1. Tositumomab (DB00081) Approved Drug
Chemical Formula: C6416H9874N1688O1987S44
Molecular Weight:
Murine IgG2a lambda monoclonal antibody against CD20 antigen (2 heavy chains of 451 residues, 2 lambda chains of 220 residues). It is produced in an antibiotic-free culture of mammalian cells. It can be covalently linked to Iodine 131 (a radioactive isotope of iodine).
Indication/Usage
For treatment of non-Hodgkin's lymphoma (CD20 positive, follicular)
Pharmacodynamics
Tositumomab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lympohomas. The antibody leads to selective killing of B-cells.
Mechanism of Action
Binds to the CD20 antigen which is found on mature B lymphocytes. The antibody binding appears to induce apoptosis, complement-dependent cytotoxicity and cell death through ionizing radiation.

2. Metabolism Half Life Route of Elimination Clearence Drug Interactions
Most likely removed by opsonization via the reticuloendothelial system when bound to B lymphocytes, or by human antimurine antibody production
Half Life
0.8 hours (mammalian reticulocytes, in vitro)
Route of Elimination
Elimination of Iodine-131 occurs by decay and excretion in the urine.
Clearence
* 68.2 mg/hr [patients with NHL]
Drug Interactions
DB00108 (Natalizumab): The immunosuppressant, Tositumomab, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
DB00072 (Trastuzumab): Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Sequence
Heavy chain 1:
QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGAIYPGNGDTSYNQKFKGKATLTVDKSSSTAYMQLSSLTSEDSAVYFCARVVYYSNSYWYFDVWGTGTTVTVSGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

3. Experimental Properties
Light chain 1:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPKPWIYAPSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
Heavy Chain 2:
QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGAIYPGNGDTSYNQKFKGKATLTVDKSSSTAYMQLSSLTSEDSAVYFCARVVYYSNSYWYFDVWGTGTTVTVSGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Light chain 2:
Experimental Properties
Melting Point: 61 °C (FAB fragment), 71 °C (whole mAb)
Hydrophobicity:
Isoelectric Point: 8.68
Affected Organisms
Human and other Mammals

4. Targets
B-lymphocyte antigen CD20,Low affinity immunoglobulin gamma Fc region receptor III-B,Complement C1r subcomponent,Complement C1q subcomponent subunit A,Complement C1q subcomponent subunit B,Complement C1q subcomponent subunit C,Low affinity immunoglobulin gamma Fc region receptor III-A,High affinity immunoglobulin gamma Fc receptor I,Low affinity immunoglobulin gamma Fc region receptor II-a,Low affinity immunoglobulin gamma Fc region receptor II-b,Low affinity immunoglobulin gamma Fc region receptor II-c
Brands
Bexxar - Galaxo Smith Kline

5. Bexxar Formulation Used/Prescribed for Dosage Contraindications
The BEXXAR therapeutic regimen is composed of the monoclonal antibody tositumomab, and the radio labeled monoclonal antibody, I-131 tositumomab. Tositumomab is supplied as a sterile, pyrogen-free, clear to opalescent, colorless to slightly yellow, preservative-free solution for intravenous administration
Formulation
The formulation contains 100 mg/mL maltose, 8.5 mg/mL sodium chloride, 1 mg/mL phosphate, 1 mg/mL potassium hydroxide, and Water for Injection, USP. The pH is approximately 7.2.
Used/Prescribed for
The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin’s lymphoma. Determination of the effectiveness of the BEXXAR therapeutic regimen is based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and Rituximab. The effects of the BEXXAR therapeutic regimen on survival are not known.
Dosage
The BEXXAR therapeutic regimen consists of 2 separate components (tositumomab and iodine I 131 tositumomab) administered in 2 separate steps (dosimetric dose and therapeutic dose) separated by 7 to 14 days.Tositumomab 450 mg by intravenous infusion.I-131 tositumomab (5 mCi I-131 and 35 mg protein) by intravenous infusion
Contraindications
The BEXXAR therapeutic regimen is contraindicated in patients with known hypersensitivity to murine proteins or any other component of the BEXXAR therapeutic regimen

6. Side- effects Drug Interactions References
Serious Allergic Reactions, Including Anaphylaxis, Prolonged and Severe Cytopenias, Secondary malignancies, Hypothyroidism, neutropenia, thrombocytopenia, anemia, infections (including pneumonia, bacteremia, septicemia, bronchitis, and skin infections), infusion reactions, asthenia, fever, and nausea
Drug Interactions
No formal drug-drug interaction studies have been conducted with tositumomab or I-131 tositumomab.
References