US20100291540A1 - Carbohydrate binding module and use thereof - Google Patents

Carbohydrate binding module and use thereof Download PDF

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Publication number
US20100291540A1
US20100291540A1 US12/464,788 US46478809A US2010291540A1 US 20100291540 A1 US20100291540 A1 US 20100291540A1 US 46478809 A US46478809 A US 46478809A US 2010291540 A1 US2010291540 A1 US 2010291540A1
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Prior art keywords
hiv
cbm
sbd
antibody mimetic
rosbd
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US12/464,788
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Inventor
Margaret Dah-Tsyr Chang
Yuan-Chuan Lee
Rong-Yuan Huang
Shu-Chuan Lin
Wei-I Chou
Shi-Hwei Liu
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National Tsing Hua University NTHU
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National Tsing Hua University NTHU
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Priority to US12/464,788 priority Critical patent/US20100291540A1/en
Assigned to NATIONAL TSING HUA UNIVERSITY reassignment NATIONAL TSING HUA UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANG, MARGARET DAH-TSYR, CHOU, WEI-I, HUANG, RONG-YUAN, LEE, YUAN-CHUAN, LIN, SHU-CHUAN, LIU, SHI-HWEI
Priority to TW098124661A priority patent/TWI391491B/zh
Priority to US12/755,242 priority patent/US8293465B2/en
Priority to JP2012510383A priority patent/JP5746149B2/ja
Priority to PCT/IB2010/001302 priority patent/WO2010131114A2/fr
Priority to CN201080021113.XA priority patent/CN103097411B/zh
Priority to EP10774609.1A priority patent/EP2430045B1/fr
Publication of US20100291540A1 publication Critical patent/US20100291540A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to an antibody mimetic of carbohydrate binding module (CBM) which specifically binds to an epitope on HIV glycoprotein.
  • CBM carbohydrate binding module
  • the present invention also relates to a method of detecting HIV glycoprotein.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • AIDS acquired immune deficiency syndrome
  • the diagnosis of HIV infection is most commonly achieved by detecting antibody against HIV.
  • Methods for laboratory diagnosis of HIV infection have evolved and offered a large number and a variety of effective methods that can prolong and improve the quality of life for HIV infected patients.
  • enzyme immunoassay (EIA) is the most commonly used method.
  • the assay is comprised of an immobilized viral antigen, which may be comprised of viral lysate, retrovirus proteins or natural or synthetic polypeptides, that reacts with blood or serum components suspected of containing HIV antibodies.
  • window stage problem limiting to the anti-HIV antibody generation time
  • the present invention provides an antibody mimetic of CBM family which specifically binds to an epitope on HIV glycoprotein.
  • the present invention further provides a method of detecting HIV glycoprotein comprising: (a) introducing into contact with a solid surface to which is bound a known quantity of CBM capable of binding to HIV glycoprotein; (b) incubating sample in contact with said surface to form CBM-HIV glycoprotein complexes; and (c) incubating the complexes and subjecting sample to a labelled HIV antigen conjugate capable of yielding a quantitatively measurable signal to score sample as positive or negative for HIV-infection.
  • FIGS. 1A and 1B show glycan recognition of RoSBD determined by Glycan array analysis.
  • FIGS. 2A and 2B show structure modeling of the VH doamin of 2G12 human monoclonal antibody (PDB ID: 1ZLS) with RoSBD (PDB ID: 2V8M).
  • FIG. 3 shows amino acid sequence alignment of the VH domain of 2G12 human monoclonal antibody (PDB ID: 1ZLS) with RoSBD (PDB ID: 2V8M).
  • FIGS. 4A , 4 B and 4 C show HIV-RoSBD binding using HIV Ag & Ab positive panel #9144532.
  • FIGS. 5A and 5B show HIV-RoSBD and HIV-AnSBD binding using HIV1 incidence/prevalence performance panel PRB601.
  • FIGS. 6A and 6B show competition of HIV-RoSBD and HIV-AnSBD binding by maltoheptaose (G7) and ⁇ -cyclodextrin ( ⁇ CD).
  • FIGS. 7A and 7B show competition of HIV-RoSBD and HIV-AnSBD binding by HIV1 gp140 antigen and 2G12 monoclonal antibody and HIV1 gp140 antigen.
  • FIGS. 8A and 8B show amino acid sequence alignment of 2G12 epitope regions of twenty one HIV1 isolates.
  • the present invention provides an antibody mimetic of CBM which specifically binds to an epitope on HIV glycoprotein.
  • CBM refers as a contiguous amino acid sequence within a carbohydrate-active enzyme with a discreet fold having carbohydrate-binding activity.
  • the CBMs are categorized into 53 families, which include several specificities such as cellulose, xylan, chitin, and starch binding.
