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WO1992008491A1 - Conjugues d'anticorps anti-idiotype et de porteurs ainsi que leur emploi en immunisation par epitope - Google Patents

Conjugues d'anticorps anti-idiotype et de porteurs ainsi que leur emploi en immunisation par epitope Download PDF

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Publication number
WO1992008491A1
WO1992008491A1 PCT/US1991/008653 US9108653W WO9208491A1 WO 1992008491 A1 WO1992008491 A1 WO 1992008491A1 US 9108653 W US9108653 W US 9108653W WO 9208491 A1 WO9208491 A1 WO 9208491A1
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vaccine
pro
gly
thr
carrier
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PCT/US1991/008653
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English (en)
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Tse Wen Chang
Michael S. C. Fung
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Tanox Biosystems, Inc.
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Publication of WO1992008491A1 publication Critical patent/WO1992008491A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • C07K16/4275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig against anti-CD4 Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/44—Antibodies bound to carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4216—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-viral Ig
    • C07K16/4225—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-viral Ig against anti-HIV Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the invention relates to epitope-directed immunization with a vaccine in which an anti-idiotype antibody (or a fragment thereof) specific for a pathogen or allergen is conjugated to a carrier, and wherein the carrier is one against which the vaccine recipient has previously been immunized or otherwise previously 15 exposed, or it is a carrier which enhances the immune response against the anti-idiotype.
  • Ab3 antibodies which, like Abl, bind to the antigen which was originally introduced. If the antigen originally introduced is a pathogen or allergen or a potential pathogen or allergen,
  • the Ab2 are, therefore, useful as vaccines, because they induce production of endogenous Ab3.
  • Vaccination is an effective means to stop the spread of the deadly disease AIDS, or Acquired Immune Deficiency Syndrome. Without an effective vaccine, the disease may increase to epidemic proportions in the general population.
  • Anti-idiotype antibodies have been suggested for use in active immunization against human immunodeficiency virus-type 1 ("HIV-1"), the causative agent of AIDS. See U.S. Patent Application Serial No. 07/454,161, filed December 21, 1989.
  • One requirement for active immunization with Ab2 is that the conformational structure of the antigen binding site of the Ab2 should be preserved during the immunization. If the conformation changes, the Ab2 will no longer bear the internal image of the antigenic determinant which Abl recognizes, and will not induce production of antigen-specific Ab3.
  • the immunogen may be a protein subunit or fixed, deactivated virus particles, rather than an anti-idiotype antibody.
  • an adjuvant is often used to augment the immune response to the immunogen. Suitable adjuvants may include
  • the immunogen in the active immunization is an anti-idiotype antibody
  • many adjuvants are not well-suited.
  • a number of adjuvants can change the conformational structure of the anti-idiotype' s antigen binding site, including those which lower the pH, e.g. , some alum preparations, or those having an oil phase, e.g., Freund's adjuvants.
  • Freund's adjuvants are suitable for use with an anti-idiotype vaccine than
  • immunogen is a potential antigen (or "hapten"
  • helper T cells bind to certain epitopes on the carrier protein, and leave the hapten's epitopes exposed so that resting, antigen-specific B cells can bind to the hapten. These resting B cells will then become activated, undergoing clonal expansion, and will mature into plasma cells which secrete antibodies against the hapten.
  • This carrier effect which underlies the fundamental mechanism of T cell -B cell cooperation in immune response, has also been shown to occur when the carrier is a peptide segment (hereinafter "the T helper peptide”) containing determinants recognized by the antigen- specific receptors on the T helper cells.
  • helper T cells will recognize the carrier. This will leave the immunogenic sites on the anti-idiotype exposed and available for binding by resting, antigen-specific B cells. These resting B cells will become activated, undergoing clonal expansion, and then will mature into plasma cells which secrete antibody (Ab3) against the anti-idiotype. More antibody against the anti-idiotype is likely to be produced than when the anti-idiotype alone is used as the vaccine. Summary of the Invention
  • the invention includes epitope-direc ted immunization with a vaccine in which an anti-idiotype antibody is conjugated to a carrier, which can be either a protein or its derived T helper peptide.
  • a carrier which can be either a protein or its derived T helper peptide.
