EP3458093A1 - Pharmazeutische zusammensetzungen mit anti-rankl-antikörpern, kalzium und vitamin d, geeignet zur behandlung und/oder prophylaxe von erkrankungen des knochenstoffwechsels und von therapiebedingten nebenwirkungen wie hypokalzämien - Google Patents
Pharmazeutische zusammensetzungen mit anti-rankl-antikörpern, kalzium und vitamin d, geeignet zur behandlung und/oder prophylaxe von erkrankungen des knochenstoffwechsels und von therapiebedingten nebenwirkungen wie hypokalzämienInfo
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- EP3458093A1 EP3458093A1 EP17728455.1A EP17728455A EP3458093A1 EP 3458093 A1 EP3458093 A1 EP 3458093A1 EP 17728455 A EP17728455 A EP 17728455A EP 3458093 A1 EP3458093 A1 EP 3458093A1
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- calcium
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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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], 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
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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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- 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
- compositions with anti-RANKL antibodies, calcium and vitamin D suitable for the treatment and / or prophylaxis of diseases of the bone metabolism and therapy-related side effects such as hypocalcemia
- the present invention includes pharmaceutical compositions comprising anti-RANKL antibodies, calcium and vitamin D suitable for the treatment and / or prophylaxis of bone metabolism disorders and therapy-related side effects such as hypocalcemia caused by the action of the anti-RANKI antibodies.
- the treatment of bone metabolism disorders such as osteoporosis, tumors including induced bone loss (CTIBL), Paget's disease, or hypocalcaemia is a major focus in medical research.
- the human bone consists of an organic matrix with inorganic salts - mainly calcium and phosphate in the form of hydroxyapatite ((Ca 3 P0 4) 2 ⁇ Ca (OH) 2) is combined.
- Ca 3 P0 4 hydroxyapatite
- OH hydroxyapatite
- bone physiology in humans is based on a constant build-up and break down (bone turnover) of bone substance.
- Bone AUF and AB construction in the course of the ongoing remodeling is hormonal (mainly by estrogen, parathyroid hormone (PTH)) and by signal transduction pathways (essentially RAN KL ("receptor activator of nuclear factor-kB ligand”) / OPG (osteoprotegerin While in childhood, and especially puberty, more bone is broken up than is broken down, in women, especially during and after menopause, there is an increasing incidence of 'bone' bone loss.
- hormonal mainly by estrogen, parathyroid hormone (PTH)
- PTH parathyroid hormone
- OPG osteoprotegerin While in childhood, and especially puberty, more bone is broken up than is broken down, in women, especially during and after menopause, there is an increasing incidence of 'bone' bone loss.
- micro-damage or interruptions of continuity occur with and without defect formation, which can heal without scarring.
- inorganic materials repetitive stresses below the fracture limit result in fatigue / fatigue failure, causing small cracks and growing until they reach a critical size and break the material.
- micro-cracks As a quasi-brittle material, which absorbs energy through the formation of small cracks (so-called "micro-cracks"), it can avoid bone fractures.
- Micro cracks were already described by Harold Frost in 1960 and are clearly limited cracks of 50-1 ⁇ Length, which occurs mainly in interstitial bone. They are usually longer according to the biomechanical load in the longitudinal axis than in the transverse axis, arise even in physiological, repetitive loads such as walking and running in the trabecular and cortical bone and occur significantly increased in age.
- micro-cracks In the bone, “micro-cracks” usually remain clinically inapparent, as they are constantly repaired and cured in the context of “remodeling”.
- the crack causes apoptosis of osteocytes which release factors, i.a. RANKL. These trigger osteoclastic resorption, with consecutive osteoblastic bone attachment.
- highly potent antiresorptive drugs such as bisphosphonates or anti-RANKL antibodies for accumulation and possibly increased susceptibility to breakage, for example in atypical femur fractures.
- Osteoblast, osteoclasts and osteocytes are essentially involved in remodeling bone remodeling. While osteoclasts break down the bone, osteoblasts can grow the bone.
- osteoclastic resorption is initially initiated, soft on then turn the osteoblastic bone cultivation follows.
- the WNT pathway for osteoblast differentiation as well as the PTH signal transduction pathway are mainly involved.
- the differentiation of hematopoietic stem cells into osteoclasts is controlled via the RANKL / OPG signal transduction pathway.
- the bone serves as a calcium reservoir for the human body and is thus crucial in the calcium phosphate homeostasis involved. Bone up and down can store excess calcium reserves from the blood or make them available again if needed.
- SRE skeletal related events
- SRE includes acute events such as pathological bone fractures, spinal cord compression, bone pain or tumor-induced hypercalcaemia, as well as therapeutic interventions such as bone irradiation or bone surgery, which may occur in patients with bone metastases or primary bone tumors, for example.
- Osteoporosis causes a decrease in bone density, which together with the reduced bone quality leads to an increased bone fracture risk.
- As osteoporosis is currently a measurable bone density reduction of less than -2.5 standard deviations (so-called T-value or English T-score) from a healthy collective (women, 30 years), measured by DXA (dual-energy X-ray absorptiometry) by the WHO are defined.
- a broken bone is called a manifest osteoporosis. Osteoporosis is thus a systemic disease of the bone, often manifested by a fracture with inadequate trauma.
- the postmenopausal bone mass loss can be up to 15% per year and leads in women with low peak bone mass very quickly to the first osteoporotic fracture.
- FIG. 1 illustrates that approximately only one third of the amount of calcium offered in the digestive tract is absorbed. 65-70% of the dietary calcium is excreted in the stool.
- the resorption process itself can additionally be influenced positively or negatively by various factors. For example, foods that are highly fortified with phosphates can extremely inhibit the absorption of calcium.
