EP2755687A2 - Arbiträr konzipiertes epitop aus drei oder mehr aminosäureresten in einem peptid zum nachweis von antikörpern und verfahren zu seiner herstellung - Google Patents

Arbiträr konzipiertes epitop aus drei oder mehr aminosäureresten in einem peptid zum nachweis von antikörpern und verfahren zu seiner herstellung

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Publication number
EP2755687A2
EP2755687A2 EP12832007.4A EP12832007A EP2755687A2 EP 2755687 A2 EP2755687 A2 EP 2755687A2 EP 12832007 A EP12832007 A EP 12832007A EP 2755687 A2 EP2755687 A2 EP 2755687A2
Authority
EP
European Patent Office
Prior art keywords
amino acid
acid residues
peptide
antibody
peptide vaccine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12832007.4A
Other languages
English (en)
French (fr)
Other versions
EP2755687A4 (de
Inventor
Zhiwei WU
Xilin WU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Y-Clone Medical Sciences Co Ltd
Original Assignee
Nanjing University
Nanjing Tech University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing University, Nanjing Tech University filed Critical Nanjing University
Publication of EP2755687A2 publication Critical patent/EP2755687A2/de
Publication of EP2755687A4 publication Critical patent/EP2755687A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the field of applied immunotechnology. More specifically, it relates to peptide vaccine design or immunogen design for producing antibodies against an epitope of arbitrary sequences, particularly those epitopes against which it is otherwise very difficult to induce antibodies in vitro.
  • Synthetic peptides offer several advantages over other forms of vaccines based on inactivated or attenuated microorganisms, including easy production, high safety and low, or even no, detrimental immune responses usually associated with inactivated or attenuated microorganisms.
  • Peptide immunogens have been widely used to induce antibodies with known epitope specificities. Thus, the epitope specificities of the resultant antibodies are determined by the immunologically dominant residues and sometimes also the flank sequences. However, often these antibodies against the
  • immunodominant sequences lack therapeutic importance because those immunodominant epitopes are subject to high degree of mutation in dealing with highly variable viruses, such as HIV, hepatitis C virus (HCV).
  • highly variable viruses such as HIV, hepatitis C virus (HCV).
  • V3 loop of the envelope gpl20 as the principal neutralizing determinant (PND) for laboratory T-cell-line-adapted (TCLA) strains of HIV-1.
  • PND principal neutralizing determinant
  • TCLA T-cell-line-adapted
  • An object of the present invention is, accordingly, to provide a novel method of immunogen design for peptide vaccines capable of eliciting therapeutically significant antibodies against virus infection, such as, for example, HIV infection.
  • Another object of the present invention is to provide a peptide vaccine capable of eliciting production of therapeutically effective antibodies in patients suffering from viral infections.
  • a further object of the present invention is to provide an antibody with binding specificity dependent only on 3 amino acid residues in the targets. The three residues may be continuous or may be interposed by other residues.
  • it is to provide an antibody that is specific to the GPG sequence of the third variable (V3) loop of the envelope gpl20.
  • the motif immunogen is a population or library of short peptides that comprise some fixed amino acid residues and some randomized residues.
  • the fixed residues are those shared by substantially all the peptide species across the library at the corresponding position while the randomized residues can be randomly any amino acid residues.
  • the fixed residues can be continuous in sequence or they can be interposed by one or more randomized residues.
  • the sequence of fixed residues are predetermined according to the intended epitope against which one wishes to raise specific antibodies.
  • the motif immunogen comprises a segment of fixed residues flanked by a segment of randomized residues in each side (FIG.l).
  • One preferred length for the immunogen is 15 residues but other lengths shall also provide satisfactory results, for example, within the range between 10 and 50. Nonetheless the present invention is not limited to any particular length of motif immunogens.
  • the synthesis of the motif immunogen can be performed by conventional methods available in the art, which can be made commercially, and thus is not part of the present invention.
  • the motif immunization strategy of the present invention it is possible to induce antibodies against any epitope constituted by any kinds of amino acid sequences, because the motif immunization can let the immunity system focus on the designated target epitope and induce the therapeutically relevant antibodies even which is not present in the human beings or normal animal serum. It must be emphasized, as it would be readily
  • randomizing with all available natural or man-made amino acids seems to be preferable, it shall also provide satisfactory results in given situations with less randomization.
  • the particular embodiments disclosed herewith were carried out with 20 nature occurring amino acids.
