ITMI20010500A1 - NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES - Google Patents
NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES Download PDFInfo
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Description
Descrizione dell'invenzione industriale avente per titolo: Description of the industrial invention entitled:
"AUTO-ANTICORPI NATURALI E IL LORO USO NELLA TERAPIA DI MALATTIE DA VIRUS DELL’IMMUNODEFICIENZA UMANA” "NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE THERAPY OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES"
La presente invenzione ha per oggetto anticorpi neutralizzanti il virus deH’immunodeficienza umana. L’invenzione si riferisce in particolare all’uso di anticorpi auto-reattivi come agenti terapeutici. The present invention relates to antibodies neutralizing the human immunodeficiency virus. The invention refers in particular to the use of self-reactive antibodies as therapeutic agents.
E’ noto che il virus dell’immunodeficienza umana (HIV) è in grado, in seguito all’infezione, di replicarsi fino a titoli molto elevati, con carichi virali plasmatici maggiori di 10<6 >copie di RNA virale / mi. It is known that the human immunodeficiency virus (HIV) is able, following infection, to replicate up to very high titers, with plasma viral loads greater than 10 <6> copies of viral RNA / ml.
Alla siero-conversione, la viremia diminuisce di diverse unità logaritmiche e può persino raggiungere livelli non rilevabili. Tuttavia, nonostante la risposta virus-specifica sia umorale che cellulare dell’ospite, negli individui infettati il virus permane e dopo molti anni di latenza si attiva, mutando spesso in forme varianti. On serum conversion, viraemia decreases by several log units and can even reach undetectable levels. However, despite both the humoral and cellular virus-specific response of the host, in infected individuals the virus persists and after many years of latency it becomes active, often changing into variant forms.
Il fallimento del sistema immunitario nello sradicare il virus dell’AIDS dopo l’infezione rimane un mistero irrisolto. The failure of the immune system to eradicate the AIDS virus after infection remains an unsolved mystery.
L’AIDS progredisce attraverso tre stadi successivi all’infezione da HIV-1. Il primo è uno stadio asintomatico durante il quale il paziente ospita il virus, i test sono sieropositivi per gli anticorpi anti-HIV ma non vi sono sintomi della malattia. Questo stadio può durare 5 o più anni. Il secondo stadio, il complesso correlato ad AIDS (ARC) e lo stadio finale, AIDS, sono sintomatici e caratterizzati da tumori e da una serie di infezioni opportunistiche. AIDS progresses through three stages following HIV-1 infection. The first is an asymptomatic stage during which the patient hosts the virus, the tests are seropositive for anti-HIV antibodies but there are no symptoms of the disease. This stage can last 5 or more years. The second stage, the AIDS-related complex (ARC) and the final stage, AIDS, are symptomatic and characterized by tumors and a series of opportunistic infections.
Subito dopo l’infezione da HIV-1 si verifica una forte risposta umorale ma l’attività di linfociti T specifici per HIV (CTL) è ritenuta essere il principale fattore nel controllo precoce della viremia. Gli anticorpi neutralizzanti contro gli isolati virali precoci sono rilevabili dopo circa un anno dall’infezione. Pertanto, il ruolo della risposta immunitaria umorale nel controllo precoce del virus è ancora controverso. A strong humoral response occurs immediately after HIV-1 infection, but the activity of HIV-specific T lymphocytes (CTL) is believed to be the main factor in the early control of viraemia. Neutralizing antibodies against early viral isolates are detectable approximately one year after infection. Therefore, the role of the humoral immune response in early virus control is still controversial.
