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Matched Legal Cases: ['Application No. 97917856', 'Application No. 03', 'Application No. 21996', 'Application No. 97917856', 'Application No. 96', 'Application No. 97917856', 'Application No. 97904948', 'Application No. 96', 'Application No. 97917856', 'Application No. 97930120', 'Application No. 97930120', 'Application No. 97930120', 'Application No. 99966466', 'Application No. 03713632', 'Application No. 01970984', 'Application No. 96921473', 'Application No. 95905987', 'Application No. 81426', 'Application No. 2004128252', 'Application No. 03', 'Application No. 96', 'Application No. 96', 'Application No. 81426', 'Application No. 97904948', 'Application No. 535610', 'Application No. 01970984', 'Application No. 21996', 'Application No. 99', 'Application No. 1006097', 'Application No. 97917856', 'Application No. 97917856', 'Application No. 2003217674', 'Application No. 26074', 'Application No. 14387', 'Application No. 35106', 'Application No. 2001290925', 'Application No. 62690', 'Application No. 35106', 'Application No. 96', 'Application No. 98', 'Application No. 98', 'Application No. 07', 'Application No. 2001290925', 'Application No. 99', 'Application No. 534947', 'Application No. 20004205164', 'Application No. 20004205165', 'Application No. 97917856', 'Application No. 96', 'Application No. 2004233505', 'Application No. 01970984', 'Application No. 97', 'Application No. 01970984', 'Application No. 2', 'Application No. 34026', 'Application No. 97917856', 'Application No. 97917856', 'Application No. 35106', 'Application No. 62690', 'Application No. 2', 'Application No. 97', 'Application No. 14387', 'Application No. 26074', 'Application No. 03', 'Application No. 1006097', 'Application No. 99', 'Application No. 501895', 'Application No. 01970984', 'Application No. 97917856', 'Application No. 2', 'Application No. 96', 'Application No. 2', 'Application No. 07014859', 'Application No. 34026', 'Application No. 200404610', 'Application No. 81426', 'Application No. 97']

Patent US7858298 - Contacting with monoclonal antibody which binds to chemokine receptor ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsThis invention provides methods for inhibiting fusion of HIV-1 to CD4+ cells which comprise contacting CD4+ cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4+ cells is inhibited. This invention also provides...http://www.google.com/patents/US7858298?utm_source=gb-gplus-sharePatent US7858298 - Contacting with monoclonal antibody which binds to chemokine receptor; blocks fusion and inhibits activation of inflammatory response; inhibiting fusion of HIV-1 to CD4+ cellsAdvanced Patent SearchPublication numberUS7858298 B1Publication typeGrantApplication numberUS 09/460,216Publication dateDec 28, 2010Filing dateDec 13, 1999Priority dateApr 1, 1996Also published asUS7935797, US20080138897, US20130211043Publication number09460216, 460216, US 7858298 B1, US 7858298B1, US-B1-7858298, US7858298 B1, US7858298B1InventorsGraham P. Allaway, Virginia M. Litwin, Paul J. Maddon, William C. OlsonOriginal AssigneeProgenics Pharmaceuticals Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (97), Non-Patent Citations (572), Referenced by (1), Classifications (17), Legal Events (3) External Links: USPTO, USPTO Assignment, EspacenetContacting with monoclonal antibody which binds to chemokine receptor; blocks fusion and inhibits activation of inflammatory response; inhibiting fusion of HIV-1 to CD4+ cellsUS 7858298 B1Abstract This invention provides methods for inhibiting fusion of HIV-1 to CD4+ cells which comprise contacting CD4+ cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4+ cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4+ cells which comprise contacting CD4+ cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4+ cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4+ cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4+ cells effective to prevent fusion of HIV-1 to CD4+ cells and a pharmaceutically acceptable carrier.
