WO1991010742A1 - Monoclonal antibody specific for non-immunodominant epitope of hiv proteins - Google Patents

Monoclonal antibody specific for non-immunodominant epitope of hiv proteins Download PDF

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Publication number
WO1991010742A1
WO1991010742A1 PCT/US1991/000319 US9100319W WO9110742A1 WO 1991010742 A1 WO1991010742 A1 WO 1991010742A1 US 9100319 W US9100319 W US 9100319W WO 9110742 A1 WO9110742 A1 WO 9110742A1
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antibody
hiv
cells
binding
conjugate
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PCT/US1991/000319
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English (en)
French (fr)
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Paul J. Higgins
Charles F. Scott, Jr.
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Replgien Corporation
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Priority to JP91503590A priority Critical patent/JPH05506142A/ja
Publication of WO1991010742A1 publication Critical patent/WO1991010742A1/en

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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6839—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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., 1984, Science 224:497). It is a pathogenic human retrovirus whose genome is capable of encoding at least six gene products.
  • the env gene encodes a 160 kDa glycosylated protein (gpl60) that is processed by proteolysis into a 120 kD external glycoprotein (gpl20) and a 41 kD transmembrane protein (gp41) .
  • gpl20 is anchored to the virion by noncovalent interactions with gp41.
  • gpl20 and gp41 are present on the surface of both virion particles and virus-infected cells.
  • Different strains of HIV vary in the amino acid sequences of proteins encoded by the viral genome, particularly in the amino acid sequence of the external envelope glycoprotein gpl20 (Starcich, 1986, Cell 45:637; Hahn et al., 1986, Science 232:1548). Over its entire length, the gpl20 polypeptide sequence varies from one HIV variant to the next by approximately 20-25%. The extent of variation is not constant over the whole envelope protein. There is a pattern of conserved and variable regions, which suggests that the protein is divided into regions responsible for distinct functions. A number of different regions have been identified; for example, the CD4 binding domain, the principal neutralizing determinant, and cytotoxic T-cell recognition determinants.
  • Pincus et al. J. Immunol. (1989) 142;3070
  • Till et al. Proc. Nat. Aca. Sci.. 1989, 86;1981 disclose anti- gp41-toxin conjugates.
  • the invention features an antibody capable of recognizing a non-immunodominant epitope of the envelope protein of HIV, wherein the binding of the antibody to the envelope protein is not blocked by serum from an HIV- infected patient.
  • antibody refers to a whole antibody molecule, or to a fragment or to a modification of an antibody, e.g. a fragment of an antibody bay be the Fab 2 fragment of the molecule, the Fab 1 fragment , or the heavy or light chain alone; and a modification, for example, may be a linear polypeptide molecule which includes both the heavy and light chains, as described in Huston et al.
  • non-immunodominant epitope means an amino acid sequence within the natural conformation of a protein that is not significantly immunogenic; i.e., does not elicit an antibody response in at least 75% of human patients.
  • An antibody directed toward a non-immunodominant region of the HIV envelope protein can, according to the invention, bind that region due to the absence or low level of potentially competitive circulating antibodies.
  • an antibody directed towards an immunodominant region of the envelope protein will be partially or completely blocked from binding the targeted envelope protein region due to the presence of antibodies in the patient due to the patient's natural immune response to HIV infection.
  • the non-immunodominant envelope region may be within the
  • Non- immunodominance can be measured in vitro by binding the antibody to a target antigen in the presence of HIV- positive human serum; an antibody specific for a non- immunodominant epitope of the target antigen will demonstrate a comparable binding efficiency to the target antigen in the presence or absence of HIV positive serum.
  • the binding efficiency of the antibody to the target antigen in the presence of HIV-positive serum is at least 80% of its binding efficiency in the absence of HIV- positive serum.
  • the non-immunodominant epitope recognized by the antibody is group common.
  • group common determinant means an antigenic portion of a protein encoded by an HIV strain that is not specific for that strain only, but is present on at least one other HIV strain.
  • the antibody is capable of binding to the surface of HIV envelope glycoprotein expressing cells; is capable of recognizing the region of the envelope protein between amino acid residues 473 and 759, inclusive, according to the numbering convention of Ratner et al., 1985, Nature 313:277; and is capable of recognizing that portion of gpl20 contained within the 473 through 759 amino acid region; one example of such an antibody is that produced by cell line A.T.C.C. No. HB 10321.