Gli anticorpi hanno scarsa affinità per l’involucro nativo come espresso sulla superficie dei virioni o delle cellule infettate ma hanno elevate affinità contro forme non native dell’involucro di HIV-1 (residuo virale) e neutralizzano i virus in modo sub-ottimale. L’involucro di HIV-1 è presentato al sistema immunitario in diverse configurazioni antigenicamente distinte, quali le sub-unità gpl60 non processata, gpl20, gp41 e l’involucro nativo, ognuna delle quali può essere importante nello scatenare una risposta anticorpale nell’infezione da HIV-1. The antibodies have low affinity for the native envelope as expressed on the surface of the virions or infected cells but have high affinity against non-native forms of the envelope of HIV-1 (viral residue) and neutralize the viruses in a sub-optimal way. The HIV-1 envelope is presented to the immune system in several antigenically distinct configurations, such as the unprocessed gpl60, gpl20, gp41 subunits, and the native envelope, each of which may be important in triggering an antibody response in the infection. from HIV-1.
Si ritiene probabile che le anormalità nella risposta umorale delle cellule B contro HIV-1 siano almeno in parte responsabili dell’inefficacia del sistema immunitario associata alla malattia correlata ad HIV-1. It is believed likely that the abnormalities in the humoral response of B cells against HIV-1 are at least partly responsible for the ineffectiveness of the immune system associated with HIV-1-related disease.
In luogo della normale risposta policlonale vista in altre infezioni, la risposta anticorpale in individui infettati da HIV-1 sembra il risultato di popolazioni anticorpali oligoclonali o monoclonali. In place of the normal polyclonal response seen in other infections, the antibody response in HIV-1 infected individuals appears to be the result of oligoclonal or monoclonal antibody populations.
E’ stato isolato un anticorpo monoclonale anti-idiotipo avente reattività specifica con un idiotipo specificamente legato dall’anticorpo monoclonale 1F7. An anti-idiotype monoclonal antibody having specific reactivity with an idiotype specifically linked by the 1F7 monoclonal antibody was isolated.
Il concetto di complementarietà idiotipica, come fenomeno di importanza fondamentale per le attività immunitarie è noto da più di venticinque anni (teoria di Jerne, 1974). Da molto tempo, si ritiene che Γ autoreattività sia associata solamente con la patologia, probabilmente poiché gli auto- anticorpi sono stati identificati per la prima volta nelle malattie autoimmuni. Tuttavia, studi recenti hanno dimostrato che auto-anticorpi naturali sono presenti in quantità misurabili nei sieri di individui normali di diverse specie. Questi auto-anticorpi naturali sono reattivi nei confronti di molecole altamente conservate. L’attività di anticorpi autoreattivi Ig era considerevolmente aumentata quando le IgG erano separate da altre proteine del siero. Questi risultati suggeriscono una regolazione di tipo idiotipico degli auto-anticorpi IgG nel siero normale. The concept of idiotypical complementarity, as a phenomenon of fundamental importance for immune activities, has been known for more than twenty-five years (Jerne theory, 1974). Self-reactivity has long been believed to be associated only with disease, probably because autoantibodies were first identified in autoimmune diseases. However, recent studies have shown that natural autoantibodies are present in measurable amounts in the sera of normal individuals of several species. These natural autoantibodies are reactive towards highly conserved molecules. The activity of self-reactive Ig antibodies was considerably increased when the IgG were separated from other serum proteins. These results suggest an idiotypic regulation of IgG autoantibodies in normal serum.
D’altra parte, poiché l’esposizione acuta all’infezione da HIV rimane sotto controllo per un certo periodo di tempo, abbiamo pensato di poter essere in grado di riprodurre alcuni di questi processi per ricostituzione immunitaria, ricorrendo specificamente alla somministrazione di anticorpi neutralizzanti HIV. On the other hand, since acute exposure to HIV infection remains under control for a certain period of time, we thought we might be able to reproduce some of these processes by immune reconstitution, specifically resorting to the administration of HIV neutralizing antibodies. .
E’ così possibile prevenire l’infezione da HIV o ritardare la comparsa della malattia con una forma di somministrazione passiva di anticorpi. It is thus possible to prevent HIV infection or delay the onset of the disease with a form of passive administration of antibodies.
