WO2009105934A1 - Anticorps monoclonal anti-rankl humain - Google Patents

Anticorps monoclonal anti-rankl humain Download PDF

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Publication number
WO2009105934A1
WO2009105934A1 PCT/CN2008/070366 CN2008070366W WO2009105934A1 WO 2009105934 A1 WO2009105934 A1 WO 2009105934A1 CN 2008070366 W CN2008070366 W CN 2008070366W WO 2009105934 A1 WO2009105934 A1 WO 2009105934A1
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antibody
rankl
human
antibodies
osteoporosis
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Chinese (zh)
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刘庆法
庄贤韩
朱化星
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SHANGHAI LEADDISCOVERY PHARMACEUTICAL CO Ltd
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SHANGHAI LEADDISCOVERY PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to drug development using recombinant antibodies for the treatment of human osteoporosis and bone damage.
  • RANK nuclear factor- ⁇ receptor activating factors
  • osteoclast differentiation factor also known as osteoclast differentiation
  • RANK and its ligand RANKL are key components of osteoclast differentiation, maturation and function [1, 2, 3, 4, 5].
  • RANKL when combined with RANK, stimulates precursor osteoclast differentiation, activates mature osteoclasts, and causes bone resorption [3, 4, 5, 6]. This was originally the normal mechanism by which the body maintains the balance of bone metabolism. However, if the bone resorption process is excessive, it may cause osteoporosis.
  • the body produces osteoprotegerin 0PG in combination with the ligand, so that the number of osteoclasts is maintained in an appropriate equilibrium state, which does not lead to excessive bone resorption. Studies have confirmed that in osteoporosis, RANKL exceeds the level of osteoprotegerin causing excessive bone resorption [5, 7, 8].
  • Osteoporosis and bone damage involve the balance and regulation of 0PG/RAM/RAML [1, 3, 6].
  • the adjustment system involves three components: RANK, RANKL and 0PG.
  • RANK receptor activator of nuclear factor-KB
  • RANK receptor activator of nuclear factor-KB
  • RANKL receptor activator of nuclear factor-KB
  • Osteogenic/stromal cells are mainly expressed on the surface of osteoclast precursors and mature osteoclasts.
  • RANK is a type 1 transmembrane protein containing 616 amino acids, of which 184 amino acids constitute the extracellular domain and 383 amino acids constitute the intracellular domain.
  • RANKL receptor activator of nuclear factor-KB igand
  • RAML ( osteoblast / stromal cel ls ), activated lymphocytes and other expression.
  • RAML belongs to the TNF ligand superfamily and is available in both membrane-bound (mRANKL) and soluble (sRANKL) forms.
  • mRANKL is a type II transmembrane glycoprotein composed of 316 amino acids with a short N-terminal intracellular In the region, sRANKL is formed by proteolytic hydrolysis of the extracellular domain of mRANKL. Both types of RAML stimulate osteoclast differentiation and bone resorption, but mRANKL is more active than sRANKL.
  • OPG steoprotegerin
  • OPG steoprotegerin
  • OPG including osteogenic/stromal cells, dendritic cells, B lymphocytes, and endothelial cell precursors and fibroblast precursors.
  • 0PG is a member of the TNF receptor superfamily and differs from other TNF receptor superfamily members in that it lacks a hydrophobic transmembrane sequence and is a soluble glycoprotein consisting of 401 amino acids.
  • 0PG has two forms of dimer and monomer outside the cell, and the two forms of 0PG have the same physiological activity [1, 3, 4, 5, 6, 7].
  • RANKL, RANK, and OPG are involved in regulating the differentiation and function of osteoclasts.
  • osteogenesis/stromal cells express RANKL on their surface, specifically recognize osteoclasts, and bind to the functional receptor RANK on their membranes.
  • the signal is transmitted to the cells, and the osteoclast precursor is stimulated to develop into mature osteoclasts.
  • RANKL can also rapidly form an actin ring in mature osteoclasts through the RANK pathway, and activate mature osteoclasts to exert bone resorption.
  • the role of RAML/RAM can be suppressed by 0PG [ 1, 3, 6].
  • 0PG can be directly combined with RAML to competitively inhibit the binding of RAML to RAM, thereby inhibiting the differentiation and function of osteoclasts.
  • 0PG can also form a trimer with the RANKL/RANK combination to directly suppress the effect of RAML/RAM [14].
  • Abnormal bone resorption occurred in mice with RAML deletion or RAM deletion, and severe bone sclerosis occurred. While 0PG-deficient mice develop osteoporosis after birth, the addition of recombinant 0PG can increase bone density. It can be seen that RANKL/RANK/0PG together constitute a key loop regulation system that regulates osteoclast differentiation and exerts bone resorption function [1, 2, 5, 6].
  • Osteoporosis is quite common in middle-aged and elderly people, especially menopausal women, due to the above-mentioned mechanism of action.
  • the market growth potential for osteoporosis at home and abroad is very strong. The main reasons are twofold: First, the population is aging, and second, the current diagnosis and treatment rate of osteoporosis is still low, even in developed countries (in the world seven Less than 25% of women with osteoporosis in the major pharmaceutical markets are diagnosed and treated).