  • the antibody is covalently linked to a toxin to form a conjugate, and the conjugate is capable of killing HIV-infected cells in the presence of human HIV+ serum; killing may occur via internalization of the antibody-toxin conjugate by HIV- infected cells.
  • the conjugate may be made at the protein level by chemically linking the antibody and the toxin molecule or at the DNA level, by cloning the DNA sequence
  • toxin is used to include the commonly designated toxins such as poisonous lectins, ricin, abrin, modeccin, diphtheria toxin, pseudomonas exotoxin or preferably the toxic A chain portions thereof, as well as other toxic agents such as radioisotopes, cytotoxic and carcinostatic drugs.
  • toxins such as poisonous lectins, ricin, abrin, modeccin, diphtheria toxin, pseudomonas exotoxin or preferably the toxic A chain portions thereof, as well as other toxic agents such as radioisotopes, cytotoxic and carcinostatic drugs.
  • Toxin may also refer to combinations of the various toxins, which can be coupled to one antibody molecule thereby accommodating variable cytotoxicity.
  • the HIV-specifi ⁇ antibody is linked to a second antibody that is specific for an effector cell to form an antibody heteroconjugate (also known in the art as heteroaggregates or heteroantibodies) .
  • the anti-HIV antibody of the heteroconjugate binds to an HIV-infected cell, i.e., the target cell to be killed, while the anti- effector antibody of the heteroconjugate binds to an effector cell such as those found within the peripheral blood lymphocyte (PBL) population, e.g., cytotoxic T lymphocytes (also known as T cells) , monocytes (in particular, acrophages) , granulocytes, or large granular lymphocytes which include cells with natural killer activity or antibody-dependent cellular cytotoxic activity, with the result that the antibody components of the heteroconjugate bridge the effector and target cells and thus promote killing of the target cell by the cytotoxic effector cell.
  • PBL peripheral blood lymphocyte
  • HIV-infected patients can be treated by administering an amount of the antibody-toxin conjugate or an antibody heteroconjugate of the invention sufficient to kill HIV-infected cells.
  • the viral envelope protein is expressed on the surface of infected cells.
  • SUBSTITUTESHEET selectively killing the.cells in which the virus is replicating using an antibody conjugate that reacts with virus-specific cell-surface antigens, the infectious cycle of the virus may be interrupted.
  • One advantage of an antibody or antibody-toxin conjugate or an antibody heteroconjugate of the invention is the non-immunodominance of the HIV envelope glycoprotein epitope that the antibody is specific for.
  • Another advantage of certain antibodies, antibody- toxin conjugates, and antibody heteroconjugates of the invention are their ability to recognize a group common determinant of the HIV envelope glycoprotein.
  • Group common determinants are portions of the envelope polypeptide that are essentially invariant among different HIV strains. Therefore, an antibody capable of recognizing a group common determinant can recognize gpl ⁇ o from any strain of HIV.
  • Treatment of an HIV- infected patient according to the invention will thus not be limited to any one strain of HIV, but will include all strains to which the target determinant is common.
  • Fig. 1 is an schematic illustration of the gpl60 protein, showing the gpl20, gp41, pl21, and pENV9 regions.
  • Fig. 2 is a graph showing results of an ELISA in which the binding specificity of the 1C1 antibody to a target antigen was tested.
  • Figs. 3(a) - 3(d) are graphs showing results of ELISAs in which the binding specificity was determined for the 1C1 antibody or a control antibody in the presence of HIV positive serum.
  • Figs. 4(a) - 4(d) are graphs showing results of FACS analyses using the 1C1 antibody.
  • gpl60 Repligen Corp. , Cambridge, MA
  • pENV9 envelope protein fragment extending from amino acid residue 473 through residue 759
  • gp 160 was prepared for immunization by emulsification in complete Freund's adjuvant (CFA) according to standard techniques (Difco Labs, Grand Island, NY) . Production of Monoclonal Antibodies
  • mice Balb/cJ female mice (Jackson Labs., Bar Harbor, ME) were immunized intraperitoneally with 70 ⁇ g per mouse of gpl60/CFA. The mice were given a booster immunization of gpl60 in an emulsification in incomplete Freund's adjuvant three weeks later. Mice were bled and the sera assayed for the presence of antibodies reactive with the immunogen. Mice showing a strong serological response
  • SUBSTITUTE SHEET were given a final booster immunization of response were given a final booster immunization of pENV9 in soluble form five weeks following the first booster immunization and, 3 days later, spleen cells from these mice were fused at a ration of 5:1 with SP2/0 (A.T.C.C. No.
