WO2019143884A1 - Clonotypes d'anticorps du vih conservés et méthodes d'utilisation - Google Patents
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Classifications
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- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
- G01N2333/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
- G01N2333/16—HIV-1, HIV-2
- G01N2333/162—HIV-1, HIV-2 env, e.g. gp160, gp110/120, gp41, V3, peptid T, DC4-Binding site
Definitions
- the present disclosure relates to compositions and methods for treating, preventing, and/or detecting an HIV infection. Further disclosed are methods for detecting conserved HIV antibody clonotypes. Also disclosed are improved methods for HIV vaccine design.
- Env The HIV-l envelope glycoprotein (Env) mediates receptor recognition and viral fusion and serves as the sole target of the neutralizing antibody response.
- the developmental pathway of Env-specific antibodies has previously been probed using high-throughput sequencing, but such analyses have focused on lone broadly neutralizing antibody (bNAb) lineages after infection.
- bNAbs comprise only a fraction of the diversity of the antibody response, which also includes antibodies with limited or no breadth.
- HIV human immunodeficiency virus
- an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO:l l, SEQ ID NO:l2, SEQ ID NO:l3, SEQ ID NO:l4, SEQ ID NO:l5, SEQ ID NO:l6, and SEQ ID NO:l7.
- an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the amino acid sequences disclosed in Table 1.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:l. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:2. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:3. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:4. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:5. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:6. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:7.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 8. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 10. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 11. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 12. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 13. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 14. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 15. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 16. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 17.
- the antibody is a monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof specifically binds to the HIV-l envelope glycoprotein (Env).
- Env HIV-l envelope glycoprotein
- disclosed herein is an isolated nucleic acid comprising a sequence that encodes an antibody or antigen binding fragment thereof as disclosed herein.
- a transfected cell comprising an expression vector comprising the nucleic acid disclosed herein.
- HIV human immunodeficiency virus
- the subject is a primate. In some embodiments, the subject is a human.
- the subject is administered the antibody or antigen binding fragment thereof prior to infection with an HIV virus. In some embodiments, the subject is administered the antibody or antigen binding fragment thereof after infection with an HIV virus.
- HIV human immunodeficiency virus
- the detecting of the binding of the antibody or antigen binding fragment thereof to the human immunodeficiency virus is determined in comparison to a control sample.
- the sample is a blood sample.
- the control sample is from an HIV negative individual or a population of HIV negative individuals. In some embodiments, the control sample is from the subject prior to HIV infection.
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- heavy chain variable gene regions from the two or more HIV infected subjects comprise the same V gene and the same J gene.
- both comparison sequences are required to use the same V gene (for example, IGHV1-69) to be considered“overlapping” or“conserved”.
- the same V gene and the same J gene for example, IGHJ6 are required to be considered“overlapping” or“conserved”.
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- V genes are utilized with the conserved CDRH3 gene regions.
- CDRH3 gene region is considered, and thus any V gene can be used.
- the V gene usage is restricted.
- the J gene usage is also restricted.
- the samples are blood samples. In some embodiments, the samples obtained after HIV infection are obtained at 6 months post infection and/or 3 years post infection.
- the conserved HIV antibody clonotype sequence is generated when the alignment of sequences results in greater than 50% identity between the two or more HIV infected subjects. In some embodiments, the conserved HIV antibody clonotype sequence is generated when the alignment of sequences results in greater than 70% identity between the two or more HIV infected subjects. In some embodiments, the conserved HIV antibody clonotype sequence is generated when the alignment of sequences results in greater than 80% identity between the two or more HIV infected subjects.
- FIG. 1 Within-donor longitudinal antibody repertoire analysis from pre-infection through chronic HIV-l infection.
- A For each donor, the number of clonotypes unique to each timepoint is shown, as well as the clonotypes shared between two or all three timepoints. Clonotypes observed in pre-infection and 3ypi samples were counted towards the number of clonotypes across all three timepoints.
- B Heatmap of V-gene usage by donor and timepoint. For each timepoint of each donor, the number of clonotypes using each V H gene (excluding orphan genes) was summed and the z-score was calculated.
- C Heatmap of CDRH3 amino acid length by donor and timepoint. For each timepoint of each donor, the number of clonotypes of each CDRH3 length was summed and the z-score was calculated. No sequences had a CDRH3 length of 35 in any sample in this study.
- FIG. 2 Identification of conserved antibody clonotypes after infection with HIV-l.
- FIG. 3 Characterization of an HIV-reactive conserved HIV antibody clonotype shared by three HIV-infected donors.
- A Multiple sequence alignment of the CDR1-CDR3 regions of the heavy chain sequences from a three-donor conserved HIV antibody clonotype. Included are antibodies CAP248_#30 and CAP3l4_#30, as well as representative CAP351 antibodies CAP35l_#805l and CAP35l_#206l4, along with IGHVl-69*l2, a top germline allele assignment for all antibodies shown. Dots within the V-gene show identity to germline, while letters show mutations from germline. B.
- C ELISA binding of antibodies CAP248_#30 and CAP3l4_#30 to a wild-type ConC gpl20 protein, ConC gpl20 with a N332A mutation, and ConC gpl20 with a D368R mutation.
- Control antibodies are VRC01 (D368R-sensitive), PGT128 (N332A-sensitive), and PGT151 (negative control).
- Heavy chain sequences as shown in Figure 3A IGHVl-69*l2 (SEQ ID NO:8l7), CAP248_#30 (SEQ ID NO:8l9), CAP3l4_#30 (SEQ ID NO:823), CAP35l_#805l (SEQ ID NO:827), and CAP35l_#206l4 (SEQ ID NO:828).
- FIG. 4 Comparison of published antibody repertoires to known HIV-reactive antibody sequences.
- A Number of donors (size of dots) with antibody heavy chain sequences with identical V-gene assignment, signature sequence features, and CDRH3 identity (y-axis) of at least 70% to a set of known HIV-reactive antibodies (x-axis).
- B Antibody heavy chain sequences with identical V-gene assignment, signature sequence features, and CDRH3 distance of at most 2 amino acids.
- V-gene deviation from germline for sequences obtained from the PDB was determined from amino acid sequence using IMGT/DomainGapAlign (Ehrenmann and Lefranc, 2011).
- FIG. 5 Longitudinal analysis of gene usage enrichment. Clonotype abundance of each V gene was normalized by timepoint for each donor as previously described (Cheadle et al., 2003). These standard scores were then tested with Z-tests, the P values of which were then adjusted using adaptive Benjamini-Hochberg correction for an FDR of 0.05. Genes with at least one P ⁇ 0.1 are shown, and all P values lower than 0.10 and 0.05 after correction are colored in this panel.
- FIG. 6 Somatic hypermutation distributions of the public (A) and private (B) clonotypes for each donor (rows), binned (columns) by identity to germline in increments of 2%, with each bin being right-open, except for 0.98-1.00, which is inclusive of 1.00.
- Heatmap color intensity is proportional to the number of sequences in each bin, for each sample.
- FIG. 7 Analysis of conserved HIV antibody clonotypes in HIV-l infection.
