WO1995016710A1 - Specific hyperimmune anti-hiv globulin for passive immunization - Google Patents

Specific hyperimmune anti-hiv globulin for passive immunization Download PDF

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Publication number
WO1995016710A1
WO1995016710A1 PCT/US1994/014445 US9414445W WO9516710A1 WO 1995016710 A1 WO1995016710 A1 WO 1995016710A1 US 9414445 W US9414445 W US 9414445W WO 9516710 A1 WO9516710 A1 WO 9516710A1
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hiv
immunoglobulin
amino acids
sequence
peptide
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PCT/US1994/014445
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English (en)
French (fr)
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United Biomedical, Inc.
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Priority to AU13724/95A priority Critical patent/AU1372495A/en
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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
    • 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

  • the World Health Organization estimates that 14 million people are now infected with Human Immunodeficiency Virus, type 1 (HIV-1) , the virus which causes AIDS. Moreover, WHO estimates that by the year 2000, 40 million individuals will have contracted HIV-1. The natural history of infection suggests that virtually all HIV-1 infected persons will eventually progress from asymptomatic infection to the morbidity and mortality associated with AIDS. Despite global investments in prevention and education campaigns, HIV infection rates are still expanding throughout the world. From a public health perspective, the development of safe and effective HIV vaccines has become an international priority.
  • HIV-1 Human Immunodeficiency Virus
  • HIV vaccine development presents several challenges, including HIV-1 variability, multiple routes/modes of virus transmission, and a lack of complete understanding of which immune responses are required for protective immunity. While vaccine development contemplates active immunization against HIV-1, another possible route for treating and preventing HIV-1 infection is available through passive immunization. Once a vaccine capable of eliciting high titers of broadly neutralizing antibodies is available, then passive immunization presents another alternative for treatment and prevention of HIV-1 infection.
  • Passive immunization is now regularly used to give short-term protection against infection.
  • passive immunization provides an immediate post-exposure prophylaxis for persons who have suffered parenteral exposure to HIV (e.g., needles sticks) and for neonates who are exposed to HIV-1 during birth.
  • a need was recognized for vaccines capable of neutralizing field isolates of HIV-l and not simply adapted virus strains.
  • the present invention addresses these needs for HIV-l passive immunization by providing hyperimmune globulin preparations raised against peptide- based immunogens capable of eliciting neutralizing antibodies against HIV-l field isolates.
  • the present invention is directed to purified immunoglobulin which elicits a neutralizing response against two or more HIV-l geographically diverse field isolates and preferably against representatives of each major strain of HIV-l, e.g. against at least 5 geographically diverse field isolates.
  • the subject immunoglobulin is prepared from a vaccinee immunized with a preparation which is contains two or more immunogens which comprise a peptide comprising a sequence of an HIV-l isolate or an HIV-l clade consensus sequence from gpl20.
  • the sequence of these peptide moieties is consistent with a segment of gpl20 shown in Fig. 2. This peptide moiety is further attached to a core sequence.
  • the immunogen is a library of peptides comprising an ensemble domain from a segment the HIV-l gpl20 sequence shown in Fig. 2, such that each sequence position in the ensemble domain contains either a single amino acid or multiple amino acids.
  • a position contains multiple amino acids, (i) the identity and ratio of those amino acids is determined by the relative prevalence of amino acids at that position or (ii) the identity of those amino acids is determined by the amino acids present at that position and the ratio of amino acids is equimolar.
  • the library is optionally linked to a substantially invariant peptide domain, such as a helper T cell epitope.
  • the library is also attached to a core branched sequence.
  • the immunogen comprises the 15 octameric peptides of Fig. 2 or the synthetic structural library (SSAL) shown Fig. 4.
  • SSAL synthetic structural library
  • the various core branched sequences to which the subject peptides or library can be attached are shown in Fig. 5.
  • Another aspect of the invention provides the subject immunoglobulin as a purified immunoglobulin preparation which can be conveniently formulated for intramuscular or intravenous administration.
  • Yet another aspect of this invention relates to a method of treating or preventing HIV-l infection which comprises administering to a patient an amount of the immunoglobulin preparation of this invention to obtain at least transient passive immunization of the patient.