La correlazione immunitaria fra protezione dall’infezione da HIV e progressione della malattia non è ben nota. L’estrapolazione dal modello murino a quello umano è incerta, ma sembra probabile che anticorpi molto efficaci siano in grado di fornire protezione. In un recente studio comparativo, solo tre anticorpi monoclonali sono risultati in grado di neutralizzare (90%) un intervallo di “dadi” di isolati primari a concentrazioni uguali o inferiori a 25 ug/ml. The immune correlation between protection from HIV infection and disease progression is not well known. The extrapolation from the mouse model to the human one is uncertain, but it seems likely that very effective antibodies are able to provide protection. In a recent comparative study, only three monoclonal antibodies were found to be able to neutralize (90%) a range of "dice" of primary isolates at concentrations equal to or lower than 25 µg / ml.
I riferimenti bibliografici pertinenti alla discussione dello sfondo dell’ invenzione sono riportati in calce alla presente descrizione. The bibliographic references relevant to the discussion of the background of the invention are reported at the bottom of this description.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
Si è ora trovato che un gruppo di anticorpi presenti nel siero di soggetti sani esenti da HIV sono in grado di neutralizzare HIV. It has now been found that a group of antibodies present in the serum of healthy HIV-free subjects are capable of neutralizing HIV.
Gli anticorpi dell’invenzione costituiscono una sotto-frazione del repertorio di anticorpi naturali del sistema immunitario che si ritengono forniscano una prima difesa nei confronti di agenti infettivi specifici e che abbiano il ruolo nell’immunoregolazione o nel controllo dell’ autoimmunità (Avrames S. et al. "Studies on naturai antibodies and auto-antibodies" Ann. Immunol,124D, 103-110, (1983). Rodman T.C. et al "Epitope for naturai antibodies of human immunodeficiency virus (HlV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein "Proc. Nati. Acad. Sci.) 0:7719-7723 (1993)). The antibodies of the invention constitute a sub-fraction of the repertoire of natural antibodies of the immune system which are believed to provide a first defense against specific infectious agents and which have a role in immunoregulation or in the control of autoimmunity (Avrames S. et al. "Studies on naturai antibodies and auto-antibodies" Ann. Immunol, 124D, 103-110, (1983). Rodman T.C. et al "Epitope for naturai antibodies of human immunodeficiency virus (HlV) -negative (normal) and HIV- positive sera are coincident with two key functional sequences of HIV Tat protein "Proc. Nati. Acad. Sci.) 0: 7719-7723 (1993)).
A causa dell’elevata connettività degli auto-anticorpi naturali, gli anticorpi dell’invenzione, indicati di seguito con la sigla MM aB, sono in grado di ristabilire la potenza degli anticorpi neutralizzanti HIV-1 al verificarsi di una ampia perturbazione nella rete idiotipica nel corso della infezione da HIV (Wang Q.L.et al., J. Clin. Invest. 96:775-780 (1995)). Due to the high connectivity of natural autoantibodies, the antibodies of the invention, indicated below with the abbreviation MM aB, are able to re-establish the potency of HIV-1 neutralizing antibodies upon the occurrence of a large perturbation in the idiotypic network in the course of HIV infection (Wang Q.L.et al., J. Clin. Invest. 96: 775-780 (1995)).
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
La presente invenzione fornisce un metodo per ottenere anticorpi neutralizzanti HIV da sieri non infetti. L’immunoterapia passiva secondo l’invenzione è sicura e permette di impedire l’infezione e di rallentare la progressione della malattia. The present invention provides a method for obtaining HIV neutralizing antibodies from uninfected sera. Passive immunotherapy according to the invention is safe and allows you to prevent infection and slow down the progression of the disease.