BACKGROUND OF THE INVENTION Chemokines are a family of related soluble proteins of molecular weight between 8 and 10 KDa, secreted by lymphocytes and other cells, which bind receptors on target cell surfaces resulting in the activation and mobilization of leukocytes, for example in the inflammatory process. Recently, Cocchi et al. demonstrated that the chemokines RANTES, MIP-1α and MIP-1β are factors produced by CD8+ T lymphocytes which inhibit infection by macrophage-tropic primary isolates of HIV-1, but not infection by laboratory-adapted strains of the virus (1). These chemokines are members of the C-C group of chemokines, so named because they have adjacent cysteine residues, unlike the C-X-C group which has a single amino acid separating these residues (2). While Cocchi et al. found that expression of HIV-1 RNA was suppressed by treatment with the chemokines, they did not identify the site of action of these molecules.
SUMMARY OF THE INVENTION This invention provides a method for inhibiting fusion of HIV-1 to CD4+ cells which comprises contacting CD4 cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4+ cells is inhibited.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Membrane fusion mediated by the HIV-1JR-FL envelope glycoprotein is inhibited by RANTES, MIP-1α and MIP-1β.
% Inhibition=100. [(Max RET−Min RET)−(Exp RET−Min RET)]/(Max RET−Min RET) where Max RET is the % RET value obtained at four hours with HeLa-env cells and CD4-expressing cells in the absence of an inhibitory compound; Exp RET is the % RET value obtained for the same cell combination in the presence of an inhibitory compound and Min RET is the background % RET value obtained using HeLa cells in place of HeLa envelope-expressing cells. FIG. 2. CD4:HIV-1 gp120 binding in the presence of human chemokines.
The binding of soluble human CD4 to HIV-1lai and HIV-1JR-FL gp120 was determined in an ELISA assay in the presence and absence of the monoclonal antibody OKT4A or recombinant human chemokines at a range of concentrations, identical to those used in the RET inhibition studies of FIG. 1: OKT4A (62-0.3 nM), RANTES (10.3-0.3 nM), MIP-1α (53.3-2.9 nM), and MIP-1β (25.6-0.8 nM). Inhibitors were added simultaneously with biotinylated HIV-1 gp120 to soluble CD4 coated microtiter plates (Dynatech Laboratories, Inc., Chantilly, Va.). Following a two hour incubation at room temperature and extensive washing, an incubation with streptavidin-horseradish peroxidase was performed for one hour at room temperature. Following additional washes, substrate was added and the OD at 492 nm determined in an ELISA plate reader. Data are representative of two independent experiments which were run in quadruplicate. FIG. 3. Specificity. time course and stage of β-chemokine inhibition of HIV-1 replication.
(a) PM1 cells (1�106) were preincubated with RANTES+MIP-1α+MIP-1β (R/Mα/Mβ; 100 ng/ml of each) for 24 h (−24 h) or 2 h (−2 h), then washed twice with phosphate buffered saline (PBS). HIV-1 (BaL env-complemented) virus (50 ng of p24; see legend to Table 1) was added for 2 h, then the cells were washed and incubated for 48 h before measurement of luciferase activity in cell lysates as described previously (10,11). Alternatively, virus and R/Mα/Mβ were added simultaneously to cells, and at the indicated time points (1 h, 3 h, etc) the cells were washed twice in PBS, resuspended in culture medium and incubated for 48 h prior to luciferase assay. Time 0 represents the positive control, to which no β-chemokines were added. +2 h represents the mixture of virus with cells for 2 h prior to washing twice in PBS, addition of R/Mα/Mβ and continuation of the culture for a further 48 h before luciferase assay. (b) PM1 cells (1�106) were infected with HIV-1 (500 pg p24) grown in CEM cells (NL4/3; lanes 1-4) or macrophages (ADA; lanes 5-8), in the presence of 500 ng/ml of RANTES (lanes 1 and 5) or MIP-1β (lanes 2 and 6), or with no β-chemokine (lanes 4 and 8). Lanes 3 and 7 are negative controls (no virus). All viral stocks used for the PCR assay were treated with DNAse for 30 min at 37� C., and tested for DNA contamination before