  • Such administration can be intramuscular or intravenous.
  • Fig. 1 depicts the principal neutralizing domain (PND) of the V3 loop of HIV-l gpl20 from isolate IIIB.
  • Fig. 2 shows 15 multivalent octamers from the V3 PND of gpl20 HIV-l isolates.
  • Fig. 3 illustrates a primary amino acid sequence alignment of a total of 16 sequences derived from gpl20 peptide, representing the principal neutralizing determinant (PND), the V3 domain, of the HIV-l.
  • Fig. 4 shows an SSAL HIV-l gpl20 V3 constructed according to a previously optimized V3 framework. Sixteen V3 sequences representative of geographically distinct HIV field isolates were used with more weight given to the Consensus S sequence to allow easier calculation of ratios for the various amino acids.
  • Fig. 5 illustrates three types of heteromeric synthetic carriers used in the production of branched SSALs: (A) dendritic, (B) linear, (C) tree-like (D) linear array and (E) a linear array with a helper T cell epitope. Attached onto the core carriers is the SSAL synthesized according to a specified mathematical and chemical representation. Each dash shown within a peptide represents a particular amino acid corresponding to a conserved position in the original protein. Each 0 represents a position where peptides in the library contain any one of a fixed number of amino acids determined from the composition of the amino acid pool used in that cycle of synthesis.
  • the present invention is based on the ability of branched peptides from the HIV-l principal neutralizing determinant (an example of which is shown in Fig. 1; SEQ ID NO:l) to elicit neutralizing antibodies of field isolates of HIV-l.
  • field isolates means the primary HIV-l virus isolate obtained from HIV-l infected patients and not passaged more than 5 times in peripheral blood mononuclear cells.
  • the present invention is directed to purified immunoglobulin which elicits a neutralizing response against two or more HIV-l geographically diverse field isolates and preferably against at least 5 field isolates.
  • the subject immunoglobulin is prepared from a vaccinee immunized with an immunogen or vaccine preparation containing two or more immunogens which comprise a peptide moiety having a sequence of an HIV-l isolate or an HIV-l clade consensus sequence from gpl20.
  • the sequence of these peptide moieties consists of the segment of gpl20 shown in Fig. 2 (SEQ ID NOS:2-16) an the peptide moiety is attached to a core branched sequence. Examples of these peptide moieties are found in U.S. Serial No. 07/726,605 filed July 9, 1991 and its related parent applications which are incorporated herein by reference and fully describe the peptide moieties and their preparation.
  • the immunoglobulins are obtained by immunization of a subject with the 15 peptides shown in Fig. 2 (which is also referred to herein as the multivalent vaccine) .
  • the immunogen is a library of peptides comprising an ensemble domain (SEQ ID N0S:2-17) from the HIV-l gpl20 sequence frame shown in Fig. 2 such that each sequence position in the ensemble domain contains either a single amino acid or multiple amino acids, and that when a position contains multiple amino acids, (i) the identity and ratio of those amino acids is determined by the relative prevalence of amino acids at that position or (ii) the identity of those amino acids is determined by the amino acids present at that position and the ratio of amino acids is equimolar, and wherein said library is optionally linked to a substantially invariant peptide domain or a core branched sequence.
  • the library is fully described in U.S. Serial No.
  • the immunogen is the structured synthetic library (SSAL) library (SEQ ID NO:18) shown in Fig. 4 or the SSAL described in Example 1(c).
  • SSAL structured synthetic library
  • the core branched sequences include dimeric, tetrameric, and octameric lysyl cores as well as the branched core structures shown Fig. 5.
  • the invention also includes the core structures of Fig. 5 which have been modified to tetrameric form.
  • the immunogen can be formulated with other synthetic immunogens for induction of cytotoxic T lymphocytes, or formulated in microparticles for oral delivery and induction of mucosal immunity. Any adjuvant or other formulation for the vaccine known in the art to aid in the development of high titer antibodies can be used with the subject immunogens.