  • the present invention may also achieve the intended effect: enhancing the intended epitope's antigencity while minimizing other competing epitopes' immunodominance. For example, if one residue is randomized with 20 avaiable candidates, the library would have 20 difference species, and with 2 such randomized residues, the result would be 400. Then with 3 residue randomization, the different species would be 8000. If the residue is randomized with 10 candidate, the number of species in the library would be 10, 100, and 1000 respectively.
  • glycan-specific antibodies or antibodies specific for glycan-peptide conformation or to modify the amino acids by other means, such as sulfation, for the induction of antibodies with unique specificity.
  • nonconventional amino acids into the randomized region of a peptide, one may significantly increase the stability of the peptide, thus improving its therapeutic or antibody induction activity.
  • the fixed residue needs not to be absolute either. While it is preferable to have the entire library share the same amino acid residue at a fixed position, it is understood that if a certain percentage of the species in the library shares an identical amino acid residues at given position it would be sufficient to give the designated motif residues enough advantage to achieve intended effect.
  • the present invention is not limited by the degree of the
  • a peptide vaccine with GPG motif as the intended epitope motif which is capable of eliciting production of antibodies in mammals with specificity depending solely on the GPG per se without being influenced by any flanking sequences, a type of antibodies that could not be made in all previously known research reports.
  • This particular peptide vaccine is a 15-mer peptide antigen library following the design pattern XXXXX XGPGX XXXXC as shown in FIG.9.
  • This peptide vaccine, referred to as V3M01 in the present invention were generated by conventional synthetic means. After Balb/c mice were immunized with the peptide vaccine, the result showed that high titer serum antibodies against GPG motif in mice.
  • Hybridoma was generated and a number of monoclonal antibodies were isolated. Immunological characterization of the antibodies demonstrated that the Mabs (monoclonal antibodies) specifically recognized GPG and are capable of neutralizing genetically diverse HIV-1 isolates that carry the GPG sequence, in a pseudovirus assay.
  • the novel peptide vaccine of the present invention has demonstrated the capability of inducing anti-serum which broadly inhibits various pseudovirus of HIV containing the sequence of GPG in the V3 loop, a motif which is highly conserved with weak immunogenicity.
  • the present invention also provides a therapeutic method that includes a step of (a) manufacturing said peptide vaccine and (b) administering an therapeutically effective amount of said peptide vaccine to the human patients suffering from viral infection.
  • the present invention further provides an antibody, possessing an epitope binding specificity solely dependent on 3 amino acid residues and not substantially influenced by another amino acid residues flanking or interposing the designated 3 amino acid residues.
  • a particular such antibody has GPG as the designated amino acid residues, which is useful in fighting with the HIV virus.
  • FIG.l is a characterization of the murine anti-serum following the fifth immunization with motif antigen V3M01 according to the present invention.
  • X-axis indicates the serum dilution multiply by 1000 so that the value of 1 means the serum is diluted by 1000 times;
  • B Murine anti- serum binding with gpl20 protein of different subtype HIV, (# means OD405 nm of binding with gpl20 shows statistic significant higher than its binding with control protein of bovine serum albumin).
  • FIG.2 is a similar characterization as FIG. 1 but it with the rabbit anti-serum following the fifth immunization withV3M01, instead of the murine counterpart, where R stands for rabbit, and 01-03 are serial numbers for each of the three rabbits, respectively (using immunogen as the antigen).
  • FIG.3 is a characterization of rabbit anti-serum after the fifth immunization with V3M01 in terms of its interacting with the motif peptide (A, B, and C for three individual rabbits respectively) and gpl20 protein (D,E, and F, for three individual rabbits respectively).
  • FIG.4 is a characterization of NJU009 in terms of its interacting with the motif peptide (A), HIV peptide (B), HIV protein (C, D) .
  • D is a bar-graph at the concentration of lOOug/ml NIU009.
  • FIG.5 characterizes NJU009's inhibitory effects on various pseudovirus.
  • FIG.6 is a characterization of the rabbit anti-serum (A) and Protein G purified poly-antibody (B) following the fifth immunization with V2M01 expressing the V2 sequence of HIV-1 according to the present invention.
  • FIG.7 shows the interacting with gpl20 of poly-antibodies induced by V2M01 from three rabbits R182, R183 and R186 (A, B, and C, respectively).
  • FIG.8 is a characterization of the rabbit anti-serum and purified poly-antibody following the fifth immunization with motif antigens according to the present invention, showing Elisa test of the titer of anti-serum with Gp41M01(A), poly-antibodies purified by Protein G with Gp41M01(B), and poly-antibodies purified by Protein G with T20 of gp41(C).
  • FIG.9 shows the amino acid sequence patterns as peptide vaccine design used in the
