ZA200306965B - Natural antibodies active against HIV virus. - Google Patents
Natural antibodies active against HIV virus. Download PDFInfo
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- ZA200306965B ZA200306965B ZA200306965A ZA200306965A ZA200306965B ZA 200306965 B ZA200306965 B ZA 200306965B ZA 200306965 A ZA200306965 A ZA 200306965A ZA 200306965 A ZA200306965 A ZA 200306965A ZA 200306965 B ZA200306965 B ZA 200306965B
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- antibodies
- hiv
- igg
- human
- neutralization
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- 241000725303 Human immunodeficiency virus Species 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 claims description 16
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 13
- 230000003472 neutralizing effect Effects 0.000 claims description 9
- 208000031886 HIV Infections Diseases 0.000 claims description 8
- 238000001042 affinity chromatography Methods 0.000 claims description 4
- 238000009169 immunotherapy Methods 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 1
- 241000700605 Viruses Species 0.000 description 7
- 238000006386 neutralization reaction Methods 0.000 description 7
- 229920002684 Sepharose Polymers 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000013641 positive control Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 101710120037 Toxin CcdB Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102100027723 Endogenous retrovirus group K member 6 Rec protein Human genes 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000010530 Virus Neutralization Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940125575 vaccine candidate Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
a © WO 02/072637 PCT/EP02/02454 “NATURAL ANTIBODIES ACTIVE AGAINST HIV VIRUS” :
The present invention relates to antibodies neutralizing the Human i Immunodeficiency Virus. Said antibodies are present in sera from normal subjects and can be used to prevent the HIV infection or to delay the onset of illness in serum positive patients. The present invention further relates to pharmaceutical preparations containing said antibodies and the use thereof in passive immunotherapy of HIV infection.
The induction of effective immune response to HIV-1 has often been restricted by the inability of any vaccine candidate to elicit antibodies capable of neutralizing infectivity of primary HIV isolates from infected individuals (1,2). On the other hand, from the analysis of sera from infected subjects resulted that neutralization of primary virus tends to be weak and sporadic (3,4). However, albeit it is difficult to raise antibodies, either during the infection or with experimental vaccines, monoclonal antibodies exist, such as
IgGlbl2, 2F5 and 2G12 (5-7), which are capable of neutralizing primary viruses of subtypes A - E. Said antibodies derive from subtype B - infected individuals and they are not raised by vaccination (8).
The earliest detectable HIV-1 specific antibody is of the IgG isotype (12), suggesting a nonconventional primary response (13). Furthermore, there are findings indicating that HIV-1 antigens react with pre-existing, antibody repertoires (14). Cross-reactive antibodies that recognize the HIV- 1 envelope have been reported (15). > It was suggested that a strong early humoral response in HIV-1 v infection may not be beneficial (16) as it would result in monoclonal and - polyclonal antibody population instead of normal polyclonal response (13).
It has been suggested that anti-idiotypic antibody 1F7 may broaden immune
CONFIRMATION COPY
7 WO 020072637 PCT/EP02/02454 . , response to HIV antigens (17).
In our earlier studies, the homology of HIV envelope protein with IgG ‘ variable protein was predicted (18,19). However, recent data suggest that
HIV-1 gp120 immunodominant epitope and a fraction of naturally-occurring
IgG antibodies share complementary structure (20.21).
It has now been found that a group of antibodies present in sera from normal, not HIV — infected individuals, are capable of neutralizing HIV virus.
The antibody active fraction was purified from sera of normal subjects by affinity chromatography using a Sepharose resin to which total human
IgG had been coupled. Observation evidenced that such anti-IgG antibodies fraction is capable of neutralizing HIV-1 infection in PBMC. The experiments were repeated using different anti-IgG preparations of various concentrations, obtained from commercial serum specimens, using affinity purified total IgG antibodies as negative control and HIVIG and mAb 4117C antibodies as positive control. The latter proved to be inactive to 92HT593B. Neutralization curves shown in Fig. 1 relate to a representative experiment carried out with HIV-1 primary isolates 92HTS593B and
SF162WT as well as with NLHX-ADA recombinant virus. Anti-IgG antibodies proved to be active against 92HTS593B and NLHX-ADA at a 50% inhibiting concentration ranging from less than 1 to 7 pg/ml.
There is little possibility for the neutralizing effects observed with the preparation of anti-IgG antibodies to be due to co-purified chemokines from i normal sera, as the concentration of these substances does not exceed 20 ng . 25 per ml of serum and no specific bands were revealed by PAGE.
