Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • 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
  • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
  • C07K14/4747—Apoptosis related proteins
• • 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
  • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
  • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
• • 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
  • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
  • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
  • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
  • G01N2333/4701—Details
  • G01N2333/4703—Regulators; Modulating activity

Definitions

• BCL-2 as a cancer marker is described in U.S. patent 8,034,549 and published patent applications US 2011-0318763 Al and US 2016-0258960 Al. While these references teach antibodies to BCL-2, an antibody meeting regulatory manufacturing requirements and having improved specificity was required.
• the present invention is directed to antibodies and fragments thereof that bind to human BCL-2.
• the antibodies may be labeled with one or more labels selected from the group consisting of a biotin label, a fluorescent label, an enzyme label, a coenzyme label, a chemiluminescent label, colloidal particles, and a radioactive isotope label.
• the invention is also directed to a hybridoma cell line that produces the antibody, and to methods of treating cancer and purifying exosomes using the antibody or antigen binding fragments thereof.
• the present invention is also directed to a method for diagnosing cancer, wherein the method comprises: reacting an anti- BCL-2 antibody with a sample collected from the subject; detecting an BCL-2 protein in the sample; and diagnosing cancer when the level of BCL-2 protein is higher in the sample than in a normal sample, wherein the sample collected from the subject is at least one clinical sample selected from the group consisting of a urine sample, saliva sample, tissue sample, a blood sample, a serum sample, a plasma sample, tears, or a mucous sample.
• the antibodies of the present invention are preferably isolated monoclonal antibodies having specific binding properties against a human BCL-2 protein, more preferably against human BCL-2 in its native form.
• the invention is also directed to anti- BCL-2 antibody based immunoassays for detecting ovarian cancer.
• Figure 3 Homology of Human and Mouse Bcl-2.
• Figure 4 shows the alignment of epitopes to Bcl-2.
• Figure 5A-C Structural predictions of Bcl-2 binding sites.
• Figure 6 is an electropherogram of a Bcl-2 antibody of the present invention.
• Figure 7 is an electropherogram of a Bcl-2 antibody of the present invention.
• Figure 8 is an image of an electrophoresis gel of a Bcl-2 antibody of the present invention.
• Figure 9 is a chromatograph of a Bcl-2 antibody of the present invention.
• Figure 10 is an isoelectric gel of a Bcl-2 antibody of the present invention.
• Figure 11 is an image of an electrophoresis gel of a Bcl-2 antibody of the present invention.
• Figure 12 is a chromatograph of a Bcl-2 antibody of the present invention.
• Figure 13 is an isoelectric gel of a Bcl-2 antibody of the present invention.
• Figure 14 is an image of an electrophoresis gel of a Bcl-2 antibody of the present invention.
• Figure 15 is an isoelectric gel of a Bcl-2 antibody of the present invention.
• Figure 16 is a chromatograph of a Bcl-2 antibody of the present invention.
• Figure 17 is an image of an electrophoresis gel of a Bcl-2 antibody of the present invention.
• Figure 18 is a chromatograph of a Bcl-2 antibody of the present invention.
• Figure 19 is an isoelectric gel of a Bcl-2 antibody of the present invention.
• Figure 20 is an image of an electrophoresis gel of a Bcl-2 antibody of the present invention.
• Figure 21 is an isoelectric gel of a Bcl-2 antibody of the present invention.
• Figure 22 is a chromatograph of a Bcl-2 antibody of the present invention.
• Figure 23 is a graph showing absorbance of antibodies of the present invention.
• Figure 24 is a DNA amino acid alignment for Clone 10A12 Heavy Chain
• Figure 25 DNA is a DNA amino acid alignment for Clone 10A12 Light Chain
• Figure 26 DNA is a DNA amino acid alignment for Clone 14A09 Heavy Chain
• Figure 27 DNA is a DNA amino acid alignment Clone 14A09 Light Chain
• Figure 28 is a photograph of a lateral flow assay.
• Figure 29 is a photograph of a lateral flow assay.
• Figure 30 is a photograph of a lateral flow assay.
• Figure 31 is a photograph of a lateral flow assay.
• Figure 32 is a photograph of a lateral flow assay.
• Figure 33 is a photograph of a lateral flow assay.
