Besilesomab

Identification

Name
Besilesomab
Accession Number
DB13979
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Besilesomab is a mouse monoclonal antibody labelled with the radioactive isotope technetium-99m for determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis [Label]. Utilised only as a diagnostic agent, besilesomab is currently approved by the EMEA for marketing and use in various European countries like Italy, France, Germany, Spain, Portugal, Norway, Sweden, the Netherlands, and the United Kingdom [3].

Protein structure
Db13979
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Technetium Tc-99m besilesomab0102XFH2B9Not AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Scintimun1 mgIntravenousCis Bio International2010-01-11Not applicableEu
Scintimun1 mgIntravenousCis Bio International2010-01-11Not applicableEu
Categories
UNII
538316W9ZU
CAS number
537694-98-7

Pharmacology

Indication

Besilesomab is radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution. This solution is indicated in adults for scintigraphic imaging - in conjunction with other appropriate imaging modalities, when possible - in determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis [Label]. When utilized as such, this medicinal product is for diagnostic use only [Label].

Associated Conditions
Pharmacodynamics

In a study employing cryo-preserved human tissues using an indirect alkaline phosphatase anti-alkaline phosphatase technique, besilesomab antibody from hybridoma supernatants demonstrated staining to cytoplasmic, membranous, and interstitial areas of primary colon carcinoma tissue, to single granulocytic cells in normal human liver and lung and to a large proportion of granulocytic cells in normal human bone marrow but not to blood vessels or connective tissue [4]. Additionally, the antibody also shows binding to the granulocytic cells of breast, kidney, parotid gland, pituitary, lymph nodes, and spleen tissues, as well as colonic, pancreatic, and some lung and breast carcinomas [4].

The purified besilesomab antibody and the prepared kit subsequently bound similarly to granulocytes in normal bone marrow, lung, liver, spleen, and colorectal carcinomas. Furthermore, the prepared kit also produced some staining in some connective tissue fibres in normal lung, some muscle fibres in normal colon, and in liver parenchymal cells [4]. In general however, besilesomab does not bind significantly to blood vessels and connective tissue [4].

Mechanism of action

Nonspecific cross-reacting antigens (NCA) is the name of a collection of highly glycosylated bacterial binding receptors expressed on human granulocytes and other tissues [1]. In particular, these glycoprotein receptors are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen (CEA) [1]. CEA is found naturally in the human body and its expression may be increased in both cancer and non-cancerous (benign) circumstances.

Besilesomab is subsequently a murine immunoglobulin monoclonal antibody of IgG1 isotype designed to recognise and bind specifically to NCA-95, or nonspecific cross-reacting antigen 95, an epitope found expressed on the cell membranes of granulocytes and granulocyte precursors [Label].

When radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution, this radiolabelled medicine is injected into patients where the monoclonal antibody carries it to target CEA on target granulocytes [Label]. When large numbers of CEA expressing granulocytes gather to the site of an infection, the radioactive monoclonal antibodies will also accumulate at such sites, where it can be detected by diagnostic scanning [Label]. The resultant images show where the radioactive besilesomab has accumulated, locating areas affected by osteomyelitis, infection, or inflammation [Label].

Furthermore, it is believed that the besilesomab accumulation is predominantly passive (via increased vascular permeability) and only partially active (via migration of human granulocytes carrying besilesomab to the infection/inflammation location) since only 10% to 20% of the injected radio-diagnostic agent binds in vivo to human circulating granulocytes [4]. Specific binding of besilesomab to activated granulocytes that have already migrated to sites of infection/inflammation might be the primary part of the detection signal [4].

TargetActionsOrganism
NCarcinoembryonic antigenNot AvailableHuman
Absorption

As the diagnostic agent is administered intravenously, it is expected that the bioavailability is 100% [4].

Approximately six hours after injection, about 1.5% of the whole body radioactivity is detected in the liver while about 3.0% is found in the spleen [Label]. Observations twenty-four hours after injection demonstrate percentages of radioactivity of 1.6% in the liver and 2.3% in the spleen [Label].

