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United States Patent [191 [11] Patent Number: 4,831,120 Aviv Et Al

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United States Patent [191 [11] Patent Number: 4,831,120 Aviv Et Al United States Patent [191 [11] Patent Number: 4,831,120 Aviv et al. [45] Date of Patent: May 16, 1989 [54] METHOD FOR RECOVERING A PURIFIED ANIMAL GROWTH HORMONE OR FOREIGN PATENT DOCUMENTS POLYPEPTIDE ANALOG THEREOF FROM 0061250 9/1982 European Pat. Off. A BACTERIAL CELL 0127305 12/1984 European Pat. Off. 2083824 3/1982 United Kingdom . [75] Inventors: Haim Aviv; Marian Gorecki, both of 8304418 12/ 1983 United Kingdom . Rehovot; Avigdor Levanon, Netania; 2138004 9/1984 United Kingdom . Amos Oppenheim, Jerusalem; Tikva Vogel, Rehovot; Elisha Zeelon, OTHER PUBLICATIONS Hashiva; Menachem Zeevi, Ramat Principles of Biochemistry, Lehninger 1982, p. 177. Gan, all of Israel Primary Examiner—Johnnie R. Brown [73] Assignee: Bio-Technology General Corp., New Assistant Examiner—Garnette D. Draper York, NY. Attorney, Agent, or Firm-John P. White [21] Appl. No.: 752,441 [57] ABSTRACT An improved vector upon introduction into a suitable [22] Filed: Jul. 3, 1985 bacterial host containing the thermolabile repressor C1 renders the host cell capable, upon increasing the tem Related U.S. Application Data perature of the host cell to a temperature at which the repressor is destroyed, of effecting expression of a de [63] Continuation of Ser. No. 514,188, Jul. 15, 1983, aban doned. sired gene inserted into the vector and production of polypeptide encoded by the gene. The vector is a dou [30] Foreign Application Priority Data ble-stranded DNA molecule which includes in 5' to 3’ order the following: a DNA sequence which contains Jul. 3, 1984 [EP] European Pat. Off. ...... .. 84107717.5 the promoter and operator PLOL from lambda bacterio [51] Int. Cl.4 ....................... .._ ..................... .. C07K 3/28 phage; the N utilization site for binding antiterminator [52] U.S. Cl. .................................. .. 530/399; 530/412; N protein produced by the host cell; a DNA sequence 530/416; 530/417; 530/418; 530/422; 530/820; which contains a ribosomal binding site for rendering 530/825; 530/427; 435/68 the mRNA of the desired gene capable of binding to [58] Field of Search ...... .. 530/399, 412, 416, 4l7—418, ribosomes within the host cell; an ATG initiation codon 530/422, 427; 435/68 or a DNA sequence which is converted into an ATG initiation codon upon insertion of the desired gene into [56] References Cited the vector; a restriction enzyme site for inserting the U.S. PATENT DOCUMENTS desired gene into the vector in phase with the ATG initiation codon; and additionally a DNA sequence 4,426,323 1/1984 Jain ..................................... .. 435/68 which contains an origin of replication from a bacterial 4,512,922 4/1985 Jones et al. 435/68 plasmid capable of autonomous replication in the host 4,612,367 9/1986 Grinnan et a1. 530/413 cell and a DNA sequence which contains a gene associ 4,656,255 4/1987 Seely . , . .. 530/417 4,658,021 4/ 1987 Goeddal et al. 530/ 399 ated with a selectable or identifiable trait which is mani 4,677,196 6/1987 Rausch et a1. .. 530/416 fested when the vector is present in the host cell. 4,693,973 9/1987 Buell . .. 530/399 4,728,609 8/1988 Bhatt et a1. ......................... .. 435/68 11 Claims, 15 Drawing Sheets US. Patent May 16,1989 Sheet 5 0f 15 4,831,120 FIGS. SUBCLON/A/G 0F TRP PRO/H075»? w/ m LE4DEP, 47/37/04 T01? mm 25 811 0F 5 GEN-'7 EcoRl Smal Ban H1 PEP 121-22: Gene l Xho! + 53m Flu-‘14y (3705f fragment H in‘? I " I Fill Maui-B1 K1871” Purify 460 bp fragment US. Patent May 16,1989 Sheet 8 of 15 4,831,120 F I EB. cww/m; OFbGH W70 4 7779 -La: FUSEA PROMO?.519 PMS/9WD @1111 i-HindII Hum: +5072: EC“! Puri F3 I.qr g FN: meT Pur: F MH conT ' Fur-d}P4 lac fr¢9mcn+ g 3 n ‘ Fragment mans Alf/@556,‘ fragment / QLOW J’aco / Ecol?! 3' mm US. Patent May 16,1989 Sheet 9 0f 15 4,831,120 ~ F 16.5. fXPPl-‘SS/UN M6614 W/fl/ Hi; PROMO r5? FnuJI Hmm; ‘ 53221: 5mm Sm.) &nm 3 .5 ' Egan: /: HIS Hin¢llI+ 8311' Par/6 smallfr'agmf . Hi n 4111'. H’kpY FnuJI 5311 Fwd]: Purify large frfggmn‘f ‘Fl/fa” ' I: I US. Patent May 16,1989 Sheet 10 of 15 4,831,120 M560 21 FIG] [1 mm at, ‘ . Pl M03' bumligation @Xonuc Egg:' Z screw ?r pad. ck’ Pstl fsél . Ewe’ . ‘3a, ' US. Patent May 16,1989 Sheet 12 of 15 4,831,120 FIBIZ. V linker: PDrZ/b/ Psi! 6C6“. p”amflgé'afndlaarfa/a‘mla? - , myme/rfcaata/b/lv I AcG rctac‘66 5:04] Eek! SW. 1 MP 1 _ OmrF Eco/(Ir Xmal ' fig/9g? / PuriF large Xml US. Patent May 16, 1989 Sheet 13 of 15 4,831,120 PL Mum ‘ Nd‘! £5021 % p 0e; Hmd In: Save [I Md ' h'f/d NM iaé?b'?fefs RjloglTc and select clan e pm/ 9”” “5%----. _. ..