WO2009108307A2 - Utilisation d’anticorps monoclonaux anti-h8 à des fins de diagnostic - Google Patents
Utilisation d’anticorps monoclonaux anti-h8 à des fins de diagnostic Download PDFInfo
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- WO2009108307A2 WO2009108307A2 PCT/US2009/001177 US2009001177W WO2009108307A2 WO 2009108307 A2 WO2009108307 A2 WO 2009108307A2 US 2009001177 W US2009001177 W US 2009001177W WO 2009108307 A2 WO2009108307 A2 WO 2009108307A2
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- Prior art keywords
- antigen
- antibody
- neisseria
- seq
- binding
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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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
- C07K16/1217—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Neisseriaceae (F)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- 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
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/22—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Neisseriaceae (F), e.g. Acinetobacter
Definitions
- the invention relates to diagnostic and therapeutic uses of antibodies or antigen- binding fragments that recognize the H8 antigen, an outer membrane protein o ⁇ Neisseriae. Some aspects relate to pharmaceutical and diagnostic compositions comprising antibodies or antigen-binding fragments that recognize the H8 antigen. Further aspects relate to diagnostic kits comprising antibodies or antigen-binding fragments that recognize the H8 antigen.
- Neisseria gonorrhoeae is the agent of non- symptomatic gonococcal infection or symptomatic disease, i.e., gonorrhea.
- Neisseria meningitidis is the agent of a rapidly progressive spinal meningitis, which may also have a non-symptomatic infective stage.
- the surfaces of such pathogens provide crucial interfaces for interactions between the pathogen and the host. While the outer membrane proteins on these surfaces are primary targets recognized and attacked by the host's immune system, diagnostic and therapeutic modalities that take advantage of these outer membrane proteins remain largely untapped from a practical, clinical perspective.
- the invention relates to the discovery and development of novel antibodies and antigen-binding fragments that recognize the H8 antigen, an outer surface membrane protein from Neisseria species such as N. gonorrhoeae and N. meningitidis.
- These novel antibodies, antigen-binding fragments, and the nucleic acid sequences encoding them provide diagnostic, therapeutic and prophylactic compositions and methods useful for the treatment or prevention of gonococcal and meningococcal infections. Some aspects are particularly useful for rapid and point of care diagnosis of Neisseria infections that cause as gonorrhea and meningococcal meningitis.
- the present invention provides clinically relevant, antibody-based diagnostic and therapeutic modalities that take advantage of the H8-antigen, an outer membrane protein, of Neisseria.
- antibodies that bind to the H8 antigen of Neisseria are provided.
- the antibody is selected from: monoclonal antibody SA5 as produced by hybridoma SA5, deposited with the American Type Culture
- the antibody is selected from: an antibody comprising a heavy chain region having the sequence set forth in SEQ ID NO. 2; an antibody comprising a light chain region having the sequence set forth in SEQ ID NO.
- the antibody is a chimeric antibody or a humanized antibody.
- antigen-binding fragments of the foregoing antibodies are provided that bind to the H8 antigen of Neisseria.
- the antigen-binding fragment is selected from: F(ab') 2 , F(ab'), F(ab), and single chain Fv.
- polynucleotides are provided.
- the polynucleotides encode at least a variable region of an immunoglobulin chain of a foregoing antibody that binds to the H8 antigen of Neisseria.
- a vector comprising the polynucleotide is provided.
- a composition is provided that comprises the polynucleotide and/or the vector.
- a host cell is provided that comprises the polynucleotide and/or the vector.
- hybridomas are provided.
- the hybridoma produces an antibody having a variable region of a foregoing antibody that binds to the H8 antigen of Neisseria.
- the antibody is selected from: SA5 and SA75.
- a method for preparing an antibody or antigen-binding fragment or immunoglobulin chain(s) thereof comprises (a) culturing a foregoing host cell or a foregoing hybridoma; and (b) isolating the antibody or antigen-binding fragment from the culture.
- an antibody or antigen-binding fragment obtainable by the foregoing preparation method is provided.
- the foregoing antibodies or antigen-binding fragments that bind to the H8 antigen of Neisseria are conjugated to a detectable label.
- the detectable label is selected from: a radioisotope, a fluorophore, a luminescent molecule, an enzyme, a biotin-moiety, an epitope tag, and a dye molecule.
- the detectable label is an enzyme selected from a phosphatase and a peroxidase.
- the detectable label is capable of activating a chemiluminescent substrate.
- the detectable label is a fluorophore selected from: FITC, TRITC, Cy3, Cy5, Alexa Fluorescent Dyes, and Quantum Dots.
- the foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria is capable of modulating an immune response against Neisseria in a subject in need thereof.
- the antibody or antigen- binding fragment is conjugated to an antibiotic compound.
- composition comprising a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria.
- the composition comprises a carrier.
- the carrier is a pharmaceutically acceptable carrier.
- a solid support is provided.
- the solid support has bound thereto a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria.
- the solid support is a reaction chamber.
- the reaction chamber is a plate well of a multi- well plate, optionally which has a number of wells selected from: 6, 12, 24, 96, 384, and 1536.
- an antigen-binding fragment that is a ligand binding molecule is provided.
- the ligand binding molecule comprises at least one complementary determining region of a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria.
- diagnostic kits comprise a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria, and one or more reagents conventionally used in immunological based diagnostic methods.
- the antibody or antigen- binding fragment is immobilized on a solid support.
- the antibody or antigen-binding fragment is in a solution.
- the diagnostic kits comprise H8-antigen immobilized to a solid support.
- the solid support is the surface of a reaction chamber.
- the reaction chamber is a plate well.
- the plate well is in a multi-well plate, optionally having a number of wells selected from: 6, 12, 24, 96, 384, and 1536.
- the antibody or antigen-binding fragment of the diagnostic kit is detectably labeled.
- at least one of the one or more reagents is a detection reagent.
- methods for determining the level of a Neisseria antigen in a sample comprise: (a) contacting the sample with any of the foregoing antibodies or antigen-binding fragments that bind to the H8 antigen of Neisseria under conditions suitable for binding of the antibody or antigen-binding fragment to the antigen, if the antigen is present in the sample, thereby forming a binding complex; and (b) detecting the binding complex.
- the sample is a biological specimen.
- methods for diagnosing a subject having, or at risk of having, a Neisseria infection comprise: (a) obtaining a biological specimen from the subject and (b) determining the level of & Neisseria antigen in the biological specimen using any of the foregoing antibodies or antigen-binding fragments that bind to the H8 antigen of Neisseria.
- methods for monitoring a. Neisseria infection in a subject having or at risk of having, a Neisseria infection are provided.
- the methods comprise: (a) obtaining a biological specimen from the subject; (b) determining the level of a Neisseria antigen in the biological specimen using any of the foregoing antibodies or antigen-binding fragments that bind to the H8 antigen of Neisseria; and (c) repeating steps (a) and (b) on one or more occasions.
- the methods further comprise administering to the subject a treatment for the Neisseria infection.
- the treatment is a prophylaxis treatment.
- the treatment comprises any of the methods, disclosed herein, for modulating the immune response in a subject having, or at risk of having, a Neisseria infection.
- the antibody or antigen-binding fragment is conjugated to a solid support surface [direct or indirectly].
- the determining comprises using an Enzyme Linked Immuno-assay (ELISA).
- the biological specimen is a cell, a tissue, saliva, gingival secretions, cerebrospinal fluid, gastrointestinal fluid, mucus, urogenital secretions, synovial fluid, blood, serum, plasma, urine, cystic fluid, lymph fluid, ascites, pleural effusion, interstitial fluid, intracellular fluid, ocular fluids, seminal fluid, mammary secretions, vitreal fluid, and nasal secretions.
