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Composition Containing Protease Produced by Vibrio and Method of Use in Debridement and Wound Healing

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Composition Containing Protease Produced by Vibrio and Method of Use in Debridement and Wound Healing Europaisches Patentamt European Patent Office 0 Publication number: 0 472 011 A1 Office europeen des brevets EUROPEAN PATENT APPLICATION 0 Application number: 91112732.2 int. CI 5: A61K 37/48, C12N 9/52, C12N 15/31, //(C12N 15/31, 0 Date of filing: 29.07.91 C12R1:63) 0 Priority: 15.08.90 US 567884 0 Inventor: Fortney, Donald Zane 13.03.91 US 670612 2114 Reese Road Westminster, Md. 21157(US) 0 Date of publication of application: Inventor: Durham, Donald Richard 26.02.92 Bulletin 92/09 20617 Beaver Ridge Road Gaithersburg, Md. 20879(US) 0 Designated Contracting States: AT BE CH DE DK ES FR GB GR IT LI LU NL SE 0 Representative: UEXKULL & STOLBERG 0 Applicant: W.R. Grace & Co.-Conn. Patentanwalte Grace Plaza, 1114 Ave. of the Americas Beselerstrasse 4 New York New York 10036(US) W-2000 Hamburg 52(DE) 0 Composition containing protease produced by vibrio and method of use in debridement and wound healing. 0 A composition for treating wounds comprising at least one pharmaceutically acceptable carrier admixed with an effective amount of a protease selected from the group consisting of: (a) an extracellular neutral protease produced by cultivation of a microorganism belonging to the genus Vibrio, said protease characterized by the following properties: i. hydrolyzes components of necrotic tissue including denatured collagen, elastin and fribrin; ii. does not substantially hydrolyze native tissue in viva, and iii. exhibits stable activity when stored at 25° C in a topical formulation; (b) a protease expressed by recombinant host cells which have been transformed or transfected with an expression vector for said protease (a); and (c) mutants and hybrids of proteases (a) and (b) which are characterized by the properties (i) to (iii). Is 1! Is SI s3s 3s U M Ss tl M as sa u ss §i is sis a n u 3s sss u u S3 s3s s- U S3 ss Ssa 3s 3s Is Is Ul ss EI 53 ss ss = S3 ss Ss rs SsS 3s §S Ss m U sa n S3s ss si Sa Ul %% U U SS B£s gs U ss ss ass sS ss S* Ss sSS St §3 U in 3s Ss is U Els ss SS 3s M SSS Ss SI ss ss ass Is si 3s Is 5as §a Is §s Sa §fa S? U CM SSs Ss U- sa Ss S3s U U Ss SsS S3 63 S3 si U Ss 3ss Is §3 » sSS §1 U U S3 £&S Sf s3 Is kI Sts Is Ss §S Si Es§ 61 13 3s 3s 3s- SI as 8-5 S3 ess §s Is 33 U SaS Ss 3s ^ 31 gas S3 U i& 11 131 S3 3s U B3 Sss SI ss IS Is gss 3s ss U ss kss Ss U U U sis §s ss s- 13s si U U 33= Is U H 8S Se5 ss- sa ss 12 sss cl §3 §e cl Us §3 cl Ss 3 s Rank Xerox (UK) Business Services EP 0 472 011 A1 FIG. I CONT.' FIG. I CONT.' GAT AAA GTC GGC ACT AAG TGT TCA ATG AAC GCG GTA AGA ACG 7B0 Val Gly Thr Ser Het Asn AAC AGC Ala Val Thr Asp225 Lys 230Lys Cys 235Asn Ser Arg GTT GAC CTG AAC GGC TCA ACT TCA GGT AAC ACC ACT TAC AGC TAT ACC 828 GAC ATG GGT TAC AGC GTT GCA GAC GTA GAA GAT GCG TTT AAC ACG GTA 1548 Val Asp Leu Asn Gly Ser Thr Ser Gly Asn Thr Thr Ser Tyr Thr Asp Met Gly Tyr Ser Val Ala Asp Val Glu Asp Ala Phe Asn Thr Val 245 250 Tyr 255 485 490 495 TGT AAC GAC TCA ACC AAC TAC AAC GAT TAC AAA GCC ATT AAC GGC GCG 876 GGC GTT AAC GCG TCT TGT GGT GCA ACT CCT CCT CCG TCT GGC GAT GTA 1596 Cys Asn Asp Ser Thr Asn Tyr Asn Asp Tyr Lys Ala lie Asn Gly Ala Gly Val Asn Ala Ser Cys Gly Ala Thr Pro Pro Pro Ser Gly Val 260 265 270 500 505 510 Asp TAC TCG CCA CTG AAC GAT GCC CAC TAC TTC GGT AAA GTG GTT TTC GAT 924 CTG GAA ATC GGT AAA CCG CTG GCC- AAC CTT TCA GGT AAC CGC AAT GAC 164 4 Tyr Ser Pro Leu Asn Asp Ala His Tyr Phe Gly Lys Val Val Phe Asp Leu Glu He Gly Lys Pro Leu Ala Asn Leu Ser Gly Asn Asn 275 280 2£5 515 520 525 Arg Asp ATG TAC AAA GAC TGG ATG AAC ACC CCA CAO CTG ACT 972 Met Het Asn Thr ThrACA Pro CTG ACG TTCPhe Gin Leu Thr ATG ACT TAC TAC ACG TTC ACA CCA AGC AGC TCA