WO1991006575A1 - Anticorps monoclonal humain specifique du vih-1 - Google Patents

Anticorps monoclonal humain specifique du vih-1 Download PDF

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Publication number
WO1991006575A1
WO1991006575A1 PCT/US1990/006506 US9006506W WO9106575A1 WO 1991006575 A1 WO1991006575 A1 WO 1991006575A1 US 9006506 W US9006506 W US 9006506W WO 9106575 A1 WO9106575 A1 WO 9106575A1
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hiv
gpl20
cells
antibody
strains
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PCT/US1990/006506
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English (en)
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James E. Robinson
Charles F. Scott
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Repligen Corporation
Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Through Its Medical Center
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Publication of WO1991006575A1 publication Critical patent/WO1991006575A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to antibodies specific for Human Immunodeficiency Virus (HIV) .
  • HIV is the proposed causative agent of Acquired Immune Deficiency Syndrome (AIDS). (Popovic et al . ,
  • gpl20 binds the cellular receptor of the virus, CD .
  • Cells expressing the envelope protein f_.se with CD4-bearing cells in culture (Lipson et al. 1986, Nature 323:725; Sodroski et al., 1986, Nature 322:470), resulting in the formation of multinucleate syncytia.
  • Both native gpl20 and recombinant gpl20 elicit antibodies that are capable of neutralizing HIV in cell culture (Robey et al., 1986, Proc. Nat. Aca. Sci.
  • HIV variants Over 100 HIV variants have been identified; among them are RF (Popovic et al . , supra) , WMJ-1 (Hahn et al., supra) , LAV (Wain-Hobson et al., 1985, Cell 40:9), ARV-2 (Sanchez-Pescador et al . , 1985, Science 227:484), and III-B (Ratner et al , , 1985, Nature
  • PNDT principle neutralizing domain
  • the principle neutralizing domain of the HIV gpl20 molecule is a 36 amino acid region of the gpl20 molecule between amino acids 303 and 338, inclusive, according to the gpl20 numbering convention of Ratner et al., supra. Over its entire length, the gpl20 polypeptide sequence varies from one HIV variant to the next by approximately 20-25%, whereas, the amino acid sequence variation among principle neutralizing determinant regions is approximately 40-50%. This highly variable region is flanked by conserved cysteine residues which may form a disulfide bond and define a "loop" region containing the largely conserved sequence Gly-Pro-Gly in its center.
  • Synthetic loop region peptides 8 amino acids or more in length, have been found to elicit the production of antibodies that neutralize.virus only from the isolates or variants of it from which the amino acid sequence of the peptide was derived.
  • HIV-l proteins have been produced by hybridoma formation or EBV transformation (Banapour et al., 1987, J. Immunol. 139:4027; Sugano et al., 1988, Biochem. and Biophys. Res. Co m. 155:1105; Morrow et al, 1988, J. Immunol. 140:941; Gorny et al., 1989, Proc. Nat. Aca. Sci. 86:1624; and Amadori et al. , 1989, AIDS Res. and Human Retroviruses 5:73). Approximately 30% of humans infected with HIV are infected with a particular HIV variant,- MN, in which the gpl20 loop region contains the sequence I-G-P-G-R.
  • the invention features a human monoclonal antibody which neutralizes MN variants of Human Immunodeficiency Virus Type I, the antibody being produced by a cell line having A.T.C.C. Accession No ⁇ Q > io ⁇ jD , and the immortalized human cell line that produces the antibody.
  • the antibody of the invention can be used to inhibit HIV infection in a human patient infected with or suspected of having been infected with HIV.
  • Administration of the antibody to a patient shortly after exposure or suspected exposure to the infectious agent may prevent the establishment of infection by the virus.
  • a patient may have accidently come into contact with HIV-contaminated blood, blood products, or bodily secretions.
  • the antibodies may also prevent the transfer of HIV from a seropositive gravid female to her offspring by administering the antibody prior to or during pregnancy, and/or by administration to the offspring at birth and thereafter.