  • X randomized amino acid residue and other letters are one-letter codes of amino acids.
  • FIG.10 is the information on env clones and their neutralization sensitivity to bnmAb in the context of pseudotyped viruses, where the concentration of antibody is the total antibody of the anti-serum of ascites purified by Protein G.
  • the Nab concentration or titer is reported as the reciprocal of the purified antibody concentration or the dilution of the plasma that produces 50% inhibition of target cell infection.
  • the negative control is the inhibition of MuLv infection. ND: not determined due to inadequate serum.
  • FIG.11 shows the titer of the anit-serum elicited by three different peptide libraries HAMOl, EM01 and OVAM01 which were designed according to the present invention, with HAMOl representing a conserved sequence in several influenza viruses and EM01 representing a conserved sequence in HCV.
  • FIG.12 shows antibody responses of an exemplary peptide vaccine V2M01 which follows the design pattern FYXXD, where the fixed residues FYD are interposed by some randomized residues indicated by XX.
  • FIG.13 shows antibody responses of another exemplary peptide vaccine Gp41M01 which follows the design pattern LDXW, where the fixed residues LDW are interposed by a randomized residue indicated by X.
  • the sequence of the immunogen motif peptide library (or novel peptide vaccine) designed as particular example of the present invention is shown in FIG.l, where X represents a randomized amino acid residue which can be any amino acid except cystein.
  • the motif peptide library were commercially synthesized in GL Biochem (Shanghai. LTD. China). The Cys (underlined) on the C- terminal was added for conjugation purposes.
  • Each peptide was chemically linked to carrier protein Keyhole Limpet Hemocyanin (KLH,obtained from Sigma, USA), and V3M01 was also conjugated to bovine serum albumin (BSA; obtained fiom Sigma, USA) as test antigen in ELISA.
  • KLH Keyhole Limpet Hemocyanin
  • BSA bovine serum albumin
  • mice were immunized subcutaneously: 100 ul vaccine peptide (1 mg/ml with the conjugate) in PBS and lOOul complete Freund' s adjuvant (CFA, 1:1 ratio) (purchased from Sigma,USA) at a final volume of 200ul.
  • Boosters were given with 50 ul 1 mg/ml vaccine peptide (in the conjugate) in PBS with 50ul incomplete Freund' s adjuvant (IFA) per mice (purchased from Sigma) at weeks 2, 5 and 8. Anti-sera were then separated for detection.
  • Blood was taken from each animal one week after each vaccination event for immune samples (i.e., at weeks 1, 3, 6, 9 and 12) .
  • Antibodies were further purified from the murine and rabbit anti- serum samples via Protein G affinity chromatography.
  • Epitope-specific mAbs were prepared according to the standard hybridoma technique. Specifically spleen cells from Balb/c mouse were fused with mouse myeloma cells (SP2/0). Antibodies were purified from the ascites of Balb/c mice by affinity chromatography. The isotype of monoclonal antibody was tested with the mouse
  • Monoclonal antibody isotyping reagents (077K4825, from Sigma,USA).
  • Recombinant gpl20s were purchased from ImmunoDiagnostics, Inc. (Woburn, MA, USA) or from the NIH AIDS Reagent Program (Bethesda, MD, USA), peptides of B and B' subtype of HIV were commercially synthesized in GL Biochem (Shanghai, LTD, China).
  • 96- well polyvinylchloride plates (Coming, NY, USA) were coated with lOOul of 8ug/ml gpl20 or peptide diluted in 50mM bicarbonate buffer, pH 9.6, and incubated at 4°C for 16 hours. Unbound peptide or
  • Full-length envelope genes were amplified by PCR directly from proviral DNA extracted from patients' uncultured peripheral blood mononuclear cells. The PCR was conducted with initial denaturation at 94 °C for 2 min, followed by 35 cycles of 94 °C for 15 s, 55°C for 30 s, and 68°C for 4 min, followed by a final extension at 68 °C for 10 min. Subtype- specific primer sequences were designed to be as conserved as possible based on the published sequences of geographical variants.
  • PCR- amplified fragments were cloned directly into the pcDNA 3.1 expression vector (Invitrogen) and verified by direct sequencing.
  • Env-bearing pseudotyped viruses were generated by co-transfection of env-expressing plasmid together with backbone construct pNL43R-E-luciferase into the 293 cells.
  • a control plasmid expressing envelope glycoprotein of HIV- 1 HXB2, SF162, or JRFL and of amphotropic murine leukemia virus was also included. Forty-eight hours post-transfection, culture supenatant was collected and tested for luciferase activity to standardize viral input in the subsequent functional analysis.
  • co-receptor CCR5 or CXCR4 were then added, and the cultures were maintained for an additional 48 h at 37 °C.
  • Neutralizing activity was measured by the reduction in lucif erase activity compared with the control.
  • the log 10 ID50 titers were calculated based on the standard algorithm used in the art.
  • NJU009 one of the most potent mAbs, was further characterized for its neutralizing activity against a panel of pseudotyped viruses consisting of 11 primary isolates and 2 laboratory strains representing subtypes B, B', C, B'C recombinant, and a number of circulating recombinant forms (CRFs) (FIGs. 5 and 10). Eleven out of 13 isolates were neutralized by NJU009 with the ND 50 ranging from 3.7ug/ml for CNE16 (B'C) to 20.5ug/ml for CNE58 (Clade C) with CNE 6 and CNE11 completely resistant to the neutralization by NJU009.