- A Number of conserved HIV antibody clonotypes (x-axis) for different junction identity clustering thresholds (colors) for each donor (y-axis).
- B Number of sequences (y-axis) with given amino acid junction identities (x-axis) between pairs of members within each of the 17 most conserved HIV antibody clonotypes.
- C Logo plots of 17 conserved HIV antibody clonotypes identified in 4 or more of the 6 CAPRISA donors whose global antibody repertoires were sequenced. Plots were generated using unique donor-deduplicated CDRH3 sequences and WebLogo as previously described (Crooks et al., 2004).
- each amino acid is proportional to sequence conservation at that position, and the amino acids are colored by physicochemical properties.
- Member CDRH3 sequences in a given conserved HIV antibody clonotype sequence were deduplicated to unique CDRH3s and then used to generate a consensus sequence. These consensus sequences were manually curated to ensure that each sequence was present in its donor, and then used to build the final inter-donor consensus sequences displayed here.
- D Retention of conserved HIV antibody clonotypes during chronic infection with HIV-l. For each pair of donors (axes), shown is the fraction of shared clonotypes at 3ypi that were also found pre-infection.
- G Neutralization data for antibodies CAP248_#30 and CAP3l4_#30. Displayed are the IC 50 values of each antibody against tier 1 viruses MN.3 and MW965.
- Sequences shown in 7C top to bottom: First column (SEQ ID NO: 17, SEQ ID NO:l6, SEQ ID NO:7, SEQ ID NO:lO, SEQ ID NO:9); second column (SEQ ID NO:8, SEQ ID NOG, SEQ ID NO: 11, SEQ ID NOG); third column (SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:6); fourth column (SEQ ID NO:l, SEQ ID NO:4, SEQ ID NOG, SEQ ID NO: 15).
- Heavy chain sequences as shown in Figure 7F IGHVl-69*l2 (SEQ ID NO:830), CAP248_#30 (SEQ ID NO:83l), CAP3l4_#30 (SEQ ID NO:832).
- FIG. 8. Analysis of sequencing data properties.
- B For each public sequence (CDR1 through CDR3) in each sample (rows) of the original sequencing run, the maximum identity (columns) found in the corresponding sample of the duplicate sequencing run was calculated.
- Heatmap color intensity is proportional to the number of antibody clonotypes for each binned identity value for each sample. Bin labels indicate the left bound, with all bins right-open except 0.99, which is inclusive of 1.00.
- C Duplication count (rows) per VDJ sequence in each of the 17 most conserved HIV antibody clonotypes (columns).
- D Number of clonotypes (y-axis) with given number of member sequences (x-axis), for the 70% junction identity threshold plus matched V- and J- gene, using complete linkage clustering. Number of sequences (x-axis) was grouped into 54 left-bound bins.
- FIG. 9 Clinical features and timepoints of sample collection for the donors in this study.
- FIG. 10 Neutralization fingerprinting for CAP287, CAP312, and CAP322 indicating differing antibody specificities among subjects with broadly neutralizing serum.
- FIG. 11 Sequencing depth information and counts of public and private clonotypes for each sample using the 70% junction region identity threshold.
- FIG. 12 Pairwise CDRH3 identity matrices of broadly neutralizing antibody lineages.
- FIG. 13 EFISA binding of antibodies Vandy HC/CAP314-1 FC, CAP314-1 HC/ CAP314-1 FC to a wild-type ConC gpl20 protein, ConC gpl20 with a N332A mutation, and ConC gpl20 with a D368R mutation.
- Control antibodies are VRC01 (D368R-sensitive), PGT128 (N332A-sensitive), and PGT151 (negative control).
- the binding assays used were on monomeric ConC gpl20.
- PGT151 is a known HIV broadly neutralizing antibody that recognizes a conformational epitope that is present on tri meric gpl40 but not monomeric gpl20, thus serves as a negative control for monomeric gpl20s like ConC here.
- FIG. 14 EC50 values of chain-swapping antibodies.
- Cleavable vs‘sc’ variants refer to the gpl20/gp4l interface. Wild type is cleaved but sometimes the single chain (‘sc’) variants are made for ease of protein production.
- the wild type gpl20/gp4l interface has a site that some broadly neutralizing antibodies target.
- The“Avi” label refers to the presence of a C-terminal AVI tag.
- HIV human immunodeficiency virus
- the terms “may,” “optionally,” and “may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur.
- the statement that a formulation “may include an excipient” is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient.
- beneficial agent and“active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect.
- beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition.
- the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like.
- the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, etc.
- treating or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder.
- the terms“treating” and“treatment” can also refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
- the term“preventing” a disorder or unwanted physiological event in a subject refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the subject may or may not exhibit heightened susceptibility to the disorder or event.
- an“effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect.
- the amount of beneficial agent that is“effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact“effective amount.” However, an appropriate“effective” amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an“effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
- An“effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- a“therapeutically effective amount” of a therapeutic agent refers to an amount that is effective to achieve a desired therapeutic result
- a“prophylactically effective amount” of a therapeutic agent refers to an amount that is effective to prevent an unwanted physiological condition.
- Therapeutically effective and prophylactically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject.
- therapeutically effective amount can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect.
- the precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the drug and/or drug formulation to be administered (e.g., the potency of the therapeutic agent (drug), the concentration of drug in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art.
- the term“pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
- the term“pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.
- the term“pharmacologically active” can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
- the term“mixture” can include solutions in which the components of the mixture are completely miscible, as well as suspensions and emulsions, in which the components of the mixture are not completely miscible.
- the term“subject” or“host” can refer to living organisms such as mammals, including, but not limited to humans, livestock, dogs, cats, and other mammals. Administration of the therapeutic agents can be carried out at dosages and for periods of time effective for treatment of a subject. In some embodiments, the subject is a human.
- controlled-release or“controlled-release drug delivery” or “extended release” refers to release or administration of a drug from a given dosage form in a controlled fashion in order to achieve the desired pharmacokinetic profile in vivo.
- An aspect of“controlled” drug delivery is the ability to manipulate the formulation and/or dosage form in order to establish the desired kinetics of drug release.
- polypeptide refers to a compound made up of a single chain of D- or L- amino acids or a mixture of D- and L-amino acids joined by peptide bonds.
- antibodies is used herein in a broad sense and includes both polyclonal and monoclonal antibodies.
- immunoglobulin molecules also included in the term“antibodies” are fragments or polymers of those immunoglobulin molecules, and human or humanized versions of immunoglobulin molecules or fragments thereof, as long as they are chosen for their ability to specifically interact with the HIV virus, such that the HIV viral infection is prevented, inhibited, reduced, or delayed.
- the antibodies can be tested for their desired activity using the in vitro assays described herein, or by analogous methods, after which their in vivo therapeutic and/or prophylactic activities are tested according to known clinical testing methods.
- IgA human immunoglobulins
- IgD immunoglobulins
- IgE immunoglobulins
- IgG immunoglobulins
- the term“monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules.
- the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired antagonistic activity.
- the disclosed monoclonal antibodies can be made using any procedure which produces monoclonal antibodies.
- disclosed monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).
