Monday, January 02, 2012 11:29:01 AM
PGN632 is the Duke-PPHM-HIV candidate, aka 11.31=AT005. Recall that the Apr’10 JEM Duke/Peregrine/HIV article abstract reported that “4 human anti-phospholipid mAbs (PGN632, P1, IS4, CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to ~10 ug/ml.” (see http://tinyurl.com/yzr2tax ). In the actual 23-pg. full article, Dr. Haynes refers to PGN632 as “the most potent [B2GPI-indep.] anti-phospholipid mAb” of the 4 tested. (see http://tinyurl.com/ydqdk59 ).
Note also that PGN632 binds to PS indep. of B2-glycoprotein I (B2GPI), unlike Bavi & FH-Bavi(PGN635) which depend on B2GPI as a binding intermediary.
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UNITED STATES PATENT APPLICATION #20110318360
Filed 9-8-09, pub. 12-29-11 - Barton F. Haynes et al
Title: “Anti-Lipid Antibodies”
USPTO.com link => http://tinyurl.com/6t43adn
ABSTRACT:
The present invention relates, in general, to anti-lipid antibodies and, in particular, to methods of inhibiting HIV-I infection using anti-lipid (e.g. anti-phospholipid) antibodies.
Inventors: Barton F. Haynes, M. Anthony Moody, Bua-Xin Liao (Durham, NC)
Assignee: DUKE UNIVERSITY
DETAILED DESCRIPTION OF THE INVENTION (a few extracts…)
[0027] The present invention relates, in one embodiment, to a method of inhibiting infection of cells (e.g. T-cells) of a subject by a CCR5-tropic strain of HIV-1. The method comprises administering to the subject (e.g., a human subject) an anti-human cell antibody (for example, an anti-lipid (e.g., anti-phospholipid) antibody), such as mAb 11.31(PGN632) or CL1), or fragment thereof, in an amount and under conditions such that the antibody, or fragment thereof, binds to cells of the patient that: i) can produce CCR5-binding chemokines, and ii) have on their surface an antigen recognized by the antibody. Binding of the antibody, or fragment thereof, induces the production of the CCR5-binding chemokines by the cells, either in the absence or in the presence of the CCR5-tropic strain of HIV-1, to a level sufficient to inhibit infection of HIV-1 susceptible cells that utilize the CCR5-receptor (e.g., T-cells). Advantageously, the antibody, or fragment thereof, is administered within 48 hours of exposure of the subject to the CCR5-tropic strain of HIV-1.
...
[0030] In accordance with the invention, the anti-lipid antibodies can be administered prior to contact of the subject or the subject's immune system/cells with CCR5-utilizing HIV-1 or within about 48 hours of such contact. Administration within this time frame can maximize inhibition of infection of vulnerable cells of the subject (e.g., T-cells) with CCR5-tropic HIV- 1. This mode of inhibition of HIV-1 is particularly effective for modifying or inhibiting the transmission event, since virtually all of the transmitted HIV-1 viral quasispecies are CCR5- tropic (Keele et al, Proc. Natl. Acad. Sci. 105:7552-7557, Epub 2008 May 19 (2008)).
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[0031] One preferred antibody for use in the invention is mAb 11.31(PGN632). This antibody was derived from an antibody library generated from PBLs of healthy donors. Whether it reflects an antibody that was being made at the time of production of the antibody library is not known. The original antibody isotype was IgM or IgD that was then converted to IgG and was further matured to optimize for high affinity PS binding. The potency of mAb 11.31(PGN632) for inhibition of CCR5-utilizing HIV-1 infection of PBMCs is broader than any other antibody reported.
...
[0034] The antibodies, and fragments thereof, described above can be formulated as a composition (e.g., a pharmaceutical composition). Suitable compositions can comprise the anti-lipid antibody (or antibody fragment) dissolved or dispersed in a pharmaceutically acceptable carrier (e.g., an aqueous medium). The compositions can be sterile and can in an injectable form. The antibodies (and fragments thereof) can also be formulated as a composition appropriate for topical administration to the skin or mucosa. Such compositions can take the form of liquids, ointments, creams, gels and pastes. Standard formulation techniques can be used in preparing suitable compositions. The antibodies can be formulated so as to be administered as a post-coital douche or with a condom.
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[0036] That anti-lipid antibodies only inhibit the infectivity of CCR5-utilizing primary isolates has significance for the mechanism of inhibition of infectivity and for the setting of utility of anti-lipid antibodies in inhibiting HIV-1 infection. That select anti-lipid antibodies (e.g. CL1 and 11.31(PGN632)) can inhibit HIV-1 infection up to 48 hours after addition of the virus show that they do not block virion binding and attachment. The data provided in the Example are compatible with the mode of action of the mAbs being induction of chemokines from monocytes and other chemokine producing cells. (See FIG. 13.) That the anti-lipid antibodies act up to 48 hours after infection show their utility for prophylaxis in, for example, the following settings:
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[0037] i) in the setting of anticipated known exposure to HIV-1 infection, the anti-lipid antibodies described herein (or binding fragments thereof) and be administered prophylactically (e.g., IV or topically) as a microbiocide,
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[0038] ii) in the setting of known or suspected exposure, such as occurs in the setting of rape victims, or commercial sex workers, or in any heterosexual transmission with out condom protection, the anti-lipid antibodies described herein (or fragments thereof) can be administered as post-exposure prophylaxis, e.g., IV or topically, and
[0039] iii) in the setting of Acute HIV infection (AHI) with an CCR5 transmitted virus, the anti-lipid antibodies described herein (or binding fragments thereof) can be administered as a treatment for AHI to control the initial viral load and preserve the CD4+ T cell pool and prevent CD4+ T cell destruction.
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THE DUKE/HAYNES/CAVD/GATES/CHAVI/NIAID HIV COLLABORATION:
Sept'10: LWW article by Barton Haynes ref's 4-2010 Duke/PPHM JEM antiPS article: http://tinyurl.com/2bsgv8m
…"HIV vaccines after STEP: Strategies for Eliciting HIV-1 Inhibitory Antibodies"
4-11-10: CHAVI Newsletter highlights the PPHM-Duke JEM article http://tinyurl.com/35eelvw
…"The study is significant because it shows that components of the adaptive immune system can activate antiviral innate immunity. Investigators believe that a vaccine that elicits polyreactive anti-PS antibodies could potentially be used to engage both the innate and adaptive immune response against HIV."
4-5-10: DukeHealth announces the 1st Duke/PPHM HIV Collab. article in JEM: http://tinyurl.com/yzr2tax
…Duke's Bart Haynes: "While the findings still have to be tested clinically, they do suggest a new way the immune system might be manipulated to thwart HIV."
…“Dr. Moody says the antibodies, PGN632, P1, IS4 and CL1, do not appear to have any pathogenic features. . . it causes them to secrete substances called chemokines that block HIV from docking with its favorite entry point into a blood cell, the CCR5 receptor.”
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THE FULL 4-5-10 JEM Duke-PPHM HIV article (23pg. PDF): http://jem.rupress.org/content/207/4/763.full.pdf+html
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