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United States Patent (19) 11 Patent Number: 4,871,835 Aviv Et Al United States Patent (19) 11 Patent Number: 4,871,835 Aviv et al. (45) Date of Patent: Oct. 3, 1989 54 ANALOGS OF HGH HAVING Lewis et al., Biochem. Biophys, Res. Comm., 92(2), 1980, ANTAGONISTIC ACTIVITY, AND USES pp. 511-516. THEREOF DeGeeter, CA, vol. 99, 1983, #157232u. Russell et al., JBC, 256, 1981, pp. 296-300. (75) Inventors: Haim Aviv; Marian Gorecki, both of Lewis et al., JBC, 253(8), 1978, pp. 2679-2687. Rehovot; Avigdor Levanon, Netania; Goeddel et al., Nature, 281, 1979, pp. 544-548. Amos Oppenheim, Jerusalem; Tikva Seebury et al., Nature, 276, 1978, pp. 795-798. Vogel, Rehovot; Pinhas E. Zeelon, Ross et al., Hormone Design, 1982, pp. 313-318. Hashiva; Menachen Zeevi, Ramat Arieh Gertler et al., Endocrinology, 116(4): 1636-1644 Gan, all of Israel (1985). Alejandro C. Paladini et al., CRC Critical Reviews in 73) Assignee: Bio-Technology General Corp., New Biochemistry, 15(1): 25-56. York, N.Y. Primary Examiner-J. R. Brown 21 Appl. No.: 691,230 Assistant Examiner-Garnette D. Draper Attorney, Agent, or Firm-John P. White 22 Filed: Jan. 14, 1985 57 ABSTRACT Related U.S. Application Data Analogs of hCGH having the activity of naturally occur ring hCH and a similar amino acid sequence varying 63 Continuation-in-part of Ser. No. 514,188, Jul. 15, 1983. from the sequence of natural hCGh by the addition of one or more amino acids, e.g. methione or methionine-leu 511 Int. Cl." .............................................. CO7K 13/00 cine, to the N-terminus of natural hCGH have been pro 52 U.S. Cl. .................................... 530/399; 530/350; duced, recovered and purified. Such analogs may be 530/806; 530/820; 530/808; 435/68; 435/70; incorporated into pharmaceutical compositions and 435/172.2; 514/2 administered to a subject to increase the level of hCGH in 58 Field of Search ............... 530/350, 399,806, 820, the subject. 530/808; 435/68, 70; 514/2 Analogs of hCGH which comprise the amino acid se 56) References Cited quence of natural hCGH from the N-terminus of which one or more amino acids have been deleted, e.g. U.S. PATENT DOCUMENTS Meth0h, have been produced, recovered and puri 4,443,539 4/1984 Fraser et al. .......................... 435/68 fied. Such analogs may be incorporated into pharma 4,658,021 4/1987 Goeddel et al. ... 530/399 ceutical compositions and administered to a subject to 4,665,160 5/1987 Seebury ............................... 530/399 lower the level of hCGH in the subject. FOREIGN PATENT DOCUMENTS A plasmid has been constructed which directs the ex 0020147 12/1980 European Pat. Off. pression of an analog of hCGH having the amino acid 0121764 10/1984 European Pat. Off. sequence methionine-leucine added to the N-terminus WO84/02534 7/1984 PCT Int'l Appl. , of natural hCH. This plasmid has been introduced into 2073245 10/1981 United Kingdom . Escherichia coli, the resulting Escherichia coli grown and OTHER PUBLICATIONS the analog recovered and purified. Seebury, DNA, 1982, vol. 1(3), p. 239. 3 Claims, No Drawings 4,871,835 1. 2 containing the PL promoter from A bacteriophage. (Ber ANALOGS OF HIGH HAVING ANTAGONSTC nard, H. V. et al., Gene (1979) 5, 59; Derom, C. et al., ACTIVITY, AND USES THEREOF Gene (1982) 17, 45; Gheysen, D. et al., Gene (1982) 17, 55; Hedgpeth, J. et al., Mol. Gen. Genet. (1978) 163, This application is a continuation in part of U.S. Ser. 5 197; Remaut, E. et al., (1981) Gene 15, 81; and Derynck, No. 514,188, filed July 15, 1983, the contents of which R., et al., Nature (1980) 287, 193. In addition, European are hereby incorporated by reference into the present patent application No. 041.767, published Dec. 16, 1981 application. describes expression vectors containing the PL pro moter from A bacteriophage. However, none of these BACKGROUND OF THE INVENTION 10 references describe the use of the CII ribosomal binding One aspect of genetic engineering involves insertion site. of foreign DNA sequences derived from eukaryotic The use of a vector containing the PL promoter from sources into Escherichia coli or other microorganisms. A A bacteriophage and the CII ribosomal binding site has further refinement concerns inducing the resulting mi been described. (Oppenheim, A. B. et al., J. Mol. Biol. croorganisms to produce polypeptides encoded by the 15 (1982) 158, 327 and Shimatake, H. and Rosenberg, M., foreign DNA. Production of polypeptides can be con Nature (1981) 292, 128.) These publications describe the sidered a two-step process, each step including numer production of increased levels of CII protein but do not ous substeps. The two steps are transcription and trans involve or describe the production of eucaryotic prote lation. To produce a polypeptide efficiently and in S. quantity both steps must be efficient. Transcription is 20 