WO2016013870A1 - Procédé pour positionner, dans le cytoplasme, un anticorps au format immunoglobuline complète par pénétration de l'anticorps à travers la membrane cellulaire, et son utilisation - Google Patents

Procédé pour positionner, dans le cytoplasme, un anticorps au format immunoglobuline complète par pénétration de l'anticorps à travers la membrane cellulaire, et son utilisation Download PDF

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Publication number
WO2016013870A1
WO2016013870A1 PCT/KR2015/007626 KR2015007626W WO2016013870A1 WO 2016013870 A1 WO2016013870 A1 WO 2016013870A1 KR 2015007626 W KR2015007626 W KR 2015007626W WO 2016013870 A1 WO2016013870 A1 WO 2016013870A1
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WIPO (PCT)
Prior art keywords
antibody
chain variable
variable region
light chain
cell
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PCT/KR2015/007626
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English (en)
Korean (ko)
Inventor
김용성
최동기
신승민
김성훈
Original Assignee
아주대학교산학협력단
재단법인 의약바이오컨버젼스연구단
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Publication date
Priority claimed from KR1020150103163A external-priority patent/KR101602870B1/ko
Priority to BR112017001304-5A priority Critical patent/BR112017001304A2/pt
Priority to EP15825418.5A priority patent/EP3173428B1/fr
Priority to AU2015292955A priority patent/AU2015292955B2/en
Priority to US15/327,369 priority patent/US10844136B2/en
Priority to JP2017525495A priority patent/JP6595592B2/ja
Application filed by 아주대학교산학협력단, 재단법인 의약바이오컨버젼스연구단 filed Critical 아주대학교산학협력단
Priority to CN201580045139.0A priority patent/CN107001481A/zh
Priority to CA2955272A priority patent/CA2955272A1/fr
Priority to RU2017103675A priority patent/RU2017103675A/ru
Priority to MX2017001010A priority patent/MX2017001010A/es
Publication of WO2016013870A1 publication Critical patent/WO2016013870A1/fr
Priority to IL250203A priority patent/IL250203B/en
Priority to ZA2017/00488A priority patent/ZA201700488B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins

Definitions

  • viruses HSV
  • toxins choleratoxin, diphtheria toxin
  • endocytosis an active intracellular transport mechanism.
  • These intracellularizations are largely classified into three pathways, including clathrin-induced endocytosis, which is involved in ligand-induced cellular internalization, or by caveolae, which is found in some toxins such as choleratoxin, dextran, and ebolavirus.
  • caveolae which is found in some toxins such as choleratoxin, dextran, and ebolavirus.
  • the endocytosis involving clathrin and caveolae begins primarily when membrane receptors bind to specific ligands.
  • the present invention is to infiltrate the cell membrane of living animal cells through the process of endocytosis and actively immobilize the complete immunoglobulin-type antibody in the cytoplasm using the endosomal escape mechanism To provide a way.
  • the cytoplasmic penetrating ability may be located in the cytoplasm by endosome escape after actively infiltrating living cells through endocytosis.
  • the light chain variable region may include CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6.
  • the light chain variable region may include CDR1 of SEQ ID NO. 7, CDR2 of SEQ ID NO. 8, and CDR3 of SEQ ID NO.
  • the heavy chain variable region that specifically binds to and inhibits the RAS was screened by the following method.
  • KRas G12D which is an activated (GTP coupled) RAS mutant
  • carcinogenesis-related RAS mutations occur mainly at residues 12, 13 and 61, and residues 12 and 13 are located in the P-loop of the RAS protein and are bound to the RAS protein.
  • Hydrolysis of GTP affects the binding of GAP (GTPase-activating protein), which induces protein structural changes in an inactive form.
  • residue 61 binds to the hydrolytic activity of GAP and prevents GTP hydrolysis. Therefore, various carcinogenic RAS mutations have the same region as the RAS G12D mutation and signal transduction (Switch I, Switch II). It is not limited to.
  • liposomes are composed of one or more lipid bilayer membranes surrounding an aqueous internal compartment that can associate themselves.
  • Liposomes can be specified by membrane type and size.
  • Small unilamellar vesicles SUVs
  • Large uni-lamellar vesicles LUV
  • Oligolamella large vesicles and multilamellar large vesicles have multiple, generally concentric, membrane layers and may be 100 nm or more in diameter. Liposomes with multiple asymmetrical membranes, ie several small vesicles contained within larger vesicles, are called multivesicular vesicles.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer, including a bioactive molecule selected from the group consisting of the antibody, or a peptide, a protein, a small molecule drug, a nanoparticle, and a liposome fused thereto.
  • a bioactive molecule selected from the group consisting of the antibody, or a peptide, a protein, a small molecule drug, a nanoparticle, and a liposome fused thereto.
  • Figure 2b is a diagram comparing the model structure using the WAM modeling of m3D8 VL and humanized light chain variable region monodomain hT0 VL, mutant hT2 VL, hT3 VL using a superimposing method.
  • Figure 6d is a result of agarose gel nucleic acid hydrolysis verification experiment to confirm the nucleic acid hydrolytic ability in cytotransmab through human light chain variable region (hT4) substitution having a cell penetrating ability grafting the CDRs of autoimmune mouse-derived antibody.
  • hT4 human light chain variable region
  • Figure 8a is a result of observing the degree of cell penetration according to the concentration of TMab4 under a confocal microscope.
  • FIG. 10 is a result of observing with a confocal microscope through a pulse-chase experiment to observe the transport process and stability of TMab4 introduced into the cell.
  • FIG. 25 shows the results of in vitro evaluation of cell growth inhibition by treatment of RGD-TMab4 and RGD-RT4 in HCT116 and PANC-1 cell lines.
  • Figure 1 is a schematic diagram showing the concept of a monoclonal antibody of the complete IgG form located in the cytoplasm through the cell infiltration named cytotransmab, in order to understand the cytoplasmic penetration of the humanized antibody light chain variable region in order to implement this, the light chain variable derived from the existing mouse Reference was made to the correlation of cytoplasmic permeability of the region single domain m3D8 VL with CDRs belonging to the light chain variable region fragment (Lee et al., 2013).
  • Example 3 Cellular Infiltration Cellular infiltration capacity and cell infiltration mechanism validation of humanized light chain variable region (VL) single domain.
  • VL variable region
  • Figure 3a is a result of observing the cytoplasmic penetration capacity of the light chain variable region single domain by confocal microscopy (confocal microscopy).
  • Figure 3b is a result of observation by confocal microscopy to verify the cytoplasmic penetration mechanism of the light chain variable region monodomain.
  • the existing literature has approved hT3 VL and FDA based on data on the location of interface residues between human antibody variable regions, the frequency and binding of specific interface residues located on opposite variable regions, and the frequency of use of interface residues in human antibodies.
  • the interface between the heavy and light chain variable regions of the therapeutic antibodies Bevacizumab (Avastin) and Adalimumab (Humira) was analyzed (Vargas-Madrazo and Paz-Garcia, 2003).
  • residues 89 and 91 included in CDR3 involved in binding between variable regions in mouse-derived CDRs of hT3 VL are regions of high human antibody use and may affect the structure of CDR3 of heavy chain variable region (VH). It was confirmed that there is.
  • the two residues were mutated to amino acids that are frequently used in human antibodies to develop hT4 VL that can be optimized for binding to human antibody heavy chain variable regions.
  • the heavy chain variable regions (Bevacizumab VH, Adalimumab VH, fused with DNA encoding the secretion signal peptide at the 5 'end to construct a heavy chain expression vector for production in the form of monoclonal antibodies in the form of complete IgG)