- Calcitriol is essential to allow the absorption of calcium and phosphate in the small intestine.
- calcitriol increases the reabsorption of calcium in the kidneys and stimulates bone mineralization (incorporation of calcium into the bone matrix).
- a negative calcium balance results when the body excretes more calcium than it can reabsorb via the intestine. If this condition persists for a long time, it leads to increased bone resorption and secondary hyperparathyroidism.
- parathyroid hormone stimulates bone resorption and thus leads to an increase in the calcium concentration in the blood, so that the calcium concentration in the blood remains relatively constant at the expense of the bone which is present in the presence of calcium deficiency
- An increase of calcium in the blood donates its calcium.
- the age-related high demand for calcium is essentially influenced by the following factors: decreasing calcium absorption in the glottal tract, low-calcium diet (low dairy products), vitamin D deficiency, little exercise, calcium storage "bone” should be replenished (build up of new bone mass), increased parathyroid hormone Blood (increased bone loss and calcium loss) or impaired renal function (decreased calcium reabsorption and less active vitamin D).
- vitamin D3 (1 ⁇ , 25-dihydroxycholecalciferol; calcitriol) promotes the absorption of calcium from the gastrointestinal tract into the blood. The maximum serum concentration is reached within three to six hours after ingestion.
- vitamin D promotes the absorption of calcium in the body. Overdosing can cause vitamin D poisoning as the body stores vitamin D. The vitamin D poisoning can lead to a strong demineralization of the bone, which leads to fractures. At the same time, high calcium serum concentrations can lead to abnormal calcification of a variety of soft tissues. In addition, kidney stones may be due to increased renal calcium excretion.
- Vitamin D deficiency results in less calcium being absorbed from the food into the bloodstream due to reduced intestinal absorption.
- Calcium and / or vitamin D deficiency is treated by supplementation with calcium and vitamin D-containing preparations.
- the use of calcium and vitamin D is not undisputed.
- the calcium deficiency means an increase in the clinical picture with an increase in fracture risk.
- the bone mineral content is reduced (T-score: ⁇ -2.5) and fractures have occurred, for example 1 to 3 vertebral body fractures.
- glucocorticoid therapy may lead to severe glucocorticoid or corticoid-induced osteoporosis with fractures.
- Preventive or therapeutic measures are recommended if> 5 mg prednisone equivalent per day for> 3 months.
- Glucocorticoid-induced bone loss has several causes. Glucocorticoids increase bone resorption at the beginning of therapy. Steroids inhibit the proliferation and function of osteoblasts and increase their apoptosis. They thereby cause a reduced formation of new bone.
- Paget's disease also known as osteodystrophia deformans, ostitis deformans, Paget's disease, or Paget's disease of currently unknown cause, with genetic, viral, and environmental factors being discussed as possible causes.
- Paget's disease is a chronic disease of bone metabolism characterized by locally increased bone remodeling associated with the risk of deformity, chronic pain and fractures, as well as articular, neurological, and cardiac complications.
- Solid primary tumors such as mammary, prostate, lung, colon or bone carcinoma (e.g., osteosarcoma) may manifest in the bone, causing bone metastases.
- Bone metastases are deposits of other tumors in the bones and can lead to pain and fractures there.
- Responsible is an increased bone loss or excess production of inferior bone substance. This reduces the stability of the bones.
- Tumor-related bone complications show a high morbidity, an increased bone fracture rate, nerve compression and sometimes unbearable pain. If more calcium is released from the bone and released into the blood, tumor-induced hypercalcaemia can develop.
- the proportion of patients with moderate or severe bone pain is by far the highest (Cleeland, CS et al., Ann One 2005, 16: 972-980).
- multiple myeloma or “plasmocytoma” or “Kahler's disease” includes a cancer of the bone marrow in which the antibody-producing cells (plasma cells) are proliferated. These malignant plasma cells multiply uncontrollably and form non-functional antibodies or parts thereof The course of the disease can be very different from moderate to highly malignant processes, which quickly lead to the death of the patient without treatment.
- the symptoms are caused by the growth of the cells or by the produced antibodies or their fragments resulting in bone pain, reduction of bone mass and bone fractures, accompanied by increased release of calcium into the blood, which can lead to tumor-induced hypercalcaemia, the number of leukocytes decreases while the large number of antibodies accumulates in the tissue and lead to functional disorders of many organs, kidney failure, and to Impaired circulation.
- Drugs for the treatment of bone metabolism disorders are known.
- the main aim of the drug therapy of osteoporosis is to stop the pathological loss of bone mass.
- the negative balance (imbalance between attachment and removal of bone substance) can be compensated either antiresorptive, by inhibiting the osteoclasts (bone loss) or anabolically, by stimulating the osteoblasts (bone structure). Only when the processes of attachment and dismantling are balanced again and an adequate supply of calcium and vitamin D is ensured can new bone mass be built up and the risk of osteoporotic fractures reduced.
- osteoclastic bone degradation can be inhibited by anti-RANKL antibodies
- anabolic drugs can be used to stimulate bone growth.
- the recombinant 1 -34 fragment of parathyroid hormone is approved for the treatment of osteoporosis.
- Anti-resorptive drugs such as anti-RANKL antibodies are currently standard in the treatment of metabolic bone diseases that require effective inhibition of bone resorption. These include the use of these classes of substances for the treatment of osteoporosis as well as - with significantly higher doses and shorter treatment intervals - for Behnadlung and / or prevention of tumor-related skeletal complications.
- Anti-RANKI antibodies or their derivatives are commonly used to treat the above-mentioned diseases such as osteoporosis or tumor-related bone diseases.