  • the immunoglobulin of the present invention is obtained by immunizing a patient with one of the subject immunogens according to a convenient vaccination schedule. Typically injections are given at 0, 1 and 6 months but any effective and convenient schedule can be used. Such schedules can readily be determined by one of ordinary skill in the art. Once a high titer of anti-HIV-l neutralizing antibody is obtained, as demonstrated by ELISA assay, neutralizing assay or other convenient measure, plasma is obtained from the patient and the Cohn Fraction II of globulin is prepared [Cohn, F.J. et al . (1946) J. Am. Chem. Soc. 68: 459] . As used herein, purified immunoglobulin is a preparation of immunoglobulin having at least the purity of immunoglobulin obtained by the Cohn II fractionation method.
  • Cohn and colleagues developed a method for fractionating human plasma with cold ethanol that enabled the production of concentrated and relatively pure gamma- globulin preparations.
  • Cohn Fraction II has as its main protein component IgG immunoglobulin, present as monomers, dimers, and aggregates (the latter two components are artifacts generated during the fractionation process) .
  • IgG immunoglobulin present as monomers, dimers, and aggregates (the latter two components are artifacts generated during the fractionation process) .
  • Such immune serum globulin (ISG) made from the plasma of many donors, tends to have high concentrations of antibody against common microorganisms, but antibodies against less common organisms may be present only in low or undetectable amounts.
  • ISG hvperimmune serum immunoglobulins
  • the IgG aggregates present in ISG or HISG are capable of causing spontaneous activation of the complement cascade, through binding of the Fc portion of the aggregated immunoglobulin to Fc receptors on complement. Because such activation can produce significant vasomotor symptoms and anaphylaxis, the dosage of ISG is limited by the necessity of intramuscular injection, allowing maxim-urn doses of only 100 to 150 mg/kg.
  • a variety of procedures have been developed to overcome the problem of IgG aggregate development and render human-derived IgG safe for IV infusion.
  • IVIG intravenous immunoglobulin
  • Yet another aspect of this invention relates to a method of treating or preventing HIV-l infection which comprises administering to a patient an amount of the immunoglobulin preparation of this invention to obtain at least transient passive immunization of the patient.
  • Such administration can be intramuscular or intravenous.
  • hyperimmune HIV immune globulin in accordance with the present invention, as prepared from vaccinated individuals, for the prevention or treatment HIV infection is possible if the donors express high titer neutralizing antibody. This results in a much safer and more uniform product than can otherwise be obtained.
  • HIVIG HIV immune globulin
  • Such treatment has special relevance in pediatrics, where the potential use of hyperimmune HIVIG can block HIV transmission from infected mothers to their newborns. Passive immunization can be accomplished in the analogous situation of hepatitis B transmission from mothers to neonates to thereby prevent neonatal hepatitis B infection.
  • specific HIV-l immunoglobulins can be an important adjunctive therapy.
  • Antibody might prevent infection of new cells or prevent spread of the virus to target organs such as the central nervous system. Further, specific HIV-l antibody may reduce the number of HIV-infected lymphocytes through antibody-dependent, cell-mediated cytotoxicity or antibody-mediated complement fixation.
  • subject immunoglobulin preparation is given to individuals to provide postexposure prophylaxis following either parenteral exposure, e.g., by accidental "needle- stick, " or direct mucous membrane contact (accidental splash) , or oral ingestion (pipetting accident) involving suspected HIV-positive materials such as blood, plasma or serum.
  • the subject immunoglobulin preparation is also indicated for prophylaxis of infants born to HIV-positive mothers. Such infants are at risk of being infected with HIV.
  • a regimen combining one dose of immunoglobulin preparation at birth with an HIV vaccine series started soon after birth may prevent development of the HIV carrier state.
  • Regimens involving either multiple doses of the immunoglobulin preparation of the invention alone, or with an HIV vaccine series alone, can have a higher efficacy than a single dose of immunoglobulin.
  • Administration of the immunoglobulin preparation of the invention either preceding or concomitant with the commencement of active immunization with an HIV vaccine provides for more rapid achievement of protective levels of HIV antibody, than when a vaccine alone is administered. Rapid achievement of protective levels of antibody to HIV is desirable in certain clinical situations, as in cases of accidental inoculations with contaminated medical instruments.