Furthermore, molecules below 50kDa were removed by dialysis of the antibodies preparations. PAGE analysis of anti-IgG preparations revealed predominant presence of IgG and very small traces of contaminant proteins.
: A possible explanation of the observed effects is that HIV-1 antigenic determinants share complementary structure with the variable regions of > natural antibodies belonging to the immune network (9,23), but in no way , this or other explanations limit the invention.
Therefore, a first aspect of the invention relates to a preparation of human antibodies raised against the total human IgG fraction, capable of neutralizing
HIV-1. Said preparation can be obtained subjecting sera from normal, not HIV- infected subjects, to affinity chromatography using resins coupled to total human IgG fraction. The final concentration of isolated anti-IgG antibodies will be preferably comprised within the range of 0.1-1000 pg/ml, more preferably : ‘within the range of 0.1-100 pg/ml. The starting material consists of a pool of sera from normal subjects. According to a further aspect, the invention relates to the use of the preparation of the invention in the prophylactic or therapeutical treatment of HIV infection, preferably HIV-1 infection.
For the use in therapy, the preparation of the invention will be suitably formulated with pharmaceutically acceptable excipients. The latter include buffering agents, stabilizing agents, solubilizers, diluents, isotonicity agents and the like. The preparation will preferably be administered parenterally, preferably through the intravenous, intradermal or intramuscular route.
According to a preferred embodiment, the preparation will be used in passive immunotherapy of HIV-1 infection.
Figure 1
Neutralization of primary HIV-1 isolates SF162WT and 92HT593B ' 25 and recombinant NL-HX-ADA virus by anti-IgG antibodies. Each titration curve represents data from a single experiment. Concentrations of anti-IgG in the various experiments were respectively 109.7, 12.3 and 80.0 pg/ml, for total IgG between 1000 and 3333 pg/ml and for HIVIG (10000 mg/ml).
7 wo 02nn2637 PCT/EP02/02454
Anti-IgG and total IgG preparations were obtained as described in the following. HIVIG was prepared from sera of HIV-1 infected subjects. . Figure 2
SDS-PAGE separation of affinity purified antibodies. Anti-IgG and total
IgG antibodies were prepared as described below. Electrophoretic separation of anti-IgG antibodies revealed a prevalent content of IgG. In addition, although weak, bands of high molecular weight proteins were also present.
EXAMPLE 1 - Preparation of anti-IgG antibodies
Anti-IgG antibodies were prepared from a pool of two normal human sera by affinity chromatography using Sepharose beads (CNBr-activated
Sepharose 4B) to which total human IgG (purified on GammaBind
Sepharose 4B affinity column) had previously been coupled. In principle, 5- 7 mg of IgG antibodies / 0.5-0.6 g of Sepharose beads were used. Binding was carried out following the indications of the manufacturer. The column was equilibrated with 5xPBS and heat-inactivated serum (1ml) was loaded and diluted to 1:1 by 5xPBS. Incubation was carried out for 1 hour at room temperature or overnight at 4°C. After washing with 30 ml of 5xPBS, bound antibodies were eluted using 0.1 M citrate, pH=2.5 into test-tubes containing base-TRIS. The collected eluate was concentrated, dialyzed (Centricon YM, 30000 MW cut-off) and analyzed through 10% SDS-PAGE, predominantly revealing the IgG band (Fig. 2).
EXAMPLE 2 - Neutralization of HIV-1 isolates by anti-IgG antibodies
Virus neutralization was evaluated in PBMC following a previously ) published protocol (22). Neutralization assays were carried out with four : . 25 different preparations of antibodies in five separated experiments.
Table 1 summarizes neutralization data against two HIV primary isolates (92HT593B, SF162WT) and a recombinant NL-HX-ADA virus.
HIVIG and mAb4117C were used as positive controls; Protein-G IgG was used as negative control.
In this test, all of the preparations of anti-IgG antibodies proved v capable of inhibiting PBMC infection by 92HT593B and NL-HX-ADA, whereas no neutralizing activity against SF162WT was observed. a 5 Table: Viral neutralization titers of purified Ig from sera from
HIV-1 infected (a) and normal (b) subjects
Primary isolate Recombinant virus 92HT593B SF162WT NLHX-ADA pg/ml % neut pg/ml %neut pg/ml % neut.