  • the antibodies may also be used for passive immunization therapy; e.g., members of high risk groups who are still HIV-seronegative can be treated at regular intervals with an antibody preparation in order to prevent the establishment of a chronic HIV infection.
  • the antibody of the invention is, because of the widespread distribution of MN variants in infected persons, useful for detecting HIV in biological samples, for screening blood supplies, and, potentially, for treating a large percentage of HIV-infected patients.
  • Other features and advantages of the invention will be apparent from the following- description of the prefered embodiments thereof, and from the claims.
  • Fig. 1 is a Western blot analysis of human monoclonal antibody (HMab) reactivity with two strains of HIV-l.
  • Fig. 2 is a dot blot showing reactivity of four HMabs with gpl20 from different HIV strains.
  • Fig. 3 is a graph showing ELISA reactivity of
  • Fig. 4 is a graph showing ELISA reactivity of N70-2.3a, N70-1.5e, N70-1.9b (of the invention) HMabs with Con-A immobilized gpl20 from eight strains of HIV-l
  • Fig. 5 is a Western blot showing reactivity of
  • the procedure for isolating cell line N70-l.9b involved the steps of isolating lymphoid cells from a human patient who was asymptomatic for HIV infection but was HIV-1-seropositive, transforming those cells with Epstein Barr Virus (EBV) to immortalize them, and screening resultant lymphoblastoid cell lines for anti-HIV._, antibody production. Transformation of Human Lymphoid Cells
  • peripheral blood B cells from HIV-l infected subjects vary greatly in their susceptibility to EBV transformation.
  • B cells from patients with severely impaired immune function and relatively low CD4 cell counts are the most resistant to transformation, whereas B cells from asymptomatic patients with relatively high CD4 cell counts tend to transform more readily.
  • transformation rates even within the population of apparently healthy asymptomatic patients are variable, and not all attempts to produce HMab's from this group have been successful.
  • N70-1.9b (A.T.C.C. Accession No. ) was obtained by EBV transformation of peripheral blood B cells obtained from an asymptomatic but HIV-1- seropositive patient. (Herein, N70-l.9b is used to designate both the cell line and the antibody it produces.) The antigenic specificity of the N70-l.9b antibody was screened by ELISA using the gpl20 envelope protein containing the principle neutralizing domain from HIVTM, and the antibody was investigated for HIV neutralization activity by inhibition of syncitium formation. The epitope recognized by N70-1.9b would also be expected to be expressed in the virus strain infecting the N70 donor.. Immortalization of Human Lymphoid Cells
  • PBMC Peripheral blood mononuclear cells
  • HMab production A critical factor in HMab production is the availability of an efficient and sensitive im unoassay for screening hundreds of microwell cultures for antibody production.
  • purified viral antigens are passively coated in wells of ELISA plates.
  • the preparation of antigens for this assay requires the production of very large amounts of virus, which then must be purified and inactivated.
  • the process of virus purification may result in significant losses of gpl20.
  • this assay may be inefficient in detecting antibodies to gpl20 and favor detection of antibodies to other ' HIV antigens.
  • EBV exposed, T cell-depleted PBMC from an HIV-l infected donor were plated at 10 cells per well in 96 well culture plates with irradiated HUCL feeder cells. Approximately 50% of the cultures were transformed after 4-5 weeks of culture. Culture fluids were then screened by ELISA for IgG antibodies reacting with fixed, immobilized HIV-infected H9 cells, as f-oliows.
  • HIV-l infected H9 cells were immobilized in Concanavalin-A (Con-A) coated assay wells and then fixed with 1:1 acetone-methanol .
  • the wells were blocked with RPMI-10% FCS for 1 hour. Fluids from 96 well cultures were transferred to wells in the assay plates. After 1 hour, wells were washed with phosphate buffered saline (PBS) containing 0.1% Triton-X 100 (PBS-TX) and then reacted with peroxidase-conjugated antibody to human IgG (Protos Labs, San Francisco, CA) . Color was developed with 100 ul tetramethylbenzidine (TMB)-H 2 0 2 as substrate. The reaction was stopped by the addition of H 2 SO. and color was read as Optical Density at 450 n in a Titertek Multiskan ELISA reader.
