View source for Obinutuzumab

{{Short description|Medication}}
{{Use dmy dates|date=October 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 477243496
| image =  

<!-- Monoclonal antibody data -->
| type = mab
| mab_type = mab
| source = zu/o
| target = [[CD20]]

<!-- Clinical data -->
| tradename = Gazyva, Gazyvaro
| Drugs.com = {{drugs.com|monograph|obinutuzumab}}
| licence_EU = yes
| DailyMedID  = Obinutuzumab
| pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Gazyva PI" />
| pregnancy_category = 
| routes_of_administration = [[Intravenous infusion]]
| ATC_prefix = L01
| ATC_suffix = FA03

| legal_AU = S4
| legal_AU_comment = <ref name="Gazyva PI">{{Cite web | url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropgazyv10515 | title=Australian Product Information - Gazyva® (obinutuzumab) | archive-url=https://web.archive.org/web/20230108233552/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropgazyv10515 |archive-date=2023-01-08}}</ref><ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410065838/https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | url-status=live }}</ref>
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="FDA Gazyva label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Gazyvaro EPAR">{{cite web | title=Gazyvaro EPAR | website=European Medicines Agency | date=5 October 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/gazyvaro | access-date=5 October 2023 | archive-date=2 March 2021 | archive-url=https://web.archive.org/web/20210302030608/https://www.ema.europa.eu/en/medicines/human/EPAR/gazyvaro | url-status=live }}</ref>
| legal_status = 

<!-- Pharmacokinetic data -->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life =  28.4 days
| excretion = 

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 949142-50-1
| PubChem = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB08935
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = none
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = O43472U9X8
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D09321
| synonyms = afutuzumab,<ref>[https://www.who.int/medicines/publications/druginformation/innlists/PLFinal101.pdf WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101] {{Webarchive|url=https://web.archive.org/web/20160303173654/http://www.who.int/medicines/publications/druginformation/innlists/PLFinal101.pdf |date=3 March 2016 }}, p 176</ref> GA101

<!-- Chemical data -->
| C=6512 | H=10060 | N=1712 | O=2020 | S=44
}}

'''Obinutuzumab''', sold under the brand name '''Gazyva''' among others, is a humanized anti-[[CD20]] [[monoclonal antibody]] used as a treatment for cancer.<ref name="FDA Gazyva label" /><ref name="Gazyvaro EPAR" /> It was originated by GlycArt Biotechnology AG and developed by [[Hoffmann-La Roche|Roche]].{{cn|date=January 2023}}

==Medical uses==
As of 2015, obinutuzumab was being used in combination with [[chlorambucil]] as a first-line treatment for [[chronic lymphocytic leukemia]].<ref name="FDA Gazyva label" /><ref name=2015EvansRev/><!--This statement presumes that the Evans review states "first-line", please verify.--> One more recent study has shown deeper and longer-lasting remissions through fixed-duration treatment regimens in combination with [[venetoclax]].<ref>{{cite journal |title=Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions |journal=NEJM |date=4 June 2019 |volume=380 |issue=23 |pages=2225–2236 |doi=10.1056/NEJMoa1815281 |url=https://www.nejm.org/doi/full/10.1056/NEJMoa1815281 |access-date=11 June 2024 |pmid=31166681 |display-authors=1 | vauthors = Fischer K, Al-Sawaf O, Bahlo J, Fink A, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner C, Langerak AW, Kreuzer K, Ritgen M, Goede V, Stilgenbauer S |url-access=subscription }}</ref>{{primary source inline|date = August 2024}}

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.<ref name="FDA Gazyva label" /><ref name="FDA_2016"/>

Obinutuzumab was not tested in pregnant women.<ref name="FDA Gazyva label">{{cite web | title=Gazyva- obinutuzumab injection, solution, concentrate | website=DailyMed | date=7 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda | access-date=16 September 2020 | archive-date=24 January 2021 | archive-url=https://web.archive.org/web/20210124010946/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df12ceb2-5b4b-4ab5-a317-2a36bf2a3cda | url-status=live }}</ref>

