Dibotermin alfa

Identification

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Name
Dibotermin alfa
Accession Number
DB11639
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Dibotermin alfa is a recombinant human bone morphogenetic protein-2 (rhBMP-2) derived from a recombinant Chinese Hamster Ovary (CHO) cell line Label. It is implanted in patients undergoing bone surgeries or those with fractures. BMPs are subfamily of the transforming growth factor-β (TGF-β) superfamily that have different actions on the bone matrix 2. BMP-2 is a potent osteoinductive protein that plays a critical role in the differentiation of osteoprogenitor cells into osteoblasts, thus promoting bone and cartilage formation 3. Through enhancing osteogenesis at the site of implantation, dibotermin alfa accelerates the healing of open tibial shaft fractures and reduces the need for secondary intervention 1. In a prospective clinical study of patients with an open tibial fracture, administration of dibotermin alfa resulted in faster fracture- or wound-healing, significantly fewer secondary invasive interventions, and reduced infection rate post-operation 1. Dibotermin alfa was approved by the EMA in 2002 as Inductos for implantation matrix. In 2004, it was approved by the FDA and is marketed as Infuse. In Infuse, rhBMP is a disulfide-linked dimeric protein molecule with two major subunit species of 114 and 131 amino acids. Each subunit is glycosylated with high-mannose-type glycans Label.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • BMP 2
  • BMP-2
  • Bone morphogenetic protein 2
  • Bone morphogenetic protein 2 (human recombinant rhBMP-2)
  • Dibotermina alfa
  • rhBMP-2
Categories
UNII
T472P45MG6
CAS number
246539-15-1

Pharmacology

Indication
  • indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard care using open fracture reduction and intramedullary unreamed nail fixation Label.
  • indicated for single-level lumbar interbody spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of non-operative treatment for this condition 5.
Pharmacodynamics

Dibotermin alfa promotes bone and cartilage formation through anabolic effects in human osteoblastic cells 3. Radiographic, biomechanical and histologic evaluation of the induced bone at the site of implantation supports that induced bone from dibotermin alfa therapy is capable of biological and biochemical function as native bone and repair abilities 5.

Mechanism of action

In the same pathway shared by endogenous BMPs, recombinant human BMP-2 (rhBMP-2) binds and initiates intracellular signal cascade through an oligomeric transmembrane receptor complex formed by type I and II serine/threonine kinase receptor proteins 4. These BMP receptors are expressed on the surface of mesenchymal cells and upon binding of BMP-2 to the BMP receptor type II, type II receptor phosphorylates and activates type I receptor. Type I receptor may also undergo autophosphorylation. Activated BMP type I receptor then phosphorylates intracellular effector proteins, the receptor-regulated Smads (R-Smads) 2. Smad1, Smad 5 and Smad 8 associate with the Co-Smad, Smad4 and once activated via complex formation, they translocate to the nucleus where they associate with other transcription factors and bind promoters of target genes to control their expression 2. This ultimately results in bone formation at the site of implantation. Dibotermin alfa causes mesenchymal cells to differentiate into cartilage- and bone-forming cells. Implantation of dibotermin alfa in trabecular bone results in transient resorption of the bone surrounding the implant, followed by replacement of degraded matrix by newly differentiated cells 5.

In human bone cells isolated from adult mandibulae, recombinant human BMP-2 (rhBMP-2) was shown to stimulate the activity of early biomarkers of osteoblast differentiation, including alkaline phosphatase and parathyroid hormone (PTH)-dependent 3', 5'-cyclic adenosine monophosphate accumulation 3. At concentrations of 500 ng/mL, rhBMP-2 also enhanced the mRNA expression level of PTH/PTH related-peptide receptor in human bone cells 3. There was evidence that rhBMP-2 inhibits 1,25-dihydroxyvitamin D3-induced osteocalcin synthesis at both the mRNA and protein level. rhBMP-2 also significantly suppressed MMP-1 production and MMP-1 mRNA expression at concentrations exceeding 500 ng/mL 3.

TargetActionsOrganism
ABone morphogenetic protein receptor type-2
ligand
Humans
ABone morphogenetic protein receptor type-1A
ligand
Humans
Absorption

Dibotermin alfa is active at the site of implantation with no detection in the serum. In rat studies with radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4-8 days 5. Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation 5.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

As recombinant human bone morphogenetic protein-2 (BMP-2), dibotermin alfa is expected to undergo nonspecific protein degradation pathway shared by endogenous BMP-2.