• Figure 34 is a photograph of a lateral flow assay.
• Figure 35 is a photograph of a lateral flow assay.
• Figure 36 is a photograph of a lateral flow assay.
• Figure 37 is a photograph of the lateral flow assay in a cassette.
• the present invention is directed to antibodies and fragments thereof that bind to human BCL-2.
• the antibodies may be labeled with one or more labels selected from the group consisting of a biotin label, a fluorescent label, an enzyme label, a coenzyme label, a chemiluminescent label, colloidal particles, and a radioactive isotope label.
• the invention is also directed to a hybridoma cell line that produces the antibody, and to methods of treating cancer and purifying exosomes using the antibody or antigen binding fragments thereof.
• the present invention is also directed to a method for diagnosing cancer, wherein the method comprises: reacting an anti- BCL-2 antibody with a sample collected from the subject; detecting an BCL-2 protein in the sample; and diagnosing cancer when the level of BCL-2 protein is higher in the sample than in a normal sample, wherein the sample collected from the subject is at least one sample selected from the group consisting of a tissue sample, a urine sample, a saliva sample, a blood sample, a serum sample, and a plasma sample.
• the antibodies of the present invention are preferably isolated monoclonal antibodies having specific binding properties against a human BCL-2 protein, more preferably against human BCL-2 in its native form.
• the invention comprises an ELISA in which a first antibody binds to Bcl-2 anchoring it to a substrate and a second antibody is labelled for identification.
• the label is typically selected from a biotin label, a fluorescent label, an enzyme label, a coenzyme label, a chemiluminescent label, colloidal particles, and a radioactive isotope label.
• antibody refers to any naturally occurring antibody or antigen-binding protein, the production of which is induced by an immune system (immunoglobulins or IgGs).
• immunoglobulins or IgGs immunoglobulins or IgGs.
• Conventional antibodies comprise two heavy chains linked together by disulfide bonds and two light chains, one light chain being linked to each of the heavy chains by disulfide bonds. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains (three or four constant domains, CH1, CH2, CH3 and CH4, depending on the antibody class).
• Each light chain has a variable domain (VL) at one end and a constant domain (CL) at its other end; the constant domains of the light chains each align with the first constant domains of the heavy chains, and the light chain variable domains each align with the variable domains of the heavy chains.
• VL variable domain
• CL constant domain
• This type of antibodies exist in camels, dromedaries and llamas along with an "unconventional" naturally occurring type of antibodies consisting of only two heavy chains, and thus being devoid of light chains.
• Other "unconventional" naturally occurring antibodies exist in in the serum of nurse sharks (Ginglymostomatidae) and wobbegong sharks (Orectolobidae). These latter antibodies are called Ig new antigen receptors (IgNARs).
• camel and shark antibodies Due to the heavy chain dimer structure characteristic of camelid and shark antibodies, these are sometimes termed “Heavy-Chain Mini-Antibodies” (mnHCAbs) or simply “Mini- Antibodies” (mnAbs) (Holliger & Hudson 2005, Nature Biotechnol 23, 1126-1136).
• the complementary determining region 3 (CDR3) of camel antibodies and shark antibodies is usually longer (comprising about 16-21 amino acids, and about 16-27 amino acids, respectively) than the CDR3 of mouse VH region (comprising about 9 amino acids) (Muyldermans et al. 1994, ProtEng 7, 1129-1135; Dooley & Flajnik2005, Eur J Immunol 35, 936-945).
• Vab variable antigen binding domain of the heavy-chain immunoglobulin
• V-NAR shk antibodies
• These smallest intact and independently functional antigen-binding fragment Vab is referred to as nano-antibody or nanobody (Muyldermans 2001, J Biotechnol 74, 277-302).
• Multivalent (etc. divalent, trivalent, tetravalent and pentavalent) Vab and/or V-NAR domains may be preferred in some instances due to their potentially higher cellular intake and retention and may be made by recombinant technology or by chemical means, such as described in WO 2010/033913.
• variable domains of the light and/or heavy chains are involved directly in binding the antibody to the antigen.
• the variable domains of naturally occurring light and heavy chains have the same general structure: four framework regions (FRs) connected by three complementarity determining regions (CDRs) (see e.g. Rabat et al. 1991, Sequences of Proteins of Immunological Interest, 5.sup.th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).
