OA12311A - Use of antibodies recognizing the interleukin-2 receptor in the prevention and / or treatment of infections with AIDS viruses. - Google Patents

Abstract

The invention concerns the use of antibodies, or analogues blocking the interleukin-2 receptor which prevents the AIDS virus from fixing itself on its target cells and/or from penetrating into said cells. The invention is useful for treating HIV infections.

Description

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Use of antibodies recognizing the interleukin-2 receptor in the prevention and / or treatment of infections with AIDS viruses. The invention relates to the use of antibodies recognizing the interleukin-2 receptor in the preparation of a medicament for the prevention and / or treatment of infections with an AIDS virus in a mammal.

AIDS viruses include human immunodeficiency virus (HIV), simian immunodeficiency virus (HIV), and immunodeficiency virus (FIV). The invention originates from the discovery of a structural-dimensional analogy between areas of interleukin-2 (IL-2) involved in the binding of IL-2 to the α, β, and γ subunits of the IL-2, and envelope proteins of SIDA viruses, in particular protein gp41 for HIV and SIV, gp36 for FIV, when these proteins are in the form of trimers. These trimers have already been described in the literature.

These structural analogies are described more particularly in patent application FR-97 14387, filed on November 17, 1997 by the applicant and in application PCT / FR-9802447, filed on November 17, 1998, which corresponds to it. The contents of these patent applications are incorporated by reference into the description of this application. In the patent applications which have just been mentioned, it is proposed in particular to prepare an AIDS vaccine agent, based on a polypeptide comprising a fragment of an IL2-like immunodominant zone of a viral envelope protein, this polypeptide being modified to induce one. immune response directed against the envelope protein but not against IL-2. Another approach to vaccinating against infections caused by AIDS viruses is a vaccine agent based on an immunogenic and non-IL2-like envelope protein polypeptide (or an immunogenic peptide mimicking said polypeptide). This is the case with the 650-690 polypeptide, in particular 660-680 (in particular 667-672) of the HIV1 gp41 protein. The numbering used here is that of the SWISSPROT bank (version 34), and reference is made in particular to the sequence having codeENV_HV1BR. Of course, any homologous peptide of the FIV or SIV envelope protein may also be used in the case of a vaccine against these viruses. The formulation of the vaccine compositions and their mode of administration are known in the art and will not be described further here. The structural analogy mentioned above has led the authors of the present invention to believe that the interleukin-2 receptor (RIL-2) plays a role in the binding of the virus to its target cells and / or its penetration into said cellulescibles.

There are several types of cells, lymphocytes and others that express on their surface one or more subunits of the IL-2 receptor.

It is therefore possible to use antibodies or antibody fractions, containing paratopes directed against the IL-2 receptor, to block, on the receptors of the target cells of the virus, the sites of interaction with the IL -2 and / or their neighborhood, and thus prevent the attachment of viral particles on these cells and / or the penetration of said viral particles in said cells, to prevent or limit the infection of subjects who have been exposed, or fearing to have been exposed , to the virus.

The term "infection" here refers to the penetration of the virus into the target cells.

The antibodies or fraction of antibodies used are those which recognize the less one of the α, β and γ subunits of the IL-2 receptor, including the antibodies which are more specifically known to the IL-2 binding site. 2 on his receiver. In both cases, these antibodies can prevent the binding of the virus to the target cells, if only by steric hindrance. The invention extends to the use of analogues of antibodies that have just been removed. The term "analogue" herein refers to any peptide mimicking the paratopes of these antibodies, or any peptide capable of binding to at least one of the IL-2 receptor α, β and γ subunits. Such peptides include fragments of IL-2 containing its binding site on the RIL-2 receptor, as well as any peptide capable of demeaning the IL-2 binding site on its receptor. This definition of the analogues, however, excludes IL-2 itself, taking into account the known risks associated with the undesirable side effects of IL-2, especially at high doses.

Antibodies directed against the IL-2 receptor of the subject to be protected (human IL-2 or IL-2 depending on the case) can be obtained according to the usual methods. Some have already been described. This may include polyclonal antibodies

I purified by affinity chromatography, monoclonal antibodies, chimeric antibodies 0123) 1 as described in patent FR-2 641 468, or bispecific antibodies recognizing two subunits of the IL-2 receptor. .