  • DNA encoding the heavy chain comprising the humanized hT0 VH) and the heavy chain constant region (CH1-hinge-CH2-CH3) was cloned into NotI / HindIII in the pcDNA3.4 (Invitrogen) vector, respectively.
  • Proteins were purified from cell culture supernatants harvested with reference to standard protocols.
  • the antibody was applied to a Protein A Sepharose column (GE healthcare) and washed with PBS (pH 7.4).
  • the antibody was eluted at pH 3.0 with 0.1 M glycine buffer and then immediately neutralized with 1 M Tris buffer.
  • the eluted antibody fraction was concentrated by exchanging buffer with PBS (pH7.4) through dialysis. Purified protein was quantified using absorbance and extinction coefficient at 280 nm wavelength.
  • an elution buffer (12 mM phosphate, pH 7.4, 500 mM NaCl, 2.7 mM KCl) (SIGMA) having a high salt was used to suppress nonspecific binding with the resin due to electrical attraction due to basic residues.
  • the flow rate is 0.5 ml / min.
  • Proteins used as protein size markers were dehydrogenase (150 kDa), albumin (66 kDa), carbonic anhydrase (29 kDa). In all monoclonal antibodies and cytotransmabs, one pole was measured and confirmed to exist as a monolith.
  • cytotransmab After combining the cytotransmab and monoclonal antibodies TMab4, Bevacizumab, Adalimumab, AvaT4, HuT4 and washed three times for 10 minutes with 0.1% PBST.
  • the labeling antibody binds to an alkaline phosphatase-conjugated anti-human mAb (SIGMA) conjugated with goat derived AP. 405 nm absorbance was quantified by reaction with p-nitrophenyl palmitate (pNPP) (SIGMA).
  • ⁇ 10 4 cells HeLa, PANC-1) per well in a 96 well plate were diluted in 0.1 ml of medium containing 10% FBS, respectively, and cultured at 12 hours, 37 degrees, and 5% CO 2 conditions. Thereafter, 1 ⁇ M of TMab4, HuT4, Adalimumab, AvaT4, and Bevacizumab were treated for 20 hours or 44 hours, and then 20 ⁇ l of MTT solution (1 mg / ml PBS) was added and further incubated for 4 hours. Formed fomazan was dissolved in 200 ⁇ l of DMSO (Dimethyl Sulfoxide), and cell viability was determined by measuring absorbance at 595 nm with an absorbance meter.
  • DMSO Dimethyl Sulfoxide
  • pLJM1 a Lenti virus vector
  • pLJM1 a Lenti virus vector
  • 3 x 10 6 HEK293T cells were placed in 1 ml of medium containing 10% FBS and incubated at 5% CO 2 , 37 ° C for 12 hours.
  • GFP11-SBP2 For expression of GFP11-SBP2 fused cytotransmab animal cells, GFP11-SBP2 was genetically fused to the heavy chain C-terminus using three GGGGS linkers. Afterwards, transient transfection of HEK293F protein-expressing cells simultaneously with the animal expression vector encoding GFP11-SBP2 and the animal expression vector encoding the cytoplasmic infiltration light chain and endosomal escape ability were performed. Was done. After the purification of GFP11-SBP2 fused cytoplasmic penetration monoclonal antibody was carried out in the same manner as in Example 5.
  • VH variable domain monodomain
  • FR (framework) of the used library uses IGHV3-23 * 04, J H 4, which are the most commonly used V genes in conventional antibodies, and a library having 9 residues in CDR3 length was used.
  • IGHV3-23 * 04, J H 4 which are the most commonly used V genes in conventional antibodies
  • a library having 9 residues in CDR3 length was used.
  • the construction of the library and yeast surface expression methods are described in detail in a previously published paper (Baek and Kim, 2014).
  • Selected Escherichia coli was cultured in LB medium in the presence of 100 ⁇ g / ml ampicillin antibiotic to absorbance of 0.6 at 37 to 600 nm, and then 0.1 mM IPTG was added for protein expression, followed by further incubation at 30 degrees for 5 hours. . Thereafter, E. coli was collected using a centrifuge, and then E. coli was pulverized using ultrasonic waves (SONICS). Only the supernatant from which E. coli pulverization was removed using a centrifuge was purified using Glutathione resin (Clontech), which specifically purified GST-tagged proteins.
  • Glutathione resin Clontech
  • the conjugated KRas G12D antigen was reacted with a library-expressed yeast at room temperature for 1 hour, followed by reaction with PE conjugated streptavidin (Streptavidin-R-phycoerythrin conjugate (SA-PE) (Invitrogen) to produce FACS (Fluorescence). Suspension was confirmed by activated cell sorting (FACS Caliber) (BD biosciences). After selection of the next screening condition by FACS analysis, antigens were bound to yeast expressing the suspended library under the same conditions as above, and then suspended by FACS ariaII instrument.
  • Humanized heavy chain variable chain libraries suspended by primary MACS and primary FACS screening were expressed on the yeast surface in the form of Fab after yeast conjugation with yeast secreting cytoplasmic infiltration light chain single chain (hT4 VL), followed by secondary FACS, 3 The second FACS screening process was conducted.
  • FIG. 16 is a flow cytometric analysis of binding ability of GTP-coupled KRas G12D alone and competitive conditions with GDP-coupled KRas G12D in the selection step to obtain specific high affinity to the above-described GTP-bound KRas G12D. Data. Through this, the heavy chain variable region (VH) -dependent library selection capable of specific binding to GTP-coupled KRas G12D was confirmed.
  • VH heavy chain variable region
  • RT4 clones were finally selected through individual clone analysis from a library having high affinity and specificity for GTP-coupled KRas G12D protein through high-speed screening.
  • FIG. 17 is an analysis of 12% SDS-PAGE in reducing or non-reducing conditions after purification of anti-Ras.GTP iMab RT4.
  • the cell penetrating ability of anti-Ras.GTP iMab RT4 was observed in cell lines with KRas mutations (PANC-1, HCT116) and cell lines with KRas wild type (HT29, HeLa).
  • Figure 26a is an experimental result confirming the tumor growth inhibitory effect of RGD-fused anti-Ras.GTP iMab RT4 in mice transplanted with HCT116 cell line.
  • Figure 26b is a graph measuring the weight of rats to identify non-specific side effects of RGD fused anti-Ras.GTP iMab RT4.