  • CRL8287 A.T.C.C. No. CRL8006 myeloma cells incapable of secreting both heavy and light immunoglobulin chains (Kearney et al., J. Immunol., 1979, 123:1548), by standard procedures based on the method of Kohler and Milstein, Nature (1975) 256:495.
  • the isotype of the 1C1 clone was determined by the ELISA method to be IgG 2a using goat-anti-mouse HRP (Zy ed Labs, San Francisco, CA) preparations which correspond to each of the major immunoglobulin isotypes.
  • the 1C1 clone was sub ⁇ loned and rescreened for the ability to bind to the Antigens described above.
  • the 1C1 subclone was expanded by intraperitoneal injection into pristane primed Balb/c mice. Ascites fluid was recovered from the mice and the antibody was purified by Protein A affinity chromatography, as described below. Amplification and Purification of Monoclonal Antibodies
  • SUBSTITUTESHEET Purified 1C1 antibody was prepared by injecting a hybridoma subclone that repeatedly tested positive by ELISA intraperitoneally into pristane-primed syngeneic mice. The ascites which developed were recovered two to three weeks after injection, and the antibody was purified as follows, and then dialyzed against PBS.
  • pl21 includes a major immunodominant epitope of the gp41 protein (Chang et al., U.S. Patent No. 4,724,175 and Wang et al., 1986, Proc. Nat. Aca. Sci. 83:6159).
  • Fig. 2 shows the results of the ELISA assay. These results demonstrate 1C1 binds specifically to both pENV9 and gpl20, but does not bind pl21.
  • the 1C1 antibody binds to a region of pENV9 that is also present in gpl20, but that is not contained within the pl21 portion.
  • an antibody specific for gp41 (Epitope, Inc., Beaverton, OR) was tested for binding to either pENV9, pl21, or gpl20, showing that the anti-gp41 antibody bound to pENV9 and pl21, but did not bind to gpl20, as expected.
  • a therapeutically useful exogenous antibody specific for the HIV envelope protein must be able to bind HIV, or HIV-infected cells expressing the envelope protein, in the presence of competing circulating antibodies.
  • the 1C1 antibody was tested for its ability to bind to target antigen in the presence of serum from an HIV-infected patient, and compared with a control antibody known to bind to an immunodominant region of gp41.
  • Figs. 3(a) - 3(d) show the results of ELISAs in which microtiter wells were coated with the capture antigen.
  • the 1C1 or control antibodies were then added in 50 ul of (1) undiluted HIV-negative serum, (2) undiluted HIV-positive serum, or (3) 0.5% BSA. After 2 hrs., the wells were washed and secondary antibody (sheep anti-mouse-HRP) which did not cross-react with human Ig was added. After 1 hr. , the secondary antibody was removed, the wells were washed, ABTS was added, and the OD 410 was measured after 30 min.
  • the 1C1 antibody was assayed for binding to the capture antigen, pENV9.
  • the results demonstrate that 1C1 bound with almost equal efficiency to pENV9 in the presence of either HIV-positive serum or HIV-negative serum (Fig. 3a) .
  • the 1C1 antibody bound with the highest efficiency to pENV9 in the presence of HIV negative serum at antibody concentrations above 0.01 ⁇ g/ml
  • the binding of this antibody to pENV9 in the presence of HIV positive serum was about 88% as efficient as binding to pENV9 in the presence of HIV negative serum at an antibody concentration of l ⁇ g/ml, and over 95% as efficient at 10 ⁇ g/ml.
  • Similar results were obtained when 1C1 binding was tested in the presence of HIV positive sera from four other patients.
  • SUBSTITUTESHEET results demonstrate that, if there are pENV9-specific antibodies present in HIV positive serum, they are present in low enough titers or have a weak binding affinity or react with different pENV9 epitope so that they do not significantly interfere with the binding of the ICl antibody to pENV9. Thus, ICl is potentially useful as a therapeutic agent.
  • Fig. 3(b) the ability of the ICl antibody to bind the pl21 protein was tested.
  • the ICl antibody did not bind pl21 at all. (The minimal reactivity observed with pl21 at ICl concentrations above O.l ⁇ /ml in 0.5% BSA was probably due to nonspecific binding.)
