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WO1994018232A1 - Procedes de generation d'anticorps anti-vih a large spectre de neutralisation et antigenes capables de provoquer la generation de ces anticorps - Google Patents

Procedes de generation d'anticorps anti-vih a large spectre de neutralisation et antigenes capables de provoquer la generation de ces anticorps Download PDF

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Publication number
WO1994018232A1
WO1994018232A1 PCT/US1994/001458 US9401458W WO9418232A1 WO 1994018232 A1 WO1994018232 A1 WO 1994018232A1 US 9401458 W US9401458 W US 9401458W WO 9418232 A1 WO9418232 A1 WO 9418232A1
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WIPO (PCT)
Prior art keywords
peptide
amino acid
hiv
candidate
atomic coordinates
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US1994/001458
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English (en)
Inventor
Albert T. Profy
Ian A. Wilson
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Repligen Corp
Scripps Research Institute
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Repligen Corp
Scripps Research Institute
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Priority to AU61366/94A priority Critical patent/AU6136694A/en
Publication of WO1994018232A1 publication Critical patent/WO1994018232A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • 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

  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • T4 lymphocytes T4 lymphocytes
  • CD4 + cells T4 lymphocytes
  • the mortality rate for AIDS patients approaches 100% (Fauci, Science 239:617, 1988).
  • the amino acid sequence of the HIV envelope glycoprotein gp120 is particularly variable; its amino acid sequence can vary by 20-25% from one strain to the next. In addition to strain to strain variability, there is a more subtle variation in genome sequence probably caused by the high error rate of reverse transcriptase.
  • any particular viral isolate consists of a cohort of quasi-species. Further, the diversity and number of quasi-species apparently differs from one HIV variant to another. There is substantial evidence that these quasi-species evolve in vivo . For example,
  • Infected individuals initially mount a humoral and cellular immune response against HIV, and there is reason to believe that an infected individual's immune response may actually encourage viral spread and the emergence of more resistant variants (McCune et al., Cell 64:351, 1991). This extreme heterogeneity makes it difficult to generate vaccines or antibodies that will be effective against a wide range of HIV strains.
  • Antibodies that have neutralizing activity against the HIV virus have been proposed for treatment of HIV infection.
  • the primary targets for neutralizing anti-HIV antibodies are within gp120, the envelope glycoprotein.
  • the loop structure within the third variable (V3) domain of gp120 is believed to be the principal neutralization domain (PND) of gp120.
  • PND principal neutralization domain
  • the V3 loop elicits predominately strain-specific neutralizing antibodies.
  • anti-V3 loop antibodies that recognize short, highly conserved sub-sequences of the loop and are capable of neutralizing a broad range of HIV isolates have been identified (Scott et al., PCT
  • the invention features methods for identifying molecules, preferably organic molecules, which will act as antigens capable of binding to or eliciting broadly neutralizing anti-HIV antibodies.
  • the invention also features methods for designing and
  • these data permit the identification of the atoms in each antigen that are important for antigen-antibody binding. More importantly, the data described herein permit one to describe the precise three-dimensional arrangement of these important contact atoms. Other molecules which include atoms having a three-dimensional arrangement similar to some or all of these contact atoms are likely to be capable of binding to and eliciting broadly neutralizing anti-HIV
  • the data presented herein also permits the identification of the atoms in antibodies 58.2 and 59.1 that are important for antigen binding. This information permits one to generate broadly neutralizing recombinant anti-HIV antibodies by engineering a suitable antibody to include these important contact atoms.