  • PBS phosphate buffered saline
  • TX Triton-X 100
  • K24-3b One transformed culture, designated K24-3b, was found to be a stable producer of .antibody, which on further testing reacted by indirect immunofluorescence with both fixed and unfixed HIV-l infected cells but not with uninfected cells. Multiple subcultures of K24-3b cells were established a ' t low cell density and all continued to produce antibody, although they ceased to grow after about 8 months. Because the original cells were plated at a relatively low cell density and the incidence of transformation was less than 50%, it is likely that the K24-3b cell line was established as a clone.
  • Virus need not be purified; only small volumes of cells grown in serum free medium are needed to yield ample quantities of antigen for Con-A immobilization. Indeed, many serum free virus stocks can be diluted 1:2 or 1:4 without diminished antigen activity and thus, as little as 100 ul of supernatant fluid can be used to prepare 20-40 96-well ELISA plates.
  • Transformed B cell culture fluid were transferred to both antigen coated and control wells of assay plates which were incubated at room temperature for 1 hour. Binding of antibodies was measured as described above. This ELISA was also used in later experiments to test the reactivity of HMabs with glycoproteins from different virus strains.
  • Ten transformed cultures produced IgG antibodies reacting with J62 glycoproteins but not with control antigen. Seven cultures produced antibodies for less than two months.
  • IgG subclass and light chain type of each antibody was determined by reactivity with murine monoclonal antibodies to the four heavy chain subclasses (Behring Diagnostics) or polyclo ⁇ al goat antibodies to lambda and kappa light chains in a sandwich ELISA, according to conventional isotyping techniques. All four HMabs are of the IgGl subclass; K24-3b, N70-1.5e, and N70-1.9b contain kappa light chains and N70-2.3a contains lambda light chains.
  • each HMab was determined using dot blot and Western blot assays. Twelve HIV-l strains were used as target antigens: strains C39, J62, SA90, SA96, and L86 were isolated from mitogen activated T cells of five asymptomatic HIV-l infected subjects by co-cultivation with activated normal T cells in medium supplemented with interleukin-2; strain SA3 was similarly isolated from a patient with AIDS; strain HiTi is described in Rasheed et al., Virology, 1986, 154:395-400; strain K3 was obtained from the Tulane Delta Primate Center, New
  • the prototype HIV-l strain was obtained from American Type Culture Collection; HTLV-III ⁇ .
  • HTLV-IIIB HTLV-III. ⁇
  • SA3, HiTi, and K3 were grown in H9 cells.
  • Strain L86 isolated from the B cell donor of one monoclonal antibody (K24-3b), ' did not replicate in continuous T cell lines and was propagated in mitogen activated cord blood T cells in medium containing 100 units per ml recombinant IL-2. To prepare antigens for
  • Extracts of 1-2 x.10 HIV-l infected cells prepared by solubilizing cells for 30 min in 1% Triton-X followed by removal of insoluble material by centrifugation in a microcentrifuge. Samples were mixed 1:1 with SDS sample buffer without reducing agents and " heated for 5 min at 95°C, Cell lysates of uninfected H9 and MT4 cells were similarly prepared. Samples were fractionated by electrophoresis in 7.5% sodium dodecyl sulfate-polyacrylamide gels, in a BioRad mini-gel apparatus. Proteins were then electrophoretically transferred to nitrocellulose membranes.
  • Western blot strips were incubated with blocking buffer (1% bovine serum albumin, 0.5% Tween 20, in 0.5 M NaCl, 10 mM Tris, pH 8), reacted first with each antibody preparation and then with alkaline phosphatase-conjugated antibodies to human or sheep IgG, as appropriate. Colored bands were developed using nitroblue tetrazolium and 5-bromo-4-chloro-3-indolyl-phosphate (NBT-BCIP, Sigma,
  • Lanes 1-5 of each of panels A and B are as follows: Lane 1, K24-3b; Lane 2, N70-2.3a; Lane 3, N70- ⁇ .5e; Lane 4, N70-l.9b; Lane 5, sheep anti-HTLV-IIIB gpl20.