Abstract

Cette invention concerne un procédé pour positionner, dans un cytoplasme, un anticorps au format immunoglobuline complète, par pénétration cellulaire active. L'invention concerne en outre une région variable de chaîne légère (VL) qui induit la pénétration active d'une membrane cellulaire de cellule vivante par un anticorps au format immunoglobuline complète et le positionnement de l'anticorps dans le cytoplasme, et un anticorps la contenant. Une molécule bioactive fusionnée à l'anticorps est en outre décrite. L'invention concerne également une composition permettant de prévenir, de traiter ou de diagnostiquer le cancer, comprenant l'anticorps ou la molécule bioactive fusionnée à celui-ci. Un polynucléotide qui code pour la région variable de chaîne légère et l'anticorps et un procédé de préparation d'un anticorps conçu pour pénétrer dans une cellule et se positionner dans le cytoplasme sont en outre décrits.
PCT/KR2015/007626 2014-07-22 2015-07-22 Procédé pour positionner, dans le cytoplasme, un anticorps au format immunoglobuline complète par pénétration de l'anticorps à travers la membrane cellulaire, et son utilisation WO2016013870A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
MX2017001010A MX2017001010A (es) 2014-07-22 2015-07-22 Metodo para posicionar en citoplasma, anticuerpo que tiene forma de inmunoglobulina completa penetrando el anticuerpo a traves de la membrana celular y uso para el mismo.
EP15825418.5A EP3173428B1 (fr) 2014-07-22 2015-07-22 Procédé pour positionner, dans le cytoplasme, un anticorps au format immunoglobuline complète par pénétration de l'anticorps à travers la membrane cellulaire, et son utilisation
AU2015292955A AU2015292955B2 (en) 2014-07-22 2015-07-22 Method for positioning, in cytoplasm, antibody having complete immunoglobulin form by penetrating antibody through cell membrane, and use for same
US15/327,369 US10844136B2 (en) 2014-07-22 2015-07-22 Method for positioning, in cytoplasm, antibody having complete immunoglobulin form by penetrating antibody through cell membrane, and use for same
JP2017525495A JP6595592B2 (ja) 2014-07-22 2015-07-22 完全型免疫グロブリン形態の抗体を細胞膜を透過して細胞質に位置させる方法およびその利用
BR112017001304-5A BR112017001304A2 (pt) 2014-07-22 2015-07-22 método para posicionamento, em citoplasma, de anticorpo contendo forma de imunoglobulina completa penetrando em anticorpo através da membrana celular e uso do mesmo
CN201580045139.0A CN107001481A (zh) 2014-07-22 2015-07-22 通过使抗体穿透细胞膜将具有完全免疫球蛋白形式的抗体定位在细胞质中的方法及其用途
CA2955272A CA2955272A1 (fr) 2014-07-22 2015-07-22 Procede pour positionner, dans le cytoplasme, un anticorps au format immunoglobuline complete par penetration de l'anticorps a travers la membrane cellulaire, et son utilisation
RU2017103675A RU2017103675A (ru) 2014-07-22 2015-07-22 Способ размещения в цитоплазме антител в виде полного иммуноглобулина путем проникновения антител через клеточную мембрану и его применение
IL250203A IL250203B (en) 2014-07-22 2017-01-19 A method for positioning, in the cytoplasm, an antibody with a complete immunoglobulic form using an antibody that penetrates the cell membrane, and its use
ZA2017/00488A ZA201700488B (en) 2014-07-22 2017-01-20 Method for positioning, in cytoplasm, antibody having complete immunoglobulin form by penetrating antibody through cell membrane, and use for same

Applications Claiming Priority (4)

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KR20140092673 2014-07-22
KR10-2014-0092673 2014-07-22
KR10-2015-0103163 2015-07-21
KR1020150103163A KR101602870B1 (ko) 2014-07-22 2015-07-21 완전한 이뮤노글로불린 형태의 항체를 세포막을 투과하여 세포질에 위치시키는 방법 및 그의 이용