- a hybridoma method a mouse or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.
- the lymphocytes may be immunized in vitro.
- the monoclonal antibodies may also be made by recombinant DNA methods.
- DNA encoding the disclosed monoclonal antibodies can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).
- Libraries of antibodies or active antibody fragments can also be generated and screened using phage display techniques, e.g., as described in U.S. Patent No. 5,804,440 to Burton et al. and U.S. Patent No. 6,096,441 to Barbas et al.
- In vitro methods are also suitable for preparing monovalent antibodies.
- Digestion of antibodies to produce fragments thereof, particularly, Fab fragments can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Examples of papain digestion are described in WO 94/29348 published Dec. 22, 1994 and U.S. Pat. No. 4,342,566.
- Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a fragment that has two antigen combining sites and is still capable of cross-linking antigen.
- the term“antibody or antigen binding fragment thereof’ or“antibody or fragments thereof’ encompasses chimeric antibodies and hybrid antibodies, with dual or multiple antigen or epitope specificities, and fragments, such as F(ab’)2, Fab’, Fab, Fv, sFv, scFv and the like, including hybrid fragments.
- fragments of the antibodies that retain the ability to bind their specific antigens are provided.
- fragments of antibodies which maintain F1IV virus binding activity are included within the meaning of the term“antibody or antigen binding fragment thereof.”
- Such antibodies and fragments can be made by techniques known in the art and can be screened for specificity and activity according to the methods set forth in the Examples and in general methods for producing antibodies and screening antibodies for specificity and activity (See Flarlow and Lane. Antibodies, A Laboratory Manual. Cold Spring Flarbor Publications, New York, (1988)).
- antibody or antigen binding fragment thereof conjugates of antibody fragments and antigen binding proteins (single chain antibodies). Also included within the meaning of “antibody or antigen binding fragment thereof’ are immunoglobulin single variable domains, such as for example a nanobody.
- the fragments can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the antibody or antibody fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove/add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc.
- the antibody or antibody fragment must possess a bioactive property, such as specific binding to its cognate antigen.
- Functional or active regions of the antibody or antibody fragment may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide.
- the term“antibody” or“antibodies” can also refer to a human antibody and/or a humanized antibody.
- Many non-human antibodies e.g., those derived from mice, rats, or rabbits
- are naturally antigenic in humans and thus can give rise to undesirable immune responses when administered to humans. Therefore, the use of human or humanized antibodies in the methods serves to lessen the chance that an antibody administered to a human will evoke an undesirable immune response.
- an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO:l l, SEQ ID NO:l2, SEQ ID NO:l3, SEQ ID NO:l4, SEQ ID NO:l5, SEQ ID NO:l6, and SEQ ID NO:l7.
- an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the amino acid sequences disclosed in Table 1.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:l. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:2. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:3. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:4. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:5. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:6. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:7.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 8. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 10. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 11. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 12. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 13. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 14.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: IS. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 16. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 17. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:l;
- Xaa is selected from Gly, lie, or Gin;
- Xab is selected from Ser, Arg, or Thr;
- Xac is selected from Tyr or Arg
- Xad is selected from Pro, Phe, or Tyr.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:2;
- Xcb is selected from Val or Ala
- Xae is selected from Leu, Ser, or Tyr;
- Xaf is selected from Ser, His, lie, or Lys.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:3;
- Xag is selected from Ala or Thr.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:4;
- Xah is selected from Ala or Gly
- Xai is selected from Ser, lie, or Thr.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:5; Ala-Arg-Xaj-Xak-Xal-Xam-Xan-Xao-Tyr-Tyr-Tyr-Met-Asp-Val (SEQ ID NO:5); wherein:
- Xaj is selected from Asp or Gly;
- Xak is selected from Val, Leu, or Tyr;
- Xal is selected from Ala, Phe, Pro, or Val;
- Xam is selected from The, Val, Trp, or Tyr;
- Xan is selected from Gly or Pro
- Xao is selected from Tyr, Asp, or Asn.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:6;
- Xap is selected from Glu, Arg, or Trp;
- Xaq is selected from Arg, Glu, or Pro;
- Xar is selected from Arg, Asn, or Tyr;
- Xas is selected from Asp, Gly, Leu, or Tyr;
- Xat is selected from Phe or Pro.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:7;
- Xau is selected from Glu, Asp, or Ser;
- Xav is selected from Ala, Ser, Thr, or Val;
- Xaw is selected from Asn or Tyr;
- Xax is selected from Tyr or Ser
- Xay is selected from Tyr, Asp, or Leu;
- Xaz is selected from Asp or Asn.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:8;
- Xba is selected from Asp, He, Lys, Leu, or Arg; and Xbb is selected from Asp, Lys, Asn, or Tyr.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO:9;
- Xbc is selected from Gly or Val
- Xbd is selected from Ser, Pro, or Trp;
- Xbe is selected from Gly or Lys
- Xbf is selected from Tyr or Leu.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 10;
- Xbg is selected from Ala, Glu, Gly, or Val;
- Xbh is selected from Gly, Leu, or Ser
- Xbi is selected from Gly, Ala, or He;
- Xbj is selected from Arg, Phe, or His.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: l l ;
- Xah is selected from Ala, His, or Gly;
- Xbk is selected from His, Tyr, Asn, or Trp;
- Xbl is selected from Leu, Ile, or Val.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 12;
- Xbm is selected from Asp or Leu;
- Xbn is selected from Leu, Pro, Arg;
- Xbo is selected from Gly, Glu, or Tyr;
- Xbp is selected from Gly, Asn, Pro, or Ser
- Xbq is selected from Asn, Pro, or Ser
- Xbr is selected from Tyr or Ala.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 13;
- Xbs is selected from Tyr, Phe, or Trp;
- Xbt is selected from Ala, His, Asn, or Ser.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 14;
- Xbu is selected from His, Asp, or Leu;
- Xby is selected from Phe, Gly, His, or Leu;
- Xbw is selected from Gly, Ser, or Trp;
- Xbx is selected from Tyr or Trp.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 15;
- Xac is selected from Tyr or Arg
- Xby is selected from Ser or Ala
- Xaz is selected from Asp or Asn.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 16;
- Xbz is selected from Glu or Asp
- Xca is selected from Leu, Phe, or He.
- the antibody or antigen binding fragment thereof comprises the amino acid sequence SEQ ID NO: 17;
- the antibody or antigen binding fragment thereof comprises an amino acid sequence which is at least 30% (for example, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%) identical to SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO:l2, SEQ ID NO:l3, SEQ ID NO:l4, SEQ ID NO:l5, SEQ ID NO:l6, or SEQ ID NO:l7.
- the antibody or antigen binding fragment thereof comprises a functional derivative of a conserved HIV antibody clonotype. In some embodiments, the antibody or antigen binding fragment thereof comprises a functional derivative of the antibody or antigen binding fragment thereof comprising an amino acid sequence selected from SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO:l l, SEQ ID NO:l2, SEQ ID NO:l3, SEQ ID NO:l4, SEQ ID NO:l5, SEQ ID NO:l6, or SEQ ID NO:l7.