Antibodies Preparat. Assay
Negative control:
Protein G IgG b) 150 8.3 150 2.9 150 -6.8 50 1.1 50 -0.5 50 -4.4 16.7 2.2 16.7 2.7 16.7 -4.4
Positive control: mAb4117C a) 100 16.1 100 100 100 98.7 33.3 9.0 333 100 33.3 96.0 11.1 5.2 11.1 100 1.1 55.0 3.7 0.4 3.7 20.4 3.7 23.2 1.2 -0.6 1.2 57.4 1.2 -8.6
Positive control:
HIVIG a) 100 88.0 100 57.4 100 93.4 33.3 62.0 333 39.9 33.3 948 11.1 444 11.1 2.1 11.1 92.4 3.7 394 3.7 -14.4 3.7 87.2 1.23 222 1.23 0.7 1.23 69.2 0.41 8.3 0.41 -3.7 0.41 54.5
Anti-IgGb) 1 1 1.87 57.4 0.62 37.6 NA ND : 0.21 6.1
Anti-IgGb) 1 2 1.23 71.8 0.41 48.9 NA ND 40 0.14 14.4
Anti-IgG b) 2 1 8.00 42.0 8.00 60.3 * 2.67 24.1 NA 2.67 14.6 0.89 5.7 0.89 13 45 ’ Anti-IgGb) 3 1 2.17 46.4 0.72 27.1 NA ND 0.24 3.3 50 Anti-IgG b) 4 1 10.97 39.8 10.97 68.7 3.66 - - NA 3.66 54.0 1.22 1.22 45.0
) © WO 02/072637 PCT/EP02/02454
LITERATURE ° 1. Mascola, JR, Snyder, SW, Weislow, OS. Belay, SM, Belshe, RB, ’ Schwartz, DH, Clements, ML, Dolin, R, Graham, BS, Gorse, GJ, Keefer, a 5 MC, McElrath, MJ, Walker, MC, Wagner, KF, McNeil, JG, McCutchan, FE, and Burke, DS: Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. J Infect Dis 1996;173:340-348. 2. Montefiori, DC, and Evans, TG: Toward and HIV type 1 vaccine that generates potent, broadly cross-reactive neutralizing antibodies. AIDS Res
Hum Retroviruses 1999;15:689-698; 3. Moore, JP, Coa, Y, Leu, Qin, L, Korber, B, and Ho, DD: Inter and intraclade neutralization of human immunodeficiency virus type 1: genetic clades do not correspond to neutralization serotypes but partially correspond to gp120 antigenic serotypes. J Virol 1996;70:427-444; 4. Weber, J, Fenyo, EM, Beddows, S, Kaleeby, P, Bjorndal, A, and the
WHO Network for HIV Isolation and Characterization: Neutralization serotypes of HIV-1 field isolates are not predicted by genetic subtype. J
Virol 1996;70:7827-7832; 5. Burton, DR, Pyati, J, Koduri, R, Sharp, SJ, Thornton, GB, Parren,
PWHI, Sawyer, LSW, Hendry, RM, Dunlop, N, Nara, PL, Lamacchia, M,
Garratty, E, Stiechm, ER, Bryson, YJ, Cao, Y, Moore, JO, Ho, DD, and . Barbas III, CF: Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 1994;266:1024-1027, ‘ 6. Mascola, JR, Louder, MK, VanCott, TC, Sapan, CV, Lambert, JS,
Muenz, LR, Bunow, B, Birx, DL, and Robb, ML: Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary
1 wo 020072637 PCT/EP02/02454 isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12. J Virol 1997;71:7198-7206; * 7. Trkola, A, Pomales, AB, Yuan, H, Kober, B, Maddon, PJ, Allaway,
GP, Katinger, H, Barbas III, CF, Burton, DR, Ho, DD, and Moore, JP: ) 5 Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-1gG. J
Virol 1995;69:6609-6617,; 8. Moore, JP, and Trkola, A: JIV type 1 coreceptors, neutralization serotypes, and vaccine development. AIDS Res Human Retroviruses 1997;13:733-736; 9. Coutinho A: Beyond clonal selection and network. Immunological
Reviews 1989;110:63-67,; 10. Avrames, S: Natural autoantibodies: from "horror autotexicus" to "gnothi seauton". Immunol Today 1991;12:154-159; 11. Moller, G: Effect of anti-immunoglobulin sera on B lymphocyte functions. Scand J Immunol 1978;8:469-474, 12. Race, EM, Ramsey, KM, Lucia, HL, and Cloyd, MW: Human immunodeficiency virus elicits antibody not detected by standard tests; implications for diagnostics and viral immunology. Virology 1991;184:716- 722; 13. Nara, PL, and Garrity, R: Deceptive imprinting: a cosmopolitan strategy for complicating vaccination. Vaccine 1998;16:1780-17787, 14. Zubler, RH, Perrin, LH, Doucet, A, Zhang, X, Huang, YP, and * Miescher, PA: Frequencies of HIV-reactive B cells in seropositive and . 25 seronegative individuals. Clin Exp Immunol 1991; 87:31-36; 15. Davis, D, Chaudhri, B, Stephens, DM, Carne, CA, Willers, C, and