  • NJU009 The absolute dependency on all three amino acid residues by NJU009 also suggests that the three amino acid residues may be in direct contact with NJU009.
  • NJU009 also exhibited comparable recognition of V3 peptides derived from various isolates (FIG. 4) and recombinant gpl20s derived from HIV-1 ADA, IIIB and a B'C recombinant isolate. Since the flank sequences of above antigens are distinct, the observation suggested that the NJU009 reactivities were GPG specific and its recognition of the epitope is minimally influenced by the sequences flanking the epitope motif.
  • the IgG genes of variable region were amplified from all six hybridoma clones by RT-PCR.
  • the deduced sequences of amino acid from the nucleotides showed that the amino acid (aa) sequences of heavy chain variable regions are 100% identical for all clones while the aa sequences of light chain variable regions of NJUOOl, NJU003 and NJU005 are identical, and NJU007, NJU008 and NJU009 are identical, suggesting that NJUOOl, 003 and 005 were likely derived from the same parental hybridoma clone and NJU007, 008 and 009 from another clone. The majority of the differences are concentrated in the CDR regions and the C-terminus of the VL region. NJU009 and 447-52D recognize the tip of the V3 loop with only one amino acid residue difference.
  • Immunization Methodology of the present invention is not limited to the GPG motif but can be applied to other sequences as well, a number of HIV-1 gpl20 sequences were selected, which are known to contain or be part of antigenic epitopes but hard to induce its specific antibodies using conventional strategies.
  • the V1V2 region for example, is known to contain epitopes that mediate cross neutralizing activities but to which few such antibodies were successfully induced.
  • a sequence of FYXXD in the V2 crown was selected as the immunogen for a number of reasons: (1) recently two broadly neutralizing mAbs, PG9 and PG16, isolated from an HIV-infected human and mapped to V2 and V3, showed that alanine replacement of F176 increased the IC50s for more than 5000 and 7000 folds, respectively, and (2) the aspartic acid (D) is part of the LDL binding sequence for integrin 4 7, the gut mucosal homing receptor for peripheral T cells. Since the lysine (K) and leucine (L) are poorly conserved among HIV-1 isolates, only the highly conserved FY and D (93, 91 and 96% conservation, respectively) were included in the construction of the epitope according to the present invention. A 15-mer peptide library was synthesized with two AA spacings between Tyrosine and Aspartic acid. All three rabbits immunized with the peptide developed strong antibody responses, reaching endpoint titers of >80000 after 5 th
  • the membrane proximal external region (MPER) of gp41 contains a number of highly conserved epitopes recognized by broadly neutralizing mabs, such as 2F5 and 4E10. Both mAbs were isolated from infected
  • the 2F5 epitope ELDKWA contains three highly conserved residues with L 663 , D 664 and W 666 at 98, 97 and 99% usage frequency, respectively.
  • a 15-mer peptide containing LDXW sequence induced antibody responses that recognized T20 (FIG. 13, FIG. 9). Based the above results, it is believed that using this targeted antibody induction technology of the present invention to design peptide vaccines, it is possible to induce antibodies to sequences of no known antigenicity or even arbitrary sequences.
  • HAM01 contained triplet residues HHP derived from aa 199-201 located within the receptor-binding subdomain of HAl and are highly conserved among different IFV subtypes and IFVs from different species.
  • EM01 contained triplet residues HRM derived from highly conserved aa316-318 located in the El protein of HCV. None of the epitopes have documented antibodies though SI 39/1, a broadly neutralizing mAb, was mapped to a conformational epitope within the HAl subdomain of IFV, consisting of residues of both upstream and downstream of HHP.
  • OVA01 contained ERK of aa 276-278 in OVA.
  • GPG antibody is unique in that none of the HIV-1 infected individuals in the panel had serum antibodies reacting with the GPG peptide while a number of sera reacted with
  • FIG. 6A and 8A shows that the rabbits immunized with V2M01 and gp41M01 produced specific anti-serum against motif immunogen. Furthermore, the anti-serum of V2M01 was also shown to bind with different gpl20 with the sequence pattern, FYXXD, in accord with the motif of V2M01(FIG. A-D). Additionally, the anti-serum of gp41M01 showed high affinity with T20 peptide of gp41, which was made up with the specific amino acid sequence,
  • LDXW identical to immunogen of gp41M01(FIG.8B).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
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  • Communicable Diseases (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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EP12832007.4A 2011-09-17 2012-09-17 Arbiträr konzipiertes epitop aus drei oder mehr aminosäureresten in einem peptid zum nachweis von antikörpern und verfahren zu seiner herstellung Withdrawn EP2755687A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161535988P 2011-09-17 2011-09-17
PCT/US2012/055771 WO2013040564A2 (en) 2011-09-17 2012-09-17 Antibody recognizing arbitrarily designed epitope of three or more amino acid residues in a peptide and method of generating thereof