use. After 2 h, the cells were washed and resuspended in medium containing the same J-chemokines for a further 8 h. DNA was then extracted from infected cells using a DNA/RNA isolation kit (US Biochemicals). First round nested PCR was performed with primers: U3+, 5′-CAAGGCTACTTCCCTGATTGGCAGAACTACACACCAGG-3′ (SEQ ID NO:1) preGag, 5′-AGCAAGCCGAGTCCTGCGTCGAGAG-3′ (SEQ ID NO:2) and the second round with primers: LTR-test, 5′-GGGACTTTCCGCTGGGGACTTTC 3′(SEQ ID NO:3) LRC2, 5′-CCTGTTCGGGCGCCACTGCTAGAGATTTTCCAC 3′ (SEQ ID NO:4) in a Perkin Elmer 2400 cycler with the following amplification cycles: 94� C. for 5 min, 35 cycles of 94� C. for 30 s, 55� C. for 30 s, 72� C. for 30 s, 72� C. for 7 min. M indicates 1 kb DNA ladder; 1, 10, 100, 1000 indicate number of reference plasmid (pAD8) copies. The assay can detect 100 copies of reverse transcripts. FIG. 4: HIV-1 env-mediated membrane fusion of cells transiently expressing C-C CKR-5.
Membrane fusion mediated by β-chemokine receptors expressed in HeLa cells was demonstrated as follows: Cells were transfected with control plasmid pcDNA3.1 or plasmid pcDNA3.1-CKR constructs using lipofectin (Gibco BRL). The pcDNA3.1 plasmid carries a T7-polymerase promoter and transient expression of β-chemokine receptors was boosted by infecting cells with 1�107 pfu of vaccinia encoding the T7-polymerase (vFT7.3) 4 h post-lipofection (9). Cells were then cultured overnight in R18-containing media and were tested for their ability to fuse with HeLa-JR-FL cells (filled columns) or HeLa-BRU cells (hatched column) in the RET assay. The % RET with control HeLa cells was between 3% and 4% irrespective of the transfected plasmid. FIG. 5 Membrane fusion mediated by the HIVLAI envelope glycoprotein is inhibited by SDF-1.
% RET resulting from the fusion of PM1 cells and HeLa-envJR-FL or HeLa-envLAI cells (as indicated on the graph) was measured in the presence of recombinant SDF-1α (Gryphon Science, San Francisco) at the indicated concentrations. Experimental method as described in the legend to FIG. 1. FIG. 6. Flow cytometric analysis of the binding of sCD4-gp120 complexes to (a) CCR5− and (b) CCR5 L1.2 cells, a murine pre-B lymphoma line.
Cells are incubated for 15 min. with equimolar (�100 nM) mixtures of sCD4 and biotinylated HIV-1JR-FL gp120 and then stained with a streptavidin-phycoerythrin conjugate, fixed with 2% paraformaldehyde, and analyzed by FACS. Cell number is plotted on the y-axis. FIG. 7. Inhibition of HIV-1 envelope-mediated cell fusion by the bicyclam JM3100, measured using the RET assay, with the cell combinations indicated.
Recombinant soluble CD4 (sCD4) and recombinant gp120 were added in a range of concentrations either individually or as an equimolar molecular complex to recombinant L1.2 cells that express human CCR5 on their cell surface. The recombinant proteins were biotinylated as indicated. Binding was detected by adding a streptavidin-phycoerythrin conjugate and measuring the fluoroescence emission at 590 nm following excitation at 530 nm. The following species were tested: b-LAI:sCD4:
complex formed between scD4 and
b-JR-FL:sCD4:
b-sCD4 alone:
biotinylated sCD4 added in the
b-JR-FL alone:
biotinylated HIV-1JR-FL gp120 added
HIV-1 Inhibitory monoclonal antibodies were added in a range of concentrations to recombinant L1.2 cells that express human CCR5 on their cell surface and used to compete the binding of a complex formed between sCD4 and biotinylated HIV-1JR-FL gp 120, whose binding was detected using a streptavidin-phycoerythrin conjugate. PA-8, -9, -10, -11 and -12 are Progenics' monoclonal antibodies that inhibit HIV-1 entry, while 2D7 is a commercially available (Pharmingen, San Diego, Calif.) ant-CCR5 monoclonal antibody that inhibits HIV-1 entry. To enhance chemokine receptor expression, both transfected and parental L1.2 cells were treated with sodium butyrate prior to assay (Wu et al., J. Exp. Med. 185:1681). DETAILED DESCRIPTION OF THE INVENTION This invention provides a method for inhibiting fusion of HIV-1 to CD4+ cells which comprises contacting CD4 cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4+ cells is inhibited.