  • the carrier is one against which the vaccine recipient has
  • the anti-idiotype antibody is preferably one which induces production of neutralizing antibodies against HIV-1, such as a carrier/anti-idiotype conjugate which induces production of neutralizing antibodies (Ab3) against the external envelope glycoprotein, gpl20, of HIV-1, against the principal neutralizing determinant ("PND") of gpl20, or against another neutralizing domain of HIV-1.
  • a carrier/anti-idiotype conjugate which induces production of neutralizing antibodies (Ab3) against the external envelope glycoprotein, gpl20, of HIV-1, against the principal neutralizing determinant ("PND”) of gpl20, or against another neutralizing domain of HIV-1.
  • PND neutralizing determinant
  • One exemplary anti-idiotype antibody which induces antibodies against the PND is AB19-4.
  • the cell line which produces AB19-4 is currently on deposit at the American Type Culture Collection ("ATCC”), Rockville, Maryland, under Accession No. HB 10315.
  • carrier preferably is HBsAg or HIV-1 p24, or a peptide of either HBsAg or HIV-1 p24 including a T helper determinant. It is known that many individuals in the high risk groups for HIV-1 infection are also at high risk for hepatitis B virus infection. Many people in these groups have already been vaccinated with the hepatitis B virus vaccine using hepatitis B surface antigen (HBsAg). Thus, HBsAg (and related T helper peptides) is a preferred carrier for conjugation with an anti-idiotype antibody which induces production of HIV-1 neutralizing antibodies.
  • the p24 peptide of HIV-1 is suitable for conjugation with an anti-idiotype antibody which induces HTV-l neutralizing antibodies.
  • the p24 peptide of HIV-1 is very conserved among different strains and isolates of HIV-1, and induces a vigorous immune response. Provided that their immune systems are not yet seriously compromised, persons previously exposed to HIV-1 will have memory helper T cells against this p24 peptide. Administration of a conjugate of this peptide and AB19-4 will cause the memory helper T cells to bind to this p24 peptide, resulting in activation of resting B cells, and ultimately in increased secretion of HIV-1 neutralizing Ab3.
  • a conjugate of HBsAg or p24 of HIV-1 (or a T helper peptide derived from HBsAg or p24) with AB19-4 is useful for HIV-1-infected individuals who produce some antibodies against
  • Monoclonal anti-idiotype antibodies such as AB19-4, are initially murine derived.
  • the conjugates of the invention also include conjugates of human (or humanized) anti-idiotypes, or fragments of human anti-idiotypes, with carriers.
  • the carriers of the invention can also include substances which induce an enhanced immune response against the anti-
  • idiotype antibody Such substances include an ⁇ -migis- ⁇ and anti-
  • the invention includes carrier/anti-idiotype conjugates and their use in epitope-directed active immunization.
  • the method of making and using this conjugate is discussed below.
  • Isolating an anti-idiotype antibody (Ab2) suitable for use with the conjugates of the invention involves several steps. First, a monoclonal antibody (Abl) against the target antigen must be produced. Using Abl as an immunogen, paratope-specific Ab2, which bear the internal image of the original antigen, are produced.
  • the Ab2 can be screened based on their binding to Abl and the extent to which the original antigen can compete with such binding.
  • the paratope-specific Ab2 are further screened based on their ability to induce, in vivo, Ab3 which, like the original Abl, bind to the antigen.
  • the Ab2 is conjugated to a carrier (which is a suitable protein or peptide) to form a conjugate of the invention.
  • a carrier which is a suitable protein or peptide
  • the method of conjugation is very well established.
  • Cross-linkers such as glutaraldehyde, or bis (sulfosuccinimidyl) suberate and preferably disulfosuccinimidyl tartarate, both available from Pierce Chemical Co., Rockford, IL (Catalogue Nos. 21579, 20591) can be used.
  • the carrier peptide and the heavy or the light chain of Ab2 can be produced as a contiguous peptide by expressing a composite gene containing the DNA segment encoding the heavy or light chain and the DNA segment encoding the carrier peptide.
  • This molecular biological method will be most appropriate for expressing shortened heavy or light chains, e.g. , the variable regions, and the T helper peptide segments of the carrier protein.
