Alemtuzumab DB 00087 Approved and Investigational Drug Chemical

Alemtuzumab (DB 00087) Approved and Investigational Drug Chemical Formula: C 6468 H 10066 N 1732 O 2005 S 40 Molecular Weight: 145453. 9 Humanized monoclonal antibody specific to lymphocyte antigens. It is a recombinant DNA-derived humanized monoclonal antibody (Campath-1 H) that is directed against the 21 -28 k. D cell surface glycoprotein, CD 52. The Campath-1 H antibody is an Ig. G 1 kappa with human variable framework and constant regions, and complementaritydetermining regions from a murine (rat) monoclonal antibody (Campath-1 G). Campath is produced in mammalian cell (Chinese hamster ovary) suspension culture in a medium containing neomycin. Indication/Usage Alemtuzumab (Campath) is a monoclonal antibody therapy used for treatment of B-cell chronic lymphocytic leukemia. Pharmacodynamics Campath is used to treat leukemia by exploiting antibody mediated lysis of CD 52 presenting cells. The CD 52 antigen is a cell surface protein found on essentially all B and T lymphocytes, a majority of monocytes, macrophages and most granulocytes. The CD 52 antigen is not present on erythrocytes or hematopoetic stem cells. In leukemia there is an excess of B and T cells, so Campath permits selective reduction of lymphocyte populations.

Mechanism of Action Campath binds to the CD 52 antigen present on most B and T lymphocytes. This binding leads to antibody-dependent lysis of leukemic cells. Metabolism Most likely removed by opsonization via the reticuloendothelial system when bound to B or T lymphocytes Half-life ~288 hrs. Volume of Distribution * 0. 18 L/kg Patents Patent no. 1339198, Canada, approved: 1997 -08 -05 expired: 2014 -08 -05 Drug Interactions DB 00072 (Trastuzumab): Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. Sequence Heavy Chain 1: QVQLQESGPGLVRPSQTLSLTCTVSGFTFTDFYMNWVRQPPGRGLEWIGFIRDKAKGYTTEYNPSVKGRVTMLVDTS KNQFSLRLSSVTAADTAVYYCAREGHTAAPFDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light Chain 1: DIQMTQSPSSLSASVGDRVTITCKASQNIDKYLNWYQQKPGKAPKLLIYNTNNLQTGVPSRFSGSGSGTDFTFTISSLQP EDIATYYCLQHISRPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR Heavy Chain 2: QVQLQESGPGLVRPSQTLSLTCTVSGFTFTDFYMNWVRQPPGRGLEWIGFIRDKAKGYTTEYNPSVKGRVTMLVDTS KNQFSLRLSSVTAADTAVYYCAREGHTAAPFDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Light Chain 2: DIQMTQSPSSLSASVGDRVTITCKASQNIDKYLNWYQQKPGKAPKLLIYNTNNLQTGVPSRFSGSGSGTDFTFTISSLQP EDIATYYCLQHISRPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR Experimental Properties Melting Point: 61°C (FAB fragment), 71°C (whole m. Ab) Hydrophobicity: 0. 431 Isoelectric Point: 8. 76

General References • Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, Waldmann H: Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood. 1983 Oct; 62(4): 873 -82. "Pubmed": http: //www. ncbi. nlm. nih. gov/pubmed/6349718 • Riechmann L, Clark M, Waldmann H, Winter G: Reshaping human antibodies for therapy. Nature. 1988 Mar 24; 332(6162): 323 -7. "Pubmed": http: //www. ncbi. nlm. nih. gov/pubmed/3127726 • IGMT "Link": http: //imgt. cines. fr/3 Dstructure-DB/cgi/details. cgi? pdbcode=1 BEY# • IGMT“ Link": http: //imgt. cines. fr/3 Dstructure-DB/cgi/details. cgi? pdbcode=1 CE 1# • IGMT "Link": http: //imgt. cines. fr/3 Dstructure-DB/cgi/details. cgi? pdbcode=8005 Brands CAMPATH – Genzyme Corporation LEMTRADA - Genzyme Corporation

CAMPATH Campath (alemtuzumab) is a recombinant DNA-derived humanized monoclonal antibody (Campath-1 H) directed against the 21 -28 k. D cell surface glycoprotein, CD 52. Campath-1 H is an Ig. G 1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from a murine (rat) monoclonal antibody (Campath-1 G). The Campath-1 H antibody has an approximate molecular weight of 150 k. D. Campath is produced in mammalian cell (Chinese hamster ovary). Campath is a sterile, clear, colorless, isotonic solution (p. H 6. 8 -7. 4) for injection to be administered as intravenous infusion. Formulation Each single use vial of Campath contains 30 mg alemtuzumab, 8. 0 mg sodium chloride, 1. 44 mg dibasic sodium phosphate, 0. 2 mg potassium chloride, 0. 2 mg monobasic potassium phosphate, 0. 1 mg polysorbate 80, and 0. 0187 mg disodium edetate dihydrate. No preservatives are added. Used/Prescribed for Campath is a CD 52 -directed cytolytic antibody indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) Dosage Administer as an IV infusion over 2 hours, Escalate to recommended dose of 30 mg/day three times per week for 12 weeks, Premedicate with oral antihistamine and acetaminophen prior to dosing Contraindications None Side- effects Most common adverse reactions (≥ 10%): cytopenias, infusion reactions, cytomegalovirus (CMV) and other infections, nausea, emesis, diarrhea, and insomnia

Drug Interactions No formal drug interaction studies have been performed with Campath References 1. http: //dailymed. nlm. nih. gov/dailymed/drug. Info. cfm? setid=4 f 5 f 7255 -7 abc-4328 -bd 1 a 2. ceaf 139 ef 3 e 0 http: //www. rxlist. com/campath-drug. htm

Lemtrada LEMTRADA (alemtuzumab) is a recombinant humanized Ig. G 1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD 52. Alemtuzumab has an approximate molecular weight of 150 k. D. LEMTRADA is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium containing neomycin. Neomycin is not detectable in the final product. LEMTRADA is a sterile, clear and colorless to slightly yellow, solution (p. H 7. 2± 0. 2) for infusion to be administered as intravenous infusion. Formulation Each 1 m. L of solution contains alemtuzumab 10 mg, dibasic sodium phosphate (1. 15 mg), disodium edetate dihydrate (0. 0187 mg), polysorbate 80 (0. 1 mg), potassium chloride (0. 2 mg), potassium dihydrogen phosphate (0. 2 mg), sodium chloride (8 mg), and water for injection. Used/Prescribed for LEMTRADA is a CD 52 -directed cytolytic monoclonal antibody indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. Dosage Administer LEMTRADA by intravenous infusion over 4 hours for 2 treatment courses. First course: 12 mg/day on 5 consecutive days. Second course: 12 mg/day on 3 consecutive days 12 months after first treatment course. Contraindications LEMTRADA is contraindicated in patients who are infected with Human Immunodeficiency Virus (HIV) because LEMTRADA causes prolonged reductions of CD 4+ lymphocyte counts.

Side- effects Most common adverse reactions (incidence ≥ 10% and > interferon beta-1 a): rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. Drug Interactions No information provided. References 1. http: //dailymed. nlm. nih. gov/dailymed/drug. Info. cfm? setid=6236 b 0 bc-82 e 9 -4447 -9 a 782. f 57 d 94770269 http: //www. rxlist. com/lemtrada-drug. htm