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(12) United States Patent (10) Patent No.: US 6,632,929 B1 Wilchek Et Al

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(12) United States Patent (10) Patent No.: US 6,632,929 B1 Wilchek Et Al USOO6632929B1 (12) United States Patent (10) Patent No.: US 6,632,929 B1 Wilchek et al. (45) Date of Patent: *Oct. 14, 2003 (54) AVIDIN DERIVATIVES AND USES THEREOF Tsurui Hironori,"PEG-Modified Avidin and Method for Separating Antigen or Antibody Using the Same', Patent (75) Inventors: Meir Wilchek, Rehovot (IL); Edward A Bayer, Raanana (IL); Heike Abstracts of Japan, Publ. No. 08012699, Publ. Date Jan. 16, Hofstetter, DeKalb, IL (US); 1996; vol. 1996, No. 5, May 31, 1996. Margherita Morpurgo, Teolo (IT) Green, M. “Avidin and Streptavidin', Methods in Enzymol (73) Assignee: Yeda Research and Development Co. Ogy, US, Academic PreSS Inc., San Diego, CA, Vol. 184, Jan. LTD (IL) 1, 1990, pp. 51-67. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Primary Examiner Mary E. Ceperley U.S.C. 154(b) by 0 days. (74) Attorney, Agent, or Firm-Browdy and Neimark, This patent is Subject to a terminal dis PL.L.C. claimer. (57) ABSTRACT (21) Appl. No.: 09/831,499 A covalent conjugate of a 4'-hydroxyaZobenzene-2- (22) PCT Filed: Nov. 10, 1999 carboxylic acid derivative (HABA) and an avidin-type (86) PCT No.: PCT/IL99/00605 molecule, of the formula: S371 (c)(1), (2), (4) Date: Aug. 7, 2001 OH (87) PCT Pub. No.: WO00/27814 A-CO-NH-B-INH CO-NH-Av PCT Pub. Date: May 18, 2000 (30) Foreign Application Priority Data Nov. 10, 1998 (IL) ................................................ 126990 (51) Int. Cl. ............................ C07K 1/00; CO7K 1/13; COOH (52) U.S. Cl. ........................ 530/409; 435/7.5; 436/526; 436/527; 436/529; 436/531; 540/455 (58) Field of Search ................................. 530/408, 409; 435/7.5; 436/526, 527, 531, 529; 540/455 wherein A is (CH), or -CH=CH-, wherein n is an (56) References Cited integer from 0-10; B is (CH), wherein n is an integer from 2 to 10; m is Zero or 1; and AV is the residue of an avidin-type U.S. PATENT DOCUMENTS molecule Selected from the group comprising native egg 5,182,203 A 1/1993 Ebersole et al. white avidin, recombinant avidin, deglycosylated avidins, FOREIGN PATENT DOCUMENTS bacterial Streptavidin, recombinant Streptavidin, truncated WO WO 97100329 3/1997 Streptavidin and other derivatives of Said avidin-type mol ecules. These HABAylated avidins are red colored in the OTHER PUBLICATIONS quinone configuration and can be used in many applications Morpurgo et al (1998), “A Chemical Approach To Illustrate in the avidin-biotin technology. the Principle of Signal Transduction Cascades Using the Advin-Biotin System”, J. Am. Chem.Soc., 120:12734-12739. 15 Claims, 4 Drawing Sheets U.S. Patent Oct. 14, 2003 Sheet 1 of 4 US 6,632,929 B1 2 HH C ? red H! AH O -At 25O 450 650 -- Biotin r Or derivative 2 H BB Ci yellow Bl O G-- H 25O 45O 650 n gos -- Avidin 2 C O l/A red 25O 45O 650 n Figure U.S. Patent Oct. 14, 2003 Sheet 2 of 4 US 6,632,929 B1 O.8 O6 E C 3 O.4 ? C O.2 E O CY) cy) C Figure 2 U.S. Patent Oct. 14, 2003 Sheet 3 of 4 US 6,632,929 B1 5-T- E 1.0 O C S < 0.5- C C C ? C C Oy-C ONo O.0-i-C -86. C 1O-5 1O-3 O-1 Antibody dilution Figure 3 U.S. Patent Oct. 14, 2003 Sheet 4 of 4 US 6,632,929 B1 Number of layers Figure 4 US 6,632,929 B1 1 2 AVIDIN DERVATIVES AND USES THEREOF Subjected to a variety of drastic conditions Such as high concentrations of denaturing agents at room temperature, e.g., 6 M guanidinium hydrochloride, 3 M guanidinium CROSS-REFERENCE TO RELATED thiocyanate, 8 M urea, 10% f-mercaptoethanol or 10% APPLICATIONS Sodium dodecyl sulfate. Under combined treatment with guanidinium hydrochloride at low pH (1.5) or upon heating The present application is the national Stage under 35 (> 70° C.) in the presence of denaturing agents or detergents, U.S.C. 371 of international application PCT/IL99/00605, the protein is denatured, and biotin is dislodged from the filed Nov. 10, 1999 which designated the United States, and disrupted binding Site. which international application was published under PCT Avidin recognizes biotin mainly at the ureido (urea-like) Article 21(2) in the English language. The entire contents of ring of the molecule. The interaction between the binding said PCT/IL99/00605 are hereby incorporated by reference. Site of avidin with the Sulfur-containing ring of the Valeric FIELD OF THE INVENTION acid side chain of the vitamin is of much lower strength. The relatively weak interaction between the carboxy-containing The present invention relates to red colored covalent 15 Side chain of biotin and avidin means that the former can be conjugates of 4'-hydroxyaZobenzene-2-carboxylic acid modified chemically and attached to a wide variety of derivatives (hereinafter HABA) and an avidin-type biologically active material; the biotin moiety of the result molecule, these conjugates referred herein as "HABAylated ant derivative or conjugate is still available for interaction avidins, and their