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United States Patent 19 11 Patent Number: 5,639,653 Bloom Et Al

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United States Patent 19 11 Patent Number: 5,639,653 Bloom Et Al USOO5639653A United States Patent 19 11 Patent Number: 5,639,653 Bloom et al. 45 Date of Patent: Jun. 17, 1997 (54) METHOD FOR PROLIFERATING Wy2V82T 56) References Cited CELLS PUBLICATIONS 75) Inventors: Barry R. Bloom, Hastings-on-Hudson; Cuthbert, J.A. et al., FASEB Journal, vol. 4(7), p. A1747, Yoshimasa Tanaka, Bronx, both of abs, 309 1990. N.Y.; Shigetoshi Sano, Nishinomiya, Chakrabarti, R. et al., The Journal of Biological Chemistry, Japan vol. 266(19), pp. 12216-12222 1991. Tanaka, Y. et al., Nature, vol. 375(6527), pp. 155-158 May 73) Assignee: Albert Einstein College of Medicine 1995. of Yeshiva University, a Division of Burk, M.R. et al., Eur, J. Immunol., vol. 25(7), pp. Yeshiva Universtiy, Bronx, N.Y. 2052-2058 1995. Morita, C.T. et al., Immunity, vol. 3(4), pp. 495-507 Oct. 21 Appl. No.: 390,881 1995. Primary Examiner Michael G. Wityshyn 22 Filed: Feb. 17, 1995 Assistant Examiner-Kristin Larson Related U.S. Application Data Attorney, Agent, or Firm-Amster, Rothstein & Ebenstein 57 ABSTRACT 63 Continuation-in-part of Ser. No. 93,528, Jul. 19, 1993, abandoned. This invention is directed to a method for stimulating the proliferation of Vy2V62 T cells comprising contacting 51 Int. C. m. C12N 5/02; C12N 5/06; Vy2V82 T cells with a Vy2V82 T cell proliferation stimu A61K31/66; CO7F 9/02 lating amount of a compound selected from the group 52 U.S. Cl. .......................... 514/102; 514/106; 514/134: consisting of a monoalkyl phosphate and an alkenyl pyro 558/155; 558/156; 435/375; 435/384 phosphate. 58 Field of Search ......................... 435/240.2: 514/102, 514/106, 134; 558/155, 156 15 Claims, 17 Drawing Sheets U.S. Patent Jun. 17, 1997 Sheet 1 of 17 5,639,653 4OOOO 3OOOO 2OOOO OOOO O.OOOO1 ALKYL PHOSPHATE (DILUTION) FG. 1A U.S. Patent Jun. 17, 1997 Sheet 2 of 17 5,639,653 125OO 1 OOOO 75OO - H MEP -O- DEP 5OOO - A - TEP 25OO O. 1 1 1 O ETHYL PHOSPHATE (LM) FG 1B U.S. Patent Jun. 17, 1997 Sheet 3 of 17 5,639,653 1OO 75 50 25 O.1 1 1O 1 OO 1000 1 OOOO MEP DERIVATIVES (uM) FG. 1 C U.S. Patent Jun. 17, 1997 Sheet 4 of 17 5,639,653 t" SSZZa - e - a 1 . CULTURED WITH: MEDIA 2M.tb MEP O 2O 40 60 8O yóT CELLS (%. CD3 CELLS) FG. 2A U.S. Patent Jun. 17, 1997 Sheet S of 17 5,639,653 AWOA; (47462a W7, ss as A. NN Mea/Af n SRS s NNS s S SNS. wer S S vSS r AW77- V82/Zea aea/WAZagasa/wa/ FG. 2B U.S. Patent Jun. 17, 1997 Sheet 6 of 17 5,639,653 689. ZOAl 93A 9WA 92OW ZZOW 5. 9 OW 9-H 6OOH N ZSCO 872 987 ZH 27-SS)O 89.SS)O 99S 3 N O CN L XGON NOW? WIS GW 3 - C) : U.S. Patent Jun. 17, 1997 Sheet 7 of 17 5,639,653 50 1 OO K562 TARGETS DAUDI TARGETS ? 40 8O -1 f f X 30 60 C C 8 20 40 f f NS N O O O 5 1 O 15 20 25 O 5 1 O 15 20 25 E/T RATIO E/T RATIO \-/ FG. 3B U.S. Patent Jun. 17, 1997 Sheet 8 of 17 5,639,653 30000 O.05 E Na 0.04 E (f)L C f) CN 2 20000 OC 0.05 f) L t 1. O 2L O.O2 22. is 10000 0.019 - O 1. O ar (CCCCIII (CCCCCCC(C) O.OO O 2O 40 6O 8O TUBE NUMBER (1 TUBE=12ml) FG 4A U.S. Patent Jun. 17, 1997 Sheet 9 of 17 5,639,653 40000 O.4 E N1 S 30000 0.35 (f) OO 2 He ! 20000 0.2 3. 2 9 aC O 10000 o 0.1 % . CC - : e - l O d P3 a simil O.O O 2O 40 6O 8O TUBE NUMBER (1 TUBE=12mL) FG. 4B U.S. Patent Jun. 17, 1997 Sheet 10 of 17 5,639,653 O 2O 4-O 6O 80 TUBE NUMBER (1 TUBE=12m) FG. 4C U.S. Patent Jun. 17, 1997 Sheet 11 of 17 5,639,653 i 5 5 S S O O O 3 3 OO O r CN (2) LISN3LN 3AW133 U.S. Patent Jun. 17, 1997 Sheet 13 of 17 5,639,653 O OFal-O 009: C OFO-O OZH– /ZZ 09ZOOZ 09|| OG’º)|- 1ç?ºl 6/ 00|| O r O - NS O r CN vur 090 (2) LISN3LN 3AW13& U.S. Patent Jun. 17, 1997 Sheet 14 of 17 5,639,653 4OOOO 3OOOO 2OOOO 1 OOOO O1 ... 1 1 1O 1OO 1 OOO ANTIGEN (LM) FIG 5D U.S. Patent Jun. 17, 1997 Sheet 15 of 17 5,639,653 25OOO 2OOOO 15OOO 1 OOOO 5OOO ... 1 1 10 100 1 OOO ANTIGEN (uM) F.G. 6A U.S. Patent Jun. 17, 1997 Sheet 16 of 17 5,639,653 25OOO 2OOOO 15000 1 OOOO 5000 ... 1 1 1O 1 OO 1 OOO 1 OOOO ANTIGEN (uM) F.G. 6B U.S. Patent Jun. 17, 1997 Sheet 17 of 17 5,639,653 5,639,653 1. 