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(12) United States Patent (10) Patent No.: US 6,352,697 B1 Cox Et Al

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(12) United States Patent (10) Patent No.: US 6,352,697 B1 Cox Et Al USOO6352697 B1 (12) United States Patent (10) Patent No.: US 6,352,697 B1 Cox et al. (45) Date of Patent: *Mar. 5, 2002 (54) SAPONIN PREPARATIONS AND USE (58) Field of Search ........................... 424/184.1, 278.1, THEREOF IN ISCOMS 424/283.1; 514/885 (75) Inventors: John Cooper Cox, Bullengarook; Alan (56) References Cited Robert Coulter, Glen Iris, both of (AU); Bror Morein, Uppsala (SE); FOREIGN PATENT DOCUMENTS Karin Lovgren-Bengtsson, Uppsala (SE); Bo Sundquist, Uppsala (SE) WO WO 88/09336 12/1988 WO WO 90/03184 4/1990 WO WO 92/06710 * 4/1992 (73) Assignee: Iscotec A.B., Stockholm (SE) WO WO 93/05789 4/1993 (*) Notice: This patent issued on a continued pros WO WO 94/O1118 1/1994 ecution application filed under 37 CFR WO WO95/09179 4/1995 1.53(d), and is subject to the twenty year OTHER PUBLICATIONS patent term provisions of 35 U.S.C. 154(a)(2). Cox, J.C. and Coulter, A.R. (1992) “Advances in Adjuvant Technology and Application' in Animal Parasite Chapter 4, Subject to any disclaimer, the term of this pp. 68–79, W.K. Young, Ed., CRC Press. patent is extended or adjusted under 35 Kensil, C.R. et al., Separation and characterization of U.S.C. 154(b) by 0 days. saponins with adjuvant from Quillaja saponaria 1991 (146) (21) Appl. No.: 08/809,987 431–437 Journal of Immunology. (22) PCT Filed: Oct. 12, 1995 * cited by examiner (86) PCT No.: PCT/AU95/00670 Primary Examiner Patrick J. Nolan S371 Date: Feb. 22, 1999 ASSistant Examiner-Gerald R. Ewoldt S 102(e) Date: Feb. 22, 1999 (74) Attorney, Agent, or Firm-Foley & Lardner (57) ABSTRACT (87) PCT Pub. No.: WO96/11711 Saponin preparations based on defined compositions of PCT Pub. Date: Apr. 25, 1996 purified Saponin fractions derived from the bark of Quillaja (30) Foreign Application Priority Data Saponaria Molina are disclosed. The Saponin preparations are useful in immunostimulating complex (iscom) matrices. Oct. 12, 1994 (AU) ............................................. PM8732 The Saponin preparations, and iscom matrices prepared (51) Int. Cl. ................................................ A61K 45/00 using them, have particular activity as adjuvants. (52) U.S. Cl. ................................ 424/278.1; 424/278.1; 424/283.1; 424/1841; 514/885 16 Claims, 8 Drawing Sheets U.S. Patent Mar. 5, 2002 Sheet 1 of 8 US 6,352,697 B1 SSd 2 O u NO trt R ? CN trigz2% - 422 O 777, CN zz CO U.S. Patent Mar. 5, 2002 Sheet 2 of 8 US 6,352,697 B1 FG 2A 30000 EXPERMENT O 20000 U.S. Patent Mar. 5, 2002 Sheet 3 of 8 US 6,352,697 B1 FIG 2C 60000 EXPER MENT lic 50000 40000 30000 20000 10000 O 0 1 2 3 4 S 6 7 8 9 10 11 12 13 11, 19 16 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 U.S. Patent Mar. 5, 2002 Sheet 4 of 8 US 6,352,697 B1 FG 3A wimmersawwas 20000 0 1 2 3 4. S 6 7 8 9 10 1 12 13 11, 15 16 7 FG 3B 40000 EXPERMENT 2b 30000 20000 10000 O 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1617 U.S. Patent Mar. 5, 2002 Sheet 5 of 8 US 6,352,697 B1 FG BC 30000 EXPERMENT 2. U.S. Patent Mar. 5, 2002 Sheet 6 of 8 US 6,352,697 B1 O t 6 7 8 9 10 11 12 13 11, 1 S 6, 17 e BH-Cho BH-PC . e BH-Chol 3H-PC U.S. Patent Mar. 5, 2002 Sheet 7 of 8 US 6,352,697 B1 FIG LC 2OOOOO 150000 100000 SOOOO 0 1 2 3 4 S 6 7 8 9 10 11 12 13 14, 19 16 17 HCH-Cho 3H-PC O 1 2 3 4, S 6 7 8 9 10 11 3H- Chot-3H-PC U.S. Patent Mar. 5, 2002 Sheet 8 of 8 US 6,352,697 B1 (fin)BSOpUIUOdes OZ9||9|fjZO||870 US 6,352,697 B1 1 2 SAPONIN PREPARATIONS AND USE Since the recognition of the adjuvant activity of Quil A THEREOF IN ISCOMS (Dalsgaard, 1974) several groups have further fractionated this material into a number of “purified'components This application is a 371 national Stage application of (Morein et al., Australian Patent Specification No. 632067; PCT/AU95/00670, filed Oct. 12, 1995. Kersten, 1990; Kensil, 1988; Kensil 1991). These compo FIELD OF THE INVENTION nents were Subsequently shown to have variable properties This invention relates to Saponin preparations, particu especially in regards to adjuvant activity, haemolytic activity larly to Saponin preparations based on defined compositions and ability to form iscoms. The use of purified Quil A of purified saponin fractions derived from the bark of components conferred two potential advantages for their use Quillaja Saponaria Molina. The invention also extends to in a human vaccine. Firstly, the purified component could be immunostimulating complex (iscom) matrices prepared characterized and therefore made reproducibly; and using these Saponin preparations, as well as to immunogenic Secondly, the components could be selected for optimal iscoms in which immunogens are incorporated into or usefulness. asSociated with an iscom matrix. Such immunogens will The immunomodulatory properties of the Quil A Saponins usually be proteins or peptides derived from bacteria, 15 and the additional benefits to be derived from these saponins Viruses or other microorganisms, but they may, in addition, when they are incorporated into an iscom have been be any other protein, peptide or other chemical entity which described in various publications, e.g. Cox and Coulter, can induce an immune response. 