- the calcium remains in the bone. Stimulation of bone degradation e.g. By parathyroid hormone is thereby more or less strongly prevented. There is a risk of hypocalcemia. Hypocalcaemia is present when the total calcium in the blood serum is below 2.2 mmol / l (9 mg / dl). Due to the drug-induced inhibition of the osteoclasts, the calcium concentration in the blood can only be compensated by a supply of calcium from outside (oral or intravenous). This is shown in FIG. PTH activates the release of calcium from the bone, which is prevented by the inhibition of osteoclasts due to the use of anti-RANKL antibodies. Therefore, the supply of calcium from the outside is essential.
- parathyroid hormone is increasingly used to balance the serum calcium level distributed.
- Parathyroid hormone indirectly increases the calcium concentration in the blood plasma by activating the osteoclasts.
- Antiresorptive therapy increases hypocalcemia by inhibiting osteoclasts.
- hypocalcaemia caused in this way can lead to cardiac arrhythmias and, in the case of particularly severe cases, even death if the hypocalcaemia is not detected and treated in time.
- hypocalcemia often remains undetected, as the calcium level in ambulatory clinical treatment is not measured at close intervals as a laboratory parameter.
- supplementation with calcium and vitamin D is now provided with the use of anti-RANKL antibodies, which can prevent hypocalcaemia.
- An unmet need for calcium and vitamin D may also increase the overall success of antiresorptive therapy, e.g. with anti-RANKL antibodies adversely affect and thus reduce the desired protection against new fractures or increase the number of fractures even if the calcium and vitamin D supplementation is omitted with antiresorptive therapy.
- pine osteonecroses As a side effect of anti-RANKL antibodies, pine osteonecroses are listed. Pine osteonecrosis may be treated with anti-RANKL antibodies and cause pain in the mouth, non-healing wounds, or dissolution of the jaw.
- cardiovascular side effects such as cardiac arrhythmia, convulsions and secondary hyperparathyroidism.
- the present invention solves these problems and provides novel pharmaceutical compositions of anti-RANKL antibodies and calcium and vitamin D and / or derivatives thereof to better enhance the diseases of bone metabolism treat or prevent these diseases and thus ensure the optimal effect, as well as treatment-related side effects such as hypocalcemia and / or improper use to prevent or prevent the latter.
- the invention relates to the use of pharmaceutical compositions comprising anti-RANKL antibodies and / or their antigen binding fragments and calcium and vitamin D for the treatment of osteoporosis, postmenopausal osteoporosis, overt osteoporosis, corticoinduced osteoporosis, osteoporosis of the male or female, Paget disease, osteogenesis imperfecta for the prophylaxis of fractures of the aforementioned diseases, as well as for use in the treatment and / or prophylaxis of anti-RANKL antibody treatment-induced hypocalcemia, characterized in that the pharmaceutical composition comprising anti-RANKL antibodies and / or their antigen binding fragments, more preferably at a dosage of 30 to 90 mg in 1 -2 ml solution (20-60 mg / ml), more preferably 50-70 mg, even more preferably 60 mg, preferably in 1 ml solution (60 mg / ml).
- composition (s) calcium is administered orally at a dosage of 400-600 mg per day, more preferably 500 mg per day, and vitamin D in a dosage of 800-1200 I.U. (International Units) Vitamin D, more preferably 1000 I.U. Vitamin D is administered orally daily.
- the invention relates to the use of pharmaceutical compositions comprising anti-RANKL antibodies and / or their antigen-binding fragments and calcium and vitamin D for the prevention of skeletal complications, in particular pathological fractures, irradiation of the bone, spinal cord compression, bone surgery, bone metastases , Pain in bone metastases, nerve entrapment or deformity due to one or more solid tumors such as breast cancer, prostate cancer, lung cancer or multiple myeloma, as well as the prophylaxis of fractures in the aforementioned diseases and for use in the treatment and / or prophylaxis of anti-RANKL Antibody therapy-induced hypocalcaemia, characterized in that anti-RANKL antibodies and / or their antigen-binding fragments are administered, preferably in a dosage of 60-180 mg in 1 -3 ml solution, more preferably 80-15 0 mg, even more preferably 120 mg, especially in 1, 7 ml solution (70 mg / ml) anti-RANKL antibodies
- the invention further relates to the use of various calcium compounds and vitamin D for use in the treatment and / or prophylaxis of therapy-related side effects, in the aforementioned embodiments, as well as pharmaceutically suitable excipients and solvents.
- Anti-RANKL antibodies are very effective antiresorptive agents and are used to treat bone metabolism disorders. Despite its effectiveness, the treatment with anti-RANKL antibodies is burdened by considerable, sometimes severe side effects.
- the present invention provides pharmaceutical compositions that significantly enhance the efficacy and safety of anti-RANKL antibody treatment.
- the pharmaceutical compositions include, in addition to anti-RANKL antibodies, calcium and vitamin D.
- RANKL is a transmembrane protein, but may also occur as a soluble protein. RANKL plays a crucial role in the formation, function and survival of osteoclasts. In multilevel myeloma and bone metastases, increased osteoclast activity occurs, which is stimulated by RANKL. This leads to increased bone loss.
- the sequence of the human RANKL protein is shown in Figure 6.
- the protein is present in various isoforms.
- amino acids 1 to 73 are missing and for isoform 3 amino acids 1 to 47 are missing.
- Anti-RANKL antibodies prevent the RANK-RANKL interaction. This reduces the number and function of osteoclasts and reduces bone loss.
