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Obinutuzumab

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Obinutuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD20
Clinical data
Trade namesGazyva, Gazyvaro
Other namesafutuzumab,[1] GA101
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life28.4 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6512H10060N1712O2020S44
Molar mass146064.72 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer.[5][6] It was originated by GlycArt Biotechnology AG and developed by Roche.[citation needed]

Medical uses

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As of 2015, obinutuzumab was being used in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia.[5][7] One more recent study has shown deeper and longer-lasting remissions through fixed-duration treatment regimens in combination with venetoclax.[8][non-primary source needed]

It is also used in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of people with follicular lymphoma as a second line treatment to a regimen containing rituximab.[5][9]

Obinutuzumab was not tested in pregnant women.[5]

Side effects

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Obinutuzumab has two black box warnings: hepatitis B reactivation and progressive multifocal leukoencephalopathy.[7][5]

In the clinical trial of obinutuzumab in combination with chlorambucil, participants experienced infusion reactions (69%; 21% grade 3/4), neutropenia (40%; 34% grade 3/4), thrombocytopenia (15%; 11% grade 3/4), anemia (12%), and pyrexia and cough (10% each). More than 20% of subjects had abnormal lab tests including low calcium and sodium, high potassium, increases in serum creatinine and liver function tests, and low albumin levels.[7]

Obinutuzumab in difficult nephropathies

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Obinutuzumab is recently reported to be safe and effective in some autoimmune diseases affecting the kidneys. It is a promising treatment of renal diseases with proteinuria, in particular patients with resistance or partial response to rituximab.[10] A single low-dose infusion of Obinutuzumab, found to be effective and safe in inducing prolonged remission in children with steroid-dependent or frequently relapsing nephrotic syndrome. This effect is particularly shown in children who have rituximab resistance or relapse after rituximab. The tolerance profile of Obinutuzumab is comparable to rituximab.[11] Similar promising results is shown in adults with Membranoproliferative glomerulonephritis treated with Obinutuzumab after resistance to rituximab, tacrolimus and cyclophosphamide. Furthermore, Obinutuzumab showed sustained clinical benefit through 2 years in patients with class III and IV Proliferative Lupus Nephritis compared to rituximab.[12]

Chemistry

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Obinutuzumab is a fully humanized monoclonal antibody that binds to an epitope on CD20 that partially overlaps with the epitope recognized by rituximab.[7]

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.[13][14]

Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.[15]

History

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Obinutuzumab was created by scientists at GlycArt Biotechnology, which had been founded in 2000 as a spin-out company of the Swiss Federal Institute of Technology in Zurich to develop afucosylated monoclonal antibodies; GA101 was one of its lead products when it was acquired by Roche in 2005.[16][17][18]

Roche developed the drug in the US through its US subsidiary, Genentech, and in Japan through its Japanese subsidiary, Chugai. Genentech partnered with Biogen Idec to explore the use of the drug for primary biliary cirrhosis but as of 2014 it appeared the development in that indication had halted.[18]

In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia, and was the first drug with breakthrough therapy designation to gain approval.[19][20]

In October 2014, NICE announced that NHS England would not fund use of the drug, due to data uncertainties in Roche's application.[21] In June 2015, NICE announced that it would fund restricted use of the drug.[22]

In their final recommendation of obinutuzumab, 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 and "$5275.50 per 28 day cycle for subsequent cycles."[23]

In February 2016, obinutuzumab was approved by the FDA under the Priority Review program for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma as a secondline treatment to a regimen containing rituximab.[9]

In January 2019, the US Food and Drug Administration (FDA) approved ibrutinib in combination with obinutuzumab for people with chronic lymphocytic leukemia/small lymphocytic lymphoma who have not received prior treatment.[24]

Research

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As of 2014 clinical trials had been conducted exploring the use of obinutuzumab as a second line monotherapy in relapsed/refractory chronic lymphocytic leukemia, as a monotherapy for relapsed/refractory non-Hodgkin lymphoma in people who had high expression of CD20; and in combination with CHOP chemotherapy as a first line treatment for people with advanced CD20-positive diffuse large B-cell lymphoma.[18] It was called GA101 during research.

