Obinutuzumab

Obinutuzumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target CD20
Clinical data
Trade names Gazyva, Gazyvaro
Legal status
Routes of
administration		 Intravenous infusion
Pharmacokinetic data
Biological half-life 28.4 days
Identifiers
CAS Number 949142-50-1 N
ATC code L01XC15
ChemSpider none
UNII O43472U9X8 YesY
KEGG D09321 YesY
Chemical data
Formula C6512H10060N1712O2020S44
Molar mass 146.1 kDa
 NYesY (what is this?)  (verify)

Obinutuzumab (called afutuzumab until 2009[1]) is a humanized monoclonal antibody, originated by GlycArt Biotechnology AG and developed by Biogen Idec, Chugai Pharmaceutical Co., and Hoffmann-La Roche Inc. for the treatment of lymphoma.[2] It acts as an immunomodulator.[3][4]

Obinutuzumab targets CD20 and kills B cells.[2] GlycArt's technology platform allowed control of protein glycosylation; the cells in which obinutuzumab is produced were engineered to overexpress two glycosylation enzymes, MGAT3 and Golgi mannosidase 2, which reduce the amount of fucose attached to the antibody, which in turn increases the antibody's ability to activate natural killer cells.[5][6]

Obinutuzumab was approved under the trade name Gazyva by the US FDA in 2013, and as Gazyvaro by the EMA in Europe, for the treatment of chronic lymphocytic leukemia in combination with chemotherapy in treatment-naive patients. Patients treated with Gazyva had median survival of 23 months before death or disease progression, compared with 11.1 months for patients on chemotherapy alone.[7]

Breakthrough therapy designation

Main article: Breakthrough therapy

On November 13, 2013 the United States Food and Drug Administration approved Gazyva for chronic lymphocytic leukemia making it the first drug to receive the coveted breakthrough therapy designation[8]

UK availability

In October 2014, NICE announced that NHS England would not fund use of the drug, due to data uncertainties in Roche's application. However in 2015; the drug is beginning to be used to treat chronic lymphocytic leukaemia.[9]

Canada availability

In their final recommendation of Obinutuzumab (Gazyva), in the January 2015 Pan-Canadian Oncology Drug Review (pERC) for treatment of chronic lymphocytic leukemia, published by the Canadian Agency for Drugs and Technologies in Health, the list price of obinutuzumab provided by the manufacturer Hoffmann-La Roche was $CDN 5,275.54 per 1,000 mg vial. At the recommended dose obinutuzumab costs $15,826.50" for the first 28 day cycle cycle and "$5275.50 per 28 day cycle for subsequent cycles."[10]

Clinical trials

In 2014, the National Cancer Institute published the results of an international randomized phase III study in which they investigated the use of obinutuzumab in previously untreated patients with chronic lymphocytic leukemia (CLL) and other health conditions. When these patients were given obinutuzumab in combination with chlorambucil, a chemotherapeutic agent, they were found to live longer without their CLL progressing than patients who received only chlorambucil. The patients that received this combination therapy were more likely to go into complete remission as well as have better overall survival than those who received chlorambucil alone. In this study, they also compared patients treated with obinutuzumab and chlorambucil to patients that were treated with rituximab and chlorambucil.[11] Rituximab is a monoclonal antibody treatment that is used to treat CLL and some B-cell non-Hodgkin lymphomas.[12] When comparing CLL patients that received the obinutuzumab combination therapy versus the rituximab combination therapy, the researchers found that the obinutuzumab patients had higher rates of complete remission as well as longer progression-free survival.[11]

Other ongoing studies are currently recruiting patients to determine if obinutuzumab in combination with other agents will be effective in treating different leukemia and lymphoma cancers. In one study, the researchers are investigating the use of obinutuzumab in combination with venetoclax, a small molecule Bcl-2 inhibitor, to determine if this combination is more effective at treating CLL than obinutuzumab with chlorambucil.[13][14] Another study is investigating the use of obinutuzumab with lenalidomide, an antineoplastic agent, in non-Hodgkins lymphomas (NHL).[15][16] By combining these therapies, the researchers hope to better target tumor cells and more efficiently eradicate them in patients with relapsing NHL.[15]

References

  1. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
  2. 1 2 Robak, T (2009). "GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies" (PDF). Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
  3. ↑ Statement On A Nonproprietary Name Adopted By The Usan Council - Afutuzumab, American Medical Association.
  4. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
  5. ↑ Ratner M. Genentech's glyco-engineered antibody to succeed Rituxan. Nat Biotechnol. 2014 Jan;32(1):6-7. PMID 24406911
  6. ↑ Umaña P et al. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol. 1999 Feb;17(2):176-80. PMID 10052355
  7. ↑ Associated Press, published in the New York Times. November 1, 2013 F.D.A. Clears New Cancer-Fighting Drug From Roche
  8. ↑ FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval, FDA News Release, FDA, November 13, 2013, retrieved July 20, 2015
  9. ↑ "NICE denies Roche cancer drug due to ‘data uncertainties’". PM Live. Retrieved 3 October 2014.
  10. ↑ "Final Recommendation for Obinutuzumab (Gazyva) for CLL Pan-Canadian Oncology Drug Review (pERC) Meeting: December 18, 2014; Early Conversion: pCODR" (PDF). Pan-Canadian Oncology Drug Review via Canadian Agency for Drugs and Technologies in Health. 27 January 2015. Retrieved 22 November 2015.
  11. 1 2 "Obinutuzumab Plus Chlorambucil for Chronic Lymphocytic Leukemia". National Cancer Institute. Retrieved 2015-11-30.
  12. ↑ "Rituximab". National Cancer Institute. Retrieved 2015-11-30.
  13. ↑ "Clinical Trials (PDQ®)". National Cancer Institute. Retrieved 2015-11-30.
  14. ↑ "Investor Update". www.roche.com. Retrieved 2015-11-30.
  15. 1 2 "Clinical Trials (PDQ®)". National Cancer Institute. Retrieved 2015-11-30.
  16. ↑ "Definition of lenalidomide - National Cancer Institute Drug Dictionary". National Cancer Institute. Retrieved 2015-11-30.
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