  • PND on the external envelope glycoprotein gpl20 of HIV-1.
  • the PND is the peptide segment on gpl20 from amino acid residue numbers 296 to 331, as determined from the gpl20 sequence of the HTLV- III B . See Devash, Y., Proc. Nat 'I. Acad. Sci. USA 87:3445-3449 (1990).
  • the PND peptide segment is in the relatively variable
  • Antibodies which target the PND are generally effective in neutralizing HIV-1 infection.
  • An Abl which targets the PND and neutralizes HIV-1 is BAT123, which is described fully in U.S. Patent Application Serial No. 07/137,861.
  • the cell line which produces BAT123 is on deposit at the ATCC under accession number HB 10438.
  • Suitable monoclonal Abl including BAT123 are produced by first immunizing an animal, preferably a mouse, with a suitable antigen.
  • the antigen is usually a pathogen or allergen or a potential pathogen or allergen.
  • the antigen can be in whole form, e.g., whole HIV-1 virions.
  • Cells infected with the virus and expressing the antigen or immunogenic domains of the virus can also be used.
  • Specific viral proteins, such as the envelope glycoproteins may be purified from the lysates of infected cells or viruses.
  • immunogenic domains of the antigen themselves, or synthetic or recombinant peptides which have the same or an immunologically equivalent sequence to these immunogenic domains, can also be used.
  • synthetic or recombinant peptides for use in immunization can be synthesized by
  • recombinant peptides containing these peptides may be biosynthesized by expressing in E. coli or eukaryotic cells the gene segments containing the appropriate coding sequences.
  • a synthetic peptide segment as an immunogen, it is usually more effective to conjugate it to a protein carrier, for example, HBsAg, hepatitis B virus core antigen, ovalbumin, bovine serum albumin, or preferably keyhole lympet hemocyanin
  • peptides can be conjugated to each molecule of the carrier to make the immunogen.
  • KLH a preferred molar ratio for peptide/KLH is 10.
  • the conjugation can be done with well established methods using glutaraldehyde or bis (sulfosuccinimidyl) suberate or preferably disulfosuccinimidyl tartrate as the cross-linkers.
  • monoclonal antibodies is to inject into each mouse 50 ⁇ g of the
  • a similar protocol can be used for immunization with native viral antigens purified from virus-infected cells.
  • a purified viral antigen is HTV-l gpl20. It can be isolated from the lysates of HIV-1-infected cells, such as the human T cell line, H9.
  • Lymphocytes from the spleens (or lymph nodes) which have been removed from the mice can be fused with myeloma cells to prepare hybridomas secreting the Abl monoclonal antibodies.
  • the fusion procedure with polyethylene glycol and other various procedures concerning the cloning and the culturing of hybridomas have been well established.
  • the preferred protocol is the well- known one described by Hudson, L. and Hay, F.C. (Practical Immunology, 2nd edition, pp. 303-313, 1980, Blackwell
  • lymphocytes are fused with non-secreting mouse myeloma cells, such as NS-1 or Sp2/0 cells, using polyethylene glycol.
  • the screening of hybridomas for monoclonal antibodies reactive with the immunogen can be performed with an enzyme linked immunosorbent assay (ELISA).
  • ELISA enzyme linked immunosorbent assay
  • a synthetic or recombinant peptide having the same sequence as a portion of the immunogen is used as the solid-phase antigen.
  • a preferred solid phase antigen is the conjugate of such a synthetic or recombinant peptide with a carrier protein different from that used with the immunogen.
  • An appropriate carrier protein can be bovine serum albumin or ovalbumin, provided they were not used as carriers in the immunization.
  • Monoclonal antibodies (Abl) specific for the immunogen will then be screened for specific binding to the intact native antigen, which, for example, can be done in this case by using immunofluorescence flow cytometric analyses of staining of HTLV-III B -infected H9 cells.
  • Abl After the Abl are isolated and characterized, they are used to immunize mice to create the Ab2. A similar protocol to that described for the Abl immunization can be used to create the Ab2. A particularly preferred protocol for this immunization, used in producing AB19-4 from BAT123, is to first conjugate Abl to KLH using glutaraldehyde as described by Maloney et al. , Hybridoma
  • mice are then immunized intraperitoneally with 100 ⁇ g of the Abl-KLH conjugate at one month intervals for three months. Three days after the final immunization, the mice are killed, and the spleen cells are isolated and fused with Sp2/0 myeloma cells to create the Ab2, using the fusion techniques set forth above. See U.S. Patent Application Serial No.07/454,161; Fung et al, J. Immunol 145:2199-2206 (1990).