  • antibody mimetic refers to an object having similar function as the antibody in terms of binding against target structure, but its structure is simpler than an antibody.
  • To produce a large amount of antibodies needs the following steps: (a) fusing single antibody-forming cells to tumor cells grown in culture. The resulting cell is called a hybridoma, (b) each hybridoma produces relatively large quantities of identical antibody molecules, and (c) allowing the hybridoma to multiply in culture, it is possible to produce a population of cells, each of which produces identical antibody molecules.
  • the preferable CBM is starch binding domain (SBD).
  • SBD starch binding domain
  • the term “SBD” used herein refers to a functional domain that can bind granular or soluble starch, increasing the local concentration of substrate at the active site of the enzyme, and that may also disrupt the structure of the starch surface, thereby enhancing the amylolytic rate.
  • starch-binding CBM families CBM20, CBM21, CBM25, CBM26, CBM34, CBM41, CBM45, CBM48 and CBM53.
  • the SBD is the member of the CBM families 20 and 21, which is derived from Aspergillus niger glucoamylase (AnSBD) and Rhizopus oyzae glucoamylase (RoSBD), respectively.
  • CBM20 and CBM21 share fairly low identity in their amino acid sequences (approximately 13.5%), they have similar secondary and tertiary structures as well as the role in enhancing enzymatic activity in terms of hydrolyzing granular starch (Tung J Y et al., Biochem. (2008) 416: 27-36).
  • the antibody mimetic of the present invention wherein the RoSBD analyses by Glycan microarray screening shows that it has the ability to bind a glycan, Man ⁇ (1,2)Man ⁇ (1,2)Man ⁇ (1,2)Man ⁇ (1,3), which is a special glycan present in the epitope of the heavily glycosylated glycoprotein gp120 of HIV.
  • 2A and 2B shows, structure modeling of the VH domain of 2G12 human monoclonal antibody crystal (PDB ID: 1ZLS) and the RoSBD crystal complexed with glycan ligand (PDB ID: 2V8M) indicates that the ⁇ -sheet secondary structures are similar between these two proteins with a low root mean square deviation (RMSD) value.
  • RMSD root mean square deviation
  • the present invention also provides a method of detecting HIV glycoprotein comprising: (a) introducing into contact with a solid surface to which is bound a known quantity of CBM capable of binding to HIV glycoprotein; (b) incubating sample in contact with said surface to form CBM-HIV glycoprotein complexes; and (c) incubating the complexes and subjecting same to a labelled HIV antigen conjugate which is capable of yielding a quantitatively measurable signal to score sample as positive or negative for HIV-infection.
  • the CBM includes but is not limited to SBD.
  • the method of the present invention, wherein said antigen of step (c) is labelled with an enzyme which is capable of producing the said signal when contact with an enzyme substrate.
  • the enzyme comprises but not limited to horse radish peroxidase (HRP), alkali phosphatases, peroxidases, ⁇ -galactosidase, glucoamylase, urease and chloramphenicol acetyltransferase.
  • HRP horse radish peroxidase
  • alkali phosphatases alkali phosphatases
  • peroxidases peroxidases
  • ⁇ -galactosidase glucoamylase
  • urease chloramphenicol acetyltransferase.
  • the emzyme is HRP.
  • the substrate includes but is not limited to 3,3′,5,5′-tetramethylbenzidibe (TMB).
  • the major targets of the antibody mimetic are the exterior envelope glycoprotein of HIV, gp120 and the transmembrane glycoprotein, gp140. These proteins are generated by cleavage of a heavily glycosylated precursor protein, gp160, by furin-like enzymes during transport through the Golgi apparatus. Each new infectious cycle is initiated when the external envelope glycoprotein gp120 binds the primary recetor, CD4, which is embedded in the plasma membrane on the surface of potential target cells.
  • the antibody mimetic of CBM which is not only can bind to the glycan structure of the envelope glycoprotein of HIV to serve as a potential therapeutic agent to block the interaction between HIV and target cells, but also can be a prophylactic vaccine against conserved but exposed epitopes on the HIV envelope glycoprotein to limit newly acquired infections.
  • the CBM has the ability to use as an antibody mimetic which can be appled to HIV detection and may further be applied as a prevention and treatment agent for HIV infection.
  • the RoSBD and AnSBD were produced by E. coli system using pET23a and pET15Bb expression vector, respectively.
  • the cell pellets of E. coli containing the recombinant protein was resuspended in binding buffer (50 mM sodium acetate, pH 5.5), and then homogenized (EmulsiFlex-C5 homogenizer).
  • binding buffer 50 mM sodium acetate, pH 5.5
  • homogenized EmulsiFlex-C5 homogenizer
  • the cell debris was removed by centrifugation at 16,000 ⁇ g for 20 min at 4° C., and the supernatant was subjected to purification by affinity chromatography equipped with amylose resin (New England Biolabs, Ipswich, Mass.).