- the antibody or antigen binding fragment thereof comprises a variant of a conserved HIV antibody clonotype. In some embodiments, the antibody or antigen binding fragment thereof comprises a variant of the antibody or antigen binding fragment thereof comprising an amino acid sequence selected from SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:l5, SEQ ID NO:l6, or SEQ ID NO:l7.
- A“functional derivative” as used herein is a protein or peptide that possesses similar immunoreactivity to the HIV-l envelope glycoprotein that is substantially similar to that of the corresponding protein or peptide.
- the functional derivatives can be identified using any of a variety of routine assays for detecting peptide antigen-antibody complexes, the presence of which is an indicator of selective binding.
- assays include, without limitation, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, western blotting, enzyme immunoassays, fluorescence immunoassays, luminescent immunoassays and the like.
- ELISA enzyme-linked immunosorbent assays
- radioimmunoassays radioimmunoassays, western blotting, enzyme immunoassays, fluorescence immunoassays, luminescent immunoassays and the like.
- Methods for detecting a complex between a peptide and an antibody are well known to those skilled in the art and are described, for example, in ANTIBODIES: A LABORATORY MANUAL (Edward Harlow & David Lane, eds., Cold Spring Harbor Laboratory Press, 2.
- a “functional derivative” of a protein or peptide can contain post-translational modifications such as covalently linked carbohydrate, depending on the necessity of such modifications for the performance of a specific function.
- the term“functional derivative” is intended to include the“variants” and“fragments” of the conserved HIV clonotypes.
- A“variant” refers to a molecule substantially similar in structure and immunoreactivity. Thus, provided that two molecules possess a common immunoactivity and can substitute for each other, they are considered“variants” as that term is used herein even if the composition or secondary, tertiary, or quaternary structure of one of the molecules is not identical to that found in the other, or if the amino acid or nucleotide sequence is not identical.
- a variant refers to a protein whose amino acid sequence is similar to the amino acid sequences of a conserved HIV clonotype, hereinafter referred to as the reference amino acid sequence, but does not have 100% identity with the respective reference sequence.
- the variant protein has an altered sequence in which one or more of the amino acids in the reference sequence is deleted or substituted, or one or more amino acids are inserted into the sequence of the reference amino acid sequence.
- the variant protein has an amino acid sequence which is at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% identical to the reference sequence.
- variant sequences which are at least 95% identical have no more than 5 alterations, i.e. any combination of deletions, insertions or substitutions, per 100 amino acids of the reference sequence. Percent identity is determined by comparing the amino acid sequence of the variant with the reference sequence using any available sequence alignment program. An example includes the MEGALIGN project in the DNA STAR program.
- Sequences are aligned for identity calculations using the method of the software basic local alignment search tool in the BLAST network service (the National Center for Biotechnology Information, Bethesda, Md.) which employs the method of Altschul, S. L., Gish, W hinder Miller, W pris Myers, E. W. & Lipman, D. J. (1990) J. Mol. Biol. 215, 403-410. Identities are calculated by the Align program (DNAstar, Inc.) In all cases, internal gaps and amino acid insertions in the candidate sequence as aligned are not ignored when making the identity calculation.
- Variants of the conserved HIV clonotypes can include nonconservative as well as conservative amino acid substitutions.
- a conservative substitution is one in which the substituted amino acid has similar structural or chemical properties with the corresponding amino acid in the reference sequence.
- conservative amino acid substitutions involve substitution of one aliphatic or hydrophobic amino acids, e.g. alanine, valine, leucine and isoleucine, with another; substitution of one hydroxyl-containing amino acid, e.g. serine and threonine, with another; substitution of one acidic residue, e.g. glutamic acid or aspartic acid, with another; replacement of one amide-containing residue, e.g.
- asparagine and glutamine with another; replacement of one aromatic residue, e.g. phenylalanine and tyrosine, with another; replacement of one basic residue, e.g. lysine, arginine and histidine, with another; and replacement of one small amino acid, e.g., alanine, serine, threonine, methionine, and glycine, with another.
- one aromatic residue e.g. phenylalanine and tyrosine
- basic residue e.g. lysine, arginine and histidine
- replacement of one small amino acid e.g., alanine, serine, threonine, methionine, and glycine
- the antibody is a monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof specifically binds to the HIV-l envelope glycoprotein (Env).
- Env HIV-l envelope glycoprotein
- the antibody binds specifically to the CD4-binding site epitope of the HIV-l envelope glycoprotein (Env). In some embodiments, the antibody binds specifically to the amino acid sequence SEQ ID NO: 18.
- the antibody binds specifically to the CD4-binding site epitope, wherein the binding is reduced in the presence of a ConC gpl20 D368R mutation in comparison to wild-type ConC gpl20. In some embodiments, the antibody binds specifically to the amino acid sequence SEQ ID NO: 19.
- the antibody comprises SEQ ID NO:20. In some embodiments, the antibody comprises SEQ ID NO: 21.
- the antibody comprises an amino acid sequence GGTFSSYG (SEQ ID NO:22), IMPFFGAP (SEQ ID NO:23), and/or ARGADGDYYYYMDV (SEQ ID NO:24).
- the antibody comprises an amino acid sequence GGTFSSYG (SEQ ID NO:22), VFPFFGSA (SEQ ID NO:25), and/or ARGADGDYRYYMDV (SEQ ID NO:26).
- the antibody or antigen binding fragment thereof is produced by active human manipulation (for example, cloning, expression from a cell line, purification, isolation, etc.) and does not encompass naturally occurring antibodies or antigen binding fragments thereof.
- disclosed herein is an isolated nucleic acid comprising a sequence that encodes an antibody or antigen binding fragment thereof as disclosed herein.
- a transfected cell comprising an expression vector comprising the nucleic acid disclosed herein.
- HIV human immunodeficiency virus
- HIV human immunodeficiency virus
- a method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof comprising: administering an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.
- HSV human immunodeficiency virus
- the subject is a primate. In some embodiments, the subject is a human.
- the subject is administered the antibody or antigen binding fragment thereof prior to infection with an HIV virus. In some embodiments, the subject is administered the antibody or antigen binding fragment thereof after infection with an HIV virus.
- these conserved antibody clonotypes are used for vaccine targeting.
- vaccines are designed and tested to specifically target the engagement of the conserved antibody clonotypes disclosed herein.
- the vaccines are designed and tested to specifically target the engagement of other conserved antibody clonotypes between multiple HIV infected subjects (including additional subjects beyond the those specifically analyzed in the examples below).
- a method for determining HIV vaccine efficacy and/or evaluating HIV vaccine design comprising the steps:
- the detecting of the binding of the antibody or antigen binding fragment thereof to the human immunodeficiency virus is determined in comparison to a control sample.
- the control sample is a subject that has not received an HIV vaccine.
- the conserved HIV antibody clonotypes are used for vaccine design, including structure-based vaccine design, that explicitly seeks to elicit a conserved clonotype, due to its neutralization profile or extra-neutralization functions.
- the conserved HIV antibody clonotypes are used for vaccine design that explicitly seeks to avoid elicitation of a conserved clonotype, by epitope masking or other means, due to its lack of neutralization or extra-neutralization functions.