  • ICl monoclonal antibody binds to the surface of cells expressing the HIV envelope glycoprotein was determined by indirect immunofluorescence and analysis by FACs (Fluorescence Activated Cell Sorter, Methods in Enzymology, 1984, Parks et al., 108:197), as follows.
  • the ICl antibody was bound to either CVl cells (A.T.C.C. No. CCL70) infected with a Vaccinia Virus recombinant containing the HIV env gene, which express both gpl20 and gp41 on their surface (CVl-Env) , or CVl
  • Fig. 4(a) the ICl antibody was bound to CVl- Env cells. If Fig. 4(a) is superimposed on Fig. 4(b), which shows a FACS profile for CVl-Lac cells incubated with the ICl antibody, there is a rightward shift (i.e., an increase) in fluorescence intensity in the CVl-Env cells compared to the CVl-lac cells, indicating that the ICl antibody binds HIV envelope glycoprotein expressing cells significantly better than the cells not expressing the envelope protein.
  • ICl binds to the target antigen in its native state, and suggests that cells expressing HIV envelope glycoprotein may be specific targets for an immunotoxin conjugate composed of ICl linked to a toxin.
  • Figs. 4(c) and 4(d) are controls in which the ICl antibody was bound to uninfected CVl cells and in which buffer alone was bound to CVl-Env Cells, respectively. (The background fluorescence that is apparent in the FACS analyses of CVl-Env and CVl-Lac cells is probably due to alterations in the cell membrane resulting from expression of foreign viral proteins.) Preparation of Antibody Conjugates of Heteroconiugates
  • the antibodies may be conjugated to cytotoxic agents and used as immunotoxins (as described in, e.g., Vitetta et al., 1987, Science 238: 1098), or incorporated onto the surface of liposomes containing anti-HIV drugs or toxins to specifically target such drugs or toxins to HIV-infected cells.
  • immunotoxin refers to a conjugate of an antibody with one or more toxins.
  • SUBSTITUTE SHEET various toxins are coupled to one antibody molecule, coupling may occur by different chemical mechanisms; for example, covalent binding, affinity binding, intercalation, coordinate binding and complexation.
  • the preferred coupling of the antibody to the toxin is, however, covalent binding either by chemical or genetic fusions.
  • the immunotoxin comprises an antibody reactive with a non-immunodominant, group common epitope of the HIV envelope protein linked to the exotoxin form Pseudomonas aeruginosa.
  • Pseudomonas exotoxin PE is particularly preferably to other toxins because large amounts are easily prepared, because humans do not usually have neutralizing antibodies against it, and because it does not need to be separated into subunits before being conjugated.
  • PE is an extremely active monomeric protein (molecular weight 66kD) , secreted by Pj. aeruginosa which inhibits protein synthesis in eukaryotic cells.
  • PE40 the truncated molecule, designated PE40, from which the cellular binding domain has been removed (Pastan et al. EP Publication No. 0 261 671) .
  • PE40 can be linked to an antibody of the invention by chemical coupling, for example, using the heterobifunctional cross-linker SPDP (N-succinimidyl-3-(2-pyridyldithiol) propionate) Sigma, St. Louis, MO) (Pastan et al, 1986, Cell 47:641), or by genetic fusion (Chaudhary et al.,) 1989, Nature 339:394).
  • SPDP N-succinimidyl-3-(2-pyridyldithiol) propionate
  • any suitable method of conjugation of the antibodies may be used; for example, preferred method involves cross- linking the antibodies using the cross-linker SPDP according to the method of Karpovsky et al. (1984, J. Exp. Med. 160:1686). Following cross-linking, the heteroconjugates are separated from fee antibody by size exclusion chromatography.
  • An antibody-toxin conjugate or heteroconjugate of the invention can be tested for target specificity and efficiency by killing by incubating the conjugate with HIV chronically-infected cells that express HIV envelope glycoprotein or with uninfected cells, and pulsing the cells with 3 H-Thymidine of 1 C-Leucine. Toxicity can be measured by a decrease in cell division or protein synthesis in the infected cells relative to the uninfected control cells. The efficiency of cell killing can be calculated using a clonogenic assay, in which infected cells are incubated with a conjugate of the invention, plated by limiting dilution (Tarwell, 1981, J. Immunol. 126.1614), and the number of surviving cells is compared to identically treated uninfected cells. Use
  • the antibody which binds to a protein that is expressed only in HIV-infected cells
  • a toxin e.g. pseudomonas exotoxin
  • the cytotoxic agent By coupling the cytotoxic agent to the antibody, a high level of toxic efficacy can be achieved specifically against the target cell with a markedly low level of non-specific toxicity.