References

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  1. ^ WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101 Archived 3 March 2016 at the Wayback Machine, p 176
  2. ^ a b "Australian Product Information - Gazyva® (obinutuzumab)". Archived from the original on 8 January 2023.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  4. ^ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  5. ^ a b c d e f "Gazyva- obinutuzumab injection, solution, concentrate". DailyMed. 7 April 2020. Archived from the original on 24 January 2021. Retrieved 16 September 2020.
  6. ^ a b "Gazyvaro EPAR". European Medicines Agency. 5 October 2023. Archived from the original on 2 March 2021. Retrieved 5 October 2023.
  7. ^ a b c d Evans SS, Clemmons AB (2015). "Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia". Journal of the Advanced Practitioner in Oncology. 6 (4): 370–4. doi:10.6004/jadpro.2015.6.4.7. PMC 4677809. PMID 26705497.
  8. ^ Fischer K, Al-Sawaf O, Bahlo J, Fink A, Tandon M, Dixon M, et al. (4 June 2019). "Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions". NEJM. 380 (23): 2225–2236. doi:10.1056/NEJMoa1815281. PMID 31166681. Retrieved 11 June 2024.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ^ a b "Obinutuzumab". U.S. Food and Drug Administration. 26 February 2016. Archived from the original on 27 March 2023. Retrieved 5 October 2023.
  10. ^ Basu B, Angeletti A, Islam B, Ghiggeri GM (11 February 2022). "New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?". Frontiers in Immunology. 13: 805697. doi:10.3389/fimmu.2022.805697. PMC 8873567. PMID 35222385.
  11. ^ Dossier C, Bonneric S, Baudouin V, Kwon T, Prim B, Cambier A, et al. (December 2023). "Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children". Clinical Journal of the American Society of Nephrology. 18 (12): 1555–1562. doi:10.2215/cjn.0000000000000288. PMC 10723910. PMID 37678236.
  12. ^ Basu B, Angeletti A, Islam B, Ghiggeri GM (11 February 2022). "New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?". Frontiers in Immunology. 13: 805697. doi:10.3389/fimmu.2022.805697. PMC 8873567. PMID 35222385.
  13. ^ Ratner M (January 2014). "Genentech's glyco-engineered antibody to succeed Rituxan". Nature Biotechnology. 32 (1): 6–7. doi:10.1038/nbt0114-6b. PMID 24406911. S2CID 26281173.
  14. ^ Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE (February 1999). "Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity". Nature Biotechnology. 17 (2): 176–80. doi:10.1038/6179. PMID 10052355. S2CID 20078393.
  15. ^ WHO Drug Information, Vol. 22, No. 2, 2008 Proposed INN: List 99 Archived 25 October 2021 at the Wayback Machine, page 123
  16. ^ "Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research". roche.com. Archived from the original on 5 February 2015. Retrieved 29 April 2015.
  17. ^ Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after... by Dr. Joël Jean-Mairet. Brussels, March 31, 2011
  18. ^ a b c Cameron F, McCormack PL (January 2014). "Obinutuzumab: first global approval". Drugs. 74 (1): 147–54. doi:10.1007/s40265-013-0167-3. PMID 24338113. S2CID 40983655.
  19. ^ "FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval" (Press release). FDA. 13 November 2013. Archived from the original on 21 August 2015. Retrieved 20 July 2015.
  20. ^ "F.D.A. Clears New Cancer-Fighting Drug From Roche". The New York Times. Associated Press. 2 November 2013. Archived from the original on 6 October 2021. Retrieved 16 September 2020.
  21. ^ "NICE denies Roche cancer drug due to 'data uncertainties'". PM Live. 3 October 2014. Archived from the original on 6 October 2014. Retrieved 3 October 2014.
  22. ^ "NICE technology appraisal guidance (TA343)". 2 June 2015. Archived from the original on 15 March 2016. Retrieved 14 March 2016.
  23. ^ "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. Archived (PDF) from the original on 18 October 2015. Retrieved 22 November 2015.
  24. ^ "FDA Approves Ibrutinib/Obinutuzumab for Treatment-Naive Patients with Chronic Lymphocytic Leukemia". Archived from the original on 4 August 2020. Retrieved 4 June 2019.
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