- the methods further comprise isolating protein from the sample or biological specimen.
- the Neisseria is selected from:
- Neisseria gonorrhoeae Neisseria meningitidis, Neisseria lactamica, Neisseria cinerea, Neisseria elongata, Neisseria ⁇ avescens, Neisseria mucosa, Neisseria polysaccharea, Neisseria sicca, and Neisseria subflava.
- the Neisseria is selected from: Neisseria gonorrhoeae and Neisseria meningitidis.
- the determining comprises contacting the sample or biological specimen with the antibody or antigen-binding fragment under conditions suitable for binding of the antibody or antigen-binding fragment to the Neisseria antigen, if the antigen is present in the sample or biological specimen, thereby forming a binding complex. In some embodiments, the determining further comprises detecting the binding complex.
- the foregoing methods comprise comparing the level of a Neisseria antigen to a reference standard.
- the reference standard is a level of Neisseria antigen in a subject that does not have a Neisseria infection.
- the reference standard is a level of Neisseria antigen in a subject that has a Neisseria infection.
- the contacting is performed in a reaction chamber.
- the antibody or antigen-binding fragment is immobilized on a solid support, wherein the solid support is optionally the surface of the reaction chamber.
- the antigen is immobilized on a solid support, wherein the solid support is optionally the surface of the reaction chamber.
- the methods further comprise adding a detection agent to the reaction chamber.
- the detection reagent comprises a secondary antibody.
- the secondary antibody is directed against the antibody or antigen- binding fragment or the antigen.
- the secondary antibody is conjugated to a detectable label selected from: a radioisotope, a fluorophore, a luminescent molecule, an enzyme, a biotin-moiety, an epitope tag, and a dye molecule.
- the detectable label is used to detect the binding complex.
- methods for modulating the immune response in a subject having, or at risk of having, a Neisseria infection are provided.
- the modulating the immune response results in a passive immunization in the subject.
- the methods comprise administering to the subject a therapeutically effective amount of a composition comprising a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria.
- the composition comprises a pharmaceutically acceptable carrier.
- the Neisseria is selected from: Neisseria gonorrhoeae, Neisseria meningitidis, and Neisseria lactamica.
- the methods comprise examining the subject to determine the existence of the Neisseria infection.
- the examining involves the use of a composition comprising a foregoing antibody or antigen-binding fragment that binds to the H8 antigen of Neisseria and optionally a foregoing diagnosing and/or monitoring method.
- the examining is performed at least once before the administering.
- the examining is performed at least once after the administering.
- the examining is performed at least once before and at least once after the administering.
- the administering is repeated on multiple occasions.
- the decision to repeat the administering is based on the result of at least one examination outcome (e.g., level of Neisseria antigen in a biological specimen obtained from the subject). In some embodiments, if the level of Neisseria antigen in a biological specimen obtained from a subject is approximately equal to the level of Neisseria antigen in a biological specimen obtained from a subject that does not have a Neisseria infection, then the administering to the subject is not performed or is performed as a prophylaxis.
- at least one examination outcome e.g., level of Neisseria antigen in a biological specimen obtained from the subject.
- the administering to the subject is performed.
- the modulating the immune response results in a passive immunization in the subject.
- the composition is administered intravenously, intramuscularly, subcutaneously, intraperitoneally, or as an aerosol.
- FIGURE 1 depicts screening of hybridoma supernatants by dot analysis for binding to gonococci: FAl 090 (wild type H8 + ) and FAl 090 (mutant H8 " ).
- FIGURE 2 depicts supernatants from clones SA5 and SA75 that were tested by western blot, using whole cell Iy sates prepared from FA 1090 (wild type H8 + ) and FAl 090 (mutant H8 " ) strains that had been transferred to Immobilon-P transfer membrane (Millipore Corporation), from SDS-PAGE. Each cell culture supernatant bound to a 21 kDa band presumed to be H8 on the wild type strain, even at dilutions of 1/10,000 of the supernatant. No binding was observed to the H8 " mutant.
- FIGURE 3 depicts binding of supernatants from clones SA5 and SA75, by whole cell ELISA, to 8 gonococcal strains (the 6 strains used to immunize the mice, FA 1090 wild type and the H8 ' mutant.
- Microtiter plates were coated with 100 ⁇ l of whole bacterial organisms (10 organisms/ml) taken from each strain. After washing, lOO ⁇ l of supernatants, diluted 10 fold, 4 times, was added to the wells and incubated for 1 hr at 37°C. After washing, lOO ⁇ l of alkaline phosphatase conjugated anti-mouse IgG was added to the wells and incubated as above. Finally, the wells were washed and/?-nitrophenyl phosphate added as the disclosing reagent.
- FIGURE 4 depicts a flow chart to class switch clones SA5 and SA75 from IgG3 ⁇ to IgGlK.
- FIGURE 5 depicts a flow chart to class switch clones SA5 and SA75 from IgG3 ⁇ to IgG2b ⁇ .
- FIGURE 6 depicts whole-cell lysate and western blot analyses for class switching of clones SA5 and SA75 from IgG3 ⁇ to IgG2b ⁇ and IgG l ⁇ .
- FIGURE 7 depicts an analysis of isotype specific binding using whole cell ELISA to compare class switched antibodies (IgG l ⁇ and IgG2b ⁇ compared to IgG3 ⁇ ).
- FIGURE 8 depicts an analysis of isotype specific binding using dot blot analysis to compare class switched antibodies (IgGlK and IgG2b ⁇ compared to IgG3 ⁇ ).
- the invention relates to the discovery and development of novel antibodies and antigen-binding fragments that recognize the H8 antigen, an outer surface membrane protein from Neisseria species such as N. gonorrhoeae and N. meningitidis.
- novel antibodies, antigen-binding fragments, and the nucleic acid sequences encoding them provide diagnostic, therapeutic and prophylactic compositions and methods useful for the treatment or prevention of gonococcal and meningococcal infections.
- Some aspects of the invention are particularly useful for rapid and point of care diagnosis of Neisseria infections that cause gonorrhea and meningococcal meningitis.
- the antibodies or antigen-binding fragments of the invention that recognize the Neisseria H8-antigen are useful as research and diagnostic reagents for detecting the presence of antigen in a sample such as a biological specimen obtained from a subject having, or suspected of having, a Neisseria infection.
- the antibodies or antigen-binding fragments disclosed herein are also capable of modulating an immune response against Neisseria in a subject in need thereof.
- the antibodies, disclosed herein relate to a monoclonal antibody, designated SA5, produced by hybridoma SA5, deposited with the American Type Culture Collection (ATCC) on , and assigned the Accession Number and a monoclonal antibody, designated SA75, produced by hybridoma SA75, deposited with the
- the invention also provides hybridomas, which offer indefinitely prolonged sources of the aforementioned monoclonal antibodies.
- methods for producing anti-H8 antibodies comprising culturing the hybridoma cells and isolating antibodies from the culture or cell or media are also disclosed.
- antibodies and antigen-binding fragments of the present invention have a heavy chain region having the sequence set forth in SEQ ID NO. 2; a light chain region having the sequence set forth in SEQ ID NO. 7; a CDRl having the sequence set forth in SEQ ID NO 3, a CDR2 having the sequence set forth in SEQ ID NO 4, and/or a CDR3 having the sequence set forth in SEQ ID NO 5; and/or a CDRl having the sequence set forth in SEQ ID NO 8, a CDR2 having the sequence set forth in SEQ ID NO 9, and/or a CDR3 having the sequence set forth in SEQ ID NO 10.