  • Antibody assays on dot blot strips were performed as for Western blots, except a goat antiseru to gpl60 of HTLV-IIIB (Rusche et al. , Proc. Natl. Acad. Sci. (USA), 1987, 84:6924-6928) was used as a positive control.
  • HMabs were tested by ELISA for reactivity with Con-A immobilized viral glycoproteins from different HIV-l strains. Theoretically, the binding of gpl20 to Con-A could block access of antibodies to some epitopes. However, we found that murine monoclonals known to react either with the CD4 binding region or the V3 hypervariable domain react strongly with Con-A immobilized gpl20 (unpublished) , indicating that epitopes within these two regions are represented in the assay.
  • one strain (L86) was grown in a serum free culture of IL-2 dependent, activated primary T cells and gpl20 released into the medium functioned well in the Con-A immobilization assay. Similar results may be achieved with other strains isolated from asymptomatic B cell donors; thus, it may become feasible to screen for antibodies reacting with antigens of homologous isolates.
  • Figure 4 illustrates the results of a similar experiment comparing the reactivities of N70-1.5e and N70-1.9b with Con-A immobilized glycoproteins derived from eight strains. (Results are a single determination.)
  • N70-2.3a served as a positive control. Both N70-1.5e and N70-2.3a reacted strongly with all eight strains, whereas N70-1.9b reacted only with J62, the strain that was used in the screening the original B cell cultures for antibody production.
  • the results indicate that N70-1.5e, like N70-2.3a, reacts with an epitope shared by all strains tested thus far, while N70-1.9b reacts with a strain-restricted epitope.
  • HMabs The reactivity of the four HMabs was investigated further using two additional target gpl60 antigens, HIV-I- ⁇ and recombinant HIV-l gF2 .
  • the results, presented in Table 1, ' show that N70-1.9b, as well as the other three HMabs, reacted strongly by ELISA with Con-A immobilized glycoproteins from HIV-I ⁇ and HIv- ⁇ gF2 .
  • ELISA and Western Blot (WB) assays were performed on four human monoclonal antibodies, N70-1.9b, N70-1.5e, K24-3b, and N70-II.3a, to determine their antigenic specificity.
  • ELISA Western Blot
  • five different recombinant proteins or protein fragments were used as test antigens: gpl60-IIIB, gpl60-RF, PB-1-IIIB, PB-l-RF, and PB-l-MN.
  • Western Blot three-different test antigens were used: gpl60-IIIB, PB-1-IIIB, and PB-l-MN.
  • Intact gpl60 polypeptide was produced in insect cells using a baculoviru ⁇ expression system.
  • ELISA was performed as follows. Each well of a 96-well Costar flat-bottom microtiter plate was coated with the antigen by placing a fifty microliter aliquot of a PBS solution containing the antigen at a final concentration of 2-10 ug/ml in each well.
  • the Con-A method described above was not used here because the antigens (proteins or peptides) are purified and, therefore, immobilized in sufficient amounts for antibody binding.
  • the antigen solution was aspirated and replaced with PBS + 0.5% BSA and incubated for 1 hour. Following incubation, the wells were then aspirated, washed, and 50 ul of the antibody was added.
  • N70-1.9b monoclonal binds the principle neutralizing domain, or loop region, of the HIV,-, gpi ⁇ o molecule.
  • N70-l.9b, N70-l.5e, and N70-II.3a were tested for their ability to bind " a fragment of the envelope protein from either the HIV-MN or the HIV-IIIB strain.
  • RP70 is the "full-loop closed” and "RP142” is the open 24mer from the principle neutralizing domain (PND) of the MN envelope protein; and "RP135" is a 24mer from the PND of the IIIB strain.
