AlaSerTyrGlnISerSerThrGlu-amide (SEQ.ID.NO.: 89) Ac-AlaAsn LyslIleSerTyrTyrlSerSerSerTh rGl u-amide (SEQ. ID.NO.: 92) Ac-AlI aAsn LyslIleSerlyrTyrl SerAl aSerlh rGlIu-amide (SEQ. ID.NO.: 93) i Ac-AlaSerTyrGlnlSerSerLeu-amide (SEQ.ID.NO.: 94) Ac-AlaAsnSerlyrGlnlSerSerSerlhrGlu-amide (SEQ. ID.NO.: Ac-AlaSerTyrGlnlSerSerSerlhrGlu-amide (SEQ.ID.NO.: 96) Ac-SerTyrGlnlSerSerSerlhrGlu-amide (SEQ.ID.NO.: 97) Ac-AlaAsnLysAlaSerlyrGlnlSerAlaSerCys-amide (SEQ.ID.NO.: 98). 20 8. An oligopeptide that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, wherein the sequence of amino acids is: hArgehaGiniSerSer (SEQ.ID.NO.: 185); and b) TyrGinISerSer (SEQ.ID.NO.: 186); wherein hArg is homoarginine and Cha is cyclohexylalanine, or the pharmaceutically acceptable salt thereof. 9. An oligopeptide that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, wherein the sequence of amino acids is: Ac-hArg(Cha)GInlSerNle-Acid (SEQ.ID.NO.; 147) Ac-hArghTyrGlnlSerSerNle-Acid (SEQ. ID.NO.: 148) Ac-hArgh(Cha)GInISerSerNle-Acid (SEQ.ID.NO.: 149) Ac-AlaAspLysAlaSerlyrGlnlSerSer-Cha-NHNH2 (SEQ.ID.NO.: 150) Ac-hArgTyrGlnlSerSerPro-Acid (S'EQ. ID.N 151) Ac-hArgTyrGlnlSerSerHis-Acid (SEQ.ID.NO.: 152) Ac-hArglyrGlnlSerAsn-Acid (SEQ.ID.NO.: 153) Ac-hArgTyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 154) Ac-(Amnf)TyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 155) H 2 NCO-hArgTyrGlnlSerSerSerLeu-Acid (SEQ.ID.NO.: 156) Ac-AlaAspLysAlaLysTyrGlnlSerSer(Cha)-NHNH2 (SEQ.ID.NO.: 157) LibcI353l .doc Ac-(DPL)TyrGlnlSerSerSerNle-Acid (SEQ.ID.NO.: 158) Ac-(imidazolyl)LysTyrGinlSerSerLeu-Acid (SEQ. ID.NO.: 159) Ac-AlaAspLysAla(hArg)TyrGlnlSerSerLeu-Acid (SEQ. ID. NO.: 160) Ac-(p-NH2-Cha)TyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 161) Ac(imidazolyl)LysTyrGlnlSerSerSerNle-Acid (SEQ. ID.NO.: 162) Ac-hArg(Cha)GlnlSerSerSerNle-Acid (SEQ. ID.NO.: 163) Ac-hArgTyrGlnlSerSerSerhArg-Acid (SEQ. ID.NO.: 164) Ac-hArgTyrGlnlSerSerSer(MeLeu) (SEQ.ID.NO.: 188) Ao-hArgTyrGln ISerSerSer(Ethylester-Leu) (SEQ. ID. NO.: 156) Ac-Al aAspLysAla(i mid azoleLys)TyrGIn lSerSerN le-Acid (SEQJD.NO.: 165) Ac-hArg(3-Iodo-Tyr)GlnISerSerSerNle-Acid (SEQ. ID.NO.: 166) Ac-hArg (Me2PO3-Tyr)GInISerSerSerNle-Acid (SEQ. ID. NO.: 167) Ac-hArglyrGlnlSerSerAsp-Acid (SEQ. ID.NO.: 168) Ac-hArg(O-Me-Tyr)GIniSerSerSerNe-Acid (SEQ.ID.NO.: 169) Ac-AlaAspLysAlaLysTyrGlnlSerSerNle-Acid (SEQ.ID.NO.: 170) Ac-hArg(Cha)GlnlSerSerSer(ethylester-Leu) (SEQ. ID.NO.: 171) Ac-(imidazolyl)Lys(Cha)GInISerSerSerNle-Acid (SEQ. ID.NO.: 172) Achr(h)Gn9re99-cd(E.I.O:13 Ac-hArg(Cha)GlnlSerSerle-Acid (SEQ. ID.NO.: 173) Ac-hArg(Cha)GInISereroNle-Acid (SEQ.ID.NO.: 174) o Ac-hArg(m-fluoro-Tyr)GInlSerSerSerNle-Acid (SEQ. ID.NO.: 176), or the pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt of a conjugate which is useful for the treatment of prostate cancer which comprises a cytotoxic agent attached to an oligopeptide, wherein the oligopeptide comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, wherein the means of attachment is a covalent bond or a chemical linker. 