REFERENCES OF THE FIRST SERIES OF EXPERIMENTS 1. Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., Lusso, P. 1995. Science. 270:1811-1815.
+R/Mα/Mβ (50/50/50)
+RANTES (100)
+R/Mα/Mβ (200/200/200)
PM1 cells were cultured as described by Lusso et al (12). Ficoll/hypaque-isolated PBMC from laboratory workers (LW) stimulated with PHA for 72 h before depletion of CD8+ Lymphocytes with anti-CD8 immunomagnetic beads (DYNAL, Great Neck, NY). CD4+ Lymphocytes were maintained in culture medium containing interleukin-2 (100 U/ml; Hofmann LaRoche, Nutley, NJ), as described previously (3). Target cells (1-2 � 105) were infected with supernatants (10-50 ng of HIV-1 p24) from 293-cells co-transfected with an L4/3env-luciferase vector and a HIV-1 env-expressing vector (10,11). α-Chemokines (R & D Systems, Minneapolis) were added to the target cells simultaneously with virus, at the final concentrations (ng/ml) indicated in parentheses in the first column. The β-chemokine concentration range was selected based on prior studies (2,3). After 2 h, the cells were washed twice with PBS, resuspended in E-chemokine-containing media and maintained for 48-96 h. Luciferase activity in cell lysates was measured as described previously (10, 11). The values indicated represent luciferase activity (cpm)/ng p24/mg protein, expressed relative to that in virus-control cultures lacking β-chemokines (100%), and are the means of duplicate or sextuplicate determinations. nd, not done. R/Mα/Mβ, RANTES + MIP-1α + MIP-1β.
RANTES and MIP-1β were strongly active when added individually, while other β-chemokines�M1P-1α, MCP-1, MCP-2 and MCP-3 (refs. 13-15)�were weaker inhibitors (Table 1a). However, MIP-1α, MIP-1β and RANTES, in combination, did not inhibit infection of PM1 cells by the TCLA strains NL4/3 and HxB2, or by the amphotropic murine leukemia virus (MuLV-Ampho) pseudotype (Table 1a). Thus, phenotypic characteristics of the HIV-1 envelope glycoproteins influence their sensitivity to β-chemokines in a virus entry assay.
+OKT4A (3ug/ml)
CD4+target cells (mitogen-activated CD4+lymphocytes or PM1 cells) were labeled with octadecyl rhodamine (Molecular Probes, Eugene, OR), and HeLa-JR-FL cells, HeLa-BRU cells (or control HeLa cells, not shown) were labeled with octadecyl fluorescein (Molecular Probes), overnight at 37� C. Equal numbers of labeled target cells and env-expressing cells were mixed in 96-well plates and β-chemokines (or CD4 MAb OKT4a) were added at the final concentrations (ng/ml) indicated in parentheses in the first column. Fluorescence emission values were determined 4 h after cell mixing (17). If cell fusion occurs, the dyes are closely associated in the conjoined membrane such that excitation of fluorescein at 450 nm results in resonance energy transfer (RET) and emission by rhodamine at 590 nm. Percentage fusion is defined as equal to 100 � [(Exp RET − Min RET)/(Max RET − Min RET)], where Max RET = %RET obtained when HeLa-Env and CD4+cells are mixed, Exp RET = %RET obtained when HeLa-Env and CD4+cells are mixed in the presence of fusion-inhibitory compounds, and Min RET = %RET obtained when HeLa cells (lacking HIV-1 envelope glycoproteins) and CD4+cells are mixed. The %RET value is defined by a calculation described elsewhere(17), and each is the mean of triplicate determinations. These values were, for HeLa-JR-FL and HeLa-BRU cells respectively: PM1 cells 11.5%, 10.5%; LW5 CD4+cells, 6.0%, 10.5%; R/Mα/Mβ, RANTES + MIP-1α + MIP-1β.