  • the invention features a method for identifying molecules capable of binding to or eliciting anti-HIV antibodies (preferably broadly neutralizing antibodies), involving (1) selecting an anti-HIV
  • the same method can be used employing antibody- contacting pharmacophores within the cyclic peptide AS.
  • the invention features a method for identifying molecules capable of binding to or eliciting anti-HIV antibodies (preferably broadly neutralizing antibodies), involving: (1) selecting a region of three to seven contiguous amino acids within the central domain of the peptide antigen RP152; (2) comparing the atomic coordinates with the backbone of the selected region with the atomic coordinates of the backbones of three to seven amino acid polypeptide sequences in a protein structure database using a
  • step (5) involves, in a model, sequentially replacing each amino acid side chain of the candidate peptide with an alternative amino acid side chain, and then rotating each replaced amino acid side chain of each candidate peptide on its alpha covalent bond to identify a minimum energy position.
  • the invention features a method for identifying molecules capable of eliciting anti-HIV antibodies (preferably broadly neutralizing antibodies), involving (1) selecting a region of three to seven contiguous amino acids within cyclic peptide AS; (2) comparing the atomic coordinates of the backbone of the selected region with the atomic coordinates of the backbones of throe to seven amino acid polypeptide sequences in a protein structure database using a
  • step (5) of the just mentioned aspect of the invention involves the steps of: (a) in a model, sequentially replacing each amino acid side chain of the candidate peptide with an alternative amino acid side; and (b) rotating each replaced amino acid side chain of each candidate peptide on its alpha carbon bond to identify a minimum energy position.
  • the invention features a recombinant, broadly neutralizing anti-HIV antibody, composed of a recombinant kappa light chain framework subgroup IV and human heavy chain framework subgroup II, wherein at least five CDR amino acids selected from the group consisting of Kabat light chain amino acids 27D, 92, 93, 94, 96 and Kabat heavy chain amino acids 33, 50 52, 53, 56, 57, 95 and 1001 are identical to the group consisting of Kabat light chain amino acids 27D, 92, 93, 94, 96 and Kabat heavy chain amino acids 33, 50 52, 53, 56, 57, 95 and 1001 are identical to the group consisting of Kabat light chain amino acids 27D, 92, 93, 94, 96 and Kabat heavy chain amino acids 33, 50 52, 53, 56, 57, 95 and 1001 are identical to the group consisting of Kabat light chain amino acids 27D, 92, 93, 94, 96 and Kabat heavy chain amino acids 33, 50 52, 53, 56,
  • the invention features a recombinant broadly neutralizing anti-HIV antibody, composed of a recombinant kappa light chain framework subgroup IV and human heavy chain framework subgroup II, wherein at least five CDR amino acids selected from the group consisting of Kabat light chain amino acids 27D, 28, 91, 92, 93, 94, and Kabat heavy chain amino acids 33, 35, 50, 52, 53, 54, 97 and 98 are identical to the corresponding 59.1 contact amino acids.
  • pharmacophore For drugs, the functionally relevant portion is referred to as a pharmacophore.
  • a pharmacophore then is an arrangement of structural features and functional groups important for biological activity. Similarly, one can identify one or more pharmacophores for a given antigen. In this case the pharmacophore is a group of atoms that play an important role in antibody binding (and therefore elicitation of antibodies).
  • Programs suitable for generating predicted three- dimensional structures from two-dimensional data include: Concord (Tripos Associates, St. Louis. MO), 3-D Builder (Chemical Design Ltd., Oxford, U.K.), Catalyst (Bio-CAD Corp., Mountain View, CA), Daylight (Abbott Laboratories, Abbott Park, IL).
  • Programs suitable for searching three- dimensional databases to identify molecules bearing a desired pharmacophore include: MACCS-3D and ISIS/3D
  • Aladdin Daylight Chemical Information Systems, Irvine CA.
  • Peptide AS is a cyclic peptide having the sequence JSIGPGRAFGZC where J and Z are connected by a hydrazone linkage and are represented by:
  • the light chain atoms are listed first starting with the amino terminal Asp (amino acid 1001) and ending with the carboxyl terminal Glu (amino acid 1215).
