Methods for reducing viral load in HIV-1-infected patients

a technology for reducing viral load and hiv-1 infection, applied in the field of reducing viral load in hiv-1infected patients, can solve the problems of poor oral bioavailability, poor efficiency of the above-mentioned coreceptors, and local injection site irritation, so as to reduce the likelihood of a subject contracting hiv-1 infection, potentiate the effect of hiv-1 inhibitory activity, and reduce the likelihood of the subject contracting

Inactive Publication Date: 2007-02-01
PROGENICS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036] The invention further provides a method for reducing the likelihood of a subject's contracting an HIV-1 infection comprising administering to the subject (a) an antibody which (i) binds to a CCR5 receptor on the surface of a CD4+ cell and (ii) inhibits fusion of HIV-1 to a CCR5+CD4+ cell, and (b) a non-antibody antagonist of a CCR5 receptor, in amounts effective to reduce the likelihood of the subject's contracting an HIV-1 infection.
[0037] This invention also provides a method of potentiating HIV-1 inhibitory activity of (i) an anti-CCR5 receptor monoclonal antibody or (ii) a non-antibody CCR5 receptor antagonist in the treatment of HIV-1 infection in a subject, comprising: administering to the subject an HIV-1 inhibitory acti...

Problems solved by technology

However, TAK-779 exhibited poor oral bioavailability (Baba et al., 2005) and local injection site irritation (Iizawa et al., 2003), and has been replaced in clinical development by a TAK-779 derivative, TAK-652 (Baba et al., 2005).
However, most of the above-mentioned coreceptors are not very efficient, are not normally coexpressed with CD4, ...

Method used

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  • Methods for reducing viral load in HIV-1-infected patients
  • Methods for reducing viral load in HIV-1-infected patients
  • Methods for reducing viral load in HIV-1-infected patients

Examples

Experimental program
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Effect test

example 1

Combination Testing of PRO 140 and HIV-1 Entry Inhibitors in the Fluorescence RET Assay

Materials and Methods

Compounds and mAbs

[0175] PRO 140 was prepared by expression in Sp2 / 0 cells using Hybridoma serum-free medium supplemented with 2 mM L-glutamine (Invitrogen, Carlsbad, Calif.). Bulk mAb was clarified using a 5.0 μm Depth filter (Sartorius, Goettingen, Germany) followed by passage over a 0.2 μm sterilizing grade filter (Sartorius). The mAb was purified by passage first over an affinity column (MabSelect Protein A column, Amersham, Piscataway, N.J.) and then by ion exchange chromatography (SP Sepharose Cation Exchange resin, Amersham). PRO 140 was nanofiltered using a Viresolve™ 10 Opticap NFP capsule (Millipore, Billerica, Mass.) followed by a 0.2 μm filter and concentrated / diafiltered over disposable TFF cartridges (Millipore). The mAb was then polished over a hydroxyapatite column (Bio-Rad, Hercules, Calif.), concentrated to 10 mg / ml in phosphate-buffered saline and store...

example 2

Combination Testing of PRO 140 with Small Molecule, Peptide and Protein Inhibitors, and HIV-1 in the HIV-1 Pseudovirus Particle (HIV-1PP) Assay

Materials and Methods

Preparation of HIV-1 Pseudoparticles

[0221] HIV-1 pseudoparticles (HIV-1pp) are generated in 293T cells by transient coexpression of an HIV-1-based NL4 / 3luc+env− plasmid and a construct encoding HIV-1JRFL Env. The NLA / 3luc+env− plasmid was obtained from the NIH AIDS Research and Reference Reagent Program (Cat. No. 3418), and the HIV-1JRFL Env was inserted into the pcDNA3.1 vector (Invitrogen). Briefly, 293T cells are calcium phosphate transfected with a 1:1 ratio of NL4 / 3luc+env− reporter vector and Env expression vector in Hepes buffer (Profection Mammalian Transfection Kit, Promega). After 16 h the transfection medium is aspirated and fresh cell culture medium (DMEM with 10% FBS, glutamine and antibiotics) is added and the incubation is continued at 37° C. for an additional 24-32 h. Cell culture supernatants are col...