  • Administration of the subject hyperimmune immunoglobulin preparation 1 month preceding or at the time of commencement of a program of active vaccination with an HIV vaccine does not interfere with the active immune response to the vaccine.
  • the subject hyperimmune immunoglobulin preparation of this invention can be administered either intramuscularly (IM) or intravenously to the newborn infant after physiologic stabilization of the infant and preferably within 12 hours of birth.
  • An HIV vaccine can be administered IM in three doses of vaccine each. The first dose is given within 7 days of birth and can be given concurrently with an immunoglobulin preparation of this invention but at a separate site. The second and third doses of vaccine can be given 1 month and 6 months, respectively, after the first. If administration of the first dose of an HIV vaccine is delayed for as long as 3 months, then a dose of the immunoglobulin preparation should be repeated at 3 months. If no vaccine is administered, additional doses of the subject immunoglobulin preparations can be repeated at 3 and 6 months. As an example, administration of IVIG usually requires 1 to 3 hr. The infusion is begun at a slow rate
  • the infusion can be increased to 1 to 3 mL/min.
  • the multivalent peptide immunogen is a sterile suspension provided in single dose vials. Each 0.5 mL dose of the vaccine contains 1.2 mg of peptide composed of mass equivalents of each of 15 synthetic branched peptides bound to alum. The aluminum content of the product does not exceed 1.14 mg per dose by assay.
  • the multivalent peptide immunogen consists of 15 synthetic branched peptides, covering the principal neutralizing domain from diverse international HIV-l isolates bound to aluminum hydroxide (alum) as an adjuvant.
  • a phosphate buffered saline solution with thimerasol as an anti-microbial preservative at a final concentration of 0.01% is the vehicle used for intramuscular administration of the suspension.
  • the composition of the 15 immunogens is shown in Fig. 2.
  • the HIV sequence is presented as synthetic peptides extended from eight methionines which are linked by peptide bonds to amino or e amino side chain groups from four lysine residues.
  • these four lysines are covalently bonded to two lysine residues which in turn are bonded to an additional lysine, forming a branched lysine structure.
  • This branched lysine structure is referred to as the heptalysyl "core" used for synthesis of branched peptides (Fig. 2) .
  • Synthesis of the branched- chain peptide is performed in two phases: 1) Preparation of the heptalysyl core resin; and 2) the simultaneous synthesis of the "arms" or branches representing the sequence of the immunogenic component.
  • the synthesis is a modification of the Merrifield solid phase process for peptide synthesis [Posnett et al (1988) J. Biol. Chem. 263:1719-1725: and Wang et al (1991) Science 254:285-288] .
  • the applied synthetic chemistry employs Fmoc derivatized protecting groups.
  • Each branched peptide is lyophilized to remove any residual volatile solvents.
  • Peptide is sampled for identity and homogeneity testing.
  • the lyophilized branched peptide is dissolved in water for injection (WFI) and each solution is adjusted to effect a final peptide concentration of 3.43 mg/mL ⁇ 0.3 mL of the mixture as determined by absorbance (A 2g0nm ) .
  • the 15 branched peptide solutions are combined in equal ratios (w/w) so as to achieve a concentration for each individual peptide in the final product of 0.229 mg/mL.
  • the buffered peptide solution is aseptically filtered (0.22 ⁇ m) .
  • the adjuvanted product is prepared by the addition of sterile aluminum hydroxide gel, in aqueous suspension, to a final concentration of 0.40% (w/w) in 20 rtiM sodium phosphate, pH 6.9 and 0.01% (w/w) thimerasol.
  • SSAL immunogen (b) Multivalent SSAL based UBI HIV-l PND peptide immunogen synthesized onto a branched heptalysyl core resin
  • the SSAL immunogen (Fig. 4) is prepared with sequences derived from the previously characterized PND-V3 region of the HIV-l gpl20 protein and synthesized onto a heteromeric branched core resin using the solid phase Fmoc chemistry with standard side chain protecting groups. Protected amino acids were added sequentially during the synthesis process from C- to N-terminus according to the mathematical and chemical representation of the library as shown in Figures 3 and 4.
