Obinutuzumab

Compound Name:ObinutuzumabMolecular Target:CD20.14Molecular Structure:humanized IgG1 monoclonal antibodyLicensed Indication:Chronic Lymphocytic Leukemia in combination with chemotherapy in treatment-na�ve patientsManufacturer and/or Distributor:Hoffmann-La Roche, Genentech Inc, Biogen IdecInitial FDA Approval2013SummaryObinutuzumab is a fully humanized glycoengineered IgG1 monoclonal antibody with potential antineoplastic activity. It is third generation type II anti-CD20 antibody, which selectively binds to the extracellular domain of the human CD20 antigen on malignant human B cells. The Fc region carbohydrates of the antibody, enriched in bisected non-fucosylated glycosylation variants, contributes to its higher binding affinity for human FcgammaRIII receptors compared to non-glycoengineered antibodies, resulting in enhanced antibody-dependent cellular cytotoxicity (ADCC) and caspase-independent apoptosis. Obinutuzumab is given by intravenous injections in cycle 1 at day 1 100 mg, 900 mg on day 2, and 1000 mg on days 8 and 15; in cycle 2 to 6, the dose is 1000 mg, administered every 28 days. Obinutuzumab was approved under the tradename GAZYVA by the FDA in 2013 for the treatment of chronic lymphocytic leukemia (CLL) in combination with chemotherapy in treatment-naïve patients. In a Phase III study of a total of 356 patients, the group treated with GAZYVA and chlorambucil showed a progression-free survival of 23 months compared with 11.1 months for patients on chlorambucil alone. It is additionally investigated in a large clinical programme, including multiple head-to-head Phase III studies compared to MabThera/Rituxan in indolent non-Hodgkin lymphoma and diffuse large B-cell lymphoma. On February 2016, the FDA approved obinutuzumab for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen. Important adverse reactions include reactivation of hepatitis B virus and Progressive Multifocal Leukoencephalopathy. Other associated risks are infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, increased infections, and musculoskeletal pain. Live vaccines should not be given to patients being treated with obinutuzimab. Tumor Lysis Syndrome (TLS), including fatal cases, has been reported in patients receiving Gazyva. Patients with high tumor burden, high circulating lymphocyte count (> 25 x 109/L) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics prior to the infusion of Gazyva.References

Package Insert: http://www.gene.com/download/pdf/gazyva_prescribing.pdf

1. Goede V, Fischer K, Busch R, Jaeger U, Dilhuydy MS et al. Chemoimmunotherapy with GA101 plus chlorambucil in patients with chronic lymphocytic leukemia and comorbidity: results of the CLL11 (BO21004) safety run-in. Leukemia. 2013 Apr;27(5):1172-4. http://www.ncbi.nlm.nih.gov/pubmed/22936013

2. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. http://www.ncbi.nlm.nih.gov/pubmed/24401022

3. Illidge T, Cheadle EJ, Donaghy C, Honeychurch J. Update on obinutuzumab in the treatment of B-cell malignancies. Expert Opin Biol Ther. 2014 Oct;14(10):1507-17. http://www.ncbi.nlm.nih.gov/pubmed/25190612

4. Burger JA. Obinutuzumab: the more the merrier? Blood. 2016 Jan 7;127(1):6-8. http://www.ncbi.nlm.nih.gov/pubmed/26744434

5. Sidaway P. Haematological cancer: Obinutuzumab effective against treatment-refractory NHL. Nat Rev Clin Oncol. 2016 Aug;13(8):466. https://www.ncbi.nlm.nih.gov/pubmed/27402577

6. Tobinai K, Klein C, Oya N, Fingerle-Rowson G. A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Adv Ther. 2016 Dec 21. https://www.ncbi.nlm.nih.gov/pubmed/28004361

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