• the CDRs in a light or heavy chain are held in close proximity by the FRs and contribute to the formation of the antigen binding site.
• antibody fragment refers to any molecule comprising one or more fragments (usually one or more CDRs) of an antibody (the parent antibody) such that it binds to the same antigen to which the parent antibody binds.
• Antibody fragments include Fv, Fab, Fab', Fab'-SH, single-chain antibody molecules (such as scFv), F(ab').sub.2, single variable VH domains, and single variable VL domains (Holliger & Hudson 2005, Nature Biotechnol 23, 1126-1136).
• microantibodies i.e. the minimum recognition unit of a parent antibody usually comprising just one CDR (Heap et al. 2005, J Gen Virol 86, 1791-1800).
• any of the fragments can be incorporated in a multivalent and/or multispecific larger molecule, e.g. mono- or bispecific Fab. sub.2, mono- or tri-specific Fab. sub.3, bis-scFv (mono- or bispecific), diabodies (mono- or bispecific), triabodies (e.g. trivalent monospecific), tetrabodies (e.g. tetravalent monospecific), minibodies and the like (Holliger & Hudson 2005, Nature Biotechnol 23, 1126-1136). Any of the fragments can further be incorporated in e.g. V-NAR domains of shark antibodies or VhH domains of camelid antibodies (nanobodies). All these are included in the term "antibody fragment".
• the term "monoclonal antibody” refers to a population of substantially homogeneous antibodies. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
• the modifier "monoclonal” is not to be construed as requiring production of the antibody by any particular method.
• the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler & Milstein 1975, Nature 256, 495-497), or may be made by recombinant DNA methods (e.g. U.S. Pat. No. 4,816,567).
• Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in, e.g., Clackson et al. 1991, Nature 352, 624-628 or Marks et al. 1991, J Mol Biol 222, 581-597, or by yet other techniques or technologies.
• a mouse or other appropriate host animal such as a hamster or macaque monkey, is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization (Harlow & Lane; Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press: Cold Spring Harbor, N.Y. (1988).
• the present invention also encompasses nucleic acid molecules encoding antibodies of the invention.
• different nucleic acid molecules encode a heavy chain variable region and a light chain variable region of an antigen-specific antibody.
• the same nucleic acid molecule encodes a heavy chain and a light chain variable regions of an antigen-specific antibody.
• DNA encoding a monoclonal antibody of the invention may be isolated and sequenced from a hybridoma cell secreting the antibody using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Sequence determination will generally require isolation of at least a portion of the gene or cDNA of interest. Usually this requires cloning the DNA or, preferably, mRNA (i.e., cDNA) encoding the monoclonal antibodies. Cloning is carried out using standard techniques (see, e.g., Sambrook et al.
• a cDNA library may be constructed by reverse transcription of polyA+ mRNA, preferably membrane- associated mRNA, and the library screened using probes specific for human immunoglobulin polypeptide gene sequences. Nucleotide probe reactions and other nucleotide hybridization reactions are carried out at conditions enabling the identification of polynucleotides which hybridize to each other under specified conditions.
• One exemplary set of conditions is as follows: stringent hybridization at 42°C. in 50% formamide, 5 times saline sodium citrate“SSC”, 20 mM Na.P04, pH 6.8; and washing in lxSSC at 55 °C for 30 minutes.
• Formula for calculating equivalent hybridization conditions and/or selecting other conditions to achieve a desired level of stringency are well known. It is understood in the art that conditions of equivalent stringency can be achieved through variation of temperature and buffer, or salt concentration as described Ausubel, et al. (Eds.), Protocols in Molecular Biology, John Wiley & Sons (1994), pp. 6.0.3 to 6.4.10.
• hybridization conditions can be empirically determined or precisely calculated based on the length and the percentage of guanosine/cytosine (GC) base pairing of the probe.
• the hybridization conditions can be calculated as described in Sambrook, et al., (Eds.), Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press: Cold Spring Harbor, N.Y. (1989), pp. 9.47 to 9.51
• the immunoassay of the present invention can be used with any suitable clinical specimen.
• Preferred specimens include urine, saliva, blood, serum, and plasma.