- the invention also provides antigen-binding fragments derived from the antibodies disclosed herein.
- Such antigen-binding fragments include those known to the skilled artisan and include F(ab') 2 , F(ab'), F(ab), single chain Fv, and any other suitable antibody fragments that bind antigen.
- Other aspects relate to chimeric or humanized antibodies.
- the monoclonal antibodies obtained from the aforementioned hybridomas may be humanized using methods known in the art. Humanization of antibodies, for example, can be accomplished using techniques described in U. S. Patent No. 5,866,692 entitled "Process for Producing Humanized Chimera Antibody,” which is incorporated herein by reference. Humanization of antibodies decreases the human immune response against foreign antibodies, and thus, may increase the effectiveness of these antibodies in human therapy.
- detectable labels include a radioisotope, a fluorophore, a luminescent molecule, an enzyme, a biotin-moiety, an epitope tag, a dye molecule, and a molecule capable of activating a chemiluminescent substrate.
- exemplary enzyme labels include phosphatases (such as, Alkaline Phosphatase (ALP)) and peroxidases (such as, Horseradish Peroxidase (HRP)).
- exemplary fluorophore labels include FITC, TRITC, Cy3, Cy5, Alexa Fluorescent Dyes, and Quantum Dots. Examples of other detectable labels are disclosed herein. These and others will be apparent to one of ordinary skill in the art.
- an appropriate detectable label will depend on the nature of the assay (e.g., diagnostic test, research assay) in which the antibody or antigen-binding fragment is to be employed.
- the detectable label may useful for detection of a target antigen (e.g., H8-antigen) by light microscopy, such a X-GaI staining; fluorescence microscopy, such as a fluorophore; or electron microscopy, such as collodial gold.
- a target antigen e.g., H8-antigen
- the detectable label facilitates detection and visualization of the target antigen by microscopy.
- detectable labels and methods of antigen detection are not so limited, and other examples are disclosed herein.
- immunoblots may employ enzymatic labels (e.g., HRP, ALP, etc.), that can be used to activate chemiluminescent or fluorescent substrates.
- enzymatic labels e.g., HRP, ALP, etc.
- detectable labels and methods of antigen detection will be readily apparent to one skilled in the art.
- it may be useful to conjugate the antibody or antigen-binding fragment to an antibiotic compound.
- Such antibody-antibiotic conjugates also referred to as antibodiotics, are known in the art (See, for example, US Patent Number 5,545,721). Conjugation of an antibiotic to an antibody or antigen-binding fragment that recognizes an antigen of a microorganism facilitates targeting of the antibiotic to the microorganism and minimize toxicity by reducing the effective dose of the antibiotic.
- antibiotics that are useful for conjugation include: penicillins, such as penicillin- G, amoxicillin, nafcillin, ampicillin, ticarcillin, and carbenicillin-V; cephalosporins, such as cefoxitin and ceforanide; polymyxins, such as polymyxin-B and colistin; vanocomycins, such as vancomycin-B, teicoplanin, and ristocetin; biosurfactants, such as circulin, EM49, polypeptin, brecistin, cerexin, tridecephin, surfactin, subsporin, mycosubtilisin, bacillomycin; and peptide antibiotics such as bacitracin, gramicidin, gramicidin-C, tyrocidine, viomycin, and capreomycin.
- penicillins such as penicillin- G, amoxicillin, nafcillin, ampicillin, ticarcillin, and carbenicillin-V
- the antibody-antibiotic conjugates are not so limited, and other appropriate antibiotics are disclosed herein and will be apparent to one of ordinary skill in the art.
- Some features of the invention extend to the hybridoma, which provides an indefinitely prolonged source of the aforementioned monoclonal antibodies.
- the immortalized hybridoma cells can be used as a source of rearranged heavy chain and light chain loci for subsequent expression and/or genetic manipulation (See examples).
- Rearranged antibody genes can be reverse transcribed from appropriate mRNAs to produce cDNA.
- the heavy chain constant region can be exchanged for that of a different isotype or eliminated altogether.
- the variable regions can be linked to encode single chain Fv regions.
- Fv regions can be linked to confer binding ability to more than one target or chimeric heavy and light chain combinations can be employed. Once the genetic material is available, design of analogs as described above which retain both their ability to bind the desired target is straightforward. Methods for the cloning of antibody variable regions and generation of recombinant antibodies are known to the person skilled in the art and are described, for example, Gilliland et al., Tissue Antigens 47 (1996), 1-20; Doenecke et al., Leukemia 11 (1997), 1787-1792.
- the coding sequences including those that encode, at a minimum, the variable regions of the heavy and light chain, can be inserted into expression systems contained on vectors which can be transfected into standard recombinant host cells.
- a variety of such host cells may be used; for efficient processing, however, mammalian cells are preferred.
- Typical mammalian cell lines useful for this purpose include CHO cells, 293 cells, or NSO cells.
- the production of the antibody or analog is then undertaken by culturing the modified recombinant host under culture conditions appropriate for the growth of the host cells and the expression of the coding sequences. The antibodies are then recovered by isolating them from the culture.
- the expression systems may be designed to include signal peptides so that the resulting antibodies are secreted into the medium; however, intracellular production is also possible.
- the invention also includes a polynucleotide encoding at least a variable region of an immunoglobulin chain of the antibodies described herein.
- the variable region encoded by the polynucleotide comprises at least one complementarity determining region (CDR) of the V H and/or V L of the variable region of the antibody produced by any one of the above described hybridomas.
- CDR complementarity determining region
- Each variable domain (the heavy chain V H and light chain V L ) of an antibody comprises three CDRs flanked by four relatively conserved framework regions (FRs).
- variable regions of the antibody can be determined, e.g., according to Kabat, Sequences of Proteins of Immunological Interest (U.S. Department of Health and Human Services, third edition, 1983, fourth edition, 1987, fifth edition 1990).
- variable domain of the antibody can be used for the construction of other polypeptides or antibodies of desired specificity and biological function.
- aspects of the invention also encompass polypeptides and antibodies comprising at least one CDR of the above-described variable domain and which advantageously have substantially the same or similar binding properties as the antibodies described in the appended examples.
- variable domains or CDRs described herein can be constructed according to methods known in the art, e.g., as described in EP-Al 0 451 216 and EP-Al 0 549 581.
- the binding affinity may be enhanced by making amino acid substitutions within the CDRs or within the hypervariable loops (Chothia and Lesk, J. MoI. Biol. 196 (1987), 901-917) which partially overlap with the CDRs as defined by Kabat.
- aspects also relate to antibodies or antigen-binding fragments wherein one or more of the mentioned CDRs comprise one or more, preferably not more than two amino acid substitutions.
- the antibody includes in one or both of its immunoglobulin chains two or all three CDRs of the variable regions of antibodies SA5 or SA75.
- Polynucleotide encoding the above described antibody or antigen-binding fragments may be, e.g., DNA, cDNA, RNA or synthetically produced DNA or RNA or a recombinantly produced chimeric nucleic acid molecule comprising any of those polynucleotides either alone or in combination.
- the polynucleotide is part of a vector.
- Such vectors may comprise further genes such as marker genes which allow for the selection of the vector in a suitable host cell and under suitable conditions.
- the polynucleotide is operatively linked to expression control sequences allowing expression in prokaryotic or eukaryotic cells.
- Expression of said polynucleotide comprises transcription of the polynucleotide into a translatable mRNA.
- Regulatory elements ensuring expression in eukaryotic cells preferably mammalian cells, are well known to those skilled in the art. They usually include regulatory sequences that facilitate initiation of transcription and optionally poly- A signals that facilitate termination of transcription and stabilization of the transcript. Additional regulatory elements may include transcriptional as well as translational enhancers, and/or naturally associated or heterologous promoter regions.