However, non pathological, unusual accumulations of the radioactive agent can be detected in the spleen (up to 6% of patients), in the bowel (up to 4% of patients), in the liver and bone marrow (up to 3% of patients), and in the thyroid and kidneys (up to 2% of patients) [Label].

Volume of distribution

In the besilesomab clinical trial Study 7D-101SZ-A, volumes of distribution were determined as approximately 4L - which was close to the plasma volume - in the central compartment, whether calculated from plasma radioactivity or from intact monoclonal antibody concentrations; the peripheral compartment was somewhat greater, at about 6L for both methods [4].

Protein binding

Studies demonstrate that prepared kit besilesomab binds up to 97.45% and 96.58% of peripheral blood granulocytes in males and females respectively and less than 5% of other peripheral blood cells [4]. Moreover, no significant binding of the antibody to other human peripheral blood cells like erythrocytes, platelets, lymphocytes, and monocytes was observed [4]. As well, besilesomab demonstrates no cross-reactivity with human platelets [4].

Metabolism

The besilesomab antibody is mainly metabolized via hepatic clearance into amino acids [4]. Nevertheless, liver uptake of radioactivity was observed to be minimal under trial conditions and liver impairment is considered unlikely to affect besilesomab metabolism and elimination in any clinically significant manner [4].

The total blood radioactivity occurring from the administration of besilesomab is generally the result of the contribution of radioactive intact labelled antibody and other radioactive moieties like metabolized antibody fragments, smaller radiometabolites, and free technetium (Tc99m) [4].

Route of elimination

Measurement of radioactivity levels in urine shows that up to 14% of the administered activity is excreted via the bladder during the 24 h post-injection period. Low renal clearance activity (of 0.2 L/h for a glomerular filtration rate of approximately 7 L/h) also suggests that the kidney is not the primary route of besilesomab elimination [Label].

Additionally, over 30 hours rat pharmacokinetic studies also similarly demonstrated that 31-34% of the radioactivity was excreted in the urine and only 7-13% in the faeces [4]. The faecal elimination was observed primarily from the 17h time period onward [4].

Furthermore, while radioactivity associated with intact antibody tends to stay in the vascular compartment for a long time, metabolized radioactive fragments, small radio-metabolites, and free pertechnetate (Tc99m) clears quickly from blood and will accumulate in the kidneys and further in the urine [4]. In all besilesomab studies to date, approximately 14% of the injected radioactivity was recovered in the urine, which was only collected for 24 hours after administration [4].

Half life

Whole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0-2 h) and a late phase (5-24 h) [Label]. After correcting for the decay of radionuclide, the calculated half-life of the early phase is approximately 0.5 h while the late phase demonstrates a calculated half-life of 16 h [Label]. The terminal half-life in man is estimated to be approximately 23 h [4].

Clearance

Once administered into the body, prepared technetium (Tc99m) besilesomab can be metabolized into free amino acids, smaller radioactive fragments, or even free pertechnetate (Tc99m) [4]. The besilesomab clinical study 7D-101SZ-A consequently reports separate estimated clearance rates of 0.322 L/h and 0.242 L/h that were calculated using monitored plasma radioactivity and from monitored intact monoclonal antibody concentrations, respectively [4].

Toxicity

The most commonly reported adverse reaction associated with the use of besilesomab is the development of Human Anti-Mouse Antibodies (HAMA) after a single administration [Label]. Patients who have developed HAMA may potentially have a higher risk for hypersensitivity reactions. Screening for possible previous exposure to murine monoclonal antibodies and tests for the presence of HAMA in prospective patients should be made prior to administrating besilesomab [Label]. Moreover, because the incidence of developing HAMA appears to be dose related with besilesomab, the recommended dosage is restricted to no more than 250 micrograms of antibody per injection [2]. Patients who are HAMA positive are consequently contraindicated from using besilesomab [Label].