  • the heavy chain atoms are then listed beginning with the amino terminal Asp (amino acid 2001) and ending with the carboxyl terminal Arg (amino acid 2226).
  • the peptide atoms are listed next beginning with Gly (amino acid 3002) and ending with Gly (amino acid 3012).
  • the coordinates for antibody 59.1 bound to peptide RP142 are presented in Appendix B in standard Brookhaven database format.
  • the light chain atoms are listed first starting with the amino terminal Asp (amino acid 1) and ending with th*3 carboxyl terminal Arg (amino acid 215).
  • the heavy chain atoms are then listed beginning with the amino terminal Gin (amino acid 1001) and ending with the carboxyl terminal Thr (amino acid 1221).
  • the peptide atoms are listed next beginning with His (amino acid 2002) and ending with Thr (amino acid 2011).
  • the contact data for antibody 59.1 and RP142 peptide are presented in Table 2 in standard Brookhaven database notation.
  • the first column indicates the bond type (van der Waals, hydrogen bond or short hydrogen bond).
  • the second column indicates the antibody atom involved.
  • the amino acid are indicated first by their single letter code where the prefix "1" indicates the light chain and the prefix "2" indicates the heavy chain.
  • the amino acid number (according to the numbering scheme above) is indicated next followed by the identification of the atom.
  • the third column indicates the peptide amino acid involved by its single letter code (with the prefix "3" followed in the next column by the amino acid number (according to the numbering scheme above) followed by the identification of the atom involved.
  • the last column indicates the bond length in angstroms.
  • the Phe residue of the peptide is only in contact with CDR H2, and in particular is stacked with the imidazole ring of His-53.
  • CDRs H1 and H3 are in contact with the ends of the peptide.
  • the buried Arg side chain is contacted by several residues including Asp-98 and Leu-100 of the light chain and Glu-99, Tyr-33, and His-36 of the heavy chain. There are thus two positive and two negative charges in the binding pocket when the peptide is bound.
  • This structure is consistent with immunological data which suggest that the epitope for this antibody is HIGPGRAF. in which many different amino acids are tolerated at the underlined positions.
  • the specificity for the Phe residue may be eliminated by mutating CDR H2 and the specificity for the His residue may be eliminated by mutating CDR H3.
  • Table 1 lists the contacts between cyclic peptide AS and antibody 58.2. Any subset of at least five and preferably at least seven contacting atoms, up to 10-15 atoms, can constitute a pharmacophore which can be used to identify structurally related compounds using any of the modeling programs listed herein or any similar structure modeling program.
  • a contact between atoms on the antibody and antigen is meant a hydrogen bond or a Van der Waals interaction; only contacting atoms pairs are listed in Table 2.
  • HIV- III B a Arg replaces the lle of HIV-MN and it appears the positively charged Arg side chain would be in close contact with Glu-97 of CDR L3 providing an electrostatic contact not present in a complex between 59.1 and an HIV- MN peptide.
  • Table 2 lists the contacts between RP142 and antibody 59.1. Any subset of at least five and
  • preferably at least seven atoms can constitute a
  • pharmacophore which can be used to identify structurally related compounds using any of the modeling programs listed herein or any similar structure modeling program. Once one or more suitable compounds have been identified, their structures can be modeled and docked with a computer model of antibody 59.1 (or 58.2) to look for the presence of unwanted repulsive interactions or distortions. Molecular mechanics can then be used to calculate and minimize conformational energy and maximize attractive interactions.
  • Novel prospective antigens identified using the methods described herein can be used to generate broadly neutralizing anti-HIV antibodies using standard
  • Molecules to be used as immunogens can be either unconjugated or conjugated to an immunogenic carrier, e.g., keyhole limpet hemocyanin (KLH) or ovalbumin, using succinyl maleimidomethyl cyclohexanylcarboxylate (SMCC) as a conjugation agent using standard techniques.