  • osteoporosis patients There are 10 million osteoporosis patients and 18 million low-bone people in the United States, and the number of fractures caused by osteoporosis is 1.5 million per year.
  • One-half and one-eighth of women over the age of 50 and men in the United States have a risk of osteoporosis-related fractures.
  • European statisticians estimate that there are 3 million osteoporosis patients in the UK, and one-third and one-twelfth of women and men over the age of 50 are developing this disease.
  • the onset of osteoporosis is not limited to a particular race, culture, age or gender, although there is no corresponding large epidemiological survey in the country.
  • the incidence of osteoporosis in different age groups in China is: 21% for 50-60 years old, 58% for 60-70 years old, and nearly 100% for those over 70 years old.
  • China is a country with a large population and the country with the largest population.
  • the total number of potential patients with osteoporosis (including low bones) in China is estimated to be about 87 million, accounting for nearly 7% of the country's total population.
  • the number of people over the age of 60 in China has accounted for about 9% of the total population, and the degree of aging of the society is still rising, the number of patients suffering from such diseases is expanding.
  • the number of new patients is 7 million per year.
  • bone damage can also occur due to the above mechanisms in the development and treatment of certain malignant tumors and autoimmune diseases, such as periodontitis, rheumatoid arthritis, bone cancer, and Bone cancer due to metastasis of malignant tumors has a high proportion of bone damage.
  • Osteoporosis or bone damage can also be caused by the use of drugs such as hormones to treat certain diseases.
  • Monoclonal antibody, therapeutic monoclonal antibody and its development Monoclonal antibody drugs have been greatly developed in the past decade. Several products have been successfully developed in terms of anti-TNFa-related diseases and have achieved great success. Due to huge market demand, these drugs are still in high-intensity development [9, 10, 11, 12] At present, the methods for obtaining monoclonal antibodies are mainly hybridomas, mainly involving rodents (such as mice, rabbits), birds (such as chickens), primates (such as macaques, baboons, etc.) and humans. In addition, research on camelid antibodies has increased in recent years. Monoclonal antibodies have also been developed using mouse humanized antibodies.
  • Another important requirement for being a candidate drug is whether it is easy to manufacture. This requires the production of antibodies to be produced on a large scale and at low cost. The most important indicator of this is the amount of antibody that can be produced per liter of culture medium, the so-called expression level [9, 10].
  • the E. coli expression system has the advantages of mature method, simple process, high yield, short cycle and low production cost.
  • E. coli Due to lack of glycosylation ability, it can not catalyze glycosyl transfer on Fc, and is not suitable for expression of intact antibodies, but can be used for expression of antibody fragments such as Fab, Fv, scFv, etc., plus PEGylation technology, through this artificial glycosylation Modifications to achieve or approximate the properties of natural antibodies.
  • the upcoming CDP-870 is produced using E. coli at a cost that is reduced to a quarter of other TNF inhibitor drugs.
  • the antibody library technology is a method for obtaining antibodies that can be obtained from the hybridoma technology at the end of the last century. It has been greatly developed in the past two decades and has gradually become an indispensable important technology for antibody engineering. Evolution, antibody modification, and antibody maturation have played an important role [13, 14, 15].
  • RANKL antagonists and their clinical application: As mentioned above, RANKL is one of the main factors causing osteoporosis and bone damage, and there are numerous studies showing that it is ankylosing spondylitis, psoriasis and rheumatoid arthritis. The main mediators of bone damage in patients and osteoporosis in the elderly and postmenopausal women [16, 17, 18, 19, 20].
  • This project is based on the whole human Na'ive combinatorial antibody library.
  • a fully human antibody with neutralizing ability to human RANKL was obtained, and its heavy and light chains were used by molecular biology techniques.
  • the variable region gene was cloned and the biologically active full length and Fab forms were successfully expressed in CH0 cells and E. coli. By PEGylation, a PEGylated Fab was successfully obtained.
  • Directed evolution, phage display and Combination of evolved mutants a strategy to recover the neutralization properties of the scFv version of BCF2, a neutralizing monoclonal antibody specific to scorpion toxin Cn2, Juarez-Gonzalez VR, Riafio-Umbarila L, Quintero-Herndndez V,
  • Phage display as a tool for the directed evolution of enzymes Ana Fernandez-Gacio, Marilyne Uguen and Jacques Fastrez, 2003, Trends in Biotechnology, 21 (9) :408-414 ⁇ 0PGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis, Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, 01iveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM, 1999, 28;397