- the conserved HIV antibody clonotypes are used for identification of targets of germlinetargeting immunogens.
- HIV human immunodeficiency virus
- HIV human immunodeficiency virus
- HIV human immunodeficiency virus
- an antibody or antigen binding fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17; and
- the detecting of the binding of the antibody or antigen binding fragment thereof to the human immunodeficiency virus is determined in comparison to a control sample.
- the sample is a blood sample.
- the control sample is from an HIV negative individual or a population of HIV negative individuals.
- the control sample is from the subject prior to HIV infection.
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- a method for detecting conserved HIV antibody clonotypes comprising the steps:
- heavy chain variable gene regions from the two or more HIV infected subjects comprise the same V gene and the same J gene.
- both comparison sequences are required to use the same V gene (for example, IGHV1-69) to be considered“overlapping” or“conserved”.
- the same V gene and the same J gene for example, IGHJ6 are required to be considered“overlapping” or“conserved”.
- V genes are utilized with the conserved CDRH3 gene regions.
- CDRH3 gene region is considered, and thus any V gene can be used.
- the V gene usage is restricted.
- the J gene usage is also restricted.
- sequence runs herein cover parts of the heavy chain variable region (for example, the sequences generally start at the end of the first framework region, and go through the beginning of the 4 th framework region). This means that most of Framework 1 and Framework 4 is not reported in the examples below. However, one of skill in the art can extend the sequence runs to include the entire sequence of the heavy chain variable region.
- the samples are blood samples. In some embodiments, the samples are taken from the two or more HIV infected subjects before and after HIV infection. In some embodiments, the samples are taken from the two or more HIV infected subjects after HIV infection.
- the samples obtained after HIV infection are obtained at 6 months post infection and/or 3 years post infection. In some embodiments, the samples obtained after HIV infection are obtained at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months post infection and/or 1, 2, 3, 4, 5, or more years post infection. Samples can also be used from subjects taken at any time after HIV infection.
- the conserved HIV antibody clonotype sequence is generated when the alignment of sequences results in greater than 30% identity (for example, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%) between the two or more HIV infected subjects.
- the antibodies disclosed herein can be used in vaccine manufacturing for quality control purposes (called“lot release”).
- Each batch (or“lot”) of vaccine antigen manufactured can be tested in an ELISA assay or other immunological assay to characterize the antigen in each lot or batch of vaccine preparation.
- This quality control helps ensure consistency of vaccine antigen between various production lots or batches.
- the binding activity of a given lot of vaccine may be determined according to well-known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation.
- HIV human immunodeficiency virus
- the sample is a biological sample.
- the sample is a vaccine lot (or batch).
- the antibodies disclosed herein are analyzed for binding to an HIV antigen in the sample, for use in the quality control purposes for manufacturing vaccines and ensuring consistency across vaccine lots or vaccine batches.
- a method for ensuring consistency between HIV vaccine manufacturing lots comprising the steps:
- control vaccine sample is a reference vaccine standard for comparison of all lots of vaccine lots or batches. In some embodiments, the control vaccine sample is a second test vaccine sample from a second test vaccine lot.
- a method for detecting conserved HIV antibody clonotypes in a subject comprising the steps:
- a method for detecting conserved HIV antibody clonotypes in a subject comprising the steps:
- the comparison of sequences results in detection of a conserved HIV antibody clonotype in a subject when there is greater than 30% (for example, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 99%, or more) identity between the sequence of the sample and the known conserved HIV antibody clonotype.
- the comparison of sequences results in detection of a conserved HIV antibody clonotype in a subject when there is complete (100%) identity between the sequence of the sample and the known conserved HIV antibody clonotype.
- the known conserved HIV antibody clonotype sequence can be an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:lO, SEQ ID NO:l l, SEQ ID NO:l2, SEQ ID NO:l3, SEQ ID NO:l4, SEQ ID NO:l5, SEQ ID NO:l6, SEQ ID NO:l7, or a sequence disclosed in Table 1.
- the amino acid sequences are compared.
- the nucleic acid sequences encoding the amino acid sequences are compared.
- the nucleic acid sequence is isolated.
- the nucleic acid sequence is recombinant.
- the nucleic acid sequence is non-naturally occurring.
- the antibody, or antigen binding fragment thereof is isolated.
- the antibody, or antigen binding fragment thereof is recombinant.
- the antibody, or antigen binding fragment thereof is non-naturally occurring.
- the antibody, or antigen binding fragment thereof is a monoclonal antibody.
- a recombinant nucleic acid sequence encoding a heavy chain of an antibody comprising a heavy chain CDR1 from Table 1, a heavy chain CDR2 from Table 1, and a heavy chain CDR3 from Table 1.
- a heavy chain CDR1 from Table 1 a heavy chain CDR1 from Table 1
- a heavy chain CDR2 from Table 1 a heavy chain CDR3 from Table 1.
- any of the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 sequences disclosed herein can be used in combination together.
- a recombinant nucleic acid encoding a heavy chain of an antibody comprising a heavy chain sequence selected from the group consisting of SEQ ID NOs:20-2l, 27-585, 819, 823, 827, 828, 831, 832, 841, 842, 848, 850, and 851.
- a recombinant nucleic acid encoding a light chain of an antibody comprising a light chain sequence selected from the group consisting of SEQ ID NOs: 834, 838, 845, and 849.
- a recombinant nucleic acid sequence encoding a heavy chain of an antibody comprising heavy chain CDR1, CDR2, and CDR3 regions of SEQ ID NOs:20-2l, 27-585, 819, 823, 827, 828, 831, 832, 841, 842, 848, 850, or 851.
- a recombinant nucleic acid sequence encoding a light chain of an antibody comprising light chain CDR1, CDR2, and CDR3 regions of SEQ ID NOs: 834, 838, 845, or 849.
- a monoclonal antibody comprising a heavy chain CDR1 from Table 1, a heavy chain CDR2 from Table 1, and a heavy chain CDR3 from Table 1.
- a monoclonal antibody comprising a heavy chain CDR1 from Table 1, a heavy chain CDR2 from Table 1, and a heavy chain CDR3 from Table 1.
- any of the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 sequences disclosed herein can be used in combination together.
- a monoclonal antibody comprising a heavy chain sequence selected from the group consisting of SEQ ID NOs:20-2l, 27-585, 819, 823, 827, 828, 831, 832, 841, 842, 848, 850, and 851.
- a monoclonal antibody comprising a light chain sequence selected from the group consisting of SEQ ID NOs: 834, 838, 845, and 849.
- a monoclonal antibody comprising heavy chain CDR1, CDR2, and CDR3 regions of SEQ ID NOs:20-2l, 27-585, 819, 823, 827, 828, 831, 832, 841, 842, 848, 850, or 851.
- a monoclonal antibody comprising light chain CDR1, CDR2, and CDR3 regions of SEQ ID NOs: 834, 838, 845, or 849.1n some embodiments, the antibody selectively binds an HIV virus protein.