Hypersensitivity to besilesomab or to any other murine antibodies or to any of the excipients associated with the active besilesomab radio-diagnostic agent is subsequently a contraindication [Label].

Some patients have also reported hypotension as a common adverse reaction [Label].

As exposure to ionizing radiation is linked with cancer induction and a potential for developing hereditary defects, the use of radio-diagnostic besilesomab in pregnant women is considered a formal contraindication [Label]. If in doubt about a woman's potential pregnancy, alternative techniques to not using ionizing radiation should be considered and/or offered instead to the patient [Label].

Moreover, although it is not known if besilesomab is excreted in human milk, the potential risk to a breast-fed child cannot be excluded [Label]. Furthermore, while consideration should be given to the possibility of perhaps delaying the administration of radionuclide agents until the mother has ceased breastfeeding or perhaps certainly choosing alternative radoopharmaceuticals with more appropriate secretion activity, if the use of besilesomab is absolutely necessary then the mother's breastfeeding should be stopped for three days and any expressed feeds during that time discarded [Label]. The time period of three days corresponds to 10 half-lives of technetium (Tc99m)(60 hours) [Label]. At that time, the remaining activity represents about 1/1000 of the initial activity in the body [Label].

In general, close contact with infants and pregnant women should be restricted for patients who have been administered besilesomab during the first 12 hours after the injection [Label].

Since besilesomab contains sorbitol, patients having any rare hereditary conditions of fructose intolerance should not be administered this medicine [Label].

Because no sufficient data regarding the safety and efficacy of using besilesomab in children below the age of 18 years exists, the use of besilesomab in this patient population is not recommended [5].

Even though data regarding the repeated dosing of besilesomab is extremely limited, the use of besilesomab should only be used once in a patient's lifetime [Label].

Other medicines that can inhibit inflammation or affect the hematopoietic system (like antibiotics and corticosteroids) can lead to false negative results. Such agents should therefore not be administered together with, or a short time before the injection of besilesomab [Label].

Preclinical data obtained with the non-radioactive compound revealed no special hazard for humans based on conventional studies of safety pharmacology, single-dose and repeated dose toxicity, although antimurine antibodies were found in all dose groups (including controls) in a repeated-dose study in monkeys [Label]. Genotoxicity studies conducted to test for potentially genotoxic impurities were also negative. Long-term carcinogenicity studies and toxicity to reproduction have not yet been carried out [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Besilesomab.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Besilesomab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Besilesomab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Besilesomab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Besilesomab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Besilesomab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Besilesomab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Besilesomab.
AmatuximabThe risk or severity of adverse effects can be increased when Amatuximab is combined with Besilesomab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Besilesomab.
Food Interactions
Not Available

References

General References
  1. Klein ML, McGhee SA, Baranian J, Stevens L, Hefta SA: Role of nonspecific cross-reacting antigen, a CD66 cluster antigen, in activation of human granulocytes. Infect Immun. 1996 Nov;64(11):4574-9. [PubMed:8890209]
  2. Stefan Dubel, Janice M. Reichert (2014). Handbook of Therapeutic Antibodies, Volume 3: Approved Therapeutic Antibodies (3rd ed.). John Wiley & Sons. [ISBN:978-3-527-32937-3]
  3. European Medicines Agency: Scintimun (besilesomab) Product Information [Link]
  4. EMA Assessment Report For Scintimun (International Nonproprietary Name: besilesomab) [Link]
  5. Making bone inflammation/infection simpler to detect: Scintimun 1mg Monograph [Link]
  6. Granulocyte-binding antibody constructs, their preparation and use: US Grant US5645817A (Monoclonal antibody amino acid sequence) [Link]
External Links
Wikipedia
Besilesomab
FDA label
Download (134 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

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

Properties

State
Solid
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
Human
Pharmacological action
No
General Function
Not Available
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
Q14081
Uniprot Name
Carcinoembryonic antigen
Molecular Weight
4903.595 Da

Drug created on January 20, 2018 07:58 / Updated on November 02, 2018 09:13