  • RANK is essential for osteoclast and lymph node development, William C. Dougall, Moira Glaccum, Keith Charrier, et al, 1999, Genes & Dev., 13: 2412-2424.
  • RANKL/RANK/0PG The Role of Regulatory Systems in the Pathogenesis of Periodontitis, Zhang Jing, E1 Cavity Medicine Research, August 2005, Vol. 21, No. 4.
  • the molecular mechanism of osteoclastogenesis in rheumatoid arthritis Nobuyuki Udagawal, Shigeru Kotake2, Naoyuki Kamatan, et al , 2003, Arthritis Res., 4:281-289.
  • the object of the present invention is to disclose an anti-human RANKL antibody and a gene encoding the same.
  • Another object of the present invention is to disclose a Fab antibody of the above anti-human RANKL antibody and a PEGylated product thereof.
  • a third object of the present invention is to disclose the pharmaceutical use of the above anti-human RANKL antibody and its Fab antibody.
  • the invention features an anti-human RANKL antibody comprising a light chain amino acid sequence comprising SEQ ID NO: 2 and a heavy chain amino acid sequence comprising SEQ ID NO: 4.
  • Another aspect of the invention discloses a polynucleotide encoding the light chain of the above anti-human RANKL antibody, preferably, the sequence of the polynucleotide comprises SEQ ID NO: 1.
  • a third aspect of the invention discloses a polynucleotide encoding the heavy chain of the above anti-human RANKL antibody.
  • the sequence of the polynucleotide comprises SEQ ID NO: 3.
  • a polynucleotide encoding a full-length heavy chain of the anti-human RANKL antibody is disclosed, preferably the polynucleotide sequence comprises SEQ ID NO: 6.
  • the Fab antibody of the above anti-human RANKL antibody is disclosed.
  • the above Fab antibody is PEGylated.
  • the use of the above anti-human RANKL antibody or Fab antibody thereof for the preparation of a medicament for treating osteoporosis and bone damage associated with RANKL, such as preparation of senile osteoporosis, bone mass after menopause in women is disclosed.
  • a drug that causes bone damage caused by diseases such as loose rheumatoid arthritis is disclosed.
  • the anti-human RANKL antibody or Fab antibody of the present invention can be used for treating osteoporosis or bone damage in rheumatoid arthritis, certain cancers, postmenopausal women, the elderly, and the like.
  • the invention adopts the human hybridoma technology, obtains an anti-human RANKL whole human antibody, and physicochemical and biological activity of the antibody Preliminary analysis of the sex indicates that the antibody has a good affinity with human RANKL, and can effectively neutralize the physiological role of RANKL in promoting osteoclast formation in vitro.
  • the antibody since all of its amino acid sequences are completely identical to human antibodies, its immunogenicity to the human body is minimized.
  • the expression of Fab small molecule antibodies by the E. coli expression system is greatly reduced, and there is no side effect caused by effects such as complement binding and ADCC.
  • Figure 1 Schematic representation of the structure of a mammalian cell expression vector.
  • the ampicillin resistance gene AMP and origin of replication 0 are from PUC57
  • the eukaryotic promoter Pcmv is derived from human cytomegalovirus
  • the SV40 Ori and SV40 PolyA signals are derived from the SV40 virus.
  • Its resistance gene Neo (R) is derived from pCDNA3.1 (Invitrogen).
  • Figure 2 HPLC detection of target antibodies. The figure shows that there is only one target band, and the integral shows that its purity is over 98%.
  • Figure 3 Effect of anti-human RANKL antibody on osteoclast formation. The data in the figure is the result of counting TRAP stained cells. The ordinate is the number of osteoclasts formed; the abscissa is the antibody concentration, and the range is as described in the text.
  • the basic strategy of the present invention is to obtain the variable regions of the heavy and light chains of the anti-human RANKL antibody from the antibody library, and obtain the Fab and the full-length forms thereof based on the same, in order to evaluate the medicinal value thereof. .
  • Example 1 Screening of anti-human RANKL antibody gene variable region from antibody library
  • RNA samples from nearly 3,000 healthy young people from 22 provinces or municipalities including 15 nationalities (1 ml per person) were used to extract total RNA with TRIZ0L (GIBC0 BRL), and the heavy chain and light were amplified according to the following literature.
  • TRIZ0L GIBC0 BRL
  • Haidaris CG Malone J, Sherri ll LA, Bl iss JM, Gaspari AA, PlayStation RA, Sul l ivan MA., Recombinant human antibody single chain variable fragments reactive with Candida albicans surface antigens. J Immunol Methods. 2001 Nov 1; 257
  • the constructed antibody library was placed in -80C for storage.
  • the frozen antibody library strain 1 ml, after thawing at 37 degrees, add 14 ml of fresh LB medium and incubate at 37 °C for 16 hours in a 50 ml triangle flask.
  • Purified human RANKL protein (product of Orbigen) was used as an antigen, and a 25 ml cell culture flask was coated by a conventional method.
  • the cells obtained above were diluted to 100,000 cells/ml and cultured on a 1.5% agar plate to which 0.1% ampicillin was added to obtain a monoclonal antibody.