- a monoclonal-antibody comprising an antibody heavy chain (HC) sequence (variable region), and an antibody light chain (LC) sequence (variable region), which antibody is selected from the group consisting of:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising: a heavy chain sequence comprising SEQ ID NO:84l;
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- an antibody comprising:
- a monoclonal-antibody comprising an antibody heavy chain (HC) variable region, which comprises heavy chain CDR1 to CDR3 sequences, and an antibody light chain (LC) variable region, which comprises light chain CDR1 to CDR3 sequences, which antibody is selected from the group consisting of:
- an antibody comprising: heavy chain CDR1 to CDR3 sequences:
- a CDR1 sequence which is SEQ ID 839
- a CDR2 sequence which is SEQ ID 836
- a CDR3 sequence which is SEQ ID 840
- an antibody comprising: heavy chain CDR1 to CDR3 sequences:
- the antibody is a variant (a functionally active variant) of a parent antibody, wherein the number of point mutations is either 0, 1 , 2, or 3 point mutations in each of the CDR sequences, and/or the variant (functionally active variant) comprises CDR sequences that share at least 60% sequence identity to the parent CDR sequences.
- composition comprising a pharmaceutically acceptable carrier and an active compound disclosed herein (for example, an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: lO, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, a sequence disclosed in Table 1, or any of the antibody sequences disclosed herein).
- an active compound disclosed herein for example, an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO
- the composition further comprises an additional therapeutic agent.
- Excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 2lst Edition (Lippincott Williams & Wilkins, 2005).
- excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydro
- the excipients may be chosen based on what the composition is useful for.
- the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray.
- Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
- Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
- cross-linked poly(vinyl-pyrrolidone) crospovidone
- sodium carboxymethyl starch sodium starch glycolate
- Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
- stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
- Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), polyvinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- polyoxyethylene ethers e.g. polyoxyethylene lauryl ether [Brij 30]
- polyvinylpyrrolidone diethylene glycol monolaurate
- triethanolamine oleate sodium oleate
- potassium oleate ethyl oleate
- oleic acid ethyl laurate
- Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
- acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
- Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
- antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
- EDTA ethylenediaminetetraacetic acid
- salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
- citric acid and salts and hydrates thereof e.g., citric acid mono
- antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
- antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
- Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
- Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
- preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
- the preservative is an anti-oxidant.
- the preservative is a chelating agent.
- Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer
- Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
- Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckt
- Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
- composition may further comprise a polymer.
- exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar
- composition may further comprise an emulsifying agent.
- emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic poly acrylates, such as poly(meth)acrylic acid, and esters amide and hydroxyalkyl amides thereof, natural emulsifiers (e.g.
- acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.
- carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
- carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
- Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- the emulsifying agent is cholesterol.
- Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
- the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents
- injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
- acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80.
- the injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
- Solid compositions include capsules, tablets, pills, powders, and granules.
- the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay,
- the dosage form may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.
- the active compound is admixed with an excipient and any needed preservatives or buffers as may be required.
- the ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons .
- Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
- dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin.
- the rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel.
- the active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result.
- the exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular active ingredient, its mode of administration, its mode of activity, and the like.
- the active ingredient, whether the active compound itself, or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
- the active ingredient may be administered by any route.
- the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
- routes including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual;
- the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.
- an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
- the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
- Vaccine design strategies attempting to recapitulate a specific antibody response rely on a thorough understanding of the target response. To date, no such systems-level understanding of the humoral response against HIV-1 exists, as most previous efforts have focused on the characterization of single antibody lineages within a select few individuals.
- next-generation sequencing was used to interrogate the antibody repertoires of multiple HIV-infected donors from a time before infection through the periods of acute and chronic infection.
- Env The HIV-1 envelope glycoprotein (Env) mediates receptor recognition and viral fusion, and serves as the sole target of the neutralizing antibody response (Pancera et al., 2014; Ward and Wilson, 2015).
- the developmental pathway of Env-specific antibodies has been probed previously using high-throughput sequencing (Bonsignori et al., 2016; Doria-Rose et al., 2014; Huang et al., 2016; Liao et al., 2013; Wu et al., 2011), but such analyses have focused on single broadly neutralizing antibody (bNAb) lineages after infection.
- bNAbs comprise only a fraction of the antibody response within a given individual, which also includes antibodies with limited or no breadth.
- antibody repertoire sequence analysis was performed to examine distinctive characteristics of the pre- and post-infection repertoires of multiple donors.
- the global immunoglobulin heavy chain repertoires of six South African donors from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) were longitudinally sequenced from before infection through acute and chronic infection, as well as paired heavy and light chain sequencing of the Env-specific post-infection repertoires of two additional CAPRISA donors.
- the resulting analysis provides novel therapeutics for treating or preventing a human immunodeficiency virus (HIV) infection.
- HIV human immunodeficiency virus
- Antibody variable genes in peripheral blood cell samples from three timepoints categorized as pre-infection, 6 months post-infection (6mpi), or 3 years post-infection (3ypi), were sequenced for each of the six CAPRISA donors (Figure 9).
- the pre-infection timepoints ranged from 30 to 2 weeks before infection, with the exception of donor CAP322, for whom the earliest available sample was at 2 weeks post-infection.
- All CAPRISA donors were infected with clade C viruses (Rademeyer et al., 2016), but exhibited diverse neutralization phenotypes, including substantial variation in neutralization breadth between 0 and 61% on a representative panel of diverse HIV-l strains (Figure 9).
- conserved F1IV antibody clonotypes were not restricted to germline sequences, and exhibited a wide distribution of V- gene deviation from germline ( Figure 6). Although these sequence groups are not technically biological clones (as they were derived from multiple individuals and thus are not derived from a single B cell), conserved F1IV antibody clonotypes were defined as groups of sequences with the same V H gene, the same J H gene, the same junction length, and CDRF13 amino acid sequences of high identity between donors (Materials and Methods).
- the antibody sequences were analyzed using a range of junction region identity thresholds during the clonal assignment procedure (Figure 7A).
- conserved F1IV antibody clonotypes were identified for all threshold values, including at 100% junction identity.
- identities between members of known bNAb lineages can be as low as -30% ( Figure 12)
- a conservative threshold of 70% was selected, in which all members of a clonotype would have at least 70% junction region identity to all other members of the clonotype. This threshold aimed at allowing reasonable inclusion of intra- clonal evolution without allowing highly divergent sequences from different donors to be grouped together.
- IGF1V1-69*12 heavy chain (F1C) sequence (germline sequence reference):
- CDR2 IIPIFGTA (SEQ ID NO:818)
- CDR1 GGTFSSWP (SEQ ID NO:820)
- CDR2 VMPLFGAP (SEQ ID NO:821)
- CDR3 ARGRDGD YR YYMD V (SEQ ID NO:822)
- CDR2 IIPLFGMP (SEQ ID NO: 825)
- CDR3 GRGADGDYYYYMDV (SEQ ID NO: 826)
- CAP35l_#805l heavy chain (F1C) sequence (truncated version of “Vandy F1C” sequence below):
- CDR2 IMPFFGAP (SEQ ID NO:23)
- CDR3 ARGADGDYYYYMDV (SEQ ID NO:24)
- CDR1 GYTFTSYG (SEQ ID NO: 644)
- CDR2 ISGYNGDT (SEQ ID NO: 829)
- CDR3 ARGADGDYRYYMDV (SEQ ID NO:26).