- anti-RANKL antibody includes all RANKL-binding molecules which bind to at least one epitope of RANKL and thus influence the activity of RANKL, ie block or diminish the binding of RANKL to RANK, such that activation of RANKL
- Figure 6 SEQ ID NO 7
- epitope refers to a binding site on an antigen, in this case RANKL, to which the anti-RANKL antibody specifically binds
- the epitope can bind to a primary amino acid sequence of RANKL, which is typically at least 3 amino acids, usually at least 5 or Example 8-10 amino acids Depending on the 3-dimensional structure of RANKL, the epitope may also bind amino acids that are not sequential in sequence, but are located nearby due to the 3-dimensional structure.
- the term “specifically binds” means that the antibody is capable of interacting with at least 2, preferably 3, more preferably 4 amino acids of an epitope, for example according to the "key-lock principle”.
- binding affinity means that the antibody binds to a RANKL molecule and substantially not to other proteins or molecules, and the antibody may cross-react with RANKL molecules from other species, but the antibody should not be given to others Bind molecules such as RANK.
- a bond is generally considered to be specific if the binding affinity is greater than 10 -5 M.
- the specific binding affinity is preferably from about 10 "11 to 10" 8 M (KD), preferably about 10 "11 to 10- 9 M.
- substantially does not bind means that the anti-RANKL antibody of this invention does not bind another protein, in particular has a cross-reactivity of less than 30%, preferably 20%, more preferably 10%, especially less than 9.8, 7,6, or 5% binds another protein or molecule.
- polypeptide is synonymous with the term “protein”. Proteins contain one or more amino acids linked by covalent bonds. They may be subject to post-translational modifications such as glycosylations. This is well known.
- antibody includes a protein having one or more antigen-binding domains encoded at least in part by immunoglobulin genes or portions thereof
- An "immunoglobulin” is an “antibody.”
- the antibody typically comprises a glycosylated tetramer (s), consisting of 2 light chains of approximately 25 kDa each and 2 heavy chains of approximately 50 kDa 2 types of light chains exist in antibodies: lambda and kappa
- the light chains consist of one variable domain and one constant domain VL and CL
- immunoglobulins are classified into 5 classes: A, D, E, G, and M, and some become subgroups for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
- the heavy chains each have a variable and three IgG and IgA and four constant domains for IgM and IgE. These are referred to as VH and CH1, CH2, CH3.
- IgM antibodies contain 10 antigen binding sites.
- the basic unit consists of two heavy H chains and two light L chains.
- IgM is the first immunoglobulin produced during an immune response and activates the complement system.
- the body's naturally produced IgM antibodies are secreted by B1 cells (CD20 + , CD20 + , CD27 + , CD43 + and CD70 + cells).
- B1 cells CD20 + , CD20 + , CD27 + , CD43 + and CD70 + cells.
- repelling invading microorganisms they are involved in tissue homeostasis through the clearance of apoptotic and altered cells through complement-dependent mechanisms. They inhibit inflammatory processes and remove altered cells.
- IgA antibodies contain 2-5 of the 4-chain units that can form units together with the J chain. IgA can occur as a monomer (ie only one molecule) or as a dimer (two molecules attached to the long ends of the antibody-ys-psone). The dimers are the so-called secretory IgA (slgA).
- Each light chain contains an N-terminal variable (V) domain (VL) and a constant domain (CL).
- Each heavy chain contains an N-terminal V domain (VH), 3 or 4 C domains (CHs) and a hinge region.
- the constant domains of the antibody are not directly involved in antigen binding, but may have various effector functions, for example in antibody-dependent cellular toxicity. If an antibody exerts cellular toxicity, it is preferably the IgG1 subtype, while the IgG4 subtype does not have this capability.
- the compound of VH and VL forms an antigen-binding site.
- Each L chain is linked to the H chain via a covalent disulphide bridge, while the two H chains are linked by one or more disulphide bridges, depending on the H chain isotype.
- the VH and VL domains consist of four regions with relatively highly conserved sequences (FR1, FR2, FR3, and FR4) that provide the framework for the three regions with hypervariable sequences, the complementary determining regions, CDRs.
- the CDRs are essentially responsible for the interaction between antigen and antibody. CDRs are more specifically referred to as CDR1, CDR2 and CDR3.
- CDR regions of the heavy chain are designated H1, H2 and H3, while the CDR regions of the light chain are designated L1, L2 and L3.
- variable refers to the portion of the immunoglobulin domain that contains variability in the sequence and defines the specificity and binding affinity of a particular antibody, such as variable domains. The variability is not evenly distributed in the antibody, it focuses on the sub Domains of the respective light and heavy chains, which are referred to as hypervariable regions, or CDRs.
- variable domains The less conserved regions or non-hypervariable regions of the variable domains are the so-called framework regions (FR), which often have a beta-sheet structure.
- FR regions and the CDRs form the structure that recognizes and binds the antigen (Kabat EA, Wu, TT, Perry, H., Gottesman, K. and Foeller, C. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition NIH Publication No. 91-3242).
- the constant domains are not directly involved in antigen-antibody binding, but mediate other reactions such as antibody-dependent and cell-mediated cytotoxicity and complement activation.
- CDR refers to the complementary determining region (CDR).
- the CDRs are referred to as CDR 1 -3 as shown above, those of the light chain as CDRL1, CDRL2 and CDRL3, and the heavy chain variable regions include as CDRH1, CDRH2 and CDRH3.
- CDRs contribute significantly to the activity of the antibody.
- the exact length of the CDRs is classified and numbered differently in different systems.
- CDRs are referred to below as Kabat, Chothia. All systems have overlaps in terms of the designation of the hypervariable region within the variable sequence (Kabat et al., Chothia et al., J. Mol. Biol., 1987, 196; 901 and Mac Callum et al., J. Mol. Biol., 1996, 262: 732), reference is made essentially to the numbering of Kabat.