Half life

When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys 5.

Clearance

At the site of implantation, dibotermin alfa is expected to be slowly released from the matrix and rapidly cleared when taken up into the systemic circulation 5.

Toxicity

Supportive treatment is recommended in case of overdose. Use of Inductos in patients undergoing cervical spine surgery in amounts lower than or similar to those for lumbar interbody fusion has been associated with reports of localised oedema severe enough to result in airway compromise 5.

There is no evidence of significant hazards on humans based on non-clinical data of acute and repeated exposure toxicity and genotoxicity studies 5. In reproductive toxicity studies in rats, intravenous administration of dibotermin alfa was associated with increased fetal weight and increased fetal ossification. The clinical relevance of this effect is unknown 5. In human tumour cell lines in vitro, dibotermin alfa did not display any potential for promotion of tumour growth or metastasis 5. Studies investigating the carcinogenicity of dibotermin alfa have not been conducted.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T: Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002 Dec;84-A(12):2123-34. [PubMed:12473698]
  2. Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB: Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop. 2011 Sep;35(9):1271-80. doi: 10.1007/s00264-011-1301-z. Epub 2011 Jun 23. [PubMed:21698428]
  3. Takiguchi T, Kobayashi M, Suzuki R, Yamaguchi A, Isatsu K, Nishihara T, Nagumo M, Hasegawa K: Recombinant human bone morphogenetic protein-2 stimulates osteoblast differentiation and suppresses matrix metalloproteinase-1 production in human bone cells isolated from mandibulae. J Periodontal Res. 1998 Nov;33(8):476-85. [PubMed:9879521]
  4. Ghodadra N, Singh K: Recombinant human bone morphogenetic protein-2 in the treatment of bone fractures. Biologics. 2008 Sep;2(3):345-54. [PubMed:19707367]
  5. EMA Label: InductOs Summary of Product Characteristics [Link]
External Links
UniProt
P12643
Wikipedia
Bone_morphogenetic_protein_2
ATC Codes
M05BC01 — Dibotermin alfa
FDA label
Download (713 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedEducational/Counseling/TrainingOsteoarthritis (OA)1
1CompletedTreatmentBone Degenerative Changes / Degenerative Disorder of Bone / Osteoarthritis (OA)1
1CompletedTreatmentRadius Fractures1
2CompletedTreatmentFracture Bone2
2, 3TerminatedTreatmentFracture Bone1
3CompletedNot AvailableRegeneration of Alveolar Tissue After Maxillary Sinus Floor Augmentation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6.
Specific Function
Activin receptor activity, type ii
Gene Name
BMPR2
Uniprot ID
Q13873
Uniprot Name
Bone morphogenetic protein receptor type-2
Molecular Weight
115200.475 Da
References
  1. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T: Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002 Dec;84-A(12):2123-34. [PubMed:12473698]
  2. Ghodadra N, Singh K: Recombinant human bone morphogenetic protein-2 in the treatment of bone fractures. Biologics. 2008 Sep;2(3):345-54. [PubMed:19707367]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6.
Specific Function
Atp binding
Gene Name
BMPR1A
Uniprot ID
P36894
Uniprot Name
Bone morphogenetic protein receptor type-1A
Molecular Weight
60196.915 Da
References
  1. Nickel J, Dreyer MK, Kirsch T, Sebald W: The crystal structure of the BMP-2:BMPR-IA complex and the generation of BMP-2 antagonists. J Bone Joint Surg Am. 2001;83-A Suppl 1(Pt 1):S7-14. [PubMed:11263668]
  2. Kirsch T, Nickel J, Sebald W: Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2. FEBS Lett. 2000 Feb 25;468(2-3):215-9. [PubMed:10692589]
  3. Kirsch T, Nickel J, Sebald W: BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II. EMBO J. 2000 Jul 3;19(13):3314-24. doi: 10.1093/emboj/19.13.3314. [PubMed:10880444]
  4. Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI, Knaus P: Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell. 2000 Mar;11(3):1023-35. [PubMed:10712517]

Drug created on October 17, 2016 15:29 / Updated on June 04, 2019 07:25