  • the purified RoSBD/AnSBD was dialyzed against sodium acetate buffer (50 mM, pH 5.5) using an Amicon® Ultra-15 centrifugal filter devices (Millipore) PL-10 (10 kDa cutoff) after 30 kDa cutoff (Lin S C, et al., BMC Biochem. (2007) 8: 9-21 and Liu W T, et al., Biochem. Biophys. Res. Commun. (2008) 377: 966-970).
  • RoSBD was produced in E. coli system using pET23a expression vector and purified using amylose resin as previously described. Glycan microarray analyses were conducted by the Consortium for Functional Glycomics, Core H facility. The array contained a total of 377 different natural and synthetic glycans and version 3.1 (http//:www.functionalglycomics.org/static/consortium/resources/resourcecoreh11.shtml) was used for the analyses reported here. Briefly, RoSBD was diluted to 200 mg/mL in sodium acetate binding buffer (50 mM sodium acetate pH 5.5, 1% BSA and 0.05% Tween-20).
  • sodium acetate binding buffer 50 mM sodium acetate pH 5.5, 1% BSA and 0.05% Tween-20.
  • the secondary antibody incubation was performed with Alexa 488 -labeled goat anti-mouse IgG at 5 mg/mL in PBS buffer for one hour in a humidified chamber, followed by wash steps.
  • the binding image was read in a Perkin-Elmer Microarray XL4000 scanner and analyzed using Imagene (V6) image analysis software.
  • FIG. 1A illustrated the glycan array screening result of RoSBD.
  • FIG. 1B showed the molecular structure of the special Man ⁇ (1,2)Man ⁇ (1,2)Man ⁇ (1,2)Man ⁇ (1,3) with the strongest signal.
  • FIGS. 2A and 2B showed the modeling result of the VH domain of 2G12 human monoclonal antibody (PDB ID: 1ZLS, left panel) and RoSBD (PDB ID: 2V8M, right panel).
  • VH domain was located on the heavy chain of 2G12, and bound with N-linked glycans.
  • Superimposition of both 2G12 and RoSBD structures indicated that the ⁇ -sheet secondary structures were similar between these two proteins, and most glycan ligand binding residues were localized in similar orientation (the RMSD value of structure comparision was 2.43 ⁇ ). It also proved the structure homology between RoSBD and a general antibody.
  • HIV Ag & Ab positive panel ID#9144532, SeraCare Life Sciences, Milford, Mass.
  • Anti-HCV mixed titer performance panel ID# PHV205-24, SeraCare Life Sciences, Milford, Mass.
  • This HIV Ag & Ab positive panel was identified as HIV antigen positive by Perkin Elmer EIA and anti-HIV antibody positive by Abbott EIA.
  • HRP coupled E HRP coupled E.
  • HIV1 recombinant gp120 antigen conjugate (0.05 ⁇ g/mL) was added and reacted at 37° C. for 30 min. This conjugate could bind with the human anti-HIV1 antibody in HIV Ag & Ab positive panel directly.
  • HCV test sample and HCV recombinant antigen (Core+NS3+NS5)-HRP conjugate (0.33 ⁇ g/mL) were analyzed following the same protocol in parallel. Finally, the plates were developed by adding 100 ⁇ L 3,3′,5,5′-tetramethylbenzidibe (TMB) at 37° C. for 30 min.
  • TMB 3,3′,5,5′-tetramethylbenzidibe
  • the absorbance was measured at 450 nm in ELISA reader after the reaction was stopped by addition of 100 ⁇ L 2 N H 2 SO 4 in each well. These absorbance values were compiled as a statistical value (Cut off value; COV) and described in terms of cut off index (COI) value.
  • the COI value was calculated as the OD value of test sample divided by COV. If a sample has an absorbance higher than the COV, i.e. COI value is greater than 1, it is considered to be positive in the assay.
  • FIG. 4A revealed that the maximal COI value of RoSBD binding was 2.298 (HIV).
  • FIG. 4B demonstrated the specificity of the RoSBD employing Anti-HCV mixed titer performance panel. The difference was statistically significant (P ⁇ 0.0001).
  • PRB601 HIV1 incidence/prevalence performance panel
  • FIGS. 5A and 5B revealed that the detection rate of the traditional HIV-1 p24 Antigen Assay was only 20.0%, whereas those of RoSBD coated EIA (93.3%) AnSBD coated EIA 86.7% were much higher.
  • FIG. 6A showed that the COI value of HIV Ag & Ab positive panel decreased in the presence of maltoheptaose and ⁇ -cyclodextrin.