- amino acid or “amino acid residue” refers to amino acids known in the art selected from the group consisting of alanine (ala or A); Arginine (Arg or R); Asparagine (Asn or N); Aspartate, (Asp or D); Cysteine (Cys or C), glutamine (Gin or Q); Glutamic acid (Glu or E); Glycine (Gly or G); Histidine (His or H); Isoleucine (oil or I); Leucine (Leu or L); Lysine (Lys or K); Methionine (Met or M); Phenylalanine (Phe or F); Proline (Pro or P); Serine (Ser or S); Threonine (Thr or T); Tryptophan (Trp or W); Tyrosine (Tyr or Y); Valine (Val or V), where modified, synthetic or rare amino acids can also be used.
- CDR hypervariable region
- L chain immunoglobulin light
- H chain heavy chain
- the CDRs are the most variable parts of the receptors and are responsible for their diversity.
- the three complementarity determining regions CDR1, CDR2 and CDR3 are loops at the end of a V domain of antibodies. They come into direct contact with an antigen.
- At least two methods are known in the art to identify CDRs: one approach based on cross-species sequence variability (Kabat et al.) And another approach based on crystallographic studies of the antigen-antibody complex (Chothia, C. et al. J. Mol. Biol., 196: 901-917 (1987)).
- framework region is known to those skilled in the art and refers to the portions of the variable region of the antibody that exists between the hypervariable regions, the CDRs.
- framework regions are typically referred to as framework regions 1-4 (FR1, FR2, FR3 and FR4) and form the backbone for the 6 CDRs, three of the light chain, and three of the heavy chain) in three-dimensional space to provide an antigen-binding surface.
- the invention encompasses all anti-RANKL antibodies that are considered interchangeable and have antigen-binding function by the Kabat Numbering System, i. can bind to a RANKL epitope.
- Antibody means a monoclonal, polyclonal, monospecific, bispecific, bifunctional, single chain, synthetic, recombinant, mutant, human, humanized, chimeric antibody (Harlow and Lane, “Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, USA ) which binds to a RANKL molecule or a derivative that retains or substantially retains the binding capacity. Domain antibodies (dAbs) and nanobodies are also encompassed by the term “antibodies”.
- a bispecific or bifunctional antibody is a hybrid artificial antibody with 2 different heavy / light chains and two different binding sites.
- the term and methods of preparation are well known to those skilled in the art (e.g., Songsivilai & Lachmann, Clion Exp Immunol 79: 315-321 (1990); Kostelny et al., J. Immunol 148, 1547-1553 (1992).
- antibody also includes a bifunctional or bispecific antibody and antibody constructs such as Fvs (scFv) from single chain or antibody fusion proteins
- scFv single chain Fv fragment
- the antibody can be human or humanized.
- humanized antibody means that at least one complementary determining region (CDR) such as CDR3 and preferably all 6 CDRs have been replaced by CDRs from a human antibody with the desired specificity. Constant region (s) of the antibody replaced by the constant region (s) of a human antibody.
- a human antibody As an alternative to the humanized antibody, a human antibody is provided.
- Transgenic animals such as mice are capable of producing human antibodies after immunization without typical mouse antibody sequences. They can form fully human antibodies (e.g., Jakobovits et al., Proc. Natl. Acad., U.S.A., 90: 2551 (1993)).
- so-called phage display technology can be used to produce human antibodies or antigen-binding fragments. The techniques are known (Mc Cafferty et al., Nature 348: 552-553 (1990); Johnson, Kevin S. and Chiswell, David J., Curr. Opin. Struct. Biol. 3: 564-571 (1993)).
- antigen-binding fragment refers to a fragment of the term "antibody” as defined above, such as separate light and heavy chains, Fab, Fab / c, Fv, scFv, Fd, dAb, Fab ', F (ab') 2
- the binding fragment may comprise a light chain variable region and a heavy chain variable region, not necessarily both at the same time.
- the invention also encompasses hybrid antibodies in which a pair of H and L chains are obtained from a first antibody while the other pair of dog L chains are obtained from another second antibody.
- a pair of L and H chains are derived from anti-RANKL antibodies.
- each L-H chain pair binds different epitopes of a RANKL-specific antigen.
- Such hybrids can also be formed using humanized H or L chains.
- the invention also encompasses other bispecific antibodies, e.g. those containing two separate antibodies covalently linked by their constant regions.
- the size of the antigen-binding fragment can only be the minimum size required to provide a desired function. It may optionally comprise a further amino acid sequence, either native to the antigen-binding fragment or from a heterologous source, as desired.
- Anti-RANKL antigen-binding fragments may comprise 5 contiguous amino acid residues from an antibody V region sequence. Also included are polypeptides having 7 amino acid residues, more preferably about 10 amino acid residues, more preferably about 15 amino acid residues, even more preferably about 25 amino acid residues, even more preferably about 50 amino acid residues, even more preferably about 75 amino acid residues from the antibody L or H chain V region include. Even more preferred are polypeptides comprising the entire antibody L or H chain V region.
- Substitutions may range from the alteration or modification of one or more amino acid residues to the complete redesign of a region, such as e.g. rich in the V region.
- Amino acid residue substitutions if present, are preferably conservative substitutions that do not adversely affect the folding or functional properties of the peptide.
- Groups of functionally related amino acid residues within which conservative substitutions can be made are glycine / alanine, valine / isoleucine / leucine; Asparagine / glutamine, aspartic acid / glutamic acid;
- Antibodies may be glycosylated or unglycosylated, modified after translation (eg, acetylation and phosphorylation), or synthetically modified (eg, binding of a labeling group).