  • the protected amino acid reagent added at each of these cycles (representing a variant position) , consists of a collection of amino acid types, where the total concentration of amino acids at the variant position is identical to that of non-variable positions, but the ratio of each type is set by the algorithm shown in Fig. 4. All deprotection and cleavage methods were carried out identical to standard procedures applicable to the Fmoc chemistry of the synthesis.
  • Example 2 Following the synthesis of the e-NH 2 -lysine protected linear AKAKAKAK-resin, the four side chain e-NH 2 presentation groups of the lysine residues were deprotected by 2% hydrazine in DMF. The branched alanyl-lysyl resin provides better presentation of the HIV-l PND arms of the branched immunogen. The rest of the manufacturing processes after the synthesis and cleavage of the HIV-l PND SSAL are as described in Example 1(a) and 1(b) .
  • Example 2 Example 2
  • HIV-l PND-peptide based immunogens manufactured as described in Example l(a-c), are used to elicit varying degrees of specific neutralizing antibodies against HIV-l.
  • the clinical immunization protocols are designed to maximize the production of efficacious HIV-l neutralizing antibodies in the vaccinees, multiple immunizations, e.g. five or more injections, are employed until the desired titers is achieved. Doses can range from 300 ⁇ g to 1000 ⁇ g per injection and can be given for example on days 0, 28, 56, 84, 112, 140, 168 and 336, or any combination of these schedules.
  • IMMUNOGENICITY STUDIES OF MULTIVALENT BRANCHED PEPTIDES REPRESENTING INTERNATIONAL HIV-l ISOLATES Globally diverse HIV-l isolates were grouped into clades or distinct subtypes as described in Myers et al. (1992) Human Retroviruses and AIDS 1992. New Mexico: Theoretical Biology and Biophysics. However, extensive variation has now been recognized within each clade.
  • the multivalent HIV-l immunogen (Fig. 2) , encompasses all of the major subtypes of HIV-l to provide a broad spectrum of neutralizing antibody activity.
  • Table 6 depicts the range of neutralization activity against HIV-l MN by antibodies to PNDs from geographically diverse viruses.
  • the 15 branched peptides were injected into two rabbits subcutaneously with 100 ⁇ g of each peptide in a mixture with 0.5% alum with complete and incomplete adjuvant at week 0, 4 and 6 weeks post injection.
  • the serum was tested at 9 weeks post injection.
  • the serum contained antibodies that were broadly reactive as shown in Table 1.
  • Table 2 demonstrates that in a "highly stringent" test for neutralizing antibody, that HIV-l field isolates from Cambodia, Thailand, Djibouti, North American, Brazil, Zambia and Kenya were neutralized by branched peptide antisera. These data also demonstrate that mixtures of peptides can elicit a neutralizing antibody to globally diverse HIV-l isolates.
  • Hyperimmune Anti-HIV immunoglobulin (Human) from a subject immunized with the multivalent or SSAL immunogen is prepared as a sterile solution of immunoglobulin (15%- 18% protein) by the cold alcohol fractionation from pooled plasma of individuals previously vaccinated with a specific class of peptides, who subsequently developed high titers of antibody to the principal neutralizing determinants of the HIV (Cohn 1946) .
  • the product is stabilized with a low concentration of salt, such as glycine and is preserved with a trace amount of thimerosal.
  • the solution has a neutral pH.
  • One infectious unit (i.u.) is the minimum virus required to start an infection and typically contains about 1000 to 10,000 virions.
  • Hyperimmune anti-HIV immunoglobulin (Human) provides passive immunization for individuals exposed to the HIV.
  • Human can also receive multiple doses of an HIV-l PND peptide-based vaccine for active immunization to allow long-term protection of HIV-l infection.
  • the administration of the usual recommended dose of this immunoglobulin generally results in a detectable level of circulating anti-HIV which persists for approximately 2 months or longer.
  • the highest antibody (IgG) serum levels by the intramuscular route can be seen between days 3 to 7 following initial administration. Mean values for half- life are usually between 17.5 and 25 days.
