Tositumomab (DB00081) Approved Drug Chemical Formula: C6416H9874N1688O1987S44 Molecular Weight: 143859.7 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.

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

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: -0.4144 Isoelectric Point: 8.68 Affected Organisms Human and other Mammals

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

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

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 http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=11680 http://www.rxlist.com/bexxar-drug.htm