- Anti-RANKL antibodies containing amino acid sequence changes are also provided. These changes may include deletions, insertions, substitutions of single or multiple amino acids. As a result, post-translational modifications may also be subject to change.
- Changes in the CDRs of the light and heavy chain are most useful, especially in the hypervariable regions, but FR changes in the light and / or heavy chain may also be considered. If a CDR sequence comprises 6 amino acids, 1 to 3 amino acids can be changed. If it contains 15 amino acids, 1 -6 amino acids can be changed. When CDRs in the light and / or heavy chain are changed, the altered amino acid sequence should be at least 60%, more preferably 65%, even more preferably 70%, more preferably 75%, most preferably 80% identical to the original CDR sequence , Therefore, it depends on the length of each CDR how high the identity is with the original CDR.
- CDRs may have different levels of identity to the original CDR, e.g. CDRH 1 can be 90% identical while CDRL2 is 83% identical.
- FIG. 8 An exemplary heavy chain anti-RANKL antibody protein sequence is shown in Figure 8 (SEQ ID NO 2).
- FIG. 14 Another exemplary heavy chain anti-RANKL antibody protein sequence is shown in Figure 14 (SEQ ID NO 8).
- FIG. 15 Another exemplary light chain protein sequence of an anti-RANKL antibody is shown in Figure 15 (SEQ ID NO 9).
- the antigen-binding fragments of the anti-RANKL antibody are also included.
- Prolia (contains denosumab, anti-RANKL antibody and is approved as a medicinal product) is marketed by Amgen GmbH. It contains 60mg Denosumab solution for injection. Each pre-filled syringe contains 60 mg denosumab in 1 ml solution (60 mg / ml). The recommended dose of Prolia is 60 mg, administered as a single subcutaneous injection once every 6 months (thigh, abdomen or upper arm).
- Prolia is used to treat osteoporosis in postmenopausal women to prevent vertebral and non-vertebral fractures, and to increase bone mineral density Men with osteoporosis and increased fracture risk, as well as concomitant treatment in women with breast cancer receiving adjuvant treatment with aromatase inhibitors and in men with prostate cancer receiving hormone ablation therapy, if there is an increased risk of fracture.
- Xgeva medicine, also contains anti-RANKL antibodies (Denosumab, Amgen, each vial contains 120mg denosumab in 1.7ml solution (70mg / ml)).
- Xgeva is used to prevent skeletal complications (pathological fracture, bone irradiation, spinal cord compression, or bone surgery) in adults with bone metastases due to solid tumors and in the treatment of adults and skeletally mature adolescents with giant cell tumors of the bone that are unresectable or at Surgical resection is likely to result in severe morbidity.
- the SPC only recommends adequate intake of calcium and vitamin D; the exact dosage is not indicated.
- the adequate daily total calcium intake is 1000 mg. Calcium is absorbed through the diet so that the required daily dose can be achieved with a calcium-rich diet. Calcium intake of more than 2500mg per day is considered problematic as it may increase the risk of kidney stones formation. Due to various publications on cardiovascular side effects due to the excessive intake of calcium, many patients have refrained from taking enough calcium even with anti-RANKL antibodies.
- a supplementation with a pharmaceutical composition with 1000-1500mg calcium per day becomes an oversupply with sufficient calcium-containing nutrition with calcium, which increases the risk of cardiovascular side effects.
- a lower dosage is provided in the present invention to treat or prevent hypocalcemia and cardiovascular side effects.
- the preferred amount of calcium in the pharmaceutical composition is 400-600 mg of calcium per day, more preferably 500 mg of calcium per day, in order to maintain a basal calcium level even on a low-calcium diet and not to be oversupplied with the risks mentioned and consequently unacceptable to patients. 46% of men and 55% of women do not receive the recommended daily intake of calcium according to the results report of Germany's "National Consumption Study II.” In the age group 51-80 years, the average total intake is between 490-1790 mg of calcium per day.
- 500mg of calcium per day should be taken according to the technical information of Xgeva, but in combination with 400 I.E. Vitamin D per day.
- the studies for Xgeva were targeted at US patients. In the US, a large number of foods are supplemented with vitamin D, such as milk, orange juice, breads or cereal. In Germany and the EU, this is essentially not the case, so that according to the invention a higher amount of vitamin D 800-1200 I.E. per day, more preferably 1000 I.U. Vitamin D per day.
- the higher amount of vitamin D is able to promote the transport of a potentially lower amount of calcium from the gastrointestinal tract into the blood and to achieve a sufficient calcium serum level despite the lower amount of calcium.
- Vitamin D is provided daily for the prophylaxis and treatment of hypocalcemia.
- the increased vitamin D ensures that the small amount of calcium of 400-600mg, preferably 500mg of calcium daily, keeps the normal level of calcium above 2.2 mmol / l (9 mg / dl).
- the vitamin D level is easily measurable.
- the combination according to the invention is provided for a vitamin D serum concentration not lower than 20 ng / ml (50 nmol / l serum).
- a vitamin D serum concentration not lower than 20 ng / ml (50 nmol / l serum).
- severe deficiency ⁇ 10 ng / ml serum
- 200,000 IU should be substituted over 10 days and then 20,000 IU weekly.
- an initial substitution of 100,000 IU should be made and then a maintenance of 20,000 IU / week.
- a deficiency 21-30ng / ml serum
- a substitution of 20,000 IU / week should be made.
- the daily substitution according to the invention of 800-1200 IU vitamin D, more preferably 1000 IU, is applicable.
- Vitamin D is insufficient to maintain the vitamin D level within the normal range of 31-60 ng / ml of serum upon administration of the pharmaceutical composition of anti-RANKL antibodies and calcium of the present invention.