- IGFlVl-69*l2 heavy chain (F1C) sequence (germline sequence reference):
- CAP248_#30 light chain (LC) sequence is:
- CAP3l4_#30 light chain (LC) sequence is (also referred to as C992 LC):
- sequence features known to be important for HIV-l recognition such as a requisite tryptophan in the fifth position preceding the framework 4 region for 3BNC60 (Scheid et al., 2011) and gpl20-binding putative VRC01 precursors (Yacoob et al., 2016), were included as additional constraints in the comparison.
- many observed sequences had low identity to known HIV-l antibodies.
- thirty-seven known HIV-reactive antibodies had matches with at least 70% CDRH3 identity, in addition to matching V-gene and sequence feature requirements, to antibodies in the examined samples (Figure 4A). With these search parameters, as many as ⁇ 70 donors were matched to a given HIV-reactive antibody.
- HIV- reactive antibodies included antibodies with extra-neutralization functions, weakly neutralizing antibodies, putative vaccine-elicited antibody precursors, and putative bNAb precursors, and spanned a range of CDRH3 lengths from 10 to 19 amino acids.
- the antibody heavy chain repertoires of multiple HIV-infected donors were interrogated at multiple timepoints, through next-generation sequencing and systems immunology analysis.
- Antibody sequence repertoires in chronic HIV-l infection appeared to diverge from their pre-infection repertoires. While sampling depth cannot be excluded as a possible explanation for the observed repertoire turnover, virus-induced turnover or a more general property of B cell repertoire dynamics could also explain this observation.
- PBMCs peripheral blood mononuclear cells
- Preprocessing was carried out using pRESTO (Vander Heiden et al., 2014) as follows: 1 ) Paired-end reads were interleaved and reads with a mean Phred quality score below 20 were removed. 2) Orientation of sequences was corrected to the forward orientation (V to J) as necessary. 3) V-region primers were masked and C-region primers were cut. Sequences with no match to primers were discarded. 4 ) Duplicate sequences were removed and a duplication count of each sequence was annotated. 5) All sequences with duplication count of 1 were removed. A wide distribution of duplication counts was observed (Figure 8C).
- IGHV and IGHJ gene annotations for each group of sequences were determined by the first gene assignment of gene assignments within each junction length. Within these larger groups, sequences differing from one another by a threshold distance within the junction region were defined as clonotypes by complete-linkage clustering. Distance was determined using an amino acid Hamming distance normalized to the length of the junction. Amino acid distance was used during clustering because this is the determinant of antibody molecular recognition; however nucleotide and amino acid identities were generally very similar (Figure 8E). Single cell sorting
- Paired chain antibody sequencing for CAP248 and CAP314 was carried out by Atreca (Redwood City, CA) on IgG cells sorted into microtiter plates at one cell per well by FACS. Briefly, cryopreserved PBMCs were stained with the following antibodies: CD14-FITC (HCD14), CD3-FITC (UCHT1), IgM-A488 (MHM-88), IgD-A488 (IA6-2), CD19-BV421 (HIB 19) or CD19-PE (SJ25C1), CD20-PECy7 or CD20-BV711 (2H7), CD38-PECy7 or CD38-PerCPCy5.5 (HIT2), CD27-BV510 (0323) from BioLegend and IgA-FITC (IS11- 8E10) from Miltenyi.
- antigen-specific cells were isolated using CAP45 SOSIP.664 trimeric protein.
- antigen-specific cells were isolated using ConC gpl20.
- the sorted antigen-specific B cells were cultured for 4 days in IMDM medium (Invitrogen) in the presence of FBS, Normocin, IL-2 (PeproTech), IL-21 (PeproTech), rCD40 ligand (R&D Systems), and His-Tag antibodies (R&D Systems), prior to single cell sequencing.
- a list of 113 HIV -reactive antibodies was curated manually from the Protein Databank and CATNAP (Yoon et al., 2015), and CDRH3 sequence and V-gene usage of each antibody was determined using ANARCI (Dunbar and Deane, 2016) with IMGT numbering.
- Publicly available antibody sequencing datasets collected from the Short Read Archive and the European Nucleotide Archive, in addition to the samples presented in this study, were processed via MiXCR (Bolotin et al., 2015). Briefly, reads in each sample were aligned with the mixer align command and clustered by junction sequence and V-gene assignment using the mixer assemble command with the -OseparateByV true flag.
- each donor was represented by a 45-dimensional vector, with each dimension having a value of 1 or 0 based on if that donor was part of each of the 45 pairwise comparisons that occurred across the 3 timepoints.
- MiXCR software for comprehensive adaptive immunity profiling. Nat Meth 12, 380-381.
- IMGT/V-QUEST the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 36.
- IMGT/DomainGapAlign IMGT standardized analysis of amino acid sequences of variable, constant, and groove domains (IG, TR, MH, IgSF, MhSF). Cold Spring Harb. Protoc. 6, 737-749.
- IgBLAST an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 41, W34— W40.
- CATNAP A tool to compile, analyze and tally neutralizing antibody panels. Nucleic Acids Res. 43, W213-W219.
- Sequencing data preprocessing was performed, including pre-processing and postalignment steps. Preprocessing can be done in many different permutations of these or similar steps.).
- Orientation of sequences is corrected to the forward orientation (V to J) as necessary.
- V-region and C-region primers are masked or cut.
- Duplicate sequences are removed, and each unique sequence is annotated with a duplication count.
- Sequences with a low duplication count are removed as a quality control measure. Sequences with a duplication count above the threshold are kept for subsequent analysis. If molecular barcodes were used in sequencing: i. Low quality reads (ie, mean Phred score below 20) are removed.
- V- and C- region PCR primers are cut or masked.
- Sequences are annotated by their unique molecular barcodes and barcode annotation is propagated to each sequence read mate pair.
- a consensus/conserved sequence is generated for each set of sequences sharing the same unique molecular barcode.
- v. Paired-end consensus reads are assembled into full-length sequences.
- Sequences with a low duplication count (ie, of only 1) are removed as a quality control measure. Sequences with a duplication count above the threshold are kept for subsequent analysis.
- Each sequence is annotated for V, D, and J gene usage using an alignment program specifically designed for antibody sequences (for example, IgBLAST 2 ) to align to a reference database of germline sequences.
- an alignment program specifically designed for antibody sequences for example, IgBLAST 2
- Germline sequence databases can be complied from publicly available germline allele sequences from IMGT or GenBank, or from a custom database of germline sequences inferred from high-throughput sequencing experiments using germline-inference tools, or a combination of the two (for example, IMGT 3 ).
- Non-functional sequences and sequences with CDRH3 lengths below a threshold ie, 5 amino acids are removed. All samples of interest are combined into a single dataset, with each sequence annotated for its sample of origin (the following steps must be performed simultaneously on all sequences from all samples of interest for the identification of conserved HIV antibodies)
- Sequences are partitioned into groups based on common IGHV and IGHJ gene annotation and junction region lengths. Partitioning by IGHV and IGHJ gene annotation can use either:
- sequences within a threshold identity to one another within the junction region are clustered using hierarchical clustering. These resulting clusters are defined as clonotypes.