  • an immunogenic carrier e.g., keyhole limpet hemocyanin (KLH) or ovalbumin
  • KLH keyhole limpet hemocyanin
  • SMCC succinyl maleimidomethyl cyclohexanylcarboxylate
  • Antibodies may be prepared by intraperitoneal immunization of mouse strains (e.g., Balb/c, C57BL/6, A.SW, B10.BR, or B10.A, Jackson Labs., Bar Harbor, ME). Immunized mice can be given booster immunizations of the immunogen, either in an emulsification of incomplete Freund's adjuvant or in soluble form (e.g, two to three times at two to four week intervals) following the initial immunization. Mice were bled and the sera assayed for the presence of antibodies reactive with the immunogen or RP142. Mice showing a strong serological response are boosted, and (3-5 days later) spleen cells from these mice are fused with, for example, NS-1
  • each well of a 96-well Costar flat-bottom microtiter plate is coated with the peptide by placing a 50 ⁇ l aliquot of a PBS solution containing the peptide at a final concentration of 0.1-10 ⁇ g/ml in each well.
  • the peptide solution is then aspirated and replaced with PBS + 0.5% BSA. Following incubation, the wells are
  • a peptide titration assay can be used as an initial screen to predict if a given anti-V3 loop
  • the antibody will have strong neutralization activity.
  • the antibody is tested for its ability to prevent syncytia formation among gp120 expressing CD4+ cells in the presence of competitor peptide whose
  • V3 loop sequence is derived from a V3 loop sequence. This assay can be used to test for potential neutralization activity of any anti-V3 loop antibody towards any HIV isolate by using a peptide derived from the V3 loop from the HIV isolate of interest as the competitor.
  • Syncytia formation is measured in the presence of an anti-V3 monoclonal antibody mixed with one or more test peptides representing V3 loop sequences of a variety of HIV isolates.
  • test peptide In the peptide titration assay, the test peptide, at a series of concentrations ranging from 10 ⁇ M to
  • the HIV gp120 envelope protein produced and presented on the surface of these cells enables them to bind to the CD4 receptor on other cells, resulting in cell fusion and the formation of syncytia.
  • Antibodies that bind to the V3 loop of the gp120-expressing cells can inhibit syncytia formation. If the test peptide competes with the gp120 epitope recognized by the antibody for binding with the anti-V3 loop antibody, syncytia formation occurs.
  • test peptide does not compete with the cell surface epitope recognized by the antibody for binding with the anti-V3 loop antibody, syncytia formation in the presence of peptide is inhibited relative to syncytia formation in the absence of the peptide.
  • the recombinant vector pSC25 containing the HIV env gene and the lacZ gene of E. coli expressed from a second vaccinia virus promoter, and flanked by vaccinia viral sequences which together encode thymidine kinase (TK), was used to produce the recombinant virus.
  • TK thymidine kinase
  • a recombinant vector that contains DNA encoding an envelope gene having the specificity of the HIV-MN variant was prepared by removing a 570 bp Bglll fragment (encoding 180 amino acids) from the HIV-III B env gene which spans the region of the VS loop in pSC25, and replacing it with the analogous Bg1ll fragment from the HIV-MN env gene.
  • the resulting plasmid, pSCR2502 contained a hybrid envelope gene which encoded an
  • envelope protein having the principal neutralizing domain of the MN virus and the remainder of the env gene
  • a smaller region of the HIV-MN gp160 protein can be used in place of the 180 amino acid replacement just described; e.g., DNA encoding the 36 amino acid V3 loop from any HIV strain can be inserted into the envelope- encoding DNA in place of the corresponding III B DNA sequence.
  • a recombinant could be used which contains the complete HIV-MN env gene. Multiple HIV envelope expressing strains are useful for assessing the specificity of an antibody.
  • the recombinant vector pSCR2502 was transfected into CV-1 host cells that had been pre-infected with vaccinia virus containing an intact TK gene.
  • the HIV envelope gene was integrated into the viral DNA by homologous recombination between the TK sequences on the vector and the TK sequences within the viral genome.
