Chemistry:Obinutuzumab

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Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer and active lupus nephritis.[1][2][3] It was originated by GlycArt Biotechnology AG and developed by Roche.[4]

Medical uses

As of 2015, obinutuzumab was being used in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia.[1][5] One more recent study has shown deeper and longer-lasting remissions through fixed-duration treatment regimens in combination with venetoclax.[6][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.[1][7]

Obinutuzumab was not tested in pregnant women.[1]

Side effects

Obinutuzumab has two black box warnings: hepatitis B reactivation and progressive multifocal leukoencephalopathy.[5][1]

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.[5]

Chemistry

Obinutuzumab is a fully humanized monoclonal antibody that binds to an epitope on CD20 that partially overlaps with the epitope recognized by rituximab.[5]

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.[8][9]

Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.[10]

History

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.[11][12][13]

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.[13]

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.[14][15]

In October 2014, NICE announced that NHS England would not fund use of the drug, due to data uncertainties in Roche's application.[16] In June 2015, NICE announced that it would fund restricted use of the drug.[17]

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."[18]

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.[7]

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.[19]

In October 2025, the US Food and Drug Administration (FDA) approved obinutuzumab for the treatment of adult patients with active lupus nephritis who are receiving standard therapy, making it the first anti-CD20 monoclonal antibody approved for this indication.[3]

Research

Chronic lymphocytic leukemia

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.[13] It was called GA101 during research.[citation needed][20]

Nephropathies

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.[21] 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.[22] 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.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Gazyva- obinutuzumab injection, solution, concentrate". 7 April 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda. 
  2. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Gazyvaro EPAR
  3. ↑ 3.0 3.1 "FDA Approves Obinutuzumab (Gazyva) for Lupus Nephritis" (in en). HCPLive. 2025-10-20. https://www.hcplive.com/view/fda-approves-obinutuzumab-gazyva-for-lupus-nephritis. 
  4. ↑ "To Market, To Market—2013". Annual Reports in Medicinal Chemistry. 49. Elsevier. 2014. pp. 437–508. doi:10.1016/b978-0-12-800167-7.00027-4. ISBN 978-0-12-800167-7. 
  5. ↑ 5.0 5.1 5.2 5.3 "Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia". Journal of the Advanced Practitioner in Oncology 6 (4): 370–4. 2015. doi:10.6004/jadpro.2015.6.4.7. PMID 26705497. 
  6. ↑ "Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions". NEJM 380 (23): 2225–2236. 4 June 2019. doi:10.1056/NEJMoa1815281. PMID 31166681. https://www.nejm.org/doi/full/10.1056/NEJMoa1815281. Retrieved 11 June 2024. 
  7. ↑ 7.0 7.1 "Obinutuzumab". 26 February 2016. https://www.fda.gov/drugs/resources-information-approved-drugs/obinutuzumab. 
  8. ↑ "Genentech's glyco-engineered antibody to succeed Rituxan". Nature Biotechnology 32 (1): 6–7. January 2014. doi:10.1038/nbt0114-6b. PMID 24406911. 
  9. ↑ "Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity". Nature Biotechnology 17 (2): 176–80. February 1999. doi:10.1038/6179. PMID 10052355. 
  10. ↑ "Proposed INN: List 99". WHO Drug Information 22 (2): 123. 2008. https://www.who.int/entity/medicines/publications/druginformation/issues/INN-PList-No99.pdf. 
  11. ↑ "Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research". roche.com. http://www.roche.com/media/store/releases/med-cor-2005-07-19.htm. 
  12. ↑ "Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after...". Innovation in Healthcare from Research to Market. Brussels. 31 March 2011. https://ec.europa.eu/research/health/pdf/event04/joel-jean-mairet-31032011_en.pdf. 
  13. ↑ 13.0 13.1 13.2 "Obinutuzumab: first global approval". Drugs 74 (1): 147–54. January 2014. doi:10.1007/s40265-013-0167-3. PMID 24338113. 
  14. ↑ "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.
  15. ↑ "F.D.A. Clears New Cancer-Fighting Drug From Roche". 2 November 2013. https://www.nytimes.com/2013/11/02/business/fda-clears-new-cancer-fighting-drug-from-roche.html. 
  16. ↑ "NICE denies Roche cancer drug due to 'data uncertainties'". 3 October 2014. http://www.pmlive.com/pharma_news/nice_denies_roche_cancer_drug_due_to_data_uncertainties_603342. 
  17. ↑ "NICE technology appraisal guidance (TA343)". 2 June 2015. https://www.nice.org.uk/guidance/ta343. 
  18. ↑ "Final Recommendation for Obinutuzumab (Gazyva) for CLL Pan-Canadian Oncology Drug Review (pERC) Meeting: December 18, 2014; Early Conversion: pCODR". Pan-Canadian Oncology Drug Review via Canadian Agency for Drugs and Technologies in Health. 27 January 2015. https://www.cadth.ca/sites/default/files/pcodr/pcodr-gazyva-cll-fn-rec.pdf. 
  19. ↑ "FDA Approves Ibrutinib/Obinutuzumab for Treatment-Naive Patients with Chronic Lymphocytic Leukemia". https://www.lymphoma.org/newsarchive/fda-approves-ibrutinib-imbruvica-in-combination-with-obinutuzumab-gazyva-for-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll/. 
  20. ↑ "Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity". Blood 115 (22): 4393–4402. June 2010. doi:10.1182/blood-2009-06-225979. PMID 20194898. 
  21. ↑ 21.0 21.1 "New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?". Frontiers in Immunology 13. 2022-02-11. doi:10.3389/fimmu.2022.805697. PMID 35222385. 
  22. ↑ "Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children". Clinical Journal of the American Society of Nephrology 18 (12): 1555–1562. December 2023. doi:10.2215/cjn.0000000000000288. PMID 37678236. 



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