example 3

Combination Testing of PRO 140 with Small Molecule, Peptide and Protein Inhibitors in the HIV-1 Authentic Virus Replication Assay

Materials and Methods

Preparation of PBMCs

[0235] Replication of authentic HIV-1 is measured in activated peripheral blood mononuclear cells (PBMCs) using the monocyte / macrophage-tropic HIV-1 clone, JRFL (HIV-1JRFL), for these studies.

[0236] PBMCs are isolated from 4 separate donors (Leukopacks) by centrifugation on a Ficoll gradient. CD8 cells are depleted using RosetteSep CD8 Depletion Cocktail (#15663, StemCell Research, Vancouver, BC). Cells are diluted to 4×106 / ml and added in equal parts to three T175-cm2 flasks and then stimulated by adition of one of the following media: IL-2 Medium [RPMI 1640 (#10-040-CV, Cellgro, Herndon, Va.), 10% FBS (#35-010-CV), 2 mM L-Glutamine (#25-005-CI), 100 U / ml IL-2 (Sigma, St. Louis, Mo.)]; PHA 5 Medium: [IL-2 Medium with 5 ug / ml Phytohemagglutinin PHA-P(PHA) (#L8754, Sigma, St. Louis, Mo.), filtered]; or PHA 0.5 ...

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Abstract

This method provides a method for reducing HIV-1 viral load in an HIV-1-infected human subject which comprises administering to the subject at a predefined interval effective HIV-1 viral load-reducing doses of (a) a humanized antibody designated PRO 140, or of (b) an anti-CCR5 receptor monoclonal antibody. This invention also provides a method for inhibiting in a human subject the onset or progression of an HIV-1-associated disorder, the inhibition of which is effected by inhibiting fusion of HIV-1 to CCR5+CD4+ target cells in the subject. This invention also provides a method for treating a subject infected with HIV-1 comprising administering to the subject (a) a monoclonal antibody which (i) binds to a CCR5 receptor on the surface of the subject's CD4+ cells and (ii) inhibits fusion of HIV-1 to the subject's CCR5+CD4+ cells, and (b) a non-antibody CCR5 receptor antagonist, in amounts effective to treat the subject.

Description

[0001] This application claims benefit of U.S. Provisional Application No. 60 / 702,064, filed Jul. 22, 2005; U.S. Provisional Application No. 60 / 701,889, filed Jul. 23, 2005; U.S. Provisional Application No. 60 / 711,528, filed Aug. 26, 2005; and U.S. Provisional Application No. 60 / 715,619, filed Sep. 9, 2005; the contents of each of which in its entirety is hereby incorporated by reference into this application.[0002] This invention was made with support under United States Government Grant Nos. A1046871 and A1066329 from the National Institute of Allergy and Infectious Diseases. Accordingly, the United States Government has certain rights in the subject invention.[0003] Throughout this application, various publications are referenced in parentheses by author name and date, or by a patent or patent publication number. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of each of these publications in its...

Claims

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Application Information

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IPC IPC(8): C12Q1/68G01N33/53
CPCA61K31/4178A61K39/39A61K39/3955A61K31/496A61K38/1709A61K31/551A61K38/195A61K31/7072A61K31/506A61K2039/505A61K39/39541A61K31/351C12Q1/701C07K2317/24A61K2039/55511C07K2316/96A61K31/46C07K16/2866A61K2300/00C07K2317/76A61P31/18A61P43/00A61K39/395
Inventor OLSON, WILLIAM C.MADDON, PAUL J.PEVEAR, DANIEL C.ISRAEL, ROBERT J.MURGA, JOSE D.
Owner PROGENICS PHARMA INC
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