Of course, the invention extends to the use of any antibody fragment containing a paratope directed against the IL-2 receptor, for example Fab, Fab 'and Ffcb 3 fragments.

Treating with anti-RIL-2 antibodies does not weaken immune defenses, as it has been observed in studies leading to the invention that such antibodies generally do not have a marked immunosuppressive effect.

It can not be excluded, however, that some anti-RIL-2 antibodies may have an immunosuppressive effect. Such an effect would obviously be undesirable, and it is obvious that only antibodies having no marked immunosuppressive effect can be used in accordance with the present invention.

In the present application, it is considered that an antibody has no marked immunosuppressive effect when, in conventional tests for invitro lymphoproliferation (induced for example by the mitogen of pokeweed, concanavalin A, or IL-2), the inhibition, caused by the antibody, of the proliferation, does not exceed 25%, and in particular does not exceed 20%. Such non-immunosuppressive antibodies can therefore be selected by simple routine experiments.

The amounts of antibodies or antibody fractions needed to block the RIL-2 sites can be determined for each species and for each antibody by simple routine in vitro experiments. The same is true for the peptide analogues of these antibodies.

The medicament obtained according to the invention may be in the form of injectable solutions or in the form of freeze-dried preparations making it possible to reconstitute an injectable solution at the time of use. Such a drug can be administered in vivo intravenously, or ex vivo by addition to samples of blood to be reinjected. In the case of antibodies, for example, there is administered between 1 and 100 mg of active ingredient per kg of body weight per day. For antibody fragments or other peptide analogues, molar doses equivalent to those just given are used. Treatment is continued as long as the viral load of the treated individual is detectable.

To show that the blocking of RIL-2 sites by antibodies is likely to prevent the entry of the virus into its target cells, the following experimental model can be used:

Infectious cells expressing the α, β, and γ subunits of IL-2: MT4 or HUT102. Anti-RIL2 antibody: 33B31 also called ARIL-2 (anti-aRIL2); -clone A41 (anti-PRIL2); NÎAB234 marketed by R & D System (anti-vRIL2).

The cells are preincubated with at least one anti-RIL2 antibody at a temperature of 4 ° C, one hour before contacting the virus. The possible intracellular intravenous penetration of the virus is revealed with a fluorescent antibody (clone KC57 FITC) directed against the core of the virus.

Claims (12)

5 Ο72371 CLAIMS 1. Use of antibodies or fragments or analogs of said antibodies, recognizing at least one of the α, β and γ subunits of the interleukin-2 receptor, in the preparation of a medicament for be administered in vivo to prevent or limit the penetration of an immunodeficiency virus into its target cells and / or to prevent the attachment of the virus to its target cells, in a mammal that has been exposed, or likely to have been exposed to said virus, wherein said antibodies, fragments or analogs are selected such that, in vitro mitochondrial induced mitochondrial pokeweed, concana-valine A or IL-2 induced inhibition, induced by said antibodies, fragments or analogs, proliferation does not exceed 25%. The use according to claim 1, wherein said inhibition of proliferation does not exceed 20%. 3. Use according to any preceding claim, wherein said analogs are any peptide capable of mimicking the paratopes of said antibodies, or any peptide other than IL-2, capable of binding to at least one of α, β and γ subunits of the IL-2 receptor, or any peptide capable of mimicking the binding site of IL-2 on its receptor. The use according to claim 3, wherein said peptide is a fragment of IL-2. The use according to any of the preceding claims, wherein said antibodies, or fragments or analogs, are capable of binding to the IL-2 receptor α-subunit. The use according to any one of the preceding claims, wherein said antibodies, or fragments or analogs, are capable of binding to the β-subunit of the IL-2 receptor. The use according to any one of the preceding claims, wherein said antibodies, or fragments or analogs, are capable of binding to the γ subunit of the IL-2 receptor. 8. Use according to any one of the preceding claims, wherein said virus is HIV. 9. Use according to any one of the preceding claims, wherein said virus is FIV. 10. Use according to any one of the preceding claims, wherein said virus is SIV. 11. Use according to any one of the preceding claims, wherein said medicament is to be administered in vivo. 12. Use according to any of claims 1 to 10 wherein said medicament is added to blood samples for reinjection.