  • the clones on the above plates were cultured on 96-well deep well plates, one clone per well, and a total of 960 clones (10 96-well plates) were prepared.
  • the above 2G8 strain was amplified in 100 ml of LB medium, and plasmid DNA was purified using Promega's plasmid DNA extraction and purification kit.
  • the above plasmid was digested with DNA, and the fragment was digested on a 1.5% agarose gel electrophoresis, and a band of about 360 bp was taken for gel recovery, and the resulting fragment was a heavy chain variable region.
  • the above plasmid DNA was separated on a 1.5% agarose gel electrophoresis, and a band of about 320 bp was taken for gel recovery, and the resulting fragment was a light chain variable region.
  • the heavy chain variable region and the light chain variable region are respectively correspondingly constant
  • the regions are spliced to form a coding region for the full-length heavy chain and the full-length light chain.
  • the coding regions of the above full-length heavy and light chains are inserted into an expression vector to constitute an expression vector for the full-length antibody.
  • the expression vector used in this experiment used phCMV-I I (Fig. 1).
  • a vector such as pcDNA3.1 of Provigen and pCI-Neo of Promega can also be used.
  • Example 2 Transient expression of recombinant antibodies in CHO cells and preparation of small samples
  • the expression vector carrying the antibody gene constructed above was amplified by inoculating Escherichia coli DH5a strain in 100 ml of LB medium, and the plasmid DNA was extracted with Qiagen's Ultrapure Plasmid DNA Purification Kit. There are many similar products on the market to choose from.
  • the purified plasmid DNA was transfected into CH0 cells using Invitrogen's Lipofamine kit, and the manufacturer's instructions were followed. PEI25000 or other companies' transfection reagents or kits are also available.
  • CHO DHFR (-) cells (ATCC No. CRL-9096) cultured in 24 hours were added to 5 ml of fresh E302 medium to achieve a seeding density of 2x10e5 cells/ml; after 37 hours of culture at 37 degrees The cells were collected at 450Xg and transferred to 1 ml of fresh DMEM medium. After careful reselection of the cells, co-transfection was performed according to the manufacturer's instructions. After co-transfected CH0 cells were cultured for 48 hours, 50 ⁇ l of the supernatant was taken for detection of antibody expression by ELISA.
  • RAW264. 7 (ATCC No. TIB-71, Manassas, Va.) is a tumor-derived macrophage cell line induced by Abelson mouse leukemia virus, which can differentiate into osteoclasts in the presence of RANKL. Simonet et al. (1997, Cell 89 p. 309) and Lacey et al. (1998, Cell 93 p. 165) describe in detail the detection of osteoclasts in RAW cell culture in the presence of RANKL. RAW cells can be stimulated by ligands to differentiate into osteoclasts, and their differentiation can be understood by detecting the activity of TRAP (Tartrate resistant acid phosphatase (TRAP). Therefore, anti-human RANKL antibody pairs The effects of osteoporosis or bone damage can also be detected.
  • TRAP Steartrate resistant acid phosphatase
  • TRAP converts para-nitrophosphate to para-nitrophenol, which can be quantified at 405 nm.
  • the activity of TRAP is a surrogate for osteoclast development and is associated with an optical density of 405 nm.
  • a set of data on the optical density and anti-RANKL antibody concentration reflects the inhibition of osteoclast formation by the antibody.
  • TRAP staining was used. Multinucleated TRAP positive staining is a characteristic marker of osteoclasts, which is the basis for the design of this trial.
  • RAW 264. 7 cells were used as test materials, 1 10 4 cells/well were seeded in 24-well plates, and cultured for 24 hours, respectively, with 50 ng/ml RAML and different concentrations (10 ng to 500 ng/ml), cells were changed every 3 days. 1 time.
  • TRAP Day 6 anti-tartaric acid phosphatase staining (Sigma-Aldrich, 387-A, USA), cells were fixed in citrate/acetone solution for 1 minute, and incubation solution with naphthol AS BI phosphate as substrate Incubate for 1 hour at 37 °C, wash 3 times with distilled water, counterstain for 2 minutes with hematoxylin. After drying, the xylene is transparent, sealed with DPX (polystyrene + butyrate + xylene), and observed under light microscope.
  • TRAP-positive cells were osteoclasts, and the number of TRAP-positive multinucleated osteoclasts (3 nuclei) was counted by microscopy.
  • the test results are shown in Figure 3.
  • the antibody concentrations were: 0, 0. 001, 0. 01, 0. 05, 0. 1, 1. 0, 10.
  • Ong/ml o As can be seen from the data in the figure, the anti-human RANKL antibody of the present invention has good The ability of neutralizing RANKL to stimulate osteoclast formation.
  • variable region of the above 2G8 anti-human RANKL antibody was subjected to DNA sequencing, and the sequencing work was entrusted to Shanghai Keikang Co., Ltd.
  • the results are as follows:
  • Example 5 Study on the antagonism of RAML by 2G8Fab-PEG.
  • the purified antibody of the above Example 4 was tested for its neutralizing ability to RANKL by the following method.
  • the prepared Fab was antagonized by the RANKL neutralization ability test as described in Example 3, and it was found that 2G8Fab has a good neutralization effect (see Fig. 3 for the results).