  • Recombinants containing the HIV envelope gene were selected by infection of TK- cells and plating on media containing bromodeoxyuridine (BUdR) and X-gal.
  • BUdR bromodeoxyuridine
  • X-gal is a chromogenic substrate cleaved by the product of the lacZ gene which results in the production of blue plaques where the lacZ gene is expressed and further identifies the recombinant virus which also contains the HIV-env gene.
  • Two biological assays can be used to as a more refined measurement HIV neutralizing activity.
  • These assays use reverse transcriptase (RT) activity as a measurement of viral activity.
  • RT reverse transcriptase activity
  • the reduction in reverse transcriptase activity under a given set of conditions is a measure of viral neutralization.
  • a reduction in reverse transcriptase activity of 90% under a given set of conditions is a standard measure of viral
  • the Std. SN assay measures RT activity at a single time point 7 days post-infection. As a result, it is possible to compare a number of conditions with relatively few assays.
  • the 7 day time point used in the Std. SN assay may not include the period of optimal viral replication. As result, in some instances, the Std. SN assay will not permit accurate determination of the effectiveness of the added anti-HIV agents.
  • the Ex. SN assay measures RT activity at several timepoints out to 15 (or 20) days post-infection and thus is more likely to include the period of optimal viral activity for any given viral isolate. Therefore, the Ex. SN assay is preferred.
  • HIV-MN Three HIV isolates are commonly used in the Std. SN and Ex. SN assays: HIV-MN, HIV-IIIB and HIV-Ala.
  • HIV- Ala is considered a relevant field isolate because it has had low passage in CEM cells. (The sequence of the HIV- Ala V3 loop has been reported to be the most
  • the viruses used in this assay can be propagated in H9 cells (ATCC, Rockville, MD; or AIDS Research and Reference Reagent Program, Rockville, MD) for 15-30 days to
  • Newly formed virions are harvested from the supernatant of infected cells and used to infect test cultures as described below.
  • the Ex. SN assay is identical to the Std. SN assay except that media is replenished twice during the course of the assay (at day 7 post-infection and at day 12 post- infection). Aliquots are assayed for RT activity (as described above) at 7, 12 and 15 days post-infection.
  • An Infectivity Reduction Assay which measures the difference between the infectious dose of a virus in the presence and absence of a standard dilution of an anti-HIV agent, can be used as an even more
  • PBMC peripheral blood mononuclear cells, prepared by standard methods
  • the IRA is performed as follows. Viral isolates are serially diluted 10-fold in RPMI containing 10% fetal bovine serum. For each dilution of virus, approximately 20 ⁇ g of antibody is then inoculated onto 1 x 10 6 CEM-ss or PBMC in a 24-well plate. The cultures are maintained for the appropriate number of days (calibrated for the virus used, for example, HIV-MN is 21 days and 14 days for Duke 6587-5. Cultures are split 3 times a week (if PBMCs are used, they are supplemented with IL-2 three times a week to maintain optimal virus replication conditions). Virus replication (infectious units) is monitored by reverse transcriptase activity as described above. The
  • infectious titer of virus plus the antibody is compared to the infectious titer of virus plus media.
  • Tables 3 and 4 list the Kabat amino acid numbers corresponding to the identified contact amino acids in antibodies 58.2 and 59.1 respectively. This information can be used to identify vthich amino acids should be exchanged for contact amino acids.
  • variable region the antigen binding portion
  • constant region the portion involved with providing structural stability and other biological functions
  • polypeptide chain antibodies and these methods may be adapted to produce antibodies useful in the methods and compositions of the invention.
  • Established procedures would allow construction, expression, and purification of such a hybrid monoclonal antibody.
  • Quadromas can be used to generate bispecific antibodies (Reading et al., U.S. Patent Nos. 4,474,893 and 4,714,681).
  • the patents and publications referred to herein are hereby incorporated by reference.