- the pharmaceutical composition comprising anti-RANKL antibodies for the treatment of osteoporosis, postmenopausal osteoporosis, overt osteoporosis, corticoinduced osteoporosis, osteoporosis of the man or woman, Paget's disease, osteogenesis imperfecta, for the prophylaxis of fractures of the aforementioned diseases, as well as for use in the treatment and / or prophylaxis of anti-RANKL antibody therapy-induced hypocalcemia, preferably at a dosage of 30 to 90 mg in 1 -2 ml solution (20-60 mg / ml), more preferably 50-70 mg more preferably 60mg, preferably in 1ml solution (60mg / ml) administered subcutaneously annually or biannually.
- the pharmaceutical composition comprising anti-RANKL antibodies in the field of oncology for the treatment and / or prophylaxis of skeletal complications, in particular due to solid tumors, preferably breast, prostate, lung, colon or bone carcinoma (osteosarcoma), pathological fractures, Bone irradiation, spinal cord compression or bone surgery, bone metastases, pain in bone metastases, nerve entrapment, deformities due to one or more solid tumors such as breast cancer, prostate cancer, lung cancer or multiple myeloma, as well as the prophylaxis of fractures in the aforementioned diseases and for use in the treatment and / or prophylaxis of anti-RANKL antibody treatment-induced hypocalcaemia, preferably at a dosage of 60-180 mg in 1 -3 ml solution, more preferably 80-150 mg, even more preferably 120 mg, especially in 1, 7 ml solution (70 mg / ml) Anti-RANKL antibody administered subcutaneously for at least 3-4 weeks.
- solid tumors
- the anti-RANKL antibody being a monoclonal, polyclonal, monospecific, bispecific, bifunctional, single-chain, synthetic, recombinant, mutant, human, humanized, chimeric, IgG, IgA, IgM or IgE antibody, an antigen binding fragment or an antibody construct such as Fvs (scFv) from single chain or antibody fusion proteins or a fragment thereof, in particular separate light and heavy chains, Fab, Fab / c, Fv, scFv, Fd, dAb, Fab 'or F (ab ') 2, wherein a fragment comprises a variable region of the light chain and / or a variable region of the heavy chain.
- Fvs scFv
- calcium citrate includes all known pharmaceutically acceptable calcium compounds, in particular but not limited to calcium citrate, other designations: tricalcium citrate, TCC, tricalcium dicitrate, tricalcium di- [2-hydroxy-1,2,3 -propantricarboxylate] tetrahydrate, E 333, Ci 2 HioCa 3 Oi 4, CAS numbers: 813-94-5 (anhydrous), 5785-44-4 (tetrahydrate); Calcium gluconate monohydrate ⁇ H2O, CAS numbers: 299-28-5 (anhydrous) and 66905-23-5 (monohydrate)); Calcium lactate gluconate, a double salt of lactic and gluconic acid present in admixture, other designations: CLG, calcium lactate gluconate, calcium lactogluconate, E 327, E 578, CAS numbers: 1 1 1 16-97-5, 814-80-2 (calcium lactate Pentahydrate), 18016-24-5 (calcium gluconate monohydrate
- vitamin D includes vitamin D or its derivatives, especially, but not limited to, vitamin D3 (cholecalciferol, C27H44O, CAS number: 67-97-0), calcitriol (1,25-dihydroxyvitamin D3, 1 a , 25-dihydroxycholecalciferol, 1, 25 (OH) 2 vitamin D3, 1, 25 (OH) 2 D3, (5Z, 7E) - (1S, 3R) -9,10-Seco cholesta-5,7,10 (19 ) -triene-1, 3,25-triol, CAS number: 32222-06-3) or 1 ⁇ , 25-dihydroxycholecalciferol (biologically active form of vitamin D3), alphacalcidol (1 ⁇ -hydroxyvitamin D3), 24,25 Dihydroxyvitamin D3 or calcifediol (25-hydroxyvitamin D3 25-hydroxycholecalciferol, CAS number: 19356-17-3, IUPAC name: (6R) -6 - [(1
- the pharmaceutical compositions are suitable for the treatment and / or prophylaxis of side effects of anti-RANKL antibodies, especially Kieferosteonekrosen associated with pain in the mouth, non-healing wounds to the dissolution of the jaw, hypocalcemia, cardiovascular side effects such as arrhythmia, convulsions , and secondary hyperparathyroidism, to be used.
- anti-RANKL antibodies especially Kieferosteonekrosen associated with pain in the mouth, non-healing wounds to the dissolution of the jaw, hypocalcemia, cardiovascular side effects such as arrhythmia, convulsions , and secondary hyperparathyroidism, to be used.
- the amounts of anti-RANKL antibody given above in an infusion solution of 1 -3ml in a pharmaceutically acceptable solution such as isotonic saline or isotonic sorbitol-sodium acetate polysorbate solution, isotonic sorbitol-sodium acetate solution, isotonic glucose solution or others pharmaceutically acceptable isotonic solutions of appropriate pH.
- calcium and vitamin D are provided with pharmaceutically suitable auxiliaries, in particular lactose, starch, acidulants, especially citric acid and malic acid, acid regulators, in particular sodium bicarbonate and sodium carbonate, humectants, in particular sorbitol, xylitol and inulin, release agents, in particular tricalcium phosphate, edible fatty acids, in particular magnesium salts, in particular magnesium stearate, natural and nature identical and other aromas and flavors, sweeteners, in particular sodium cyclamate, aspartame and saccharin sodium, maltodextrin, dyes, in particular beetroot juice powder and riboflavin-5'-phosphate, silica, especially finely divided, silica hydrate, phenylalanine, arabic gum, Sucrose, gelatin, corn starch, soybean oil, glycerol, DL-alpha-tocopherol, isomalt, sodium bicarbonate, sodium dihydrogencarbonate, sodium citrate
- anti-RANKL antibodies calcium and vitamin D, optionally with pharmaceutically suitable excipients and / or liquids, especially as effervescent tablets, swallowing tablets or capsules, chewable tablets, effervescent granules, direct granules, drink solutions, drops, Sublingual sprays, as infusion solution concentrates, final infusions,
- Injection solution concentrates, injection solutions or syringes provided individually or together.