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Abstract

L'invention porte sur des anticorps se liant de façon spéciale au ligand kappa B nucléaire facteur récepteur activateur (RANKL) humain, qui ont la région variable à chaîne légère représentée par SEQ ID N°2 et la région variable à chaîne lourde représentée par SEQ ID N°4. L'invention porte également sur les polynucléotides codant pour les anticorps, l'anticorps Fab et l'anticorps Fab pegylé anti-RANKL humain. Ces anticorps peuvent être utilisés pour la fabrication de médicaments pour le traitement de l'ostéoporose ou d'un endommagement du squelette.
PCT/CN2008/070366 2008-02-27 2008-02-27 Anticorps monoclonal anti-rankl humain Ceased WO2009105934A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011116527A1 (fr) * 2010-03-26 2011-09-29 Qing Fa Liu Anticorps monoclonaux anti-rankl humain et leurs utilisations
CN109890845A (zh) * 2016-10-28 2019-06-14 伊莱利利公司 抗rankl抗体及其用途
WO2022187440A1 (fr) * 2021-03-03 2022-09-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Proprotéine la en tant que nouveau régulateur de l'ostéoclastogenèse

Citations (2)

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WO2001091793A1 (fr) * 2000-05-26 2001-12-06 Smithkline Beecham Corporation Anticorps monoclonaux contre le ligand rank, utilises pour le traitement d'etats pathologiques lies au ligand rank
US6740522B2 (en) * 1996-12-23 2004-05-25 Immunex Corporation Antibodies against ligand for receptor activator of NF-kB

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US6740522B2 (en) * 1996-12-23 2004-05-25 Immunex Corporation Antibodies against ligand for receptor activator of NF-kB
WO2001091793A1 (fr) * 2000-05-26 2001-12-06 Smithkline Beecham Corporation Anticorps monoclonaux contre le ligand rank, utilises pour le traitement d'etats pathologiques lies au ligand rank

Non-Patent Citations (1)

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Title
KOSTENUIK P. J. ET AL.: "Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength", CURRENT OPINION IN PHARMACOLOGY, vol. 5, no. 6, December 2005 (2005-12-01), pages 618 - 625, XP005134774, DOI: doi:10.1016/j.coph.2005.06.005 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011116527A1 (fr) * 2010-03-26 2011-09-29 Qing Fa Liu Anticorps monoclonaux anti-rankl humain et leurs utilisations
CN102741286A (zh) * 2010-03-26 2012-10-17 刘庆法 以pae技术开发的抗人rankl单抗及其应用
CN102741286B (zh) * 2010-03-26 2013-12-25 刘庆法 以pae技术开发的抗人rankl单抗及其应用
CN109890845A (zh) * 2016-10-28 2019-06-14 伊莱利利公司 抗rankl抗体及其用途
CN109890845B (zh) * 2016-10-28 2022-07-01 伊莱利利公司 抗rankl抗体及其用途
WO2022187440A1 (fr) * 2021-03-03 2022-09-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Proprotéine la en tant que nouveau régulateur de l'ostéoclastogenèse

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