In 1982 Shatzman and Rosenberg presented a poster the production of mRNA from the gene (DNA). Trans at the 14th Miami Winter Symposium (Shatzman, A. R. lation is the production of polypeptide from the mRNA. and Rosenberg, M., 14 Miami Winter Symposium, ab A critical substep of the transcription process is initia stract p981982). This abstract provides a non-enabling tion, i.e., the binding of RNA polymerase to a promot disclosure of the use of a vector containing PL from A er-operator region. The sequence of deoxyribonucleo 25 bacteriophage, Nut and the CII ribosomal binding site to tide bases which is the promoter region may vary and synthesize a “eucaryotic' polypeptide (SV40 small T thereby effect the promoter's relative efficiency which antigen is actually not a eucaryotic polypeptide but a depends on the affinity of the RNA polymerase for the viral protein) in an amount greater than 5% of the cell promoter. protein in an unnamed bacterial host. The operator used The efficiency of translation is affected by mRNA 30 is not defined. Neither an origin of replication nor a stability. Increased mRNA stability permits improved gene for a selectable phenotype is identified. This sys translation. Although the exact determinants of mRNA tem with which the vector is used is described as includ stability are not precisely known, it is known that ing certain host lysogens into which the vector can be mRNA secondary structure as determined by the se stably transformed. The present invention in one em quence of its bases has a role in stability. ' 35 bodiment, i.e., pMG100, may have certain similarities to The initial substep of translation involves binding of this vector. However, it is not transformed into a host the ribosome to a base sequence on the mRNA known lysogen, but rather into suitable E. coli host strains a the Shine-Dalgarno sequence or the ribosomal binding which contain the thermolabile repressor CI and the N site (RBS). The synthesis of polypeptides begins when gene but from which the rest of the lysogen has been the ribosome migrates along the mRNA to the AUG removed. Moreover, it has been employed to produce start codon for translation. Generally these codons are bGH and hCGH analogs in amounts in excess of 20% to . found approximately 10 bases "downstream' from the total cell protein. Shine-Dalgarno site. Factors which increase the effi In addition, in other embodiments of this invention ciency of translation include those which enhance bind ribosomal binding sites which differ from CII are em ing of the ribosomes to the Shine-Dalgarno site. It has 45 ployed. Also, in the presently most preferred vectors, been shown that the secondary structure of the mRNA pND5 and its derivatives, nonessential sequences have in the region of the Shine-Dalgarno sequence and the been removed to create a vector permitting polypeptide AUG codon and the distance between the Shine-Dal production in amounts which are more than 10% garno sequence and the AUG codon each plate a criti greater than those obtained with pMG100. cal role in determining the efficiency of translation are SO Recently, applicants have learned of the existence of premature termination and attenuation. Efficiency of a pending M. Rosenberg U.S. patent application Ser. translation can be improved by removing the attenua No. 457,352 by the National Institutes of Health, Dept. tion sites. of Health and Human Services, U.S.A. Portions of this A difficulty encountered in attempts to produce high application have been obtained from the National Tech amounts of eukaryotic polypeptides in bacterial cells 55 nical Information Service, U.S. Dept. of Commerce. involves the inability of cells producing large amounts However, the claims are not available and are main of mRNA to grow efficiently. This difficulty can be tained in confidence. The available portions of the ap eliminated by preventing transcription by a process plication have been reviewed. This disclosure is not known as repression. In repression genes are switched enabling. It indicates that the host is important (p8, line off due to the action of protein inhibitor (repressor 17) but fails to identify any suitable host. It further protein) which prevents transcription by binding to the depends upon the use of a M. mutant which is not speci operator region. After microorganisms have grown to fied (p4, line 20). It indicates that the host contains desired cell densities, the repressed genes are activated lysogens (p8, line 18) unlike the present invention in by destruction of the repressor or by addition of the which the host is not lysogenic. It mentions cloning and molecules known as inducers which overcome the ef 65 expression of a eucaryotic gene, monkey metalloth fect of the repressor. ionein gene, (p7, line 18) but does not provide details.
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