- Figure 1 shows a representation of the calcium supply from the gastrointestinal tract into the blood and in the bones, as well as the influencing factors that promote or reduce calcium intake.
- Figure 2 shows the consequences of an insufficient calcium intake through the diet.
- Figure 3 shows the increase and decrease of bone mass in the course of human life and the increased bone fracture risk in old age with a decrease in bone mass.
- Figure 4 shows the increased calcium requirement with increasing age by reduced real calcium intake.
- FIG. 5 Hypocalcaemia is present when the total calcium in the blood serum is below 2.2 mmol / l (9 mg / dl). Due to the drug-induced inhibition of the osteoclasts, the calcium concentration in the blood can only be compensated by a supply of calcium from outside (oral or intravenous). This is shown in FIG.
- FIG. 6 shows an exemplary protein sequence for RAN KL (SEQ ID NO 7).
- FIG. 7 shows an exemplary cDNA sequence for the heavy chain of an anti-RANKL antibody (SEQ ID NO 1).
- FIG. 8 shows an exemplary protein sequence for the heavy chain of an anti-RANKL antibody (SEQ ID NO 2).
- Figure 9 shows an exemplary DNA sequence for the light chain of an anti-RANKL antibody (SEQ ID NO 3).
- Figure 10 shows an exemplary protein sequence for the light chain of an anti-RANKL antibody (SEQ ID NO 4).
- Figure 11 shows an exemplary protein sequence for the heavy chain variable region of an anti-RANKL antibody (SEQ ID NO 5).
- Figure 12 shows an exemplary protein sequence for the light chain variable region of an anti-RANKL antibody (SEQ ID NO 6).
- FIG. 13 shows a further exemplary protein sequence for the heavy chain of an anti-RANKL antibody (SEQ ID NO 8).
- FIG. 14 shows a further exemplary protein sequence for the light chain of an anti-RANKL antibody (SEQ ID NO 9).
- Vitamin D deficiency is a common diagnosis in osteopathic practice. At baseline, 89 out of 423 patients had vitamin D deficiency, which was below the normal levels of 20ng / ml serum and 50 nmol / l, respectively.
- the maintenance dose was 1000 I.U. daily vitamin D.
- a maintenance dose of 400 I.E. Vitamin D daily was insufficient to maintain vitamin D levels at normal levels.
- Table 1 shows that a maintenance dose of 1000 I.U. Vitamin D is suitable to keep the vitamin D level within the normal range:
- Table 2 shows in the left column the daily intake of calcium in the diet in mg. The daily intake of less than 1000mg by food leads to a negative calcium balance. This results in a secondary hyperparathyroidism and bone substance is lost. A daily supply less than 500mg of calcium is associated with an increased fracture risk for non-vertebral fractures.
- the chair-rising test allows a statement about the strength conditions and the fall risk of the test person.
- the subject is asked to come as soon as possible Arms crossed in front of the chest five times from a chair of usual height (about 46 cm seat height) to get up without the use of the arms and sit down again. If this does not succeed 5x in succession, then not the seconds are noted, but the number of successful executions. If more than 10-1 1 second is required, one must assume an increased risk of falling.
- Table 3 The Chair Rising test was performed on three osteoporosis patients prior to initiating therapy with 60 mg anti-RANKL antibody / denosumab (Prolia) + 500 mg calcium + 1000 IU vitamin D3 (left column) and 6 months later repeated (middle column). The improvement is indicated in% in the right column.
- Table 5 The following data from osteoporosis patients in Table 5 shows the serum calcium and vitamin D3 levels with 60 mg anti-RANKL antibody / denosumab (Prolia) twice daily and oral calcium intake of 500 mg daily and 1000 IU daily of vitamin D3.
- Table 5 The patients with osteoporosis received 60 mg denosumab half-yearly, 500 mg calcium daily and 1000 IU daily vitamin D3:
- Example 4 show that the combination according to the invention is suitable for normalizing the 25 (OH) vitamin D level within 3 to 6 months, above 20 ng / ml and 20 9 g / l, respectively, and thereby reducing the fracture risk.
- a daily supplementation according to the invention with 500 mg of calcium soothed for a balanced calcium balance.
- the data show that the combination according to the invention is suitable for increasing the 25 (OH) vitamin D serum level over 20ng / ml or 20 ⁇ 9 / i Avenue within 3-6 months normalize and produce a positive calcium balance in almost all patients.
- the patients were free of side effects, in particular no Kieferosteonekrosen, non-healing wounds up to the dissolution of the jaw, treatment-induced Hypokalzämien, cardiovascular side effects such as myocardial infarction, atrial fibrillation, cardiac arrhythmias, secondary hyperparathyroidism, convulsions and / or numbness on.
- solid tumors preferably breast, prostate, lung, colon or bone carcinoma (osteosarcoma), no (pathological) fractures, radiation of the bone, spinal cord compression or surgery on the bone, bone metastases , Pain in bone metastases, nerve entrapment, deformities due to one or more solid tumors such as breast cancer, prostate cancer, lung cancer or multiple myeloma.
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US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
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