==Side effects==
Obinutuzumab has two [[black box]] warnings: [[hepatitis B]] reactivation and [[progressive multifocal leukoencephalopathy]].<ref name=2015EvansRev/><ref name="FDA Gazyva label" />

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.<ref name=2015EvansRev/>

==Obinutuzumab in difficult 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.<ref>{{cite journal | vauthors = Basu B, Angeletti A, Islam B, Ghiggeri GM | title = New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are? | journal = Frontiers in Immunology | volume = 13 | pages = 805697 | date = 2022-02-11 | pmid = 35222385 | pmc = 8873567 | doi = 10.3389/fimmu.2022.805697 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Dossier C, Bonneric S, Baudouin V, Kwon T, Prim B, Cambier A, Couderc A, Moreau C, Deschenes G, Hogan J | title = Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children | journal = Clinical Journal of the American Society of Nephrology | volume = 18 | issue = 12 | pages = 1555–1562 | date = December 2023 | pmid = 37678236 | doi = 10.2215/cjn.0000000000000288 | pmc = 10723910 }}</ref> 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.<ref>{{cite journal | vauthors = Basu B, Angeletti A, Islam B, Ghiggeri GM | title = New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are? | journal = Frontiers in Immunology | volume = 13 | pages = 805697 | date = 2022-02-11 | pmid = 35222385 | pmc = 8873567 | doi = 10.3389/fimmu.2022.805697 | doi-access = free }}</ref>

==Chemistry==
Obinutuzumab is a [[Humanized antibody|fully humanized]] monoclonal antibody that binds to an [[epitope]] on CD20 that partially overlaps with the epitope recognized by [[rituximab]].<ref name=2015EvansRev>{{cite journal | vauthors = Evans SS, Clemmons AB | title = Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia | journal = Journal of the Advanced Practitioner in Oncology | year = 2015 | volume = 6 | issue = 4 | pages = 370–4 | doi = 10.6004/jadpro.2015.6.4.7 | pmid = 26705497 | pmc = 4677809 }}</ref>

GlycArt's technology platform allowed control of protein [[glycosylation]]; the cells in which obinutuzumab is [[industrial fermentation|produced]] were [[genetic engineering|engineered]] to overexpress  two glycosylation enzymes, [[MGAT3]] and Golgi [[mannosidase]] 2, which [[Afucosylated monoclonal antibodies|reduce the amount of fucose attached to the antibody]], which in turn increases the antibody's ability to activate [[natural killer cells]].<ref>{{cite journal | vauthors = Ratner M | title = Genentech's glyco-engineered antibody to succeed Rituxan | journal = Nature Biotechnology | volume = 32 | issue = 1 | pages = 6–7 | date = January 2014 | pmid = 24406911 | doi = 10.1038/nbt0114-6b | s2cid = 26281173 }}</ref><ref>{{cite journal | vauthors = Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE | title = Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity | journal = Nature Biotechnology | volume = 17 | issue = 2 | pages = 176–80 | date = February 1999 | pmid = 10052355 | doi = 10.1038/6179 | s2cid = 20078393 }}</ref>

Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.<ref>[https://www.who.int/entity/medicines/publications/druginformation/issues/INN-PList-No99.pdf WHO Drug Information, Vol. 22, No. 2, 2008 Proposed INN: List 99] {{Webarchive|url=https://web.archive.org/web/20211025171554/https://www.who.int/medicines/publications/druginformation/issues/INN-PList-No99.pdf |date=25 October 2021 }}, page 123</ref>