L’approccio al trattamento dell’infezione da HIV secondo la presente invenzione è basato sull 'aver trovato che varianti di HIV-1 sembrano mantenere epitopi sufficientemente cross-reattivi riconosciuti da MM Ab. L’approccio è inoltre basato sul fatto che la protezione in vivo sembra correlata con direttamente con la neutralizzazione in vitro. Ad oggi, la neutralizzazione di un intervallo di isolati primari di “dadi” B è stata ottenuta solo da anticorpi monoclonali (MAB). Questi MABs erano: 12 che riconosce un epitopo che si sovrappone al sito di legame dei CD4 della gp 120; MAB 2G12 che riconosce un epitopo che comprende la base del loop V3 e la base del loop V4 di gp 120; Mah 2F5 che riconosce una sequenza lineare vicina al segmento di transmembrana di gp41. La protezione completa richiede concentrazioni seriche di anticorpi in vivo di gran lunga maggiori dei titoli di neutralizzazione del 90% misurati in tipiche prove di in vitro. The approach to the treatment of HIV infection according to the present invention is based on having found that HIV-1 variants seem to maintain sufficiently cross-reactive epitopes recognized by MM Ab. The approach is also based on the fact that in vivo protection appears to be directly correlated with in vitro neutralization. To date, neutralization of a range of primary isolates of "dice" B has been achieved only by monoclonal antibodies (MABs). These MABs were: 12 which recognizes an epitope that overlaps the gp 120 CD4 binding site; MAB 2G12 which recognizes an epitope comprising the base of the V3 loop and the base of the V4 loop of gp 120; Mah 2F5 which recognizes a linear sequence close to the transmembrane segment of gp41. Complete protection requires in vivo antibody serum concentrations far greater than the 90% neutralization titers measured in typical in vitro tests.
Per esempio, l’anticorpo b 12 fornì completa protezione nel modello del topo a 50 mg/Kg di peso corporeo, che corrisponde a una concentrazione nel siero pari a circa 500 ug/ml contro due virus primari per i quali i titoli di neutralizzazione erano di 15 e di 5 ug/ml. For example, the b 12 antibody provided complete protection in the mouse model at 50 mg / kg body weight, which corresponds to a serum concentration of approximately 500 ug / ml against two primary viruses for which neutralization titers were of 15 and 5 ug / ml.
Una dose di 10 mg di b 12 per Kg di peso corporeo offriva solo protezione parziale. Per esempio, è notevolmente più facile proteggere dall’infezione con ceppi di HIV-1 adattati a linee cellulari T prontamente neutralizzati che non da isolati primari non refrattari. A dose of 10 mg of b 12 per kg of body weight offered only partial protection. For example, it is considerably easier to protect against infection with HIV-1 strains adapted to readily neutralized T cell lines than from non-refractory primary isolates.
D’altra parte, numerosi studi sono stati effettuati prodotti a base di plasma umano iperimmune (HIVIG, immunoglobuline umane policlonali anti HIV). Ad esempio, Carpas e colleghi hanno somministrato a 10 adulti 500 mi di un prodotto di plasma immune ogni mese per tre mesi. In questo studio aperto non controllato, si rilevò una caduta dell’ antigene p24 e una caduta di RNA di HIV nel plasma a 2 mesi dallo studio. In un altro studio aperto, Jackson ha somministrato a sei adulti un prodotto di plasma immune, a una dose fra 50 e 250 mi, in base ai livelli di antigene p24 dei volontari. In un altro piccolo studio aperto condotto da Osther, 14 adulti con infezione da HIV leggermente sintomatica hanno ricevuto HIVIG porcine alla dose di 3g/giorno per 5-7 giorni. I soggetti con una conta di linfociti T CD4 maggiore di 100 cellule /mm<3 >risposero a differenza di quelli con una conta inferiore. On the other hand, numerous studies have been carried out on products based on hyperimmune human plasma (HIVIG, anti-HIV polyclonal human immunoglobulins). For example, Carpas and colleagues gave 10 adults 500ml of an immune plasma product every month for three months. In this open, uncontrolled study, a drop in the p24 antigen and a drop in HIV RNA in plasma were detected 2 months after the study. In another open study, Jackson gave six adults an immune plasma product, at a dose between 50 and 250 mL, based on the volunteers' p24 antigen levels. In another small open study by Osther, 14 mildly symptomatic HIV-infected adults received porcine HIVIG at a dose of 3g / day for 5-7 days. Subjects with CD4 T cell counts greater than 100 cells / mm <3> responded unlike those with lower counts.