- Possible regulatory elements permitting expression in prokaryotic host cells include, e.g., the PL, Lac, Trp or Tac promoter in E. coli, and examples of regulatory elements permitting expression in eukaryotic host cells are the AOXl or GALl promoter in yeast or the CMV- promoter, SV40-promoter, RSV-promoter (Rous sarcoma virus), CMV-enhancer, SV40- enhancer or a globin intron in mammalian and other animal cells.
- Beside elements which are responsible for the initiation of transcription such regulatory elements may also include transcription termination signals, such as the SV40- poly-A site or the tk-poly-A site, downstream of the polynucleotide.
- leader sequences capable of directing the polypeptide to a cellular compartment or secreting it into the medium may be added to the coding sequence of the polynucleotide and are well known in the art.
- the leader sequence(s) is (are) assembled in appropriate phase with translation, initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein, or a portion thereof, into, for example, the extracellular medium.
- the heterologous sequence can encode a fusion protein including a C- or N-terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product.
- suitable expression vectors are known in the art such as Okayama- Berg cDNA expression vector pcDVl (Pharmacia), pCDM8, pRc/CMV, pcDNAl, pcDNA3 (Invitrogen), or pSPORTl (GIBCO BRL).
- polynucleotides encoding at least the variable domain of the light and/or heavy chain may encode the variable domains of both immunoglobulin chains or only one.
- said polynucleotides may be under the control of the same promoter or may be separately controlled for expression.
- vectors, particularly plasmids, cosmids, viruses and bacteriophages used conventionally in genetic engineering that comprise a polynucleotide encoding a variable domain of an immunoglobulin chain of an antibody or antigen-binding fragment; optionally in combination with a polynucleotide that encodes the variable domain of the other immunoglobulin chain of the antibody.
- the expression control sequences will be eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells, but control sequences for prokaryotic hosts may also be used.
- Expression vectors derived from viruses such as retroviruses, vaccinia virus, adeno-associated virus, herpes viruses, or bovine papilloma virus, may be used for delivery of the polynucleotides or vector into targeted cell population. Methods which are well known to those skilled in the art can be used to construct recombinant viral vectors; see, for example, the techniques described in Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N. Y.
- polynucleotides and vectors can be reconstituted into liposomes for delivery to target cells.
- the vectors containing the polynucleotides e.g., the heavy and/or light variable domain(s) of the immunoglobulin chains encoding sequences and expression control sequences
- the vectors containing the polynucleotides can be transferred into the host cell by well known methods, which vary depending on the type of cellular host. For example, calcium chloride transfection is utilized for prokaryotic cells, whereas calcium phosphate treatment or electroporation may be used for other cellular hosts.
- N-TERTM Nanoparticle Transfection System by Sigma-Aldrich FectoFlyTM transfection reagents for insect cells by Polyplus Transfection, Polyethylenimine "Max” by Polysciences, Inc., Unique, Non- Viral Transfection Tool by Cosmo Bio Co., Ltd., LipofectamineTM LTX Transfection Reagent by Invitrogen, SatisFectionTM Transfection Reagent by Stratagene, LipofectamineTM Transfection Reagent by Invitrogen, FuGENE® HD Transfection Reagent by Roche Applied Science, GMP compliant in vivo-jetPEITM transfection reagent by Polyplus Transfection, and Insect GeneJuice® Transfection Reagent by Novagen.
- Host cells may be a prokaryotic or eukaryotic cell.
- the polynucleotide or vector which is present in the host cell may either be integrated into the genome of the host cell or it may be maintained extrachromosomally.
- the host cell can be any prokaryotic or eukaryotic cell, such as a bacterial, insect, fungal, plant, animal or human cell.
- Preferred fungal cells are, for example, those of the genus Saccharomyces, in particular those of the species S. cerevisiae.
- prokaryotic is meant to include all bacteria which can be transformed or transfected with a DNA or RNA molecules for the expression of an antibody or the corresponding immunoglobulin chains.
- Prokaryotic hosts may include gram negative as well as gram positive bacteria such as, for example, E. coli, S. typhimurium, Serratia marcescens and Bacillus subtilis.
- eukaryotic is meant to include yeast, higher plant, insect and preferably mammalian cells, such as NSO and CHO cells.
- the antibodies or immunoglobulin chains encoded by the polynucleotide may be glycosylated or may be non- glycosylated.
- Antibodies or the corresponding immunoglobulin chains may also include an initial methionine amino acid residue.
- the host may be maintained under conditions suitable for high level expression of the nucleotide sequences, and, as desired, the collection and purification of the immunoglobulin light chains, heavy chains, light/heavy chain dimers or intact antibodies, antigen-binding fragments or other immunoglobulin forms may follow; see, Beychok, Cells of Immunoglobulin Synthesis, Academic Press, N. Y., (1979).
- polynucleotides or vectors are introduced into the cells which in turn produce the antibody or antigen-binding fragments.
- transgenic animals, preferably mammals, comprising the aforementioned host cells may be used for the large scale production of the antibody or antibody fragments.
- a further embodiment relates to a method for the production of an antibody capable of modulating an immune response to a Neisseria infection in a subject in need thereof, the method comprising (a) culturing a cell or hybridoma described above; and
- the transformed host cells can be grown in fermentors and cultured according to techniques known in the art to achieve optimal cell growth.
- the whole antibodies, their dimers, individual light and heavy chains, other immunoglobulin forms, or antigen-binding fragments can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis and the like; see, Scopes, "Protein Purification", Springer Verlag, N. Y. (1982).
- the antibody or antigen-binding fragments can then be isolated from the growth medium, cellular lysates, or cellular membrane fractions.
- the isolation and purification of the, e.g., microbially expressed antibodies or antigen-binding fragments may be by any conventional means such as, for example, preparative chromatographic separations and immunological separations such as those involving the use of monoclonal or polyclonal antibodies directed, e.g., against the constant region of the antibody.
- the antibodies or antigen-binding fragments can be further coupled to other moieties for, e.g., drug targeting and imaging applications. Such coupling may be conducted chemically after expression of the antibody or antigen-binding fragments to a site of attachment or the coupling product may be engineered into the antibody or antigen-binding fragments at the DNA level.
- the DNAs are then expressed in a suitable host system, and the expressed proteins are collected and renatured, if necessary.
- Substantially pure antibodies or antigen-binding fragments of at least about 90 to 95% homogeneity are preferred, and 98 to 100% or more homogeneity most preferred, for pharmaceutical uses.
- the antibodies or antigen-binding fragments may then be used therapeutically (including extracorporeally) or in developing and performing assay procedures.
- the immunoglobulin or its encoding cDNAs may be further modified.
- the method comprises any one of the step(s) of producing a chimeric antibody, humanized antibody, single-chain antibody, Fab-fragment, bi- specific antibody, fusion antibody, labeled antibody or an analog of any one of those.
- Corresponding methods are known to the person skilled in the art and are described, e.g., in Harlow and Lane “Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988.
- xenogeneic antibodies such as human antibodies in mice
- WO 91/10741, WO 94/02602, WO 96/34096 and WO 96/33735 the antibody may exist in a variety of forms (e.g., antigen-binding fragments) besides complete antibodies; including, for example, Fv, Fab and F(ab)2, as well as in single chains; see e.g., WO88/09344.
- the antibodies or antigen-binding fragments can be further modified using conventional techniques known in the art, for example, by using amino acid deletion(s), insertion(s), substitution(s), addition(s), and/or recombination(s) and/or any other modif ⁇ cation(s) known in the art either alone or in combination.