  • These fragments contain amino acid sequences in the neutralizing domain sub-sequence of the gpl20 loop region as follows:
  • Peptide RP70 was formed into a closed loop by creation of a disulfide bond between the two cysteine residues near the ends of the amino acid sequence.
  • a method for creating such a bond is described in (Zhang et al . , 1988, Biochemistry 22:3785-3794).
  • the results in Table 5 show that N70-1.9b binds to the principle neutralizing domain of the MN variant (RP70, RP142) but not to the PND of the IIIB variant (RP135).
  • N70-1.9b were then assayed for inhibition of syncitium formation by HIV- ⁇ , infected cells.
  • recombinant Vaccinia Virus expressing the envelope gene of HIV ⁇ was used to infect cells of CD4+ human T-lymphoma line CEM (A.T.C.C. Accession No. CCL119), and the antibody was then added to the cells to screen for blockage of HIV envelope mediated cell fusion.
  • a positive result indicating the ability of the antibody to neutralize the virus, was defined to be at least a 90% inhibition of syncytia formation.
  • CEM cells were infected with r-ecombinant Vaccinia Virus expressing HIV ⁇ gpl60 derived from plasmid pSCR2502, which contains the PB-l fragment of MN; the remainder of gpl60 was of IIIB origin.
  • syncytia are induced which are inhibitable by antisera or monoclonal antibodies directed against the PND.
  • the results, shown in Table 6, show that N70-1.9b inhibits syncytia induced by vaccinia gpl60-MN over a range .of concentrations of the antibody, whereas N70-l.5e does not inhibit the formation of syncytia.
  • the human monoclonal antibody of the present invention may be administered as a passive immunization agent in effective amounts broadly ranging between about 200 mg and about 15 grams and preferably between 50 mg and .1 gram.
  • the antibody of the invention is administered parenterally, either via the intravenous or intramuscular route.
  • a typical treatment regimen would comprise administration of an effective amount of antibody administered over between about one week and about 6 months,
  • the number of treatments required to control a patient's disease may vary from individual to individual, depending upon the severity and stage of the illness and the individual characteristics of each patient being treated.
  • the total dose required for each treatment may be administered by multiple doses or in a single dose.
  • the human monoclonal antibodies may be administered alone or in conjunction with other HIV treatments, such as AZT, in order to control a patient's disease.
  • the anti-HIV treatment may be administered one or two times a week or more as determined by the patient's condition and the stage -of the_patient' s disease.
  • the human monoclonal antibody of the present invention can be incorporated into conventional pharmaceutical formulations for use in treating individuals that are afflicted with HIV or for prophylaxis in individuals at risk for such infections.
  • the pharmaceutical formulations of the invention comprising an anti-HIV effective amount, range between about 200 mg and about 15 grams, of the human monoclonal antibody of the present invention.
  • the quantity of effective dose applied by each injection is relatively unimportant since the total dosage can be reached by administration of one or a plurality of injections.
  • such formulations may comprise pharmaceutically-acceptable carriers, diluents, salts and other materials well-known in the art.
  • Isotonic saline, sterile water, 10% maltose, human serum albumin, glycine or other pharmaceutically-acceptable materials may be used as diluents, carriers or solvents in preparing the pharmaceutical formulations comprising the human monoclonal antibody of the present invention.
  • the deposited material will be maintained with all the care necessary to keep it viable and uncontaminated for a period of at least five years after the most recent request for the furnishing of a sample of the deposited microorganism, and in any case, for a period of at least thirty (30) years after the date of deposit or for the enforceable life of the patent, whichever period is longer.
  • Applicants' assignees acknowledge its duty to replace the deposit should the depository be unable to furnish a sample when requested due to the condition of the deposit. A copy of the A.T.C. Budapest Treaty deposit receipt will be furnished upon request. -

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Abstract

Un anticorps monoclonal humain spécifique du VIH-1, N7019b, est produit par la lignée de cellules désignée sous le numéro HB10290 auprès de l'A.T.C.C. Le N7019b se lie au principal domaine de neutralisation de la molécule du VIH et neutralise la formation de syncytiums par le MN-VIH-mn gp160 infecté.