Uno studio aperto di Fletcher con il prodotto di plasma iperimmune umano HIVIG somministrato a 13 pazienti 12 dei quali affetti da AIDS, a una dose da 50 a 200 mg/kg ogni mese per quattro mesi, ha rivelato un declino nell’antigene p 24 e ha migliorata la risposta proliferativa postimmunizzazione. An open study by Fletcher with the HIVIG human hyperimmune plasma product administered to 13 patients 12 of them with AIDS, at a dose of 50 to 200 mg / kg every month for four months, revealed a decline in p 24 antigen and improved the post-immunization proliferative response.
L’ anticorpo Mah 12 fu generato da una libreria combinatoriale di tipo “phage display” dove l’RNA fu prelevato da linfociti di midollo osseo di un individuo HIV-1 sieropositivo. The Mah 12 antibody was generated from a "phage display" combinatorial library where RNA was taken from bone marrow lymphocytes of an HIV-1 positive individual.
Pertanto, la presente invenzione ha per oggetto un metodo per superare i protocolli che usano HIVIG. Therefore, the present invention relates to a method for overcoming protocols using HIVIG.
I seguenti esempi illustrano l’invenzione in maggior dettaglio. The following examples illustrate the invention in greater detail.
ESEMPIO 1 EXAMPLE 1
Per la preparazione degli anticorpi dell’invenzione sono stati utilizzati campioni di siero da donatori sani. Le frazioni di immunoglobuline G furono purificate per affinità da 1 ml di siero inattivato al calore utilizzando una colonna di proteina G sefarosio cl-4B (Pharmacia Biotech, Uppsala) secondo le istruzioni del produttore. Si raccolsero 5 frazioni che furono dializzate e impiegate per la purificazione con anticorpo anti-IgG. For the preparation of the antibodies of the invention, serum samples from healthy donors were used. The immunoglobulin G fractions were affinity purified from 1 ml of heat inactivated serum using a sepharose cl-4B protein G column (Pharmacia Biotech, Uppsala) according to the manufacturer's instructions. 5 fractions were collected which were dialyzed and used for purification with anti-IgG antibody.
Le immunoglobuline G purificate su proteina G-sefarosio furono covalentemente legate a sefarosio 4B attivato con CNBr (Pharmacia Biotech, Uppsala). Si usarono circa 7 mg di IgG per 1,5 mi di gel. Gli auto-anticorpi, cioè anticorpi anti-IgG furono preparati da 1 ml di sieri inattivati al calore. Prima della cromatografia su colonna di affinità, i sieri furono filtrati attraverso un filtro con pori da 0,2 um e diluiti 1 :1 con PBS. La colonna fu equilibrata con 5 volumi di PBS. Il carico del siero fu ripetuto diverse volte a temperatura ambiente per una notte a 4°C. Dopo che i campioni erano stati caricati il gel era lavato accuratamente 5 volte con PBS fino a OD stabile a 280 mm. Gli anticorpi legati furono eluiti con acido citrico 0,1 m, pH 2.5. Le frazioni furono raccolte in tris-2M per portare Γ effluente a pH neutro. Le frazioni raccolte con la più alta densità ottica furono concentrate, dializzate e impiegate per misurare la neutralizzazione mediata da anticorpi di diversi isolati di HIV. Immunoglobulins G purified on protein G-sepharose were covalently linked to sepharose 4B activated with CNBr (Pharmacia Biotech, Uppsala). About 7 mg of IgG was used per 1.5 ml of gel. Auto-antibodies, i.e. anti-IgG antibodies were prepared from 1 ml of heat inactivated sera. Prior to affinity column chromatography, sera were filtered through a 0.2 µm pore filter and diluted 1: 1 with PBS. The column was equilibrated with 5 volumes of PBS. The serum loading was repeated several times at room temperature overnight at 4 ° C. After the samples had been loaded the gel was washed thoroughly 5 times with PBS to a stable OD at 280 mm. The bound antibodies were eluted with 0.1 m citric acid, pH 2.5. The fractions were collected in tris-2M to bring Γ effluent to neutral pH. The collected fractions with the highest optical density were concentrated, dialyzed and used to measure antibody-mediated neutralization of different HIV isolates.