- Methods for introducing such modifications in the DNA sequence underlying the amino acid sequence of an immunoglobulin chain are well known to the person skilled in the art; see, e.g., Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N. Y. and Ausubel, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N. Y. (1994).
- Modifications of the antibody or antigen-binding fragment include chemical and/or enzymatic derivatizations at one or more constituent amino acids, including side chain modifications, backbone modifications, and N- and C-terminal modifications including acetylation, hydroxylation, methylation, amidation, and the attachment of carbohydrate or lipid moieties, cofactors, and the like.
- some aspects encompass the production of chimeric proteins which include the described antibody or some fragment thereof at the amino terminus fused to heterologous molecule such as an immunostimulatory ligand at the carboxyl terminus; see, e.g., WO00/30680 for corresponding technical details.
- small polypeptides including those containing a H8-antigen-binding fragment as described above, for example containing the CDR3 region of the variable region of any one of the mentioned monoclonal antibodies.
- Such peptides may easily be synthesized or produced by recombinant means to produce a useful H8-antigen binding agent.
- Peptides can be synthesized for example, using automated peptide synthesizers which are commercially available.
- the peptides can be produced by recombinant techniques by incorporating the DNA expressing the peptide into an expression vector and transforming cells with the expression vector to produce the peptide.
- the sequence of the CDR regions, for use in synthesizing peptide antigen binding agents, may be determined by methods known in the art (See below and in the examples).
- the heavy chain variable region is a peptide which generally ranges from 100 to 150 amino acids in length.
- the light chain variable region is a peptide which generally ranges from 80 to 130 amino acids in length.
- the CDR sequences within the heavy and light chain variable regions which include only approximately 3-25 amino acids may easily be sequenced by one of ordinary skill in the art.
- the peptides may even be synthesized by commercial sources.
- any known binding assay may be employed.
- the peptide may be immobilized on a surface and then contacted with labeled H8-antigen (e.g., using the BIAcore system).
- the amount of H8-antigen which interacts with the peptide or the amount which does not bind to the peptide may then be quantitated to determine whether the peptide binds to H8-antigen.
- a surface having the aforementioned anti-H8-antigen monoclonal antibodies immobilized thereto may serve as a positive control.
- Such peptides that bind to H8-antigen are referred to herein as ligand binding molecules.
- H8-antigen binding agents also can be carried out utilizing a competition assay. If the H8-antigen binding agent being tested competes with an anti-H8-antigen monoclonal antibody, as shown by a decrease in binding of the monoclonal antibody, then it is likely that the agent and the anti-H8-antigen monoclonal antibody bind to the same, or a closely related, epitope.
- Still another way to determine whether an agent has the specificity of the anti-H8-antigen monoclonal antibodies or antigen-binding fragments described above is to pre-incubate, for example, the monoclonal antibody with H8-antigen with which it is normally reactive (i.e., binds), and then add the agent being tested to determine if the agent being tested is inhibited in its ability to bind H8-antigen. If the agent being tested is inhibited then, in all likelihood, it has the same or a functionally equivalent epitope and specificity as the anti-H8-antigen monoclonal antibodies.
- antibodies or antigen-binding fragments that react with H8 antigen may be administered to uninfected subjects to create by passive immunization a specific immune response directed against organisms or cells bearing said H8-antigen.
- H8 antigen for example H8 -antigen of N. gonorrhoeae or N. meningitidis
- Such an immune response can be prophylactic in that it would lessen or prevent an infection should the recipient subject be exposed to the H8-antigen bearing organism.
- a subject already infected with Neisseria or exhibiting symptoms of Neisseria infection may be therapeutically treated with the antibodies or fragments produced by using the antibodies or antigen-binding fragments as immunogen.
- modulating the immune response in the subject with the antibodies or antigen-binding fragments disclosed herein may result in a passive immunization of the subject to the organism bearing the antigen (e.g., Neisseria bearing the H8-antigen).
- the antigen e.g., Neisseria bearing the H8-antigen.
- Methods for passive immunization using antibodies directed against outer membrane proteins of Neisseria are known in the art (See, for example, Schmidt S, et al., Vaccine 19 (2001) 4851-4858).
- Neisseria includes Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria lactamica, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria mucosa, Neisseria poly saccharea, Neisseria sicca, and Neisseria subflava, and include all associated Neisseria subtypes and serogroups.
- N. gonorrhoeae also referred to as gonococcus, causes gonorrhoea
- N. meningitidis also referred to as meningococcus
- the antibodies and antigen-binding fragments may be formulated as a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment admixed with a pharmaceutically acceptable carrier.
- the therapeutically effective amount may be effective to significantly kill (eradicate) the infecting organism in the presence of complement, or to opsonize the infecting organism to permit phagocytic killing by the host PMNs.
- therapeutically effective amounts per unit dose of an intact antibody may range from about 0.1 to about 10 mg/kg subject weight, preferably about 1 mg/kg subject weight. In some embodiments, dose greater than 10mg/kg may be therapeutically effective.
- Unit doses may be administered from twice each day to once each day for one week. It will be recognized, however, that lower or higher dosages and other administration schedules may be employed.
- the preferred pharmaceutical compositions are similar to those used for passive immunization of subject (e.g., human) with other antibodies.
- Pharmaceutical compositions comprising a therapeutically effective amount of the antibodies or antigen-binding fragments and one or more pharmaceutically compatible ingredients.
- the pharmaceutical composition typically includes one or more pharmaceutically acceptable carriers (e.g., sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like).
- the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the pharmaceutical can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
- the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing a H8-antigen binding antibody or binding fragment in lyophilized form and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterile water) for injection.
- a pharmaceutically acceptable diluent e.g., sterile water
- the pharmaceutically acceptable diluent can be used for reconstitution or dilution of the lyophilized antibody or antigen-binding fragment.
- Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
- compositions may alternatively be formulated to control release of the active ingredients or to prolong their presence in a subject's system.
- suitable drug delivery systems include, e.g., implantable drug release systems, hydrogels, hydr ⁇ xymethylcellulose, microcapsules, liposomes, microemulsions, microspheres, and the like.
- compositions may be administered by any suitable means such as orally, intranasally, subcutaneously, intramuscularly, intravenously, intra-arterially, parenterally, intraperitoneally, or as an aerosol. Ordinarily, intravenous (i.v.) or parenteral administration will be preferred.
- the therapeutically effective amount of antibody or antigen-binding fragments will depend, inter alia, upon the administration schedule, the unit dose of antibody or antigen-binding fragment administered, whether the antibody or antigen-binding fragment is administered in combination with other therapeutic agents, the immune status and health of the subject, the therapeutic activity of the antibody or antibody fragment administered and the judgment of the treating physician.
- subject as used herein means any mammalian individual, including, e.g., humans and non-human mammals, such as primates, rodents, and dogs. Subjects specifically intended for diagnosis and treatment using the methods described herein are preferably humans.
- the antibodies or antigen-binding fragments may also be labeled and used in diagnostic methods, screening methods, or other assays for detecting antibodies reactive with H8-antigens of Neisseria in vitro or in vivo. These include, for example, enzyme-linked immunosorbent assays (ELISAs). For example, samples may be screened for the presence of antibodies reactive with H8-antigens of N. gonorrhoeae by contacting the sample with a labeled anti- H8-antigen antibody and detecting the label.
- ELISAs enzyme-linked immunosorbent assays
- antibodies or antigen-binding fragments may also be prepared and used for detecting the presence of an antigen (e.g., a Neisseria antigen) present in a sample, such isolated proteins or a biological specimen.