11. The pharmaceutically acceptable salt according to claim 10 wherein the cytotoxic agent is a member of a class of cytotoxic agents selected from the following classes: a) anthracycline family of drugs, b) the ymnca alkaloid drugs, c) the mitomycins, d) the bleomycins, e) the cytotoxic nucleosides, fD the pteridine family of drugs, g) diynenes, h) estramustine, i) cyclophosphamide, j) the podophyllotoxins, and k) the taxanes. 12. The pharmaceutically acceptable salt according to claim 10 wherein the cytotoxic agent is selected from the following cytotoxic agents: a) doxorubicin, b) carminomycin, c) daunorubicin, d) aminopterin, e) methotrexate, f) methopterin, g) dichloro-methotrexate, h) mitomycin C, i) porfiromycin, j) 5-fluorouracil, k) 6- mercaptopurine, 1) cytosine arabinoside, m) podophyllotoxin, LibcI353l .doc n) etoposide, o) etoposide phosphate, p) melphalan, q) vinblastine, r) vincristine, s) leurosidine, t) vindesine, u) estramustine, v) cisplatin, w) cyclophosphamide, x) leurosine, and y) taxol. 13. The pharmaceutically acceptable salt according to claim 10 wherein the cytotoxic agent is selected from doxorubicin and vinblastine or a cytotoxic derivative thereof. 14. The pharmaceutically acceptable salt according to claim 10 wherein the cytotoxic agent is doxorubicin or a cytotoxic derivative thereof. The pharmaceutically acceptable salt according to claim 14 of the formula I: 0 OH 0 OH OO "OH H 3 CO 0 OH 0 0 3 H H OH XL-Oligopepide-R .wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen; XL is absent or is an S 15 amino acid selected from: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl)alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline, i) norleucine, and j) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; R is hydrogen or and R 1 is C 1 -C 6 -alkyl or aryl. 16. The pharmaceutically acceptable salt according to claim 15 wherein: 20 oligopeptide is an oligomer that comprises an amino acid sequence selected from: a) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: 13), b) LyslieSerTyrGinlSer (SEQ.ID.NO.: 14), c) GlyGluAsnGlyValGlnLysAspValSerGInXaaSerleTyrISerGInThrGlu (SEQ.ID.NO.: d) GlyLysGlylleSerSerGlnTyrlSerAsnThrGluGluArgLeu (SEQ.ID.NO.: 2), e) AsnLyslleSerTyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerTyrGlnlSer (SEQ.ID.NO.: 128), g) SerTyrGinlSerSer (SEQ.ID.NO.: 129), h) LysTyrGInlSerSer (SEQ.ID.NO.: 140); and i) hArgTyrGlnlSerSer (SEQ.ID.NO.: 141); wherein hArg is homoarginine and Xaa is any natural amino acid; XL is absent or is an amino acid selected from: a) leucine, b) isoleucine, c) norleucine and d) valine; and R is acetyl, pivaloyl or benzoyl, or the pharmaceutically acceptable salt thereof. 