TCT AGC 290Tyr Lys Asp Trp 295 Leu Thr Met Thr Tyr Thr Phe Thr Pro GTA GTG ATT 1692 300 530 Tyr Ser Ser Ser Ser Ser Val Val He ATG CGT GTT CAC TAT GC-T AAC AAC TAC GAA AAC GCG TTC TGG AAT GGT 1020 535 540 Kez Arg Val His Tyr Gly Asn Asn Tyr Glu Asn Ala Phe Trp Asn Gly AAG ATC ACT GGC GGT ACA GGT GAT GCA GAC CTT TAC GTG AAA GCC- GGT 1740 305 310 315 Lys He Thr Gly Gly Thr Gly Asr Ala Asp Leu Tyr Val Lvs Ala Gly TCA TCC ATG ACC TTC GGT GAT GGC TAC AGC ACC TTC TAC CCC- CTG GTG 1068 545 550 555 Ser Ser Met Thr Phe Ser Thr Phe Pre Leu Val 325 Gly Asp Gly Tyr 330 Tyr 335 AGC AAG CCA ACC ACG ACT TCT TAC GAT TGC CGT CCA TAT AAG TAT GGT 1788 Ser Lys Pro Thr Thr Thr Ser Tyr Asp Cys Arg Pro Tyr Lys Tyr Gly GAT ATT AAC GTT AGT GCC CAC GAA GTG AGC CAC GGT TTC ACC GAA CAA 1116 565 570 575 Asp lie Asn Val Ser Ala His Glu Val Ser Kis Gly Phe Thr Glu Gin 340 345 350 AAC GAA GAG CAG TGT TCA ATT TCA GCG CAA Asn Glu Glu Gin He GCG GGT ACT ACG TAT CAC 1836 AAC TCG GGT CTG GTG TAC GAG AAT ATG TCT GGT GGT ATG AAC GAA GCG 1164 Cys Ser Ser Ala Gin Ala Gly Thr Thr Tyr His Asn Ser Gly Leu Val Tyr Glu Asn Met Ser Gly Gly Met Asn Glu Ala 580 585 590 355 360 365 GTT ATG CTG CGT GGT TAC AGC AAT TAC C-CT GGT GTA ACT TTG CGT GCT 1884 TTC TCT GAT ATT GCA GGT GAA GCA GCA GAG TTC TAC ATG AAA GGC AGC 1212 Val Met Leu Arg Gly Tyr Ser Asn Tyr Ala Gly Val Thr Leu Arg Ala Phe Ser Asp He Ala Gly Glu Ala Ala Glu Phe Tyr Met Lys Gly Ser 595 600 605 370 375 380 GAC TAA ACTCAGAATG GAACCAGTGA AGGCGCACCT TAAGGTCGCC TTTTTTGTAT 1932 GTT GAC TGG GTT GTC GGT GCG GAT ATC TTC AAA TCA TCC GGC GGT CTG Asp Ter Val Val Val Ala He Phe Ser 1260 609 385 Asp Trp Gly390 Asp 395Lys Ser Gly Gly Leu CAGGCGATCT GTGTAAACGT GACCTGATCG AAGTGAGGAT TGGCCGCCAG CGCTTGCATG CGT TAC TTT GAT CAG CCT TCG CGT GAC GGC CGT TCT ATC GAC CAT 1980 Arg Tyr Phe Asp Gin Pro Ser Ser He His AlaGCG 1308 405 Arg Asp Gly410 Arg Asp 415 TCT GAC TAC TAC AAT GGC CTG AAT GTT CAC TAC TCA AGT GGT GTA TTC 1356 Ser Asp Tyr Tyr Asn Gly Leu Asn Val His Ser Ser Val Phe 420 425 Tyr Gly430 AAC CGT GCG TTC TAC CTG CTG GCT AAC AAA GCG GGT TGG GAT GTA CGC Asn Arg Ala Phe Tyr Leu Leu Ala Asn Ala Val 1404 435 440 Lys Gly Trp445 Asp Arg AAA GGC TTT GAA GTG TTT ACC CTG GCT AAC CAA TTG TAC TGG Lys Gly Phe Glu Val Phe Thr Leu Ala Asn Gin Leu ACA GCG 1452 450 455 460 Tyr Trp Thr Ala AAC AGC ACA TTT GAT GAA GGC GGT TGT GGT GTA GTG AAA GCT GCG AGC 1500 Asn Ser Thr Phe Asp Glu Gly Gly Cys Gly Val Val Lys Ala Ala Ser 1 EP 0 472 01 1 A1 This application is a continuation-in-part application of copending U.S. Serial No. 567,884, filed August 15, 1990. Technical Field The present invention relates to debriding compositions and to methods using such compositions for debridement and/or wound healing, which contain certain proteases produced by microorganisms of the genus Vibrio. More particularly, the protease is capable of effectively digesting necrotic tissue while viable living tissue is not substantially injured. The protease also has wound healing properties. Background of the Invention The healing of wounds is a complex process which is often further complicated by the presence of non- viable, necrotic tissue in the wound area. Debridement is the process of removing the non-viable tissue 75 from a wound to prevent infection and facilitate healing. Considerable efforts have been made to discover materials capable of distinguishing between viable and non-viable tissue. The discovery of materials which would digest devitalized tissue while not attacking viable tissue would make it possible to remove the devitalized tissue without surgery. It would be a beneficial therapeutic agent in virtually all disease processes where topically devitalized tissue needs to be 20 removed from the viable organism such as burns, decubitus ulcers, pressure necroses, incisional, traumatic and pyogenic wounds, and ulcers secondary to peripheral vascular disease.
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