- Thresholds may range from 30% - 100% identity, as known HIV broadly neutralizing antibody lineages have member sequences with as low as under 30% identity to other member sequences (see Figure 3C-3D).
- Heirarchical clustering may be implemented using either single linkage, average linkage, or complete linkage. In the example here, complete linkage is used.
- Threshold identities are determined using an amino acid Hamming distance normalized to the length of the junction region.
- conserved HIV antibody clonotype sequences from sequencing experiments can be identified using a different method comparing a database of sequences of unknown specificity to a database of sequences of known HIV reactivity: a.
- Database of sequences of unknown specificity (called‘unknown database’ from here on) is preprocessed as in steps 1-2 above.
- V gene annotation for each of unknown and known sequences is same ii. If the CDRH3/j unction length is equal between unknown and known sequence iii. If CDRH3/j unction identity is above a threshold identity % or other distance metric (ie, less than a hamming distance of 3 amino acids difference)
- VRC01 -class sequences PGV04,VRC23, NIH45-46, 3BNC117, 12A12, VRC- PG20, 45-VRC01.H08.F-117225, Z258-VRC27.01, 3BNC60, 45-VRC01.H5.F-185917, VRC08, VRC08C, VRC07_l995, VRC01, VRC-PG04, or VRC01 germline precursors 02-cb 4 , 02-o 4 , 02-s 4 , 02-u 4 , 02-k 4 , 02-t 4 , 02- v 4 , 04-k 4 , 04-m 4 , the residue in the CDRH3 that is in the fifth position preceding the start of the Framework 4 region, as determined by the IMGT antibody numbering scheme 3 , must be a tryptophan.
- IgBLAST an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Research, 4/(Wcb Server issue), W34-W40. https ://doi.org/l 0.1093/nar/gkt382
- CATNAP A tool to compile, analyze and tally neutralizing antibody panels. Nucleic Acids Research, 43(Wl), W213-W219. https://doi.org/l0. l093/nar/gkv404
- the Vandy heavy chain sequence comprises:
- the Vandy heavy chain CDRs comprise:
- CDR3 ARGADGD YYYYMDV [SEQ ID NO:24],
- the Vandy heavy chain sequence is similar to sequence 828593 (SEQ ID NO:20) in Table 1. However, the sequence listed in Table 1 does not include some framework 1 and framework 4 amino acid residues.
- the Vandy light chain sequence that was originally paired with the Vandy heavy chain sequence was not recovered, as only the heavy chain was recovered from high throughput sequencing analyses, and thus the heavy chain was uncoupled from the light chain.
- Vandy heavy chain has been paired with the CAP314-1 light chain sequence and is labeled as“Vandy” in Figure 13 and Figure 14. These experiments examined the pairing of non-native heavy chain and light chain combinations and examined whether these antibodies still bind appropriately to an F1IV protein. As seen in Figure 13 and Figure 14, the pairing of non-native heavy chain and light chain maintained binding to the HIV proteins tested.
- the CAP314-1 labeled antibody was recovered to allow retention of the paired heavy chain and light chains.
- the CAP314-1 heavy chain comprises:
- the CAP314-1 heavy chain CDRs comprise:
- CDR2 FMPFFRSP (SEQ ID NO: 844)
- CDR3 ARGADGDYYYYMDV (SEQ ID NO:24)
- the CAP314-1 light chain comprises:
- the CAP314-1 light chain CDRs comprise:
- CDR1 QSVSSSY (SEQ ID NO: 846)
- CDR2 GAS (SEQ ID NO: 836)
- the Cl 746 heavy chain comprises: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSWPISWVRQAPGQGLEWMGG VMPLFGAPNYAQKFQGRLTITADSSTRTVHMELSSLRSGDTAVYYCARGRDG D YRY YMD VWGEGTP VT V S S (SEQ ID NO:848)
- the Cl 746 heavy chain CDRs comprise:
- CDR1 GGTFSSWP (SEQ ID NO:820)
- CDR2 VMPLFGAP (SEQ ID NO:82l)
- CDR3 ARGRDGDYRYYMDV (SEQ ID NO:822)
- the C1746 light chain (LC) comprises:
- the Cl 746 light chain CDRs comprise:
- the C992 heavy chain (HC) comprises:
- the C992 heavy chain CDRs comprise:
- CDR2 IIPLFGMP (SEQ ID NO: 825)
- CDR3 GRGADGDYYYYMDV (SEQ ID NO: 826)
- the C992 light chain (LC) comprises:
- the C992 light chain CDRs comprise:
- CDR2 GAS (SEQ ID NO: 836)
- CDR3 QKYDSGPRT (SEQ ID NO:840)
- the C1746 sequence above is also referred to as the CAP248_#30 sequence (as shown in Figure 3A).
- the C992 sequence above is also referred to as the CAP3l4_#30 sequence (as shown in Figure 3A).
- the 2104 F1C is the same as sequence 828499 (SEQ ID NO:528) in Table 1, except that 828499 (SEQ ID NO:528) is slightly truncated compared to 2104 F1C.
- the 2104 sequence was completed with germline framework 1 and framework 4 residues (in the sequencing scheme the primers sit into framework 1 and framework 4, so some of those residues were missed).
- the 2104 heavy chain CDRs comprise:
- CDR2 IFPFFGSA (SEQ ID NO:725)
- CDR3 ARGADGDYRYYMDV (SEQ ID NO:26).
- an antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the amino acid sequences disclosed in Table 1.
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Abstract
La présente invention concerne des compositions et des méthodes pour le traitement et/ou la prévention d'une infection par le VIH. L'invention concerne également des méthodes de détection de clonotypes d'anticorps du VIH conservés. L'invention porte en outre sur des procédés améliorés de conception de vaccin contre le VIH.
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US20090214428A1 (en) * | 2005-03-14 | 2009-08-27 | Dimitrov Dimiter S | Human Monoclonal Antibodies Against Hendra and Nipah Viruses |
US20100092992A1 (en) * | 2006-08-17 | 2010-04-15 | Peter Hornbeck | Lysine acetylation sites |
US20120058906A1 (en) * | 2008-11-07 | 2012-03-08 | Vaughn Smider | Combinatorial antibody libraries and uses thereof |
US20160264675A1 (en) * | 2015-03-03 | 2016-09-15 | Kymab Limited | Synergistic combinations of ox40l antibodies for the treatment of gvhd |
WO2016149710A2 (fr) * | 2015-03-19 | 2016-09-22 | Duke University | Anticorps neutralisant le vih-1 et leurs utilisations |
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US20170156298A1 (en) * | 2009-08-13 | 2017-06-08 | Crystal Bioscience Inc. | Transgenic animal for production of antibodies having minimal cdrs |
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US20090214428A1 (en) * | 2005-03-14 | 2009-08-27 | Dimitrov Dimiter S | Human Monoclonal Antibodies Against Hendra and Nipah Viruses |
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