- an antigen e.g., a Neisseria antigen
- biological specimens include an isolated cell, an isolated tissue, saliva, gingival secretions, cerebrospinal fluid (spinal fluid), gastrointestinal fluid, mucus, urogenital secretions, synovial fluid, blood, serum, plasma, urine, cystic fluid, lymph fluid, ascites, pleural effusion, interstitial fluid, intracellular fluid, ocular fluids, seminal fluid, mammary secretions, vitreal fluid, and nasal secretions.
- biological specimens are not so limited and other exemplary biological specimens will be readily apparent to one of ordinary skill in the art.
- a further embodiment relates to a method for detecting a Neisseria antigen in a sample comprising:
- a binding complex refers to a biomolecular complex of antibody or antigen-binding fragments bound to antigen. Binding complexes may comprise antibodies or antigen-binding fragments with a single specificity or two or more antibodies or antigen- binding fragments with different specificities. In one embodiment, a binding complex comprises two or more antibodies recognizing different antigenic sites on the same antigen. In some instances, an antibody or antigen-binding fragment may be bound to an antigen, having bound to it other biomolecules such as RNA, DNA, polysaccharides or proteins. In one embodiment, a binding complex comprises two or more antibodies recognizing different antigens.
- an antibody or antigen-binding fragment in a binding complex may itself by bound, as an antigen, to an antibody or antigen-binding fragment (e.g., a detectably labeled antibody or antigen-binding fragment).
- binding complexes may, in some instances, comprise multiple antigens and multiple antibodies or antigen-binding fragments.
- Antigens present in binding complexes may or may not be in their native in situ conformation.
- a binding complex is formed between an antibody or antigen-binding fragment and a purified protein antigen, or isolated proteins comprising antigen, wherein the antigen is not in its native in situ conformation.
- a binding complex is formed between an antibody or antigen-binding fragment and a purified protein antigen, wherein the antigen is not in its native in situ conformation and is immobilized on solid support (e.g., a PVDF membrane).
- a binding complex is formed with an antibody or antigen-binding fragment and, for example, a cell surface protein that is present in situ in a native confirmation (e.g., on the surface of a cell).
- Antibodies or antigen-binding fragments in binding complexes may or may not be detectably labeled.
- binding complexes comprise detectably labeled antibodies or antigen-binding fragments and non-labeled antibodies or antigen-binding fragments.
- binding complexes comprise detectably labeled antigen.
- antibodies or antigen-binding fragments, in binding complexes are immobilized to one or more solid supports.
- antigens, in binding complexes are immobilized to one or more solid supports. Exemplary solid supports are disclosed herein and will be apparent to one of ordinary skill in the art. The foregoing examples of binding complexes are not intended to be limiting. Other examples of binding complexes will be apparent to one or ordinary skill in the art.
- a further embodiment relates to a method for diagnosing a subject having, or at risk of having, a Neisseria infection, such infection with Neisseria gonorrhoeae, Neisseria meningitidis, or Neisseria lactamica, comprising: (a) obtaining a biological specimen from the subject and
- the antibody, or antigen- binding fragments, or antigen may be conjugated to a solid support surface, either directly or indirectly.
- Methods for conjugation to solid supports are standard and can be accomplished via covalent and non-covalent interactions.
- Non-limiting examples of conjugation methods include: adsorption, cross-linking, protein A/G - antibody interactions, and streptavidin-biotin interactions. Other methods of conjugation will be readily apparent to one of ordinary skill in the art.
- the foregoing detection, diagnosis, and monitoring methods include comparing the level of the antibody or antigen-binding fragment bound to the antigen (i.e., binding complexes) to one or more reference standards.
- the reference standard may be, for example, the level of Neisseria in a subject that does or does not have a Neisseria infection.
- the reference standard is the level of H8-antigen detected in a sample that does not contain H8-antigen (i.e., a background level).
- a background level can be determined from a sample that contains H8-antigen, by contacting the sample with non-specific antibodies (e.g., antibodies obtained from non-immune serum).
- the reference standard may be the level of H8-antigen detected in a sample that does contain H8-antigen (i.e., a positive control).
- the reference standard may be a series of levels associated with varying concentrations of H8-antigen in a sample and useful for quantifying the concentration of H8-antigen in the test sample.
- the foregoing examples of reference standards are not limiting and other suitable reference standard will be readily apparent to one of ordinary skill in the art.
- a further embodiment relates to a method for monitoring a Neisseria infection in a subject having, or at risk of having, a Neisseria infection comprising: (a) obtaining a biological specimen from the subject and
- the foregoing monitoring methods may be performed in conjunction with a therapeutic treatment regime aimed at eradicating or preventing the Neisseria infection.
- the monitoring may be employed to assess the efficacy of a therapeutic or prophylactic pharmacological intervention.
- the therapeutic or prophylactic treatment may include any one, or a combination, of those disclosed herein.
- the treatment comprises administering to subject having, or at risk of having, a Neisseria infection a therapeutically effective amount of a standard antibiotic drug or combination thereof.
- antibiotics include, but are not limited to: Aminoglycosides, such as Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin; Ansamycins such as Geldanamycin and Herbimycin; the Carbacephem, Loracarbef; Carbapenems such as Ertapenem, Doripenem, Imipenem, and Meropenem; Cephalosporins, such as Cefadroxil, Cefazolin, Cefalotin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefdinir, Cefotet
- Another embodiment relates to a diagnostic composition
- a diagnostic composition comprising any one of the above described antibodies, antigen-binding fragments, polynucleotides, vectors or cells and optionally suitable means for detection.
- the antibodies or antigen-binding fragments are, for example, suited for use in immunoassays in which they can be utilized in liquid phase or bound to a solid phase carrier.
- Examples of immunoassays which can utilize the antibody or antigen-binding fragments are competitive and non-competitive immunoassays in either a direct or indirect format.
- immunoassays examples include the Enzyme Linked Immunoassay (ELISA), radioimmunoassay (RIA) 5 the sandwich (immunometric assay), flow cytometry, the western blot assay, immunoprecipitation assays, immunohistochemistry, immuno-microscopy, lateral flow immuno-chromatographic assays, and proteomics arrays.
- ELISA Enzyme Linked Immunoassay
- RIA radioimmunoassay
- flow cytometry the western blot assay
- immunoprecipitation assays immunohistochemistry
- immuno-microscopy e.g., lateral flow immuno-chromatographic assays
- proteomics arrays examples include the antigens and antibodies or antigen-binding fragments.
- the antigens and antibodies or antigen-binding fragments can be bound to many different solid supports (e.g., carriers, membrane, columns, proteomics array, etc.).
- solid support materials examples include glass, polystyrene, polyvinyl chloride, polyvinylidene difluoride, polypropylene, polyethylene, polycarbonate, dextran, nylon, amyloses, natural and modified celluloses, such as nitrocellulose, polyacrylamides, agaroses, and magnetite.
- the nature of the support can be either fixed or suspended in a solution (e.g., beads).
- labels and methods of labeling known to those of ordinary skill in the art. Examples of the types of labels which can be used include enzymes, radioisotopes, colloidal metals, fluorescent compounds, magnetic, chemiluminescent compounds, and bioluminescent compounds.
- Radiolabeled antibodies are prepared in known ways by coupling a radioactive isotope such as H, P, 5 S, 59 Fe, or 125 I, which can then be detected by gamma counter, scintillation counter or by autoradiography.
- a radioactive isotope such as H, P, 5 S, 59 Fe, or 125 I
- antibodies and antigen-binding fragments may be suitably labeled with enzymes such as yeast alcohol dehydrogenase, horseradish peroxidase, alkaline phosphatase, and the like, then developed and detected spectrophotometrically or visually.
