Antibodies for the treatment of hiv

Abstract

The present invention relates to isolated antibodies, or the derivatives or antigen binding fragments of same, capable of binding to CXCR4 but also of inducing conformational change of the CXCR4 homodimers and able to inhibit HIV-1 primary isolate replication in PBMC. More particularly, the present invention relates to the 515H7 and 301 aE5 monoclonal antibodies, specific to the CXCR4 protein, as well as their use for the treatment of HIV infection. Pharmaceutical compositions comprising such antibodies and a process for the selection of such antibodies are also covered.

1 . An isolated antibody, or one of its antigen binding fragments or derivatives, wherein it comprises at least one complementary determining region CDR chosen from CDRs comprising the amino acid sequences SEQ ID Nos. 1 to 6 and 30 to 33 as defined by the IMGT numbering system. 
     
     
         2 . The antibody of  claim 1 , or one of its antigen binding fragments or derivatives, wherein it comprises a light chain comprising CDR-L1, CDR-L2 and CDR-L3 comprising respectively the amino acid sequence SEQ ID Nos. 1, 2 and 3; and a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 comprising respectively the amino acid sequence SEQ ID Nos. 4, 5 and 6. 
     
     
         3 . The antibody of  claim 2 , or one of its antigen binding fragments or derivatives, wherein it comprises a light chain comprising the amino acid sequence SEQ ID No. 7 and a heavy chain comprising the amino acid sequence SEQ ID No. 8. 
     
     
         4 . The antibody of  claim 2 , or one of its antigen binding fragments or derivatives, wherein it is a chimeric antibody and in that it comprises a heavy chain of sequence selected from the group consisting of SEQ ID Nos. 56, 57 or 58, and a light chain of sequence SEQ ID No. 59. 
     
     
         5 . The antibody of  claim 2 , or one of its antigen binding fragments or derivatives, wherein it is a humanized antibody and in that it comprises a heavy chain variable region of sequence consisting of SEQ ID No. 64, and a light chain variable region of sequence selected from the group consisting of SEQ ID Nos. 65, 66, 82 or 83. 
     
     
         6 . The antibody of  claim 2 , or one of its antigen binding fragments or derivatives, wherein it is a humanized antibody and in that it comprises A humanized antibody, or a derived compound or functional fragment of same, comprising a heavy chain of sequence selected from the group consisting of SEQ ID Nos. 67, 68 or 69, and a light chain of sequence selected from the group consisting of SEQ ID Nos. 70, 71, 84 or 85. 
     
     
         7 . The antibody of  claim 2 , or one of its antigen binding fragments or derivatives, wherein said functional fragment consists of the fragments Fv, scFv, Fab, F(ab′) 2 , Fab′, scFv-Fc, diabodies, or any fragment whose half-life has been increased by chemical modification. 
     
     
         8 . The antibody of  claim 7 , or one of its antigen binding fragments or derivatives, wherein it is a scFv comprising the amino acid sequence SEQ ID No. 54. 
     
     
         9 . The antibody of  claim 1 , or one of its antigen binding fragments or derivatives, wherein it comprises a light chain comprising CDR-L1, CDR-L2 and CDR-L3 comprising respectively the amino acid sequence SEQ ID Nos. 1, 2 and 30; and a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 comprising respectively the amino acid sequence SEQ ID Nos. 31, 32 and 33. 
     
     
         10 . The antibody of  claim 9 , or one of its antigen binding fragments or derivatives, wherein it comprises a light chain comprising the amino acid sequence SEQ ID No. 34 and a heavy chain comprising the amino acid sequence SEQ ID No. 35. 
     
     
         11 . An isolated nucleic acid, wherein it is chosen from the following nucleic acids:
 a) a nucleic acid, DNA or RNA, coding for an antibody, or one of its antigen binding fragments or derivatives, as claimed in one of  claims 1  to  10 ;   b) a nucleic acid comprising a DNA sequence selecting from the group of CDRs sequences consisting of SEQ ID Nos. 14 to 19 and 41 to 45;   c) a nucleic acid comprising a DNA sequence selecting from the group of heavy and light variable domains sequences consisting of SEQ ID Nos. 20, 21, 46, 47, 72, 73, 74, 86 and 87;   d) a nucleic acid comprising a DNA sequence selecting from the group of heavy and light chains sequences consisting of SEQ ID Nos. 60 to 63, 75 to 79, 88 and 89;   e) a nucleic acid comprising a DNA sequence consisting of SEQ ID No. 55;   f) the corresponding RNA nucleic acids of the nucleic acids as defined in b), c), d) or e);   g) the complementary nucleic acids of the nucleic acids as defined in a), b), c), d) and e); and   h) a nucleic acid of at least 18 nucleotides capable of hybridizing under conditions of high stringency with at least one of the CDRs of sequence SEQ ID Nos. 14 to 19 and 41 to 45.   
     