PCT/US1990/006506 1989-11-03 1990-11-02 Anticorps monoclonal humain specifique du vih-1 WO1991006575A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0478689A1 (fr) * 1989-06-05 1992-04-08 SCOTT, Charles F. Jr. ANTICORPS MONOCLONAUX HUMAINS DE LA gp 120 DU VIH-1 MN?
WO1995005196A1 (fr) * 1993-08-13 1995-02-23 Univax Biologics, Inc. Traitement de l'infection par vih a base d'anticorps
US5558865A (en) * 1991-08-22 1996-09-24 Nissin Shokuhin Kabushiki Kaisha HIV immunotherapeutics
US5922325A (en) * 1990-10-26 1999-07-13 Public Health Research Institute Of The City Of New York, Inc. Synergistic neutralization of HIV-1 by human monoclonal antibodies and other antibodies directed against the v3 loop and the CD-4 binding site of GP-120,and the use for immunotherapy of HIV-1 infection
US6432675B1 (en) 1992-06-18 2002-08-13 Roberto Crea Combinatorial polypeptide antigens

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol. 155, No. 3, issued 30 September 1988, SUGANO et al., "Human Monoclonal Antibody Against Glycoproteins of Human Immunodeficiency Virus", pp. 1105-1112. *
JOURNAL OF VIROLOGY, Vol. 61, No. 6, issued June 1987, HO et al., "Human Immunodeficiency Virus Neutralizing Antibodies Recognize Several Conserved Domains on the Envelope Glycoproteins", pp. 2024-2028. *
JOURNAL OF VIROLOGY, Vol. 62, No. 10, issued October 1988, LINSLEY et al., "Effects of Anti-gp 120 Monoclonal Antibodies on CD4 Receptor Binding by the Ex Protein of Human Immunodeficiency Virus Type 1", pp. 3695-3702. *
JOURNAL OF VIROLOGY, Vol. 62, No. 6, issued June 1988, MATSUSHITA et al., "Characterization of a Human Immunodeficiency Virus Neutralizing Monoclonal Antibody and Mapping of the Neutralizing Epitope", pages 2107-2114. *
PROC. NATL. ACAD. SCI., Vol. 86, issued March 1989, GORNY et al., "Generation of Human Monoclonal Antibodies to Human Immunodeficiency Virus", pp. 1624-1628. *
SCIENCE, Vol. 234, issued 12 December 1986, PUTNEY et al., "HTLV-III/LAV-Neutralizing Antibodies to an E. Coli-Produced Fragment of the Virus Envelope", pp. 1392-1395. *
VIROLOGY, Vol. 164, issued 1988, GURGO et al., "Envelope Sequences ot Two New United States HIV-1 Isolates", pages 531-536. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0478689A1 (fr) * 1989-06-05 1992-04-08 SCOTT, Charles F. Jr. ANTICORPS MONOCLONAUX HUMAINS DE LA gp 120 DU VIH-1 MN?
EP0478689A4 (en) * 1989-06-05 1993-06-16 Charles F. Scott Jr. Human monoclonal antibodies to hiv-1 mn? gp 120
US5922325A (en) * 1990-10-26 1999-07-13 Public Health Research Institute Of The City Of New York, Inc. Synergistic neutralization of HIV-1 by human monoclonal antibodies and other antibodies directed against the v3 loop and the CD-4 binding site of GP-120,and the use for immunotherapy of HIV-1 infection
US5558865A (en) * 1991-08-22 1996-09-24 Nissin Shokuhin Kabushiki Kaisha HIV immunotherapeutics
US6432675B1 (en) 1992-06-18 2002-08-13 Roberto Crea Combinatorial polypeptide antigens
WO1995005196A1 (fr) * 1993-08-13 1995-02-23 Univax Biologics, Inc. Traitement de l'infection par vih a base d'anticorps

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