- Suitable fluorescent labels include fluorescein isothiocyanate, fluorescamine, rhodamine, and the like.
- Suitable chemiluminescent labels include luminol, imidazole, oxalate ester, luciferin, and the like; see also the embodiments discussed herein.
- the antibodies and antigen-binding fragments may also be used in a method for the diagnosis of Neisseria infection in a subject by obtaining a biological specimen from the tested subject which may be a spinal fluid sample, a blood sample, a lymph sample or any other body fluid sample, such as a urogenital sample, as disclosed herein.
- a biological specimen from the tested subject which may be a spinal fluid sample, a blood sample, a lymph sample or any other body fluid sample, such as a urogenital sample, as disclosed herein.
- the spinal fluid may be obtained by performing a spinal tap, in which a needle is inserted into an area in the lower back of the subject where fluid in the spinal canal is readily accessible.
- the diagnostic procedure may comprise contacting the spinal fluid sample, or protein sample isolated therefrom, with an antibody, or antigen- binding fragment, under conditions enabling the formation of binding complexes between antibody or antigen-binding fragment and antigen.
- the level of such binding complexes is then determined by methods known in the art, a level significantly higher than that formed in a control sample indicating the infection in the tested subject.
- the specific antigen bound by antibodies or antigen-binding fragments may also be used.
- some aspects relate to an in vitro immunoassay comprising the antibody or antigen-binding fragment and the antigen.
- the biological specimen is cultured under conditions that allow growth of bacteria present in the specimen. Subsequently, the biological culture, or a protein sample isolated therefrom, is contacted with an antibody, or antigen-binding, fragment under conditions enabling the formation of binding complexes between antibody or antigen-binding fragment and antigen.
- level of such binding complexes is then determined, as above, by methods known in the art. A level significantly higher than that formed in a control sample indicating infection in the tested subject.
- some aspects relate to growth of bacteria obtained from a biological specimen followed by an in vitro immunoassay to detect specific bacterial antigens in the culture.
- the biological specimen is contacted with the antibody or antigen-binding fragment under conditions suitable for binding of the antibody or antigen- binding fragment to a Neisseria antigen, if the antigen is present in the sample, and formation of binding complexes consisting of antibody, or antigen-binding fragment, bound to the antigen.
- This contacting step is typically performed in a reaction chamber, such as a tube, plate well, membrane bath, cell culture dish, microscope slide, and the like.
- the antibody or antigen-binding fragment is immobilized on a solid support.
- the antigen is immobilized on a solid support.
- the solid support is the surface the reaction chamber.
- the solid support is of a polymeric membrane (e.g., nitrocellulose strip, Polyvinylidene Difluoride (PVDF) membrane, etc.).
- the solid support is a biological structure (e.g., bacterial cell surface).
- PVDF Polyvinylidene Difluoride
- Other exemplary solid supports are disclosed herein and will be apparent to one of ordinary skill in the art.
- the antibody and antigen-binding fragment is immobilized on the solid support prior to contacting with the antigen. In other embodiments, immobilization of the antibody and antigen-binding fragment is performed after formation of binding complexes. In still other embodiments, antigen is immobilized on a solid support prior to formation of binding complexes.
- a detection reagent is added to the reaction chamber to detect immobilized binding complexes. In some embodiments, the detection reagent comprises a detectably labeled secondary antibody directed against the antigen. In some embodiments, the primary antibody or antigen-binding fragment is itself detectable labeled, and is thereby the detection reagent.
- detection methods comprise the steps of immobilizing antibodies or antigen-binding fragments to a solid support; applying a sample (e.g., a biological specimen or isolated protein sample) to the solid support under conditions that permit binding of antigen to the antibodies or antigen-binding fragment, if present in the sample; removing the excess sample from the solid support; applying detectably labeled antibodies or antigen- binding fragments under conditions that permit binding of the detectably labeled antibodies or antigen-binding fragments to the antigen-bound immobilized antibodies or antigen-binding fragments; washing the solid support and assaying for the presence of label on the solid support.
- a sample e.g., a biological specimen or isolated protein sample
- the antigen is immobilized on the solid support, such as a PVDF membrane, prior to contacting with the antibody and antigen-binding fragment in a reaction chamber (e.g., a membrane bath).
- a detection reagent is added to the reaction chamber to detect immobilized binding complexes.
- the detection reagent comprises a detectably labeled secondary antibody directed against the antigen.
- the detection reagent comprises a detectably labeled secondary antibody directed against the primary antibody or antigen-binding fragment.
- the detectable label may be, for example, a radioisotope, a fluorophore, a luminescent molecule, an enzyme, a biotin-moiety, an epitope tag, or a dye molecule.
- the primary antibody or antigen-binding fragment is itself detectable labeled, and is thereby the detection reagent. Suitable detectable labels are described herein, and will be readily apparent to one of ordinary skill in the art.
- diagnostic kits suitable for home or clinical use (point of care service), comprise (a) detectably labeled and/or non-labeled antibodies or antigen- binding fragments, as antigen binding reagents (e.g., H8-antigen binding reagents); (b) a detection reagent; and, optionally, (c) complete instructions for using the reagents to detect antigens in a sample.
- the diagnostic kit includes the antibody, or antigen-binding fragment, and/or H8-antigen immobilized on a solid support. Any of the solid supports described herein are suitable for incorporation in the diagnostic kits.
- the solid support is the surface of a reaction chamber of a plate well.
- the plate well is in a multi-well plate having a number of wells selected from: 6, 12, 24, 96, 384, and 1536, but it is not so limited.
- the diagnostic kits provide a detectably labeled antibody or antigen-binding fragment. Diagnostic kits are not limited to these embodiments and other variations in kit composition will be readily apparent to one of ordinary skill in the art.
- Organisms Six strains of Neisseria gonorrhoeae (strains 8657, 8658, 8659, 8660, 8661 and 8662) were used for immunization. Eight Neisseria gonorrhoeae strains (the six strains above, strain FAl 090 [wild type] and mutant strain FAl 090 DH8), were used later for whole cell ELISA and western blots, to screen antibody supernatants.
- Organisms were grown in liquid media overnight at 37°C, stirring vigorously. Then the organisms were harvested by centrifugation, and the pellets were resuspended in sterile 0.15 M NaCl. The suspension was centrifuged again. The final pellets were resuspended in sterile distilled deionized water and lyophilized. An equal amount of each strain (by weight) was used to immunize mice.
- mice for anti-H8 antibody Six strain A/J mice (6 weeks old) were obtained from Jackson Laboratory, Bar Harbor, ME. Four mice were used for immunization. Mixtures of whole organisms (equal weight) from the six strains (above), were resuspended in 0.5 ml of sterile PBS, and injected intraperitoneally according to the following schedule:
- O mouse #3 were fused with SP2/0 myeloma cells (1.68 X lO cells) and dispensed into 30 wells.
- the production of antibody in the cell culture supernatants was monitored by: dot blot and ELISA, the latter using a mouse monoclonal isotyping kit (Zymed Laboratories, Inc).
- Most of the hybridoma wells produced antibody mixtures of Ig types and subclass antibodies that required cloning of antibody producing hybridoma cells to select hybridomas that produced a single isotype or subclass (and antibody species).
- Hybridomas producing H8 antibodies
- Hybridomas were cloned using: (1) the limiting dilution technique and (2) the soft agarose technique.
- antibody producing clones were again screened for the production of H8 antibody.
- the affinity of the antibodies was estimated by whole cell ELISA and western blot by comparing end point dilutions that gave a positive result with the underlying concentration of antibody present in the cloned supernatants.
- a high dilution endpoint, with a fixed amount of antibody was interpreted as high affinity.