ESEMPIO 2 EXAMPLE 2
La neutralizzazione di isolati primari di HIV-2 fu misurata nel saggio basato su cellule mononucleari di sangue periferico determinando la conta di cellule antigene positive utilizzando il saggio di neutralizzazione focale di fluorescenza. I risultati per gli anticorpi ottenuti nell’esempio 1 e per l’anticorpo monoclonale MAb 12 sono riportati nella successiva tabella. Neutralization of primary HIV-2 isolates was measured in the peripheral blood mononuclear cell assay by determining the antigen positive cell count using the focal fluorescence neutralization assay. The results for the antibodies obtained in Example 1 and for the MAb 12 monoclonal antibody are shown in the following table.
Tabella - Titoli di neutralizzazione di diversi anticorpi contro isolati di HIV-1 Table - Neutralization titers of different antibodies against HIV-1 isolates
ND, Non rilevato. ND, Not Detected.
a sotto -frazione di Auto -anticorpi umani IgG. a subfraction of human IgG autoantibodies.
b Anticorpi separati da sieri normali umani su Protein-G Sepharose. b Antibodies separated from normal human sera on Protein-G Sepharose.
I dati dimostrano che l’infezione di cellule mononucleate di sangue periferico da parte di NL-HX-ADA (clone molecolare ricombinante T-tropico di HIV-1 recante l’involucro HXB2 in un background NL4-3), 92HT593(isolato primario duotropico, “clade” B), SF162 (virus M-tropico) era inibita per i 150% da MAb 12 alle dosi di 0.25, 0.56 e 0.33 ug/ml, rispettivamente. Gli stessi virus HIV-1 erano inibiti per il 50% da MM Ab a 2.5, 0.3 e 0.37 ug/ml, rispettivamente. Gli anticorpi di controllo non erano neutralizzanti. The data demonstrate that infection of peripheral blood mononuclear cells by NL-HX-ADA (recombinant T-tropic molecular clone of HIV-1 bearing the HXB2 envelope in an NL4-3 background), 92HT593 (primary duotropic isolate , "Clade" B), SF162 (M-tropic virus) was 150% inhibited by MAb 12 at doses of 0.25, 0.56 and 0.33 ug / ml, respectively. HIV-1 viruses themselves were 50% inhibited by MM Ab at 2.5, 0.3, and 0.37 ug / ml, respectively. The control antibodies were not neutralizing.