• the specimens are collected and processed in conventional ways before tested using the immunoassay of the present invention.
• BCL-2 protein that will work in a sandwich ELISA format.
• peptides were be designed as antigens to regions with a high likelihood of generating specificity to the BCL-2 protein, but not cross react with BCL-x.
• Bioinformatic tools were used to analyze the protein as well as try to predict the best options for choosing peptides to be developed as antigens for the hybridoma projects.
• Antibodies were generated using C57BL mice and hybridomas were created. MBS Accession: 15-0264RB2 for Cell Line: Bcl-2-41 Pep-KLH-BA-1.3-l7D07-02Dl2 was conjugated with biotin and molar ratio quantified with (4'-hydroxyazobenzene- 2-carboxylic acid) (“HABN”) avidin assay which determined that 3.5 molecules of biotin per conjugated antibody from this hybridoma.
• HABN (4'-hydroxyazobenzene- 2-carboxylic acid)
• Antibodies were generated using C57BL mice and hybridomas were created MBS Accession: 15-0264RB1 for Ceil Line: Bcl-2-41 Pep-KLH-BA-1.3-10A12-02F02 was conjugated with biotin and molar ratio quantified with HABN avidin assay which determined that 6.2 molecules of biotin per conjugated antibody from this hybridoma.
• Antibodies were generated using C57BL mice and hybridomas w ⁇ ere created. MBS Accession: 15-0271 RBI for Cell Line: Bcl-2-61 Pep-KLH-BA-1.1-1 8E10-02G02 was conjugated with biotin and molar ratio quantified with HABN avidin assay which determined that 6.2 molecules of biotin per conjugated antibody from this hybridoma.
• Antibodies were generated using C57BL mice and hybridomas were created MBS Accession: 15-0271RB2 for Cell Line: Bcl-2-61 Pep-KLH-BA-1.
• 1-02C10-02D02- 02B07 was conjugated with biotin and molar ratio quantified with HABN avidin assay which determined that 10.5 molecules of biotin per conjugated antibody from this hybridoma.
• a sandwich ELISA was developed reproducing the standard curve performance of the Bender Platinum Bcl-2 kit, using rBcl-2 proteins above from R&D Systems and an inhouse manufactured protein. Free and biotinylated forms of mAh Bcl-2/l00 and mAh 4D7 were crossed in a sandwich ELISA with the R&D Systems protein.
• the final assay with these reagents included the SKOV-3 and HEK293 lysates. Each was run at a 1 :5 dilution in sample diluent.
• the SKOV-3 sample had a blank- subtracted OD of 0.1, confounded by the negative HEK293 lysate at 0.09.
• the 10 ng/mL protein sample ran at 0.67, which puts it in line with the Platinum ELISA kit.
• the Bcl-2-expressing lysate ran at 0.24 OD, but used an entire vial of the product for just the one assay.
• Urine sample matrices are known to interfere with
• immunoassays 2,3 often ameliorated by sample dilution.
• Hybridoma project BCL2-41 Pep-KLH-l.3 yielded 19 purified (MultiPure) fusion products; samples of each were conjugated to biotin. Four of the 19 yielded ⁇ 0.2 mg antibody and were excluded from further testing.
• Matched pair screenings were performed in two orientations: 15 Pep-41 captures x 17 Pep-61 -biotin conjugates, and 17 Pep-61 captures x 15 Pep-41 biotin conjugates. All coatings were at 2 ug/mL and all biotins were at 1 ug/mL. Samples: Negative (sample diluent) and 25 ng/mL rBcl-2 in sample diluent. The commercial mAb pairing was repeated throughout the plates for comparison.
• each of the 16 candidate capture antibodies were tested in pairs with 4 different biotin conjugates.
• Samples ranged from 0 to 20 ng/mL rBcl-2, and included 2 ug/mL rBcl- XL. None of the pairs showed any cross-reactivity to the 2 ug/mL rBcl-XL sample.
• the capture and conjugate antibody concentrations were not changed from the initial screen. The data below illustrates samples of the resulting standard curves.
• Table 7 illustrates the relative sensitivity of these pairings (absorbance values for rBcl-2 calibrators) as well as the recovery of the rBcl-2 fortifications (at 4 or 5 ng/mL).