Lachmann, PJ: The immunodominance of epitopes within the transmembrane protein (gp41l) of human immunodeficiency virus type 1 may be determined by the host's previous exposure to similar epitopes on unrelated antigens. J Gen Virol 1990;71:1975-1983; . 16. Velijovic, V, Metlas, R, Kéhler, H, Urnovitz, HB, Prljic, J, Velikovic,
N, Johnson, E, and Miller, S: AIDS epidemic at the beginning of the third
A 5 millennium: time for a new AIDS vaccine strategy. Vaccine 2000;19:1855- 1863; 17. Wang, QL, Wang, HT, Blalock, E, Moller, S, and K”hlerm H:
Identification of an idiotypic peptide recognized by autoantibodies in immunodeficiency virus-1-infected individuals. Idiotype-specific autoantibodies in AIDS 1995,96:775-780; 18. Veljkovic, V, and Metlas, R: Identification of immunoglobulin recombination elements in HIV-1 envelope gene. Immunol Lett 1991;31:11- 14; 19. Metlas, R, Veljkovic, V, Paladini, DR, and Pongor, S: Protein and
DNA sequence homology between the V3 loop of human immunodeficiency virus type 1 envelope protein gp120 and immunoglobulin variable region.
Biochem Biophys Res Commun 1991;179:1056-1062; 20. Metlas, R. Skerl, V, Veljkovic, V, Colombatti, A, and Pongor, S:
Immunoglobulin-like domain of HIV-1 envelope glycoprotein gpl20 encodes putative internal image of some common human proteins. Viral
Immunol 1994;7:215-219; 21. Metlas, R, Trajkovic, D, Srdic, T, Veljkovic, V, and Colombatti, A:
Anti-V3 and anti-IgG antibodies of normal individuals share * complementariry structures. JAIDS 1999;21:266-270; , 25 22. Pinter, A, Honnen, WJ, Tilley, SA: Conformational changes affecting the V3 and CD4-binding domains of human immunodeficiency virus type 1 gpl120 associated with env processing and with binding of ligands to these sites. J Virol 1993;67:5692-5697,
© WO 02/072637 PCT/EP02/02454 o 23. Holmberg, D, Andersson, A, Carlsson, L, and Forsgren, S:
Establishment and functional implications of B-cell connectivity. . Immunological Reviews 1989;110:89-103; 24. Ochsenbein, AF, and Zinkernagel, RM: Natural antibodies and " 5 complement link innate and acquired immunity. Immunol Today 2000;21:624-629; 25. Fearon, DT, and Locksley, RM: The instructive role of innate immunity in the acquired immune response. Science 1996;272:50-54. ) :
Claims (5)
- . WO020072637 PCT/EP02/02454 CLAIMS
- \ 1. Human antibodies aganist human IgG total fraction, capable of neutralizing HIV-1, A 5 2. Antibodies as claimed in claim 1, obtainable by subjecting sera from normal, non HIV -infected subjects, to affinity chromatography using resins bound to human IgG total fraction.
- 3. Pharmaceutical preparation containing the antibodies of claims 1-2.
- 4. The use of antibodies of claims 1 and 2 for the preparation of a 10 medicament for use in the prevention or in the treatment of HIV infections.
- 5. The use of antibodies of claims 1 and 2 for the preparation of a medicament for use in passive immunotherapy of HIV-1 infection. p
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| Publication Number | Publication Date |
|---|---|
| ZA200306965B true ZA200306965B (en) | 2004-09-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200306965A ZA200306965B (en) | 2001-03-09 | 2003-09-05 | Natural antibodies active against HIV virus. |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITMI20010500A1 (en) |
| ZA (1) | ZA200306965B (en) |
-
2001
- 2001-03-09 IT ITMI20010500 patent/ITMI20010500A1/en unknown
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2003
- 2003-09-05 ZA ZA200306965A patent/ZA200306965B/en unknown
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| Publication number | Publication date |
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| ITMI20010500A1 (en) | 2002-09-09 |
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