1992; Dalsgaard, 1974; Morein et al., Australian Patent The Saponin preparations of this invention, and iscom Specifications Nos. 558258,589915,590904 and 632067. In matrices prepared using them, have particular activity as Australian Patent Specification No. 632067, the separation adjuvants, that is as products which result in a specific of a preparation of Quil Ainto three distinct fractions called increase in the immunogenicity of a vaccine component B4B, B3 and B2 is described, along with HPLC chromato BACKGROUND OF THE INVENTION graphic procedures for this fractionation. More carefully defined and controllable procedures for the fractionation of The adjuvant properties of Saponin have been long known 25 Quil A have now been devised which result in three major as has its ability to increase antibody titres to immunogens. fractions with increasing degrees of hydrophobicity in the AS used herein the term "Saponin’ refers to a group of purification System used. Surface-active glycosides of plant origin composed of a In work leading to the present invention, it has now been hydrophilic region (usually several Sugar chains) in asso shown that Saponins derived from Quillaia Saponaria can be ciation with a hydrophobic region of either Steroid or Separated into fractions with differing chemical and biologi triterpenoid structure. Although Saponin is available from a cal properties, including the important biological properties number of diverse Sources, Saponins with useful adjuvant of adjuvant activity, haemolytic activity, ability to form activity have been derived from the South American tree iscoms and in vivo toxicity, and that particular compositions Quillaja Saponaria Molina. Saponin from this Source was of these fractions can be prepared to form novel Saponin used to isolate a “homogeneous” fraction denoted “Quil A' 35 preparations which are capable of forming good iscoms, (Dalsgaard, 1974). having optimal adjuvant activity but minimal haemolytic Acute toxicity is a major concern for both the Veterinary and toxic activity. and human use of Quil A in vaccine preparations. One way to avoid the acute toxicity of Quil A is the use of iscoms, an SUMMARY OF THE INVENTION abbreviation for Immuno Stimulating COMplexes. This is 40 primarily because Quil A is leSS toxic when incorporated According to the present invention, there is provided a into iscoms, because its association with cholesterol in the Saponin preparation comprising Saponins of Quillaia iscom reduces its affinity for cholesterol in cell membranes Saponaria, said preparation comprising from 50 to 90% by and hence its cell lytic effects. In addition, a lesser amount weight of Fraction A of Quil A (as herein defined) and from of Quil A is required to generate a similar level of adjuvant 45 50% to 10% by weight of Fraction C of Quil A (as herein effect. Iscoms are Small, cage-like Structures generally 30 to defined). 40 nm in diameter which retain this structure on freeze Preferably, the saponin preparation comprises from 50% drying. The final formulation of a typical immunogenic to 70% by weight of Fraction A and from 50% to 30% by iscom with an optimal amount of immunogenic protein is a weight of Fraction C. A particularly preferred preparation weight ratio of Quil A, cholesterol, phosphatidyl choline, 50 comprises about 70% by weight of Fraction A and about and protein (1:1:1:5). Such a typical iscom is estimated to 30% by weight of Fraction C. contain 5 to 10% by weight Quil A, 1 to 5% cholesterol and The term “Quil A' is used throughout this specification phospholipids, and the remainder protein. Peptides can be and in the claims as a generic description of a Semi-purified incorporated into iscoms either directly or by chemical Saponin fraction of Quillaja Saponaria. coupling to a carrier protein (e.g. influenza envelope protein) 55 The Saponin preparation may, if desired, include minor after incorporation of the carrier protein into iscoms. amounts (for example up to 40% by weight) of other AS an adjuvant, the iscom conferS many advantages adjuvant materials with desired immunomodulatory including powerful immunostimulatory effects, low toxicity, properties, including minor amounts of Fraction B of Quil A ability to induce both cellular (including CTL) and humoral or of other Saponins.
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