  • the Ab2 are then linked to a suitable carrier.
  • the carrier/anti-idiotype conjugate can then be administered as a vaccine for use in active immunization.
  • the carrier chosen is one which can enhance endogenous production of antibodies (Ab3), which can react with the original antigen which was used to produce Abl.
  • the carrier is one the subject has previously been immunized with or to which he has otherwise been exposed.
  • the preferred carrier proteins for use with anti-idiotypes which induce Ab3 against HIV-1 are HBsAg and HIV-1 p24.
  • the carrier can be a T helper peptide of HBsAg or HIV-1 p24. The reason that these carriers are preferred is explained in the Summary of the Invention.
  • the Ab3 which are
  • the T helper determinants of HIV-1 p24 are contained within amino acid residue numbers 213-227 (Asp Arg Val His Pro Val His Ala Gly Pro He Ala Pro Gly Gin Met Arg), numbers 233-247 (Gly Ser Asp He Ala Gly Thr Thr Ser Thr Leu Gin Glu Gin He), numbers 263-277 (Lys Arg Trp He He Leu Gly Leu Asn Lys He Val Arg Met Tyr), numbers 288-313 (Gly Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu Arg Ala Glu Gin Ala Ser Gin Glu Val). See Mills, K.H. et al, J. Immunol.
  • T helper peptides of gpl20 are at amino acid residue numbers 421-436 (Tj), having the sequence Lys Gin He He Asn Met Tip Gin Glu Val Gly Lys Ala Met Tyr Ala, and at residue numbers 105-117 (Tj), having the sequence His Glu Asp He He Asn Met Tip Gin Glu Val Gly Lys Ala Met Tyr Ala.
  • T helper peptides having any of these sequences, or immunological equivalents of these sequences, are suitable for conjugation with
  • HBsAg also contains determinants recognized by antigen- specific receptors on T helper cells. In mice, it was found that one such determinant is in the pre-S(l) region of HBsAg, amino
  • the other determinant also in the mouse pre- S(l) region is from amino acid residue numbers 94-117, having the sequence Pro Ala Ser Thr Asn Arg Gin Ser Gly Arg Gin Pro Thr Pro He Ser Pro Pro Leu Arg Asp Ser His Pro. See Milich, D.R. et al, J. Immunol 4457-4465 (1987).
  • Another mouse T cell determinant is in the pre-S(2) region of HBsAg, amino acid residue numbers 120-132, having the sequence Met Gin Trp Asn Ser Thr Ala Leu His Gin Ala Leu Gin. See Neurath et al, Science 224:392-395 (1984).
  • human T cell determinants in the S region of HBsAg has also been verified.
  • human T cell determinant is from amino acid residue numbers 4-33, having the sequence He Thr Ser Gly Phe Leu Gly Pro Leu Leu Val Leu Gin Ala Gly Phe Phe Leu Leu Thr Arg He Leu Thr He Pro Gin Ser Leu Asp (as determined from HBV strain adw).
  • Three other human T cell determinants are respectively from amino acid numbers 48-86, having the sequence Cys Leu Gly Gin Asn Ser Gin Ser Pro Thr
  • T helper peptides having any of these sequences, or immunological equivalents of these sequences are suitable carriers for conjugation with AB19-4 or other anti- idiotypes which induce Ab3 against HIV-1.
  • AB19-4 has some properties which make it particularly well-suited for use in a conjugate of the invention.
  • AB19-4 has been shown to induce, in rabbits, production of Ab3 which neutralize HTLV -111, ⁇ and HTLV-HI B . This result is somewhat unexpected because the Abl (BAT123) with which mice were
  • a conjugate of AB19-4 and HBsAg, HIV-1 p24, or HIV-1 gpl20, or a T helper peptide thereof, will therefore be useful for immunizing AIDS patients or asymptomatic individuals infected
  • the anti-idiotypes first obtained, as noted above, will usually be murine-derived.