==History==
Obinutuzumab was created by scientists at GlycArt Biotechnology, which had been founded in 2000 as a spin-out company of the [[ETH Zurich|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.<ref name="roche">{{cite web|url=http://www.roche.com/media/store/releases/med-cor-2005-07-19.htm|title=Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research|publisher=roche.com|access-date=2015-04-29|url-status=dead|archive-url=https://web.archive.org/web/20150205033013/http://www.roche.com/media/store/releases/med-cor-2005-07-19.htm|archive-date=2015-02-05}}</ref><ref>[https://web.archive.org/web/20160305002757/https://ec.europa.eu/research/health/pdf/event04/joel-jean-mairet-31032011_en.pdf Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after...] by Dr. Joël Jean-Mairet. Brussels, 31 March 2011</ref><ref name=2014reviewCameron>{{cite journal | vauthors = Cameron F, McCormack PL | title = Obinutuzumab: first global approval | journal = Drugs | volume = 74 | issue = 1 | pages = 147–54 | date = January 2014 | pmid = 24338113 | doi = 10.1007/s40265-013-0167-3 | s2cid = 40983655 }}</ref>

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.<ref name=2014reviewCameron/>

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.<ref name="FDA_2013_breakthrough">{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm |title=FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval |publisher=FDA |date=13 November 2013 |access-date=20 July 2015 |archive-date=21 August 2015 |archive-url=https://web.archive.org/web/20150821054022/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm |url-status=dead }}</ref><ref>{{cite web | title=F.D.A. Clears New Cancer-Fighting Drug From Roche | website=[[The New York Times]] | date=2 November 2013 | url=https://www.nytimes.com/2013/11/02/business/fda-clears-new-cancer-fighting-drug-from-roche.html | access-date=16 September 2020 | agency=Associated Press | archive-date=6 October 2021 | archive-url=https://web.archive.org/web/20211006234910/https://www.nytimes.com/2013/11/02/business/fda-clears-new-cancer-fighting-drug-from-roche.html | url-status=live }}</ref>

In October 2014, [[NICE]] announced that [[NHS England]] would not fund use of the drug, due to data uncertainties in Roche's application.<ref>{{cite web|url=http://www.pmlive.com/pharma_news/nice_denies_roche_cancer_drug_due_to_data_uncertainties_603342|title=NICE denies Roche cancer drug due to 'data uncertainties'|website=PM Live|date=3 October 2014|access-date=3 October 2014|archive-date=6 October 2014|archive-url=https://web.archive.org/web/20141006034448/http://www.pmlive.com/pharma_news/nice_denies_roche_cancer_drug_due_to_data_uncertainties_603342|url-status=live}}</ref>  In June 2015, NICE announced that it would fund restricted use of the drug.<ref>{{cite web | url=https://www.nice.org.uk/guidance/ta343 | title=NICE technology appraisal guidance (TA343) | date=2 June 2015 | access-date=14 March 2016 | archive-date=15 March 2016 | archive-url=https://web.archive.org/web/20160315034020/https://www.nice.org.uk/guidance/ta343 | url-status=live }}</ref>

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&nbsp;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."<ref name="CADTH">{{cite web | url=https://www.cadth.ca/sites/default/files/pcodr/pcodr-gazyva-cll-fn-rec.pdf | title=Final Recommendation for Obinutuzumab (Gazyva) for CLL Pan-Canadian Oncology Drug Review (pERC) Meeting: December 18, 2014; Early Conversion: pCODR | work=Pan-Canadian Oncology Drug Review via Canadian Agency for Drugs and Technologies in Health | date=27 January 2015 | access-date=22 November 2015 | archive-date=18 October 2015 | archive-url=https://web.archive.org/web/20151018184042/https://www.cadth.ca/sites/default/files/pcodr/pcodr-gazyva-cll-fn-rec.pdf | url-status=live }}</ref>

In February 2016, obinutuzumab was approved by the FDA under the [[Priority review (FDA)|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.<ref name="FDA_2016">{{cite web | title=Obinutuzumab | website=U.S. Food and Drug Administration | date=26 February 2016 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/obinutuzumab | access-date=5 October 2023 | archive-date=