- Supernatants from clones that yielded a high ratio were used.
- Clones that produced high affinity antibodies directed against H8 were subcloned. Purification of antibodies away from growth media was accomplished by affinity chromatography. Immunoglobulin class switching was performed later to reduce non- specific binding for example switching "sticky" IgG3 where much non-specific binding was seen to IgGl.
- IgG3 isotype antibodies often bind nonspecifically, they may not be ideal for use in diagnostic kits. Accordingly, we embarked on a strategy to switch the subclass of these IgG3 ⁇ monoclonals to IgG2b ⁇ and IgGlK.
- variable region (VH and VL) of the IgG3 ⁇ was sequenced, and is provided below (SEQ ID NO 2 and SEQ ID NO 7, respectively).
- the antibody from the cell culture supernatants from the cells producing IgG2b ⁇ and the IgGlK were affinity purified, using anti-mouse IgG-agarose (for IgG2b ⁇ ) or anti-mouse IgGl-agarose (for IgGl ⁇ ). Both antibodies, the IgG2b ⁇ and the IgGl ⁇ , were produced in large quantities for use in diagnostic assays.
- One or more samples of a H8-antigen each of known concentration are immobilized individually to one or more wells of a plate. Immobilization of the antigen is accomplished by adsorption of the antigen to the surface of the well.
- These samples of known H8-antigen concentrations constitute a standard curve (i.e., a reference standard) used to calculate H8- antigen concentrations of unknown samples from biological specimens. Plate wells are coated with protein samples, derived from biological specimens, of unknown H8-antigen concentration, diluted in the same buffer used for the H8-antigen standard curves samples.
- a concentrated solution of blocking protein such as Bovine Serum Albumin (BSA) or casein
- BSA Bovine Serum Albumin
- casein a concentrated solution of blocking protein, such as Bovine Serum Albumin (BSA) or casein
- BSA Bovine Serum Albumin
- the microtiter plate is washed (washing is repeated as needed), and an antibody, or antigen-binding fragment, specific against H8-antigen is added to microtiter plate wells under conditions that permit binding of the antibody, or antigen-binding fragment, to the immobilized antigen on the well surface, but not substantially to the blocking proteins, thereby forming binding complexes with the H8-antigen.
- the microtiter plate is washed to remove any unbound antibody or antigen-binding fragment (washing is repeated as needed). After washing, specific binding- complexes remain immobilized to the well.
- Detectably labeled secondary antibodies directed against the antibody or antigen-binding fragments are added to the wells followed by washing to remove unbound secondary antibodies.
- the secondary antibodies are conjugated to enzyme capable of converting a substrate to elicit a chromogenic, fluorogenic, or electrochemical signal.
- Results are quantified using a spectrophotometer, spectrofluorometer, or other optical/electrochemical device and the concentration of the H8-antigen in the unknown sample is determined by comparison with the standard curve (reference standard). Alternatively, the results are qualitatively evaluated against the standard curve, including a negative control, to establish if the H8-antigen is present or not present in the unknown sample.
- a plate well is coated with a known quantity of antibody or antigen-binding fragment (i.e., the antibody or antigen-binding fragment is immobilized to the plate well) that is directed against H8-antigen.
- a concentrated solution of blocking protein such as Bovine Serum Albumin (BSA) or casein, is added to all plate wells to block non-specific adsorption of H8-antigen to the plate.
- BSA Bovine Serum Albumin
- the plate wells are washed (washing is repeated as needed), and a protein sample derived from a biological specimen, or a biological specimen, is added.
- H8-antigen present in the protein sample binds to the immobilized antibody or antigen-binding fragment, thereby forming binding complexes.
- the plate is washed to remove any unbound antigen and other proteins (washing is repeated as needed). After washing, specific binding-complexes remain immobilized to the well.
- a labeled (e.g., enzyme conjugated) tertiary antibody directed against the secondary antibody is added.
- substrate is added and converted by enzyme into a color, fluorescent, or electrochemical signal.
- the absorbance, fluorescence, or electrochemical signal (e.g., current) of the plate wells are measured to determine the presence and quantity of antigen.
- Competitive ELISA (Labeled Antibody)
- Unlabeled antibodies or antigen-binding fragments which recognize H8-antigen, are incubated in the presence of a protein sample in a reaction chamber under conditions that permit binding of antibody or antigen-binding fragments to H8-antigen, if present in the sample, thereby forming complexes.
- the solution comprising binding complexes is added to an H8-antigen coated well (i.e., a well with immobilized H8-antigen), under conditions that permit any free antibody or antigen-binding fragments in the solution to bind to immobilized H8-antigen.
- a high level of antigen in a sample results in high levels of binding complexes in solution and in less binding of antibody, or antigen-binding fragments, to the immobilized antigen.
- a low level of antigen in a sample results in low levels of binding complexes in solution and more binding of antibody, or antigen-binding fragments, to the immobilized antigen.
- Antibodies or antigen-binding fragments which recognize H8-antigen, are immobilized in a plate well.
- a solution comprising a known quantity of detectably labeled H8-antigen is combined with a protein sample suspected of having H8-protein, and added to the antibody or antigen-binding fragment coated well, under conditions that permit binding of the antigen (labeled or unlabeled) to the immobilized antibodies or antigen-binding fragments. Consequently, a high level of antigen in a protein sample results in high levels of unlabeled immobilized binding complexes in the well. In contrast, a low level of antigen in a sample results in higher levels of detectably labeled immobilized binding complexes in the well.
- SEQ ID NO 1 is the nucleic acid
- SEQ ID NO 2 is the full polypeptide
- SEQ ID NO 3 is the CDRl
- SEQ ID NO 4 is the CDR2
- SEQ ID NO 5 is the CDR3
- SA5 (IgG3 K) GAA GGG AAG CTG CTC GAG TCT GGG GGA GGG TTA GTG AAG CCT GGA
- SA5 (IgG3 K) AAT TAT AAC ATT TCT TGG GTT CGC AAG ATT CCA GAG AAG AGG TTG SA75 (IgG3 K) - - - - - - - - - - - - - - - - - - - - - -
- SEQ ID NO 6 is the nucleic acid
- SEQ ID NO 7 is the full polypeptide
- SEQ ID NO 8 is the CDRl
- SEQ ID NO 9 is the CDR2
- SEQ ID NO 10 is the CDR3
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Abstract
L’invention a trait à l’utilisation, à des fins de diagnostic et de traitement, d’anticorps ou de fragments de liaison à un antigène qui reconnaissent l’antigène H8, une protéine membranaire externe des Neisseriae. Certains aspects de l’invention concernent des compositions pharmaceutiques et diagnostiques comprenant des anticorps ou des fragments de liaison à un antigène qui reconnaissent l’antigène H8. D’autres aspects concernent des kits de diagnostic comprenant des anticorps ou des fragments de liaison à un antigène qui reconnaissent l’antigène H8.
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US8759109B2 (en) | 2008-03-11 | 2014-06-24 | Urobiologics Llc | Use of female mammal's urine for determination of fetal gender related characteristics |
US10018625B2 (en) | 2008-03-11 | 2018-07-10 | Urobiologics Llc | Use of female mammal's urine for determination of fetal gender related characteristics |
US10996218B2 (en) | 2008-03-11 | 2021-05-04 | Ournextbaby Llc | Methods for chemotaxis / redox driven separation of X and Y chromosome bearing sperm and their insemination in gender specific menstrual cycles |
WO2012036691A1 (fr) | 2010-09-16 | 2012-03-22 | Urobiologics Llc | Utilisation d'urine de mammifère femelle pour la détermination de caractéristiques liées au sexe d'un fœtus |
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