- -27;_ ‘ WnhW/m?uwindm' f aim”: Rellgcd'g and Seled "/0052 é'cai/ _ Mud Sq! 8047 57077101779 179mb’ “If!” HIM-1 ll‘ (Mia/J Eco?! A’? Male; 3' A/a/e/ ‘I’ HmlI ‘(F/aw” ‘y 0-4214’ 59am»; Him/I US. Patent May 16,1989 Sheet 14 0f 15 4,831,120 F1514. Hmamj 7/472? 776C646 C .4 6444666766 A 7' 4,831,120 1 2 Numerous reports may be found in the literature METHOD FOR RECOVERING A PURIFIED concerning the cloning of eucaryotic genes in plasmids ANIMAL GROWTH HORMONE OR containing the PL promoter from )t bacteriophage. (Ber POLYPEPTIDE ANALOG THEREOF FROM A nard, H. V. et al., Gene (1979) 5, 59; Derom, C. et al., BACTERIAL CELL Gene (1982) 17, 45; Gheysen, D. et al., Gene (1982) 17, 55; Hedgpeth, J. et al., Mol. Gen. Genet. (1978) 163, This is a continuation of application Ser. No. 514,188, 197; Remaut, E. et al., (1981) Gene 15, 81; and Derynck, ?led July 15, 1983 now abandoned. R., et al., Nature (1980) 287, 193. In addition, European Patent Application No. 041.767, published Dec. 16, BACKGROUND OF THE INVENTION 1981 describes expression vectors containing the PL One aspect of genetic engineering involves the inser promoter from 1» bacteriophage. However, none of tion of foreign DNA sequences derived from eukary these references describe the use of the C11 ribosomal otic sources into Escherichia coli or other microorgan binding site. isms. A further re?nement of genetic engineering con The use of a vector containing the PL promoter from cerns inducing the resulting microorganism to produce 15 A bacteriophage and the C11 ribosomal binding site has polypeptides encoded by the foreign DNA. Production been described. (Oppenheim, A. B. et al., J. Mol. Biol. of polypeptides can be considered a two-step process, (1982) 158, 327 and Shimatake, H. and Rosenberg, M., with each step including numerous substeps. The two Nature (1981) 292, 128.) These publications describe the steps are transcription and translation. To produce a production of increased levels of C11 protein but do not polypeptide efficiently and in quantity both steps of the 20 involve or describe the production of eucaryotic prote process must be efficient. Transcription is the produc ins. tion of mRNA from the gene (DNA). Translation is the In 1982 Shatzman and Rosenberg presented a poster production of polypeptide from the mRNA. at the 14th Miami Winter Symposium (Shatzman, A. R. A critical substep of the transcription process is initia and Rosenberg, M., 14 Miami Winter Symposium, ab tion, that is, the binding of RNA polymerase to a pro 25 stract p98 [1982]). This abstract provides a non~enabling moter-operator region. The sequence of deoxyribonu disclosure of the use of a vector containing PL from A cleotide bases which make up the promoter region may bacteriophage, Nut and the C11 ribosomal binding site to vary and thereby effect the relative ef?ciency of the synthesize a “eucaryotic” polypeptide (SV40 small T promoter. The ef?ciency depends on the affinity of the antigen is actually not a eucaryotic polypeptide but a RNA polymerase for the promoter. 30 viral protein) in an amount greater than 5% of the cell The ef?ciency of translation is affected by the stabil protein in an unnamed bacterial host. The operator used ity of the mRNA. Increased stability of the mRNA is not de?ned. Neither an origin of replication nor a permits improved translation. Although the exact deter gene for a selectable phenotype is identi?ed. This sys minants of mRNA stability are not precisely known, it is tem with which the vector is used is described as includ known that mRNA secondary structure as determined 35 ing certain host lysogens into which the vector can be by the sequence of its bases has a role in stability. stably transformed. The present invention in one em The initial substep of translation involves binding of bodiment, i.e., pMGlOO, may have certain similarities to the ribosome to a base sequence on the mRNA known this vector. However, it is not transformed into a host as the Shine-Dalgarno sequence or the ribosomal bind lysogen, but rather into suitable E. coli host strains ing site (RBS). The synthesis of polypeptides begins which contain the thermolabile repressor C1 and the N when the ribosome migrates along the mRNA to the gene but from which the rest of the lysogen has been AUG start codon for translation. Generally these co removed. Moreover, it has been employed to produce dons are found approximately 10 bases “downstream” bGH and hGI-I analogs in amounts in excess of 20% of from the Shine-Dalgarno site.
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