application in the avidin-biotin technol with avidin. In turn, the avidin can be derivatized with many Ogy. other molecules, notably "probes' or reporter groups of different types. BACKGROUND OF THE INVENTION This is the crux of avidin-biotin technology (Wilchek and Avidin and Streptavidin are tetrameric proteins that, due to Bayer, 1990). Thus, a biologically active target molecule in their Strong interaction with biotin, have become widely an experimental system can be “labeled” with its biotiny useful as extremely versatile, general mediators in a broad 25 lated counterpart (a binder), and the product can then be Variety of bioanalytical applications, including Subjected to interaction with avidin, either derivatized or chromatography, cytochemistry, cell cytometry, diagnostics, conjugated with an appropriate probe. immunoassays and biosensing, gene probes and drug deliv The use of the egg-white avidin in the avidin-biotin ery (Wilchek and Bayer, 1990). The reason for their popu technology is Sometimes restricted due to the high basicity larity is based on the basic principle of the avidin-biotin (p 10.5) and presence of Sugar moieties on the avidin technology, namely, that the interaction between avidin and molecule, which may lead to nonspecific or otherwise biotin is not affected when biotin is covalently bound to undesired reactions. In recent years, the bacterial protein, macromolecules or to insoluble carriers (matrices). The Streptavidin, has largely replaced egg-white avidin for most biotin moiety can be recognized by the native avidin mol applications in avidin-biotin technology. However, the prob ecule or derivatized avidin, which contains desired reporter 35 lems with Streptavidin (high cost and biotin-independent cell groupS. binding) have prompted renewed interest in egg-white avi Avidin (from egg-white) and Streptavidin (from Strepto din as the standard for avidin-biotin technology. For this myces avidinii) are two related proteins that bind biotin with purpose, modified avidins exhibiting improved molecular similar dissociation constants of about 10M. In addition characteristics both over the native protein (and previous to the binding of biotin, many of their physical properties are 40 derivatives thereof) as well as over streptavidin, have been quite similar. Both, for example, are constructed of four prepared, Such as N-acyl avidins, e.g., N-formyl, N-acetyl non-covalently attached identical Subunits, each of which and N-Succinyl avidins. These derivatives of avidin reduce bears a Single biotin-binding Site. The Subunit M. Values are the charge of the protein, but they are all prepared via also very similar. Moreover, several short stretches in the covalent attachment to the available lysines of avidin, and Sequences of the two proteins are preserved, particularly two 45 the consequent blocking of the free amino groups hinders Trp-LyS Stretches that occur at approximately similar posi Subsequent preparation of other types of conjugates (notably tions. protein-protein conjugates Such as avidin-labeled enzymes) Despite these similarities, Several differences exist which are often prepared by crosslinking via lysine residues between the two proteins. Avidin is a disulphide-bridged 50 using bifunctional reagents (e.g. glutaraldehyde). glycoprotein containing two methionine residues, whereas A more useful and effective alternative to lysine modifi Streptavidin is not glycosylated and is devoid of Sulphur cation is the modification via arginines. In this case, the pl containing amino acid Side chains. Another significant dif of the protein is efficiently reduced and the lysines are still ference is in the tyrosine content. Avidin has only one available for subsequent interaction. Two different deriva tyrosine residue (Tyr-33), whereas streptavidin has six 55 tives of avidin which are modified in this manner are tyrosine residues at positions 22, 43, 54, 60, 83 and 96. commercially available. One, Extravidin(R), can be obtained Interestingly, the Single tyrosine residue of avidin is located in various functionally derivatized or conjugated forms from in a region which contains a Sequence identical with that of Sigma Chemical Company (St. Louis, Mo.). A second , one of the streptavidin tyrosine residues (Tyr-43 in the NeutraLite AvidinTM (a product of Belovo Chemicals, stretch Thr-Gly-Thr-Tyr). 60 Bastogne, Belgium) is additionally modified and can be Each avidin monomer binds one molecule of biotin. The purchased in bulk quantities. unique feature of this binding, of course, is the Strength and Although the reduction of the p of egg-white avidin specificity of formation of the avidin-biotin complex. The Solves one of the problems, the presence of the oligosac resultant affinity constant, estimated at 1.6x10" M for charide residue remains a Serious Source of nonspecific avidin and 2.5x10" M' for streptavidin, is the highest 65 (biotin-independent) interaction which restricts its applica known for a protein and an organic ligand.
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