  • Murine-derived anti-idiotypes will often induce endogenous antibodies against their Fc region, in addition to inducing the HTV-l neutraUzing Ab3. Production of endogenous antibodies to the Fc region is not necessary or desired. In fact, production of such antibodies against the Fc region could reduce the immunogenic effect of the anti-idiotype vaccine before it could function to induce production of Ab3.
  • the preferred anti-idiotypes for use in the conjugates of the invention have human constant regions. These include whole human anti-idiotypes, chimeric anti-idiotypes wherein the variable region is of murine origin and the constant region is of human origin, and anti-idiotypes wherein only the complementarity determining regions are of murine origin and the remainder of the variable regions, and the entire constant regions, are of human
  • helper T cells In order to provide a determinant recognized by the antigen-specific receptors on helper T cells, it is preferable to conjugate the human (or humanized) anti-idiotypes to a carrier to which the recipient has been previously exposed.
  • conjugate rather than conjugating a whole anti- idiotype to the carrier, it is more preferable that one conjugate the carrier with anti-idiotype F(ab') 2 , Fab, or Fv fragments, none of which have a Fc portion.
  • the chimeric and humanized anti-idiotypes can be produced by transfecting non-producing mouse myeloma cells with the
  • hybrid genomic DNA, or cDNA If one is making a chimeric anti-idiotype, the hybrid genomic DNA or cDNA will contain the human constant regions and the mouse variable region. If one is making an anti-idiotype in which only the CDRs are of mouse
  • the hybrid genomic DNA or cDNA will contain human constant regions, mouse CDR regions, and the remainder of the variable regions will be human.
  • Human anti-idiotypes can be produced by using human expression libraries (e.g., Stratagene Corp., La Jolla, California) to produce fragments of human anti-idiotypes (V H , V L , F v , Fd, Fab, or F(ab') 2 ).
  • Conjugates suitable for vaccination can be made from the anti-idiotype fragments Fab, F(ab') 2 , or Fv, or one can use the fragments to construct whole human anti-idiotypes using techniques similar to those for producing chimeric anti-idiotypes.
  • the conjugates of the invention are administered subcutaneously or intramuscularly. They can be administered together with appropriate adjuvants, such as threonyl muramyl dipeptide.
  • either of the conjugates which induce Ab3 against HTV-l can be administered in conjunction with antibodies which effect passive immunization against HIV-1.
  • HIV-1 neutralizing antibodies which are preferably those Abl having idiotopes which are not recognized and neutralized by the Ab2 which is used concomitantly
  • Passive immunization is likely to be most effective in a person previously exposed to HIV-1, but whose immune system is not yet seriously compromised.
  • the neutralizing antibodies which are introduced will lower the viral titer. It may lower it to the point where remaining virus can be eliminated by the body's immune defense mechanisms.
  • the conjugate will induce production of HTV-l neutralizing antibodies which can exist for long periods. Passive immunization is also likely to be useful for pregnant women who are HIV-1 infected. It is known that where
  • mice Animal experiments can be used to determine whether the carrier/anti-idiotype conjugate is more effective than an anti- idiotype alone in inducing production of Ab3.
  • a first group of mice is injected with saline.
  • a second group of mice is immunized with ovalbumin or another carrier protein other than HBsAg.
  • a third group is immunized with HBsAg.
  • each of the second and third groups of mice is injected subcutaneously twice with 10 ⁇ g of the selected carrier, together with adjuvants.
  • the adjuvant is Freund's complete adjuvant
  • the adjuvant is Freund's incomplete adjuvant.
  • the first group of mice receive injections of adjuvants alone, without the specific immunogen.
  • mice After an appropriate period passes for an immune response against the immunogens to occur, the control mice, the ovalbumin- immunized mice, and the HBsAg-immunized mice are immunized with an AB19-4/HBsAg conjugate in Freund's incomplete adjuvant. Those in the third group should yield the highest titer of Ab3 against HTV-l.
  • mice can also be used.