  • Hyperimmune anti-HIV immunoglobulin (human) from subjects immunized with the multivalent or SSAL vaccine is prepared as a sterile, dried, highly purified preparation of immunoglobulin G (IgG) which is derived from the cold ethanol fractionation process and is further purified using ultrafiltration and ion exchange adsorption (Stiehm 1988) .
  • IgG immunoglobulin G
  • this preparation contains approximately 50 mg of protein per mL, of which at least 90% is gamma globulin.
  • the reconstituted product contains approximately 0.15 M sodium chloride and has a neutral pH.
  • Stabilizing agents used in the preparation are glucose, polyethylene glycol (PEG) , glycine, and albumin (human) .
  • the manufacturing process for the hyperimmune anti- HIV immunoglobulin (Human) isolates IgG without additional chemical or enzymatic modification and Fc portion is maintained intact. It contains all the IgG antibody activities which are present in the donor population. On the average, the distribution of IgG subclasses present in this product is the same as is present in normal plasma. Only trace amounts of IgM and IgA are present in the preparation.
  • This product is prepared from large pools of human plasma derived from healthy donors, prescreened to be free from HIV, HCV, HTLV and HBV infections by multiple diagnostic testings. These individuals have been hyperimmunized with the immunogens of the subject invention (i.e. those with HIV-l V3 PND peptides adjuvanted in alum, as described in Example 1(a) to (d) , according to a specific immunization schedule (Example 2) so as to allow the production in these vaccinated donors high titers of neutralizing antibodies directed against "primary field isolates" of HIV-l.
  • An ELISA titer from each of the vaccinees of >1,000 with an end point titer absorbance 492nm value of >0.2 is usually obtained.
  • Such serum titer usually corresponds to a quantitative measurement of virus neutralizing activity of from 0.01 mg/mL/10 i.u. to 0.1 mg/mL/10 i.u. [i.e. containing -0.01 mg-0.1 mg of HIV PND specific IgG per mL of serum that are capable of completely neutralizing (100%) 10 infectious units of primary field isolates of HIV-l] .

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PCT/US1994/014445 1993-12-13 1994-12-13 Specific hyperimmune anti-hiv globulin for passive immunization WO1995016710A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002007760A2 (en) * 2000-07-21 2002-01-31 Ice Biologics Limited Therapeutic agent against aids comprising anti hiv goat antibody
US7323557B2 (en) 1999-11-16 2008-01-29 Geneart Ag Genome of the HIV-1 inter-subtype (C/B') and use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AIDS RESEARCH AND HUMAN RETROVIRUSES, Volume 6, Number 9, issued 1990, DURDA et al., "HIV-1 Neutralizing Monoclonal Antibodies Induced by a Synthetic Peptide", pages 1115-1123. *
AIDS, Volume 4, Number 10, issued 1990, AKERBLOM et al., "Neutralizing Cross Reactive and Non-Neutralizing Monoclonal Antibodies to HIV-1 Gp120", pages 953-960. *
PROC. NATL. ACAD. SCI. U.S.A., Volume 86, issued September 1989, JAVAHERIAN et al., "Principal Neutralizing Domain of the Human Immunodeficiency Virus Type 1 Envelope Protein", pages 6768-6772. *
SCIENCE, Volume 250, issued 14 December 1990, JAVAHERIAN et al., "Broadly Neutralizing Antibodies Elicited by the Hypervariable Neutralizing Determinant of HIV-1", pages 1590-1593. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323557B2 (en) 1999-11-16 2008-01-29 Geneart Ag Genome of the HIV-1 inter-subtype (C/B') and use thereof
US7332588B1 (en) 1999-11-16 2008-02-19 Geneart Ag Genome of the HIV-1 inter-subtype (C/B) and use thereof
WO2002007760A2 (en) * 2000-07-21 2002-01-31 Ice Biologics Limited Therapeutic agent against aids comprising anti hiv goat antibody
WO2002007760A3 (en) * 2000-07-21 2002-04-18 Ice Biolog Ltd Therapeutic agent against aids comprising anti hiv goat antibody

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