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Cited By (11)

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Publication number Priority date Publication date Assignee Title
WO2017204606A1 (fr) * 2016-05-27 2017-11-30 오름테라퓨틱 주식회사 Anticorps pénétrant dans le cytosol et utilisation associée
CN109790212A (zh) * 2016-05-27 2019-05-21 奥隆制药 细胞溶质穿透抗体及其用途
KR20190132338A (ko) * 2019-11-21 2019-11-27 오름테라퓨틱 주식회사 세포질 침투 항체 및 이의 용도
WO2019235426A1 (fr) 2018-06-04 2019-12-12 中外製薬株式会社 Molécule de liaison à un antigène présentant une demi-vie modifiée dans le cytoplasme
WO2019235581A1 (fr) 2018-06-06 2019-12-12 国立大学法人大阪大学 MÉTHODE DE TRAITEMENT ET/OU DE PRÉVENTION DE MALADIES LIÉES À LA Regnase-1
WO2020047345A1 (fr) 2018-08-31 2020-03-05 Yale University Compositions et méthodes d'utilisation d'anticorps de pénétration cellulaire en association avec des modulateurs de points de contrôle immunitaire
US10787487B2 (en) 2018-06-21 2020-09-29 Orum Therapeutics Inc. Cell/tissue-specific cell-penetrating antibodies
US10851177B2 (en) 2014-07-22 2020-12-01 Orum Therapeutics Inc. Method for inhibiting intracellular activated RAS using intact immunoglobulin-type antibody having cytosol-penetrating ability and use thereof
US10961301B2 (en) 2011-04-01 2021-03-30 Yale University Cell-penetrating anti-DNA antibodies and uses thereof inhibit DNA repair
US11590242B2 (en) 2016-06-15 2023-02-28 Yale University Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors
WO2024081736A2 (fr) 2022-10-11 2024-04-18 Yale University Compositions et procédés d'utilisation d'anticorps de pénétration cellulaire

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10961301B2 (en) 2011-04-01 2021-03-30 Yale University Cell-penetrating anti-DNA antibodies and uses thereof inhibit DNA repair
US10851177B2 (en) 2014-07-22 2020-12-01 Orum Therapeutics Inc. Method for inhibiting intracellular activated RAS using intact immunoglobulin-type antibody having cytosol-penetrating ability and use thereof
CN109790212A (zh) * 2016-05-27 2019-05-21 奥隆制药 细胞溶质穿透抗体及其用途
WO2017204606A1 (fr) * 2016-05-27 2017-11-30 오름테라퓨틱 주식회사 Anticorps pénétrant dans le cytosol et utilisation associée
US11155641B2 (en) 2016-05-27 2021-10-26 Orum Therapeutics Inc. Cytosol-penetrating antibody and use thereof
EP3466970A4 (fr) * 2016-05-27 2020-01-15 Orum Therapeutics Inc. Anticorps pénétrant dans le cytosol et utilisation associée
AU2017271189B2 (en) * 2016-05-27 2020-02-20 Orum Therapeutics Inc. Cytosol-penetrating antibody and use thereof
US11590242B2 (en) 2016-06-15 2023-02-28 Yale University Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors
WO2019235426A1 (fr) 2018-06-04 2019-12-12 中外製薬株式会社 Molécule de liaison à un antigène présentant une demi-vie modifiée dans le cytoplasme
WO2019235581A1 (fr) 2018-06-06 2019-12-12 国立大学法人大阪大学 MÉTHODE DE TRAITEMENT ET/OU DE PRÉVENTION DE MALADIES LIÉES À LA Regnase-1
US10787487B2 (en) 2018-06-21 2020-09-29 Orum Therapeutics Inc. Cell/tissue-specific cell-penetrating antibodies
WO2020047345A1 (fr) 2018-08-31 2020-03-05 Yale University Compositions et méthodes d'utilisation d'anticorps de pénétration cellulaire en association avec des modulateurs de points de contrôle immunitaire
KR102091195B1 (ko) 2019-11-21 2020-03-19 오름테라퓨틱 주식회사 세포질 침투 항체 및 이의 용도
KR20190132338A (ko) * 2019-11-21 2019-11-27 오름테라퓨틱 주식회사 세포질 침투 항체 및 이의 용도
WO2024081736A2 (fr) 2022-10-11 2024-04-18 Yale University Compositions et procédés d'utilisation d'anticorps de pénétration cellulaire

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