  • the third group of mice should also produce higher antibody liters than the fourth and fifth

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Abstract

Procédés et produits d'immunisation par épitope à l'aide d'un vaccin comprenant un anticorps anti-idiotype. L'anticorps anti-idiotype est conjugué à un porteur. Le porteur est une protéine contre laquelle le receveur du vaccin a été préalablement immunisé ou à laquelle il a été préalablement exposé d'une autre façon, ou un segment de peptide de ladite protéine contenant des déterminants reconnus par les récepteurs spécifiques de l'antigène sur les lymphocytes T auxiliaires, ou un anticorps augmentant la réaction immunitaire contre l'anti-idiotype. Le porteur ne doit pas modifier la conformation de l'anti-idiotype après conjugaison. L'anticorps anti-idiotype est de préférence un anticorps induisant la production d'anticorps neutralisants contre le VIH-1, auquel cas le porteur préféré est HBsAg ou p24 du VIH-1, ou un peptide T auxiliaire dérivé de HBsAg ou de p24 du VIH-1. Il est souhaitable que l'anticorps anti-idiotype induise la production d'anticorps neutralisants contre la glycoprotéine d'enveloppe externe gp120 du VIH-1, et il est préférable qu'il les induise contre le déterminant neutralisant principal de gp120. On peut citer à titre d'exemple l'anticorps anti-idiotype AB19-4.
PCT/US1991/008653 1990-11-20 1991-11-19 Conjugues d'anticorps anti-idiotype et de porteurs ainsi que leur emploi en immunisation par epitope WO1992008491A1 (fr)

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WO1995032735A3 (fr) * 1994-05-31 1996-02-29 Immune Network Res Ltd Inversion des deviations constatees dans le repertoire des lymphocytes, pour prevenir ou soigner une maladie
US6193982B1 (en) 1995-04-27 2001-02-27 The United States Of America As Represented By The Department Of Health & Human Services Anti-cyanovirin antibody with an internal image of gp120, a method of use thereof, and a method of using a cyanovirin to induce an immune response to gp120
US6420336B1 (en) 1995-04-27 2002-07-16 The United States Of America As Represented By The Department Of Health And Human Services Methods of using cyanovirins topically to inhibit viral infection
US6428790B1 (en) 1995-04-27 2002-08-06 The United States Of America As Represented By The Secretary Department Of Health And Human Services Cyanovirin conjugates and matrix-anchored cyanovirin and related compositions and methods of use
US6780847B2 (en) 1995-04-27 2004-08-24 The United States Of America As Represented By The Department Of Health And Human Services Glycosylation-resistant cyanovirins and related conjugates, compositions, nucleic acids, vectors, host cells, methods of production and methods of using nonglycosylated cyanovirins
US7048935B2 (en) 1995-04-27 2006-05-23 The United States Of America As Represented By The Department Of Health And Human Services Cyanovirin conjugates and matrix-anchored cyanovirin and related compositions and methods of use
US7339037B2 (en) 2001-03-22 2008-03-04 The United States Of America As Represented By The Department Of Health And Human Services Glycosylation-resistant cyanovirins and related conjugates, compositions, nucleic acids, vectors, host cells, methods of production and methods of using nonglycosylated cyanovirins
US7422746B2 (en) 1999-12-22 2008-09-09 Altermune, Llc Chemically programmable immunity
US7645743B2 (en) 1999-12-22 2010-01-12 Altermune, Llc Chemically programmable immunity
US7754420B2 (en) 1995-04-27 2010-07-13 The United States Of America As Represented By The Department Of Health And Human Services Methods of using cyanovirins to inhibit viral infection
US8604184B2 (en) 2009-05-05 2013-12-10 The United States Of America As Represented By The Secretary Of The Air Force Chemically programmable immunity

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Cited By (17)

* Cited by examiner, † Cited by third party
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WO1995032735A3 (fr) * 1994-05-31 1996-02-29 Immune Network Res Ltd Inversion des deviations constatees dans le repertoire des lymphocytes, pour prevenir ou soigner une maladie
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US7048935B2 (en) 1995-04-27 2006-05-23 The United States Of America As Represented By The Department Of Health And Human Services Cyanovirin conjugates and matrix-anchored cyanovirin and related compositions and methods of use
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US8591910B2 (en) 1999-12-22 2013-11-26 Altermune Technologies Llc Chemically programmable immunity
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