• Peptide 41 Ab is in bold.
• Peptide 61 Ab is in normal font.
• Lake Pharma isolated RNA from each sample and cloned the Heavy Chain Variable region (VH) and Light Chain Variable region (VL) by RACE PCR followed by ligation into a suitable vector. Multiple isolates of each clone were sequenced for each VH and VL.
• the nucleotide sequences obtained from Lake Pharma for each clone was submitted to IgBlast to determine the Complementarity-determining regions (“CDR”) and Framework Regions (“FR”) regions as well as determine the Vh, Dh, and Jh heavy chain (HC) gene usage and the VI and Jl light chain (LC) gene usage for each clone.
• CDR Complementarity-determining regions
• FR Framework Regions
• CDR1 is GYSFTSYW (SEQ ID NO 15 and CDR2 is IDPSDSET (SEQ ID N016 ) and CDR3 is ERGDYYY GS S YF AY (SEQ ID NO 17)
• amino acid sequence is coded by the DNA sequence of SEQ ID NO 18:
• CDR1 is TGAVTTSNY (SEQ ID NO 20) and CDR2 is GTT (SEQ ID NO 21 ) and CDR3 is ALWFSNHFWV (SEQ ID NO 22)
• amino acid sequence is coded by the DNA sequence of SEQ ID NO 23 :
• the homology is generally a homology of 80% or more, preferably a homology of 90% or more, more preferably a homology of 95% or 96% or 97%, 98% or more, most preferably a homology of 99% or more.
• an amino acid sequence including a substitution, deletion, or addition of one to several amino acid residues in the heavy chain or light chain amino acid sequence it is also possible to select an antibody having a cytotoxic activity equivalent to that of each of the above-described antibodies.
• the number of amino acid residues to be substituted, deleted, or added is generally 10 or fewer, preferably 5 to 6 or fewer, more preferably 2 to 3 or fewer, most preferably 1.
• CDR1 is GYTFTDYY (SEQ ID NO 25) and CDR2 is ANPYNGVT (SEQ ID NO 26) and CDR3 is ARS SFD V (SEQ ID NO 27)
• amino acid sequence is coded by the DNA sequence of SEQ ID NO 28:
• CDR1 is KSLLYKDGKTY (SEQ ID NO 30) and CDR2 is LVS (SEQ ID NO 31) and CDR3 is QQPVEYPFT (SEQ ID NO 32) [132]
• the amino acid sequence is coded by the DNA sequence of SEQ ID NO 33 :
• the homology is generally a homology of 80% or more, preferably a homology of 90% or more, more preferably a homology of 95% or 96% or 97%, 98% or more, most preferably a homology of 99% or more.
• an amino acid sequence including a substitution, deletion, or addition of one to several amino acid residues in the heavy chain or light chain amino acid sequence it is also possible to select an antibody having a cytotoxic activity equivalent to that of each of the above-described antibodies.
• the number of amino acid residues to be substituted, deleted, or added is generally 10 or fewer, preferably 5 to 6 or fewer, more preferably 2 to 3 or fewer, most preferably 1.
• Example 2 The antibodies described in Example 2 were tested for use in a lateral flow assay.
• each of the 5 clones was spotted at 0.5mg/mL on 4mm wide strips using moderate flow nitrocellulose membrane, (10 strips per clone so that negative vs. +l00ng/mL positive sample can be analyzed for each of the 5 clones), with a basic striping buffer, & a control spot (rPA).
• the sample pads and nitrocellulose were untreated.
• each of the 5 clones were conjugated to 40nm gold under a standard conjugation protocol: middle pH, with medium-strong loading of the antibody onto the gold, a standard gold blocker, and then combined the gold conjugates 1 :1 with a basic conjugate diluent containing sugar, buffer, protein & surfactant.
• (+) 2ng/mL; 30 min incubation, l: lK detector + l : lK SA-HRP; 4xPBST wash, Xtreme TMB T w/stop; read at 405nm (200ng/well capture in lxPBS for lhr; BSA block, w/stabilcoat on Greiner plates)
• the best pairs are shown in bold.
• the best pairs for LFS are the A12 detector with E10 or C10 capture.
• the secondary set was A09 detector and A12 capture

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