Publications (2)

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EP2755687A2 true EP2755687A2 (de) 2014-07-23
EP2755687A4 EP2755687A4 (de) 2015-04-08

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EP12832007.4A Withdrawn EP2755687A4 (de) 2011-09-17 2012-09-17 Arbiträr konzipiertes epitop aus drei oder mehr aminosäureresten in einem peptid zum nachweis von antikörpern und verfahren zu seiner herstellung

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EP (1) EP2755687A4 (de)
JP (2) JP2014527085A (de)
CN (1) CN104039350B (de)
AU (2) AU2012308212A1 (de)
CA (1) CA2855781A1 (de)
HK (1) HK1200359A1 (de)
WO (1) WO2013040564A2 (de)

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US10245313B2 (en) 2014-10-24 2019-04-02 Versitech Limited DNA motif compounds and methods for inducing specific antibodies and cellular immunity
CN111153996B (zh) * 2020-01-10 2021-12-14 苏州睿瀛生物技术有限公司 G蛋白偶联受体的抗体及其制备方法和g蛋白偶联受体试剂盒

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JAVAHERIAN K ET AL: "PRINCIPAL NEUTRALIZING DOMAIN OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENVELOPE PROTEIN", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 86, no. 17, 1 September 1989 (1989-09-01), pages 6768-6772, XP000068860, ISSN: 0027-8424, DOI: 10.1073/PNAS.86.17.6768 *
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See also references of WO2013040564A2 *

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WO2013040564A2 (en) 2013-03-21
JP2017141291A (ja) 2017-08-17
JP2014527085A (ja) 2014-10-09
WO2013040564A3 (en) 2013-06-27
AU2017251715A1 (en) 2017-11-09
CN104039350A (zh) 2014-09-10
HK1200359A1 (en) 2015-08-07
CA2855781A1 (en) 2013-03-21
CN104039350B (zh) 2019-07-05
AU2012308212A1 (en) 2014-03-27
EP2755687A4 (de) 2015-04-08

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