     
         12 . A vector comprising a nucleic acid as claimed in  claim 11 . 
     
     
         13 . A host cell comprising a vector as claimed in  claim 12 . 
     
     
         14 . A transgenic animal with the exception of man comprising at least one cell transformed by a vector as claimed in  claim 12 . 
     
     
         15 . A process for production of an antibody, or one of its antigen binding fragments or derivatives, as claimed in one of  claims 1  to  10 , wherein said process comprises the following stages:
 a) culture in a medium and appropriate culture conditions of a cell as claimed in  claim 13 ; and 
 b) the recovery of said antibodies, or one of its antigen binding fragments or derivatives, thus produced starting from the culture medium or said cultured cells. 
 
     
     
         16 . An antibody, or one of its functional fragments or derivatives, obtainable or obtained by a process as claimed in  claim 15 . 
     
     
         17 . The antibody of  claims 1  to  10  and  16  as a medicament. 
     
     
         18 . The antibody, or one of its functional fragments or derivatives, of  claims 1  to  10  or  16  to  17 , wherein it inhibits HIV-1 KON primary isolate replication in PBMC with an IC 90  of at least 5 μg/ml, preferably at least 10 μg/ml. 
     
     
         19 . A composition comprising by way of active principle a compound consisting of an antibody, or one of its antigen binding fragments or derivatives, as claimed in one of  claims 1  to  10  and  16  to  18 . 
     
     
         20 . The composition as claimed in  claim 19  as a medicament. 
     
     
         21 . The composition as claimed in  claims 19  and  20  for the prevention or for the treatment of HIV infection. 
     
     
         22 . The composition as claimed in  claim 21 , wherein said HIV infection is a X4-tropic HIV infection. 
     
     
         23 . The composition as claimed in  claim 21 , wherein said HIV infection is a X4/R5-tropic HIV infection. 
     
     
         24 . The composition according to  claims 19  to  23 , wherein it comprises at least a second anti-HIV compound selected among the compounds capable of specifically inhibiting HIV entry and/or replication. 
     
     
         25 . The composition according to  claim 24 , wherein said at least second anti-HIV compound is selected among the group consisting of antiretroviral drugs such as HIV protease inhibitors (PI), nucleoside/nucleotide HIV reverse-transcriptase inhibitors (NRTI/NtRTI), non-nucleoside HIV reverse-transcriptase inhibitors (NNRTI), HIV entry inhibitors, HIV integrase inhibitors. 
     
     
         26 . The composition according to  claim 24  or  25 , wherein said at least second anti-HIV compound is an anti-CCR5 compound. 
     
     
         27 . The composition according to  claim 26 , wherein said anti-CCR5 compound is the Maraviroc. 
     
     
         28 . Process for the screening and/or the identification of molecules as CXCR4 antagonist antiviral agents comprising the steps of:
 a) selecting cells expressing CXCR4,   b) incubating said cells with an antibody, or one of its antigen binding fragments or derivatives, of  claims 1  to  10  or  16  to  18 , and   c) evaluating the tested molecules for their potential inhibition of the binding between the antibody, or one of its antigen binding fragments or derivatives, to CXCR4, and   d) selecting molecules capable of said inhibition.   
     
     
         29 . The use of an antibody, or one of its antigen binding fragments or derivatives, according to one of  claims 1  to  10  and  16 , and/or of a composition according to one of  claims 19  to  27  for the preparation of a drug for inhibiting HIV replication. 
     
     
         30 . The use of an antibody, or one of its antigen binding fragments or derivatives, according to one of  claims 1  to  10  and  16 , and/or of a composition according to one of  claims 19  to  27 , for the preparation of a drug for HIV disease prevention or treatment. 
     
     
         31 . A method for HIV prevention or treatment, wherein said method comprises a step consisting of administering to a patient in need thereof, an antibody, or one of its antigen binding fragments or derivative, according to one of  claims 1  to  10  and  16  and/or of a composition according to one of  claims 19  to  27 . 
     
     
         32 . A method according to  claim 31 , wherein it comprises also a step consisting of administering to said patient, an anti-CCR5 compound.