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ITMI20010500 ITMI20010500A1 (en) | 2001-03-09 | 2001-03-09 | NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES |
US10/469,870 US20040106771A1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodie active against hiv virus |
APAP/P/2003/002852A AP2003002852A0 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against HIV virus |
EP02727364A EP1366080B1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against hiv virus |
DK02727364T DK1366080T3 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies against HIV virus |
CNA028060636A CN1494554A (en) | 2001-03-09 | 2002-03-06 | Natural HIV virus antibody |
JP2002571550A JP4601252B2 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against HIV virus |
ES02727364T ES2278022T3 (en) | 2001-03-09 | 2002-03-06 | ACTIVE NATURAL ANTIBODIES AGAINST HIV VIRUS. |
YUP-701/03A RS51011B (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against hiv virus |
EEP200300377A EE200300377A (en) | 2001-03-09 | 2002-03-06 | Natural anti-HIV antibodies |
BR0207931-3A BR0207931A (en) | 2001-03-09 | 2002-03-06 | Natural Antibodies Active Against HIV Viruses |
MXPA03007976A MXPA03007976A (en) | 2001-03-09 | 2002-03-06 | Natural antibodie active against hiv virus. |
CA002440131A CA2440131A1 (en) | 2001-03-09 | 2002-03-06 | Antibodies against human igg total fraction, and uses thereof in neutralising and treating hiv-1 |
AU2002257620A AU2002257620B2 (en) | 2001-03-09 | 2002-03-06 | Natural antibodie active against HIV virus |
PCT/EP2002/002454 WO2002072637A1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodie active against hiv virus |
RU2003125554/15A RU2003125554A (en) | 2001-03-09 | 2002-03-06 | NATURAL ANTIBODIES ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS (HIV) |
SI200230478T SI1366080T1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against hiv virus |
DE60216422T DE60216422T2 (en) | 2001-03-09 | 2002-03-06 | NATURAL ANTIBODY WITH EFFECT TO HIV VIRUS |
HU0303423A HUP0303423A3 (en) | 2001-03-09 | 2002-03-06 | Natural antibody active against hiv virus |
PT02727364T PT1366080E (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against hiv virus |
CZ20032418A CZ20032418A3 (en) | 2001-03-09 | 2002-03-06 | Pharmaceutical preparation |
PL02366785A PL366785A1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodie active against hiv virus |
KR1020037011648A KR100871455B1 (en) | 2001-03-09 | 2002-03-06 | Natural antibodies active against HIV virus |
IL15775302A IL157753A0 (en) | 2001-03-09 | 2002-03-06 | Natural antibody active against hiv virus |
AT02727364T ATE346870T1 (en) | 2001-03-09 | 2002-03-06 | NATURAL ANTIBODIVE EFFECT AGAINST THE HIV VIRUS |
TNPCT/EP2002/002454A TNSN03066A1 (en) | 2001-03-09 | 2003-07-08 | Natural antibodies active against hiv virus |
HR20030701A HRP20030701A2 (en) | 2001-03-09 | 2003-09-02 | Natural antibodies active against hiv virus |
IL157753A IL157753A (en) | 2001-03-09 | 2003-09-04 | HUMAN ANTI IgG ANTIBODIES CAPABLE OF NEUTRALIZING HIV VIRUS |
ZA200306965A ZA200306965B (en) | 2001-03-09 | 2003-09-05 | Natural antibodies active against HIV virus. |
NO20033934A NO20033934L (en) | 2001-03-09 | 2003-09-05 | Natural antibody active against the HIV virus |
US11/507,450 US20070020290A1 (en) | 2001-03-09 | 2006-08-22 | Natural antibodieactive against HIV virus |
CY20071100205T CY1108852T1 (en) | 2001-03-09 | 2007-02-15 | NATURAL ANTIBODY INVOLVED IN HIV |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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ITMI20010500 ITMI20010500A1 (en) | 2001-03-09 | 2001-03-09 | NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES |
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ITMI20010500A1 true ITMI20010500A1 (en) | 2002-09-09 |
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ITMI20010500 ITMI20010500A1 (en) | 2001-03-09 | 2001-03-09 | NATURAL AUTO-ANTIBODIES AND THEIR USE IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS DISEASES |
Country Status (2)
Country | Link |
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IT (1) | ITMI20010500A1 (en) |
ZA (1) | ZA200306965B (en) |
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2001
- 2001-03-09 IT ITMI20010500 patent/ITMI20010500A1/en unknown
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2003
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