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Abstract

L'invention concerne des procédés d'identification de molécules actives en tant qu'antigènes capables de provoquer la génération d'anticorps anti-VIH à large spectre de neutralisation, ainsi que des procédés de production d'anticorps recombinants anti-VIH à large spectre de neutralisation.
PCT/US1994/001458 1993-02-12 1994-02-09 Procedes de generation d'anticorps anti-vih a large spectre de neutralisation et antigenes capables de provoquer la generation de ces anticorps Ceased WO1994018232A1 (fr)

Priority Applications (1)

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AU61366/94A AU6136694A (en) 1993-02-12 1994-02-09 Methods for generating broadly neutralizing anti-hiv antibodies and antigens capable of eliciting same

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US1748593A 1993-02-12 1993-02-12
US08/017,485 1993-02-12

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023474A1 (fr) * 1998-10-21 2000-04-27 The University Of Queensland Ingenierie des proteines
WO2002024219A1 (fr) 2000-09-22 2002-03-28 Queensland University Of Technology Complexe du facteur de croissance
WO2006063415A1 (fr) 2004-12-17 2006-06-22 Monash University Régulation du clivage par des métalloprotéases de protéines de surface d'une cellule
WO2011063477A1 (fr) 2009-11-30 2011-06-03 Queensland University Of Technology Chimères de fibronectine/facteur de croissance
EP2357195A1 (fr) 2003-02-05 2011-08-17 Queensland University Of Technology Complexe de facteur de croissance et modulation de la migration et de la croissance cellulaire
US9090706B2 (en) 2003-02-05 2015-07-28 Queensland University Of Technology Fibronectin: growth factor chimeras
WO2019173794A1 (fr) * 2018-03-09 2019-09-12 Atreca, Inc. Anticorps anti-vih
WO2019173801A1 (fr) * 2018-03-09 2019-09-12 Atreca, Inc. Acides nucléiques codant pour des anticorps anti-vih
US11760789B2 (en) 2017-06-22 2023-09-19 University Of Maryland, Baltimore Broadly neutralizing antibodies against HIV

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1990003984A1 (fr) * 1988-10-03 1990-04-19 Repligen Corporation Proteines et peptides du vih utiles pour le diagnostic, la prophylaxie ou la therapie du sida

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Title
BIOPHYSICAL CHEMISTRY, Volume 29, Number 3, issued April 1988, PIOTR ZIELENKIEWICZ et al., "Methods of Molecular Modelling of Protein-Protein Interactions", pages 219-224. *
PROTEINS: STRUCTURE, FUNCTION AND GENETICS, Volume 14, issued 1992, ENRICO A. STURA et al., "Crystallization, Sequence, and Preliminary Crystallographic Data for an Antipeptide FAB 50.1 and Peptide Complexes with the Principal Neutralizing Determinant of HIV-1 GP120", pages 499-508. *
SCIENCE PROGRESS, Volume 75, issued 1991, C.J. SUCKLING, "Chemical Approaches to the Discovery of New Drugs", pages 323-359. *
SCIENCE, Volume 249, issued 24 August 1990, GREGORY LAROSA et al., "Conserved Sequence and Structural Elements in the HIV-1 Principal Neutralizing Determinant", pages 932-935. *
SCIENCE, Volume 251, issued 15 February 1991, GREGORY LAROSA et al., "Conserved Sequence and Structural Elements in the HIV-1 Principal Neutralizing Determinant: Corrections and Clarifications", page 811. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023474A1 (fr) * 1998-10-21 2000-04-27 The University Of Queensland Ingenierie des proteines
US7092825B1 (en) 1998-10-21 2006-08-15 The University Of Queensland Protein engineering
WO2002024219A1 (fr) 2000-09-22 2002-03-28 Queensland University Of Technology Complexe du facteur de croissance
EP2385063A2 (fr) 2000-09-22 2011-11-09 Queensland University of Technology Complexe d'un facteur de croissance
EP2385064A2 (fr) 2000-09-22 2011-11-09 Queensland University of Technology Agents qui séparent un complexe du facteur de croissance
EP2357194A1 (fr) 2003-02-05 2011-08-17 Queensland University Of Technology Complexe de facteur de croissance et modulation de la migration et de la croissance cellulaire
EP2357195A1 (fr) 2003-02-05 2011-08-17 Queensland University Of Technology Complexe de facteur de croissance et modulation de la migration et de la croissance cellulaire
US9090706B2 (en) 2003-02-05 2015-07-28 Queensland University Of Technology Fibronectin: growth factor chimeras
WO2006063415A1 (fr) 2004-12-17 2006-06-22 Monash University Régulation du clivage par des métalloprotéases de protéines de surface d'une cellule
WO2011063477A1 (fr) 2009-11-30 2011-06-03 Queensland University Of Technology Chimères de fibronectine/facteur de croissance
US11760789B2 (en) 2017-06-22 2023-09-19 University Of Maryland, Baltimore Broadly neutralizing antibodies against HIV
US12331105B2 (en) 2017-06-22 2025-06-17 University Of Maryland, Baltimore Broadly neutralizing antibodies against HIV
WO2019173794A1 (fr) * 2018-03-09 2019-09-12 Atreca, Inc. Anticorps anti-vih
WO2019173801A1 (fr) * 2018-03-09 2019-09-12 Atreca, Inc. Acides nucléiques codant pour des anticorps anti-vih

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