==== Reference: Usmani SS, Bedi G, Samuel JS, Singh S, Kalra S, Kumar P, et al. (2017) THPdb: Database of FDA-approved peptide and protein therapeutics. PLoS ONE 12(7) e0181748.====

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Primary information
ThPP IDTh1123
Therapeutic Peptide/Protein NameDenosumab
SequenceHeavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR view full sequnce in fasta
Functional ClassificationIIIc
Molecular Weight144700
Chemical FormulaC6404H9912N1724O2004S50
Isoelectric PointN.A.
HydrophobicityN.A.
Melting Point (℃)N.A.
Half Life25.4 days
DescriptionNovel, fully human IgG2 monoclonal antibody, specific to receptor activator of nuclear factor kappa-B ligand (RANKL). It suppresses bone resorption markers in patients suffering from metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Each light chain consists of 215 amino acids and the heavy chain consists of 448 amino acids. FDA approved on June 1, 2010.
Indication/DiseaseProlia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It reduces the incidence of vertebral, nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. It can also be used in men with osteoporosis at high risk for fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
PharmacodynamicsIn clinical studies, treatment with 60 mg of Prolia resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Prolia.
Mechanism of ActionDenosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.
ToxicityIn patients with postmenopausal osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. In male patients with osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. In patients experiencing bone loss due to hormone ablation for cancer, the most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials
MetabolismN.A.
AbsorptionWhen 60 mg of denosumab was subcutaneously administered to healthy subjects after fasting for 12 hours, the pharmacokinetic parameters are as follows: Cmax = 6.75 mcg/mL; Tmax= 10 days (range of 3 to 21 days); AUC (0-16 weeks) = 316 mcg day/mL. Denosumab does not accumulate following multiple doses once every 6 months. The pharmacokinetics of denosumab were not affected by the formation of antibodies.
Volume of DistributionN.A.
ClearanceN.A.
CategoriesBone Density Conservation Agents and Monoclonal antibodies
Patents NumberCA2274987
Date of Issue25/01/16
Date of Expiry23/12/21
Drug InteractionN.A.
TargetN.A.
Information of corresponding available drug in the market
Brand NameProlia
CompanyAmgen.
Brand DiscriptionProlia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Prescribed forTreatment Of Postmenopausal Women With Osteoporosis At High Risk For Fracture,Treatment To Increase Bone Mass In Men With Osteoporosis, Treatment Of Bone Loss In Men Receiving Androgen Deprivation Therapy For Prostate Cancer, Treatment Of Bone Loss In Women Receiving Adjuvant Aromatase Inhibitor Therapy For Breast Cancer
Chemical NameN.A.
FormulationEach 1 mL single-use prefilled syringe of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2. Each 1 mL single-use vial of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2
Physcial AppearnceSterile, preservative-free, clear, colorless to pale yellow solution
Route of AdministrationN.A.
Recommended DosageN.A.
ContraindicationHypocalcemia. Pregnancy. Hypersensitivity
Side EffectsHypocalcemia, Serious Infections, Dermatologic Adverse Reactions, Osteonecrosis of the Jaw, Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Useful Linkhttp://www.rxlist.com/prolia-drug.htm drugs.com/prolia-html http://www.prolia.com/
PubMed ID23159111, 16872263
3-D StructureTh1123 Heavy chainor (Download)Th1123 Light chain (View) or (Download)