17. The pharmaceutically acceptable salt according to claim 14 which is selected from: Libd/03531.doc 114 O OH 0 OH o Q "'OH H,"0 0 OH 0 OH X wherein X is: AsnLysileSerTyrGlnSer- (SEQ.ID.NO.: 13), AsnLyslieSerTyrGlnSerSer- (SEQ.ID.NO.: 16), AsnLysileSerTyrGlnSerSerSer- (SEQ.ID.NO. :17), AsnLysileSerTyrGlnSerSerSerThr- (SEQ. ID.NO.: AsnLysileSerTyrGlnSerSerSerlhrGlu- (SEQ. ID.NO.: 3), AlaAsnLysieSerlyrGlnSerSerSerThrGlu- (SEQ.ID.NO.: 11), N-terminus Ac AlaAsnLysileSerTyrGlnSerSerSerThr- (SEQ.ID.NO.: 117), Ac AlaAsnLysileSerTyrGlnSerSerSerlhrLeu (SEQ.ID.NO.: Ac AlaAsnLysAlaSerTyrGlnSerAlaSerThrLeu (SEQ. ID.NO.: 118), Ac AlaAsnLysAlaSerTyrGlnSerAlaSerLeu- (SEQ.lD.NO.: 119), 15 Ac AlaAsnLysAlaSerTyrGlnSerSerSerLeu- (SEQ. lD.NO.: 120), Ac AlaAsnLysAlaSerTyrGlnSerSerLeu- (SEQ.ID.NO.: 121). Ac SerTyrGlnSerSerSerLeu- (SEQ.ID.NO.: 144), hArgTyrGlnSerSerSerLeu- (SEQ.lD.NO.: 145). Ac-LysTyrGlnSerSerSerLeu- (SEQ.ID.NO.: 124), or (Compound 4) 20 Ac-LysTyrGinSerSerNie- (SEQ.lD.NO.: 146). N-terminus or the pharmaceutically acceptable salt thereof. 18. A conjugate which is useful for the treatment of prostate cancer of the formula 1: 0 OH 0 OH OH 0 0 HC N OH XL-Oligopepfide-R wherein: oligopeptide is an oligomer that comprises an amino acid sequence selected from: a) hArgChaGlnlSerSer (SEQ.ID.NO.: 185); and LibcI353l .doc b) TyrGInISerSer (SEQ.ID.NO.: 186); wherein hArg is homoarginine and Cha is cyclohexylalanine; XL is absent or is an amino acid selected from: a) leucine, b) isoleucine, c) norleucine and d) valine; and R is acetyl, pivaloyl or benzoyl, or the pharmaceutically acceptable salt thereof. 19. A conjugate which is useful for the treatment of prostate cancer which is selected from: Ac-hArgTyrGln-SerSerPro-dox(3') (SEQ. ID. NO.: 151) Ac-hArgTyrGln-SerPro-dox(3') (SEQ. ID. NO.: 177) Ac-hArglyrGln-SerSerSerNle-dox(3') (SEQ. ID. NO.: 154) Ac-ArnffyrGln-SerSerSerNle-dox(3') (SEQ.ID.NO.: 155) H2NCO-hArgTyrGln-SerSerSerLeu-dox(3') (SEQ.ID.NO.: 156) Ac-LysTyrGln-SerSerfte-dox(3') (SEQ.ID.NO.: 146) Ac-LysTyrGln-SerLysNle-dox(3') (SEQ. D. NO.: 178) 15Ac(cis-p-NH 2 Cha)TyrGlnSerSerNledox(3') (SEQ. ID.NO.: 161) Ac-AlaAspLysAla(hArg)TyrGIn-SerSerLeu-dox(3') (SEQ.ID.NO.: 160) Ac-hArglyrGln-SerAsn-dox(3') (SEQ.ID.NO.: 153) Ac-hArgTyrGln-SerSerHis-dox(3') (SEQ.ID.NO.: 152) Ac-(i mid azolyl) LysTyrGln-SerSerLeu-dox(3') (SEQ.ID.NO.: 159) Ac-(imidazolyl)LysTyrGlnSerSerSerNle-dox(3') (SEQ. ID. NO.: 162) 2o. Ac-hArg(Cha)Gln-SerSerSerNle-dox(3') (SEQ.ID.NO.: 163) Ac-hArg(Me 2 PO 3 Tyr)Gn-SerSerSerNle-dox(3') (SEQ.ID.NO.: 167) Ac-hArgTyrGln-SerSerSerhArg-dox(3') (SEQ.ID.NO.: 164) Ac-hArg(3-Iodo-Tyr)Gln-SerSerSerN Ie-dox(3') (SEQ. ID. NO.: 166) c-hArg(O-Me-Tyr)Gln-SerSerSerNle-dox(3') (SEQ.ID.NO.: 169) Ac-hArg(p-NH 2 -Phe)Gln-SerSerSerNle-dox(3') (SEQ.ID.NO.: 179) ~*Ao-hArg(Cha)Gln-SerSerNle-dox(3') (SEQ.ID.NO.: 174) Ac-hArg(Cha)Gln-SerProNle-dox(3') (SEQ.ID.NO.: 175) Ac(imidazolyl)Lys(Cha)GlnSerSerSerNle-dox(3') (SEQ.ID.NO.: 172) Ac-hArg(7-HO-IIC)Gln-SerSerSerNle-dox(3') (SEQ. ID.NO.: 180) Ac-hArg(3-Fluoro)TyrGlnSerSerSerNle-dox(3') (SEQ. ID.NO.: 176) Ac-(ornithine)TyrGIn-SerSerSerNle-dox(3') (SEQ. ID.NO.: 181) Ac-LysAlaAlaSerSerSerLeu-dox(3') (SEQ. D. NO.: 183) Ac-hArgh(Cha)Gln-SerSerNle-dox(3') (SEQ. ID.NO.: 