  • the use of the toxic agent is possible because the antibody to which the agent is coupled will carry the agent specifically to the target (in this case, HIV-infected cells) , thereby sparing non-infected cells from the toxin.
  • the antibodies of the invention can be incorporated into conventional pharmaceutical formulations for use in treating'individuals that are
  • 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 material may be used as diluents, carriers or solvents in preparing the pharmaceutical formulations comprising antibodies of the invention.
  • the pharmaceutical compositions may be in a variety of dosage forms which include solid, semi-solid and liquid forms as powders, pills, tablets, liquid solutions or suspension, suppositories, polymeric microcapsule, liposomes or injectable or infusible substances.
  • the pharmaceutical formulations may be administered using conventional methods which include, but are not limited to, intravenous, oral, subcutaneous, intraperitoneal or intralymphatic.
  • the antibody, immunotoxin or heteroconjugates of the invention may be administered in conjunction with other treatments to augment the effectiveness of the treatment.
  • SUBSTITUTE SHEET host are disclosed by Neuberger et al. (WO Publication No. 86/01533) and Morrison et al. (EP Publication No. 0 173 494) , hereby incorporated by reference.
  • 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' assignee acknowledges its duty to replace the deposit should the depository by 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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PCT/US1991/000319 1990-01-16 1991-01-16 Monoclonal antibody specific for non-immunodominant epitope of hiv proteins WO1991010742A1 (en)

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JP91503590A JPH05506142A (ja) 1990-01-16 1991-01-16 Ｈｉｖ蛋白質の非免疫支配エピトープに特異的なモノクローナル抗体

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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
DE19809785A1 (de) * 1998-03-08 1999-09-09 Bergter Radioimmunpharmakon zur Behandlung der HIV-1-Infektion
US6797492B2 (en) 1991-05-17 2004-09-28 Merck & Co., Inc. Method for reducing the immunogenicity of antibody variable domains
WO2007084692A2 (en) * 2006-01-20 2007-07-26 Welson Pharmaceuticals, Inc. Immunoconjugates for treatment of infectious diseases
WO2007134037A3 (en) * 2006-05-15 2008-11-27 Immunomedics Inc Methods and compositions for treatment of human immunodeficiency virus infection with conjugated antibodies or antibody fragments
US8481041B2 (en) 2005-04-06 2013-07-09 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US9687547B2 (en) 2015-05-28 2017-06-27 Immunomedics, Inc. T20 constructs for anti-HIV (human immunodeficiency virus) therapy and/or vaccines
US10730933B2 (en) 2015-12-05 2020-08-04 Centre Hospitalier Universitaire Vaudois HIV binding agents

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Gene, Volume 52, issued 1987, A SRINIVASAN et al, "Molecular characterization of human immunodeficiency virus from Zaire: nucleotide sequence analysis identifies conserved and variable domains in the envelope gene", pages 71-82, see page 78, figure 5 and page 80. *
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US6797492B2 (en) 1991-05-17 2004-09-28 Merck & Co., Inc. Method for reducing the immunogenicity of antibody variable domains
DE19809785A1 (de) * 1998-03-08 1999-09-09 Bergter Radioimmunpharmakon zur Behandlung der HIV-1-Infektion
WO1999045969A2 (de) * 1998-03-08 1999-09-16 Wolfgang Bergter Radioimmunpharmakon zur behandlung der hiv-1-infektion
DE19809785C2 (de) * 1998-03-08 2000-02-10 Wolfgang Bergter Radioimmunpharmakon zur Behandlung der HIV-1-Infektion
WO1999045969A3 (de) * 1998-03-08 2000-02-17 Wolfgang Bergter Radioimmunpharmakon zur behandlung der hiv-1-infektion
US8481041B2 (en) 2005-04-06 2013-07-09 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US9839689B2 (en) 2005-04-06 2017-12-12 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
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JPH05506142A (ja) 1993-09-16
EP0511300A4 (en) 1993-05-26
EP0511300A1 (de) 1992-11-04
CA2073060A1 (en) 1991-07-17

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