  • the competition occurred when 10 mM maltoheptaose or ⁇ -cyclodextrin was added to the RoSBD coated plate, strongly indicating that maltoheptaose and ⁇ -cyclodextrin could act as competitors for RoSBD binding to HIV Ag & Ab positive panel, and the competitive inhibition rate of 10 mM maltoheptaose and ⁇ -cyclodextrin was respectively 24.4% and 23.1%.
  • HIV Ag & Ab positive panel was separately mixed with the same volume of 500 nM human IgG 1 secondary antibody, 2G12 monoclonal antibody, and 250 nM HIV1 gp140 antigen at 37° C. for 1 hr. After adding the mixture to (a) RoSBD coated (100 nM in 0.05 M Tris-Hcl, pH 8) and (b) AnSBD coated plate (100 nM in 0.05 M sodium bicarbonate buffer, pH 9.5) individually at 37° C. for 1 hr, 100 pL HRP coupled HIV1 recombinant gp120 antigen conjugate (0.05 ⁇ g/mL) was used for detection.
  • RoSBD coated 100 nM in 0.05 M Tris-Hcl, pH 8
  • AnSBD coated plate 100 pL HRP coupled HIV1 recombinant gp120 antigen conjugate (0.05 ⁇ g/mL) was used for detection.
  • FIGS. 7A and 7B showed that the COI value of HIV Ag & Ab positive panel decreased in the presence of 2G12 human monoclonal antibody.
  • the competition occurred when 500 nM 2G12 was added to the RoSBD ( FIG. 6A ) and AnSBD ( FIG. 6B ) coated plate. These results indicated the competition of 2G12 occurred, compared to the negative result of human IgG 1 .
  • the competitive inhibition rate of 500 nM 2G12 was 28.9% on RoSBD and 28.4% on AnSBD.
  • no competition was observed in the presence of 500 nM IgG 1 .
  • the competition was more obvious in the presence of 250 nM HIV1 gp140 with an inhibition rate of 42.9% for RoSBD and 40.1% for AnSBD.
  • FIGS. 8A and 8B illustrates multiple sequence alignment of the 2G12 human monoclonal antibody epitope region of twenty-one HIV1 isolates (SEQ ID NO: 4 to SEQ ID NO: 23) were compared (SEQ ID NO: 3).
  • the 2G12 epitope covers mainly on the high-mannose or hybrid glycans of residue N295, N332, N339, N386, N392, and N448 on gpl20 of HIV1 IIIB and JR-FL isolates (Sanders R W, et al., J. Virol. (2002) 76: 7293-7305 and Scanlan C N, et al., J. Virol. (2002) 76: 7306-7321).

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US12/464,788 US20100291540A1 (en) 2009-05-12 2009-05-12 Carbohydrate binding module and use thereof
TW098124661A TWI391491B (zh) 2009-05-12 2009-07-22 醣類結合模組及其應用
US12/755,242 US8293465B2 (en) 2009-05-12 2010-04-06 Method for the detection of human immunodeficiency virus envelope (HIV) glycoprotein utilizing carbohydrate binding module (CBM) 20 or 21
JP2012510383A JP5746149B2 (ja) 2009-05-12 2010-05-12 抗ウイルス炭水化物結合モジュール組成物及び使用方法
PCT/IB2010/001302 WO2010131114A2 (fr) 2009-05-12 2010-05-12 Module de liaison au glucide et son utilisation
CN201080021113.XA CN103097411B (zh) 2009-05-12 2010-05-12 糖类结合模块及其用途
EP10774609.1A EP2430045B1 (fr) 2009-05-12 2010-05-12 Module de liaison au glucide et son utilisation

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US10919981B2 (en) 2014-08-22 2021-02-16 Nectagen, Inc. Affinity proteins and uses thereof
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US7662918B2 (en) * 2005-03-03 2010-02-16 Simpson Biotech Co., Ltd. Recombinant protein comprising starch binding domain and use thereof
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Lin, S.-C., et al., June 2007, Role of the linker region in the expression of Rhizopus oryzae glucoamylase, BMC Biochemistry 8:9(1-12). *
Paldi, T., et al., 2003, Glucoamylase starch-binding domain of Aspergillus niger B1: molecular cloning and functional characterization, Biochem. J. 372:905-910. *

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JP5746149B2 (ja) 2015-07-08
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TW201040280A (en) 2010-11-16
WO2010131114A3 (fr) 2011-11-24
US8293465B2 (en) 2012-10-23
EP2430045B1 (fr) 2015-07-08
TWI391491B (zh) 2013-04-01
EP2430045A2 (fr) 2012-03-21
CN103097411B (zh) 2016-09-28
CN103097411A (zh) 2013-05-08
WO2010131114A2 (fr) 2010-11-18
US20100291601A1 (en) 2010-11-18

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