149) Ac-AlaArgLysAlaSerlyrGln-SerLeu-dox(3') (SEQ. ID. NO.: 193) and Ac-(Orn)IyrGIn-SerSerSerLeu-dox(3') (SEQ. ID. NO.: 194) or the pharmaceutically acceptable salt thereof. A conjugate which is useful for the treatment of prostate cancer of the formula 11: Libc/O353l .doc H 3 C HO "CH 3 CH 3 N 0CH3 N 0 Q N-H c n""oligopeptide-NH2 CH 3 t C-terminus wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen; XL is absent or is an amino acid selected from: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl)alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline, i) norleucine, and j) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; or XL is NH(CH 2 )nNH; R is hydrogen or R 1 is C 1 -C 6 -alkyl or aryl; R 19 is hydrogen or acetyl; and n is 1, 2, 3, 4 or 5, or the pharmaceutically acceptable salt thereof. 10 21. The pharmaceutically acceptable salt of a conjugate according to claim 20 of the formula II: H 3 C HO I CH 3 CH 3 NN OO N-HH CH3 c'I' oligopeptide-NH 2 cH 3 C-terminus wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen, or the pharmaceutically acceptable salt thereof. 22. The conjugate according to claim 20 which is selected from: H 3 C HO N HO N CH3 I CH 3 N O N 0 OH N-H O OH (SEQ.ID.NO.: 183) H 3 NH-NleSerSerSerGInTyrLys-Ac H 3 3 I H N-terminus Compound 14 or Libc/03531.doc (SEQ.ID.NO.: 184) Compound or the pharmaceutically acceptable salt thereof. 23. A conjugate which is useful for the treatment of prostate cancer which comprises two cytotoxic agents attached to a oligopeptide, wherein the oligopeptide comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, wherein the means of S.attachment is a covalent bond or a chemical linker, or the pharmaceutically acceptable salt thereof. 24. The conjugate according to claim 23 which is Q H 3 C HO -CH CH3 N O H3 o 0 *OH *N-H o OH C-terminus S N-H (SEQ.ID.NO.: 184) CCH 3 3 LeuAsnLysAlaSerTyrGInSerSerLeu CH3 OH H 3 C NH 0 HCO O OH O Q Q,,OH OH 0 OH 0 (Compound or the pharmaceutically acceptable salt thereof. An oligopeptide not including semenogelin I and II, fibronectin in or IGF2P-3, that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen. 26. The oligopeptide according to claim 25 wherein the sequence of amino acids is a) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: 13), b) LyslleSerTyrGInlSer (SEQ.ID.NO.: 14), Libc/03531 .doc c) GlyGiuAsnGlyVaIGlnLysAspVaISerGlnXaaSerlleTyrlSerGinThrGlu(SEQ.ID.NO.: d) GlyLysGlyiieSerSerGlnTyrlSerAsnThrGiuGiuArgLeu(SEQ. ID.NO.: 2), e) Asn LyslI eSerTyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerTyrGlnISer (SEQ.ID.NO.: 128), g) SerlyrGiniSerSer (SEQ.ID.NO.: 129); h) LysTyrGiniSerSer (SEQ.ID.NO.: 140); or i) hArgTyrGlnlSerSer (SEQ. ID. NO.: 141); wherein hArg is homoarginine and Xaa is any natural amino acid. 27. The oligopeptide according to claim 26 wherein the sequence of amino acids is a) AsnLyslleSerTyrGlnISerSer (SEQ. ID.NO.: 16), b) AsnLyslleSerTyrGlnlSerAla (SEQ. ID.NO.: 130), c) AsnLyslleSerTyrGlnlSerSerSer (SEQ. ID.NO.: 17), 15 