2 METHOD FOR PROLIFERATING Vy2V82T the yö T cell clone DG.SF68, which expresses Vy2V82, CELLS when cultured with crude reaction mixtures of the following alkylphosphates: methyl phosphate (solid square), monoet STATEMENT OF GOVERNMENT INTEREST hyl phosphate (solid circle), n-propyl phosphate (solid 5 triangle), n-butyl phosphate (solid diamond), amyl phos This application is a continuation-in-part of application phate (open square), isopropyl phosphate (open circle), Ser. No. 08/093,528, filed Jul 19, 1993, now abandoned the isoamyl phosphate (open triangle), and secbutyl phosphate contents of which is incorporated by reference herein. (open diamond). FIG. 1B depicts the selective stimulation of This invention was made with government support under yó T cell clone SD9 by monoethyl phosphate (MEP, solid Grant No. NTH AI07118. As such, the government has square), diethyl phosphate (DEP solid circle), and triethyl certain rights in this invention. 10 phosphate (TEP, solid triangle). FIG. 1C depicts the stimu lation of the yá T cell clone SD9 by monoethyl phosphate BACKGROUND OF THE INVENTION (MEP, solid square), its hydroxyl derivative (B-hydroxyethyl T cells are thymus-derived cells in the immune system phosphate, open circle), and its carboxyl derivative which mediate cellular immune reactions and regulate (phosphoglycolic acid, open triangle). The percentage of the immune response. T lymphocytes (T cells) are divided into 15 maximal proliferation is shown. two subgroups by their usage of T cell receptors. About FIGS. 2A and 2B depict the effect of MEP on primary 90-98% of T cells have a? receptors (a? T cells) which PBMC and the specificity in the response of y& T cells to recognize antigenic peptides bound to major histo monoalkyl phosphate ligands. FIG. 2A depicts the expan compatibility complex I or Imolecules. About 2-10% of T 20 sion by MEP of yöT cells in primary cultures of PBMC as cells have yá receptors (yö T cells). determined by two-color FACS analysis. The increase of yö A major human yöT cell subset expressing Vy2 and V82 T cells by MEP is comparable to that stimulated by M. germlines (i.e. Vy2V62 T cells) is found in human myco tuberculosis (M.tb) lysates. FIG. 2B depicts the two-color bacterial lesions (Modlin, R. L., et al. Nature 339:544-548 FACS analysis showing that yoT cells expanded in primary (1989)). Vy2Vö2T cells have been shown to expand acutely 25 culture by MEP exclusively expressed V82. The percentages in response to mycobacterial pathogens such as M. tuber in the quadrants of interest are shown. culosis and M. luprae, bacterial pathogens such as Gram FIGS. 3A and 3B depict the effect of MEP on yöT cell positive and Gram-negative bacteria, as well as parasites clones and heterogeneity in the response of Vy2/VS2T cel, such as Plasmodium vivax (Kabelitz, D., et al. J. Exp. Med. clones to monoalkyl phosphate ligands. FIG. 3A shows the 171:667-679 (1990); Panchamoorthy, G., et al. J. Immunol. 30 proliferation in response to MEP was restricted to y& T cell 147:3360-3369 (1991); De Libero, G., et al. J. Exp. Med. clones expressing the Vy2/V62 receptor. The stimulation 173:1311-1322 (1991); Hara, T., et al. J. Clin. Invest. indices for the response to phytohemagglutinin (positive 90:204-210 (1992); Goerlich, R., et al. Eur: J. Immunol. control) were greater than 6 for all clones, with a mean value 21:2613-2616 (1991); and Goodier, M., et al. Int. Immunol. of 47.3. FIG. 3B shows the cytolytic activity of primary yö 4:33-41 (1992)). In addition, certain hematopoietic tumor 35 T cells expanded by MEP on tumor cell lines K562 and cell lines such as Daudi and RPMI 8226 are specifically Daudi, with 30 M MEP for 7 days (solid circle), with 30 recognized and lysed by Vy2V82 T cells (Fisch, P., et al. uMMEP for days on cell lines depleted of V82 cells by BB3 Science 250:1269-1273 (1990); Selin, L. K., et al. Scand. J. antibody and magnetic beads (Dynal)(solid triangle), and Immunol. 36:107-117 (1992)). medium only (solid square). E/T represents the effector to Because Vy2V82 T cells recognize antigens which are 40 target ratio. expressed by a variety of diseases in humans, there exists a FIGS.
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