REFERENCES OF THE SECOND SERIES OF EXPERIMENTS 1. Levy, J. A., Mackewicz, C. E. & Barker, E. Immunol. Today 17, 217-224 (1996).
REFERENCES OF THE THIRD SERIES OF EXPERIMENTS 1. Bleul, C. C., et al. (1996) Nature 382:829-833
1) Plate out L1.2-CCR5′ cells (approx. 500,000/well). 2) Add inhibitor for 1 hour at room temperature. 3) Wash and add biotinylated sCD4 (2.5 μg/ml) and biotinylated gp120 (5 μg/ml), then incubate for 2 hours at room temperature. 4) Wash and incubate with streptavidin-phycoerythrin (100 ng/nl). 5) Wash and measure the amount of bound gp120/sCD4 using a fluorometric plate reader exciting at 530 nm and reading emission at 590 nm. Using this method, inhibition of binding of gp120/sCD4 to CCR5 by CC-chemokines (FIG. 7) and antibodies to CCR5 that block HIV-1 infection (not shown) have been demonstrated.
2. Add cells to 96-well plate (�3�105 cells/well)
6. Prepare an equimolar (�50 nM) mixture of sCD4 and biotinylated gp120. Add 40 μl of sCD4:biotinylated gp120 complex per well. (Final volume in well=80 μL). Shake plate to suspend cells in protein solution. Incubate ac room temperature for one hour.
% Inhibition=[Max−Reading]/[Max−Min] Max=Average of values in wells containing [sCD4: biotinylated gp120 w/CCR5+/L1.2 cells, no inhibitor] Min=Average of values in wells containing sCD4:biotinylated gp120 w/L1.2 cells, no inhibitor. 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Chem., 269:15918-15924.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS20090326011 *Jun 13, 2006Dec 31, 2009Luca AristaAzab i cyclo [3 . 1 . 0] hexane derivatives as dopamin d3 receptor modulators* Cited by examinerClassifications U.S. Classification435/5, 424/148.1, 424/160.1International ClassificationC12Q1/70, A61K39/42Cooperative ClassificationG01N2500/10, C07K2316/96, C07K16/2866, G01N2333/162, G01N33/56988, G01N33/566, G01N2333/70514, G01N2333/7158, C07K2/00European ClassificationG01N33/566, G01N33/569K2, C07K16/28HLegal EventsDateCodeEventDescriptionJan 15, 2013ASAssignmentOwner name: CYTODYN, INC., OREGONFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PROGENICS PHARMACEUTICALS, INC.;REEL/FRAME:029633/0837Effective date: 20130108Sep 19, 2000ASAssignmentOwner name: PROGENICS PHARMACEUTICALS, INC., NEW YORKFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ALLAWAY, GRAHAM P.;LITWIN, VIRGINIA M.;MADDON, PAUL J.;AND OTHERS;SIGNING DATES FROM 19991228 TO 20000821;REEL/FRAME:011183/0826Nov 17, 1998ASAssignmentOwner name: PROGENICS PHARMACEUTICALS, INC., NEW YORKFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OLSON, WILLIAM C.;ALLAWAY, GRAHAM P.;LITWIN, VIRGINIA M.;AND OTHERS;SIGNING DATES FROM 19980727 TO 19980810;REEL/FRAME:009608/0335RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google