d) AlaAsnLyslleSerTyrGlnlSerSerSer (SEQ.ID.NO.: 18), e) LyslleSerlyrGlnlSerSerSerThrGlu (SEQ.ID.NO.: 19), G) IyG IuAsn GlyVaIG In LysAspVaISerG InArg Seri IeTyrISerGInTh rG Iu (SEQ. ID.NO.: 4), g) GlyGluAsnGlyVaIGInLysAspVaISerGInSerSerIeTyrISerGInThrGlu (SEQ. ID.NO.: h) AlaAsn Lysll eSerTyrTyrlSer (SEQ.ID.NO.: 131), i) AlaAsnLysAlaSerTyrGlnlSer (SEQ. ID.NO.: 132), j) SerlyrGlnlSerSerThr (SEQ.ID.NO.: 133), k) SerTyrGiniSerSerSer (SEQ.ID.NO.: 134), 1) LysTyrGInISerSerSer (SEQ. ID.NO.: 142), hArgTyrGlnlSerSerSer (SEQ.ID.NO.: 143), or n) SerTyrGlnlSerSerLeu (SEQ.ID.NO.: 135). 28. The pharmaceutically acceptable salt according to claim 26 wherein the .:*amino acid sequence is a) AsnLyslleSerTyrGlnlSerSer (SEQ.ID.NO.: 16), b) AsnLyslleSerlyrGlnlSerAla (SEQ. ID.NO.: 130), c) AsnLyslleSerTyrGlnISerSerSer (SEQ.ID.NO.: 17), d) AlaAsn LyslIleSerTyrGlInISerSerSer (SEQ.ID.NO.: 18), e) LyslleSerlyrGlnlSerSerSerThrGiu (SEQ.ID.NO.: 19), f) GlyGluAsnGlyVaIGInLysAspVaISerGInArgSerlIeTyriSerGInThrGlu (SEQ. ID.NO.: 4), g) GlyGluAsnGlyVaIGInLysAspVaISerGInSerSerIeTyrISerGInThrGlu (SEQ. ID.NO.: h) AlaAsn LyslIleSerTyrTyrlSer (SEQ. ID.NO.: 131), i) AlaAsnLysAlaSerTyrGlnlSer (SEQ.ID.NO.: 132), j) SerTyrGlnlSerSerThr (SEQ.ID.NO.: 133), k) SerlyrGInlSerSerSer (SEQ.ID.NO.: 134), I) LysTyrGlniSerSerSer (SEQ. ID.NO.: 142), mn) hArgTyrGlnlSerSerSer (SEQ.ID.NO.: 143), or n) SerTyrGlnlSerSerLeu (SEQ.ID.NO.: 135). Libc103531 .doc 29. The oligopeptide according to claim 26 wherein the amino acid sequence is a) AsnLyslleSerlyrGinlSerSerSerThr (SEQ. ID.NO.: b) AlaAsn Lys I eSerTyrGlnlSerAla (SEQ.ID.NO.: 136), c) AsnLyslleSerTyrGlnlSerSerSermrGlu (SEQ.iD.NO.:3), d) Al aAsn LyslIleSerTyrGlniSerSerSerTh rGlu (SEQ. ID.NO.: 11), e) GlyGluAsnGlyVaIGlnLysAspVaiSerGInArgSerlIeTyrISerGInmhrG~u (SEQ. ID.NO: 4), 0 AlaAsn Lys IleSerTyrTyrISerSer (SEQ. ID.NO.: 137), g) Al aAsn LyslIleSerTyrTyrlSerAla (SEQ. ID.NO.: 138), h) AlaAsnLysAlaSer~yrGlniSerAla (SEQ.ID.NO.: 139), or i) AlaSerTyrGlSerSerLeu (SEQ. ID.NO.: 94). The oligopeptide according to claim 26 wherein the amino acid sequence is a) GlyArgLysAlaAsnLyslleSerTyrGlnSerSersermrGluGluArgArgLeuHisTyrGlyGluAsnGly (SEQ. ID. NO.: 6). 31. The oligopeptide according to claim 25 which is selected from: AsnArgileSerTyrGiniSer (SEQ.ID.NO.: 21), AsnLysValSerTyrGlnlSer (SEQ.ID.NO.: 22), Asn Lys MetSerTyrGlnjISerSer(S EQ. ID. NO.: 23), AsnLysLeuSerTyrGlnlSerSer (SEQ.ID.NO.: 24), Asn LyslIleTh rTyrGlnlISerSerSer(S EQ. ID. NO.: Asn LyslIleSerPheGlnlSerSerSer (SEQ.ID.NO.: 26), Asn LyslIleSerTrpGlnlSerSerSerThr (SEQ. ID.NO.: 21), Asn LyslIleSerTyrAsnlSerSerSerThr (SEQ.ID.NO.: 28), *Asn LyslIleSerTyrGlnlmrSerSerThr (SEQ. ID.NO.: 29), Asn LyslIleSerTyrGlnlSer (SEQ. ID.NO.: Gln LyslIleSerTyrGlnlSerSer (SEQ.ID.NO.: 31), AsnArg IleThrTyrGlnlSerSerSer (SEQ. ID.NO.: 32), AsnArg IleSerPheGlnlSerSerSerThr (SEQ.ID.NO.: 33), AsnArg IleSerTrpGlnlSerSerSerThr (SEQ.ID.NO.: AsnArg lleSerTyrGlnlmhrSerSermhr (SEQ.ID.NO.: 36), AsnLysleThrTyrGlnlrhrSerSerThr (SEQ. ID.NO.: 37), AsnLysLeuSerTyrGlnlThrSerSerThr (SEQ. ID.NO.: 38), GlnLysLeuSerTyrGlnlSerSerSerThr (SEQ. ID.NO.: 39), AsnArgLeuSerTyrGlnllhrSerSerThr (SEQ. ID.NO.: AsnLysValSerPheGlniSerSerSerThr (SEQ.ID.NO.: 41), AsnArgValSerlrpGlnlSerSerSerThr (SEQ.[ID.NO.: 42), Gin LysValSerTyrGlnlSerSerSerThr (SEQ. ID.NO.: 43), GlnLyslleSerTyrGlnlThrSerSerThr (SEQ. ID.NO.: 34), or Asn LyslIleSerTyrGlnlSerSerSerThr (SEQ.ID.NO.: 44). 32. The oligopeptide according to claim 25 which is Libc103531 .doc AlaAs nLyslIleSerTyrGlInlSerSerSerTh rGl u-amide (SEQ. ID.NO.: 11) Ac-AlaAsn LyslIleSerTyrGIn lSerSerSerThrLeu-(SEQ. I D. NO.: Ac-AlaAsn LyslIleSerTyrGl nlSerSerSerlhrGI u-amide-(S EQ. I D. NO.: 11) Ac-AlaAsn Lys I IeSerTyrGlnlSerSerSerTh rLeu-amide-(S EQ. I D. NO.: Ac-Al aAsn Lys IleSerTyrGlnlSerAlaSerTh rGI u-amnide-(S EQ.ID. NO.: 73) Ac-AlaAsn LyslI eSerTyrGInISerSerLysTh rGlu-amide-(S EQ. I D. NO.: 74) Ac-AlaAsn LyslIleSerTyrGlnlISerSerTh rGlu-amide-(S EQ. I D. NO.: Ac-AlaAsn LyslIleSerTyrGlnlISerSerG InTh rGlu-amnide-(S EQ. I D. NO.: 78) Ac-AlaAsn LyslIleSerTyrGlnlISerAlaLysTh rGlu-amnide-(S EQ. I D. NO.: 79) Ac-AlaAsn LyslIleSerTyrGlnlISerTh rGlu-amide-(S EQ. I D. NO.: 81) Ac-AlaAsnLysSerlyrGlnlSerSerlhrGlu-amide-(SEQ. ID.NO.: 82) Ao-AlaAsnLysAlaSerTyrGlnlSerAlaSerThrGlu-amide (SEQ.ID.NO.: 84) Ac-AlaAsnGluIleSerTyrGInISerAlaSerThrGlu-amide (SEQ. ID.NO.: Ac-Asn LyslIleSerTyrGlnlISerSer-amide (SEQ.ID.NO.: I16) 15 Ac-LyslleSerTyrGlnlSerSer-amnide (SEQ.ID.NO.: 86) Ac-SerTyrGlnlSerSerlhrGlu-amide (SEQ.ID.NO.: 87) Ac-AlaSerTyrGlnlSerSerThrGlu-amide (SEQ. ID.NO.: 89) Ac-Al aAsn LyslIleSerlyrTyrlSerSerSerTh rGlu-amide (SEQ.ID.NO 92) Ac-Al aAsn LyslIleSerTyrTyrlSerAlaSerTh rGlu-amide (SEQ.I D.NO.: 93) Ac-AlaSerTyrGlnlSerSerLeu-amide (SEQ.ID.NO.: 94) *-l~ne~r~ie~re~ri-md .9QI.N. Ac-Ala~SerTyrGnSerSerSerThrGlu-amide (SEQ.ID.NO.: 9) Ac-ASerTyrGnl~eSerSer~ehrGu-amide (SEQ. ID.NO.: 9) Ac-AlaAsnLysAlaSerlyrGlnlSerAlaSerCys-amide (SEQ.ID.NO.: 98). 33. An assay for determining proteolytic activity of free prostate specific antigen in a sample, comprising the steps of: reacting a substrate, wherein the substrate is an oligopeptide that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, with the sample; and detecting whether the substrate has been cleaved. 34. The assay according to claim 33 wherein the step of detecting whether the substrate has been cleaved comprises analysing the assay mixture by high performance liquid chromatography. An assay for identifying compounds which inhibit the proteolytic activity of prostate specific antigen, comprising: reacting a substrate, wherein the substrate comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, with free prostate specific antigen in the presence of a test substance; and detecting whether the substrate has been cleaved, in which the ability of the test substance to inhibit proteolytic activity of prostate specific antigen is indicated by a decrease in the cleavage of the LibcIO353I .doc substrate as compared to the cleavage of the substrate in the absence of the test- substance. 36. The assay according to claim 35 wherein the step of detecting whether the substrate has been cleaved comprises analysing the assay mixture by high performance liquid chromatography. 37. A conjugate which is useful for the treatment of prostate cancer which comprises a cytotoxic agent attached to a oligopeptide, wherein the oligopeptide comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, wherein the means of attachment is a covalent bond or a chemical linker. 38. The conjugate according to claim 37 wherein the cytotoxic agent is a member of a class of cytotoxic agents selected from the following classes: a) anthracycline family of drugs, b) the vinca alkaloid drugs, c) the mitomycins, d) the S. bleomycins, e) the cytotoxic nucleosides, f) the pteridine family of drugs, g) 15 diynenes, h) estramustine, i) cyclophosphamide, and h) the podophyllotoxins. 39. The conjugate according to claim 37 wherein the cytotoxic agent is selected from the following cytotoxic agents: a) doxorubicin, b) carminomycin, c) daunorubicin, d) aminopterin, e) methotrexate, f) methopterin, g) dichloromethotrexate, h) mitomycin C, i) porfiromycin, j) 5-fluorouracil, k) 6- 20 mercaptopurine, I) cytosine arabinoside, m) podophyllotoxin, n) etoposide, o) etoposide phosphate, p) melphalan, q) vinblastine, r) vincristine, s) leurosidine, t) vindesine, u) estramustine, v) cisplatin, w) cyclophosphamide, and x) leurosine. 40. The conjugate according to claim 37 wherein the cytotoxic agent is selected from doxorubicin and vinblastine or a cytotoxic derivative thereof. 41. The conjugate according to claim 37 wherein the cytotoxic agent is doxorubicin or a cytotoxic derivative thereof. 42. The conjugate according to claim 40 of the formula I: O OH O OH ,0 0 OH H 3 CO O OH H 3 C N H OH XL-oligopeptide-R wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen; XL is absent or is an amino acid selected from: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl)alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline, and j) norleucine; R is hydrogen or and R1 is C 1 -C 6 -alkyl or aryl. Libc/03531.doc 43. The conjugate according to claim 42 wherein: oligopeptide is an oligomer that comprises an amino acid sequence selected from: a) AsnLyslleSerTyrGlnlSer (SEQ.ID.NO.: 13), b) LysileSerTyrGiniSer (SEQ.ID.NO.: 14), c) G IyG IuAsn GIyVaI GinLysAspVaISerGInXaaSerl leTyrISerGlnTh rGI u(SEQ.ID. NO.: d) GlyLysGiylleSerSerGlnTyrlSerAsnlhrGluGluArgLeu(SEQ. ID.NO.: 2), e) Asn LyslIleSerlyrTyrlSer (SEQ.ID.NO.: 127), f) AsnLysAlaSerTyrGInlSer (SEQ. ID.NO.: 128), g) SerTyrGiniSerSer (SEQ.ID.NO.: 129), and h) hArgTyrGlnlSerSer (SEQ.ID.NO.: 141); wherein hArg is homoarginine and Xaa is any natural amino acid; XL is absent or is an amino acid selected from: a) leucine, b) isoleucine, and d) valine; and R is acetyl, pivaloyl or benzoyl. 44. The conjugate according to claim 41 which is selected from: 0 OH 0 0. 0 OH 0 15 OH X wherein X is: H2N-AsnLysileSerTyrGlnSer-C(O)- (SEQ. ID.NO.: 13), H2N-AsnLysileSerTyrG~nSerSer-C(O)- (SEQ. ID.NO.: 16), H2N-AsnLysileSerTyrGlnSerSerSer-C(O)- (SEQ. ID.NO.: 17), SQI.O 1) 0H 2 N-AsnLysileSerTyrGlnSerSerSerThr~-C(O)- (SEQ.ID.NO.: 1), H2N-AlAsnLysileSerTyrGnSerSerSerhrGlu-C(O)- (SEQ. ID.NO.: AHN-AlaAsnLysileSerTyrGnSerSerSerhrl-C(O)- (SEQ.ID.NO.: 117), AcHN-AlaAsnLysileSerTyrGlnSerSerSerThr~-C(O) (SEQ. ID.NO.: 17), N-AlaAsn LysleSeryrGnSererSerThrLeu-C(O)- (SEQ. ID. NO.: AcHN-AlaAsnLysAlaSerTyrGlnSerAlaSer~rLeu-C(O)- (SEQ.ID.NO.: 11), AcHN-AlaAsnLysAlaSerTyrGlnSer~laSerLeu-C(O)- (SEQ.ID.NO.: 119). AcHN-AlaAsnLysAlaSerlyrGIn~SerSerLeu-C(O)- (SEQ. ID.NO.: 12), AcHN-AaSerynysSerrlSerSerLeu-C(O)- (SEQ.ID.NO.: 1 21), 3o AcHN-SerlyrGnSerSerSerLeu-C(O)- (SEQ. ID.NO.: 14), N-hLrgyrGnSerSerSerLeu-C(O)- (SEQ. ID. NO.: 124), o AcHN-LysTyrGlnSerSer~le-C(O)- (SEQ.ID.NO.: 14)o The conjugate according to claim 40 of the formula 1I: Libc/O353l .doc 123 H 3 C HO CH 3 N 0C N CH 3 O O O N-H 0 OH CH 3 O N o CH 3 CH 3 oligopeptide- NH 2 wherein: oligopeptide is an oligopeptide which is specifically recognised by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen. 46. An oligopeptide, that comprises a sequence of amino acids that is recognised and selectively proteolytically cleaved by free prostate specific antigen, substantially as hereinbefore described with reference to any one of the examples. 47. An assay for determining proteolytic activity of free prostate specific antigen in a sample, substantially as hereinbefore described with reference to any one of the examples. 0 48. An assay for identifying compounds which inhibit the proteolytic activity of prostate specific antigen, substantially as hereinbefore described with reference to any one of the examples. 49. A conjugate which is useful for the treatment of prostate cancer which comprises a cytotoxic agent attached to a oligopeptide, substantially as hereinbefore described with reference to any one of the examples. 5 50. A pharmaceutical composition comprising an effective amount of at least one conjugate according to any one of claims 18 to 24, 35 to 44 or 49 together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor. 51. A method for the treatment or prophylaxis of prostate cancer in a mammal, which method comprises administering to said mammal an effective amount of at least one conjugate according to 2 any one of claims 18 to 24, 35 to 44 or 49 or of a composition according to claim :52. At least one conjugate according to any one of claims 18 to 24, 35 to 44 or 49 or a composition according to claim 50 when used for the treatment or prophylaxis of prostate cancer in a mammal. [R:\LIBAA]0001 .doc:NJC 124 53. Use of at least one conjugate according to any one of claims 18 to 24, 35 to 44 or 49 in the manufacture of a medicament for the treatment or prophylaxis of prostate cancer in a mammal, Dated 22 October, 1999 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON &FERGUSON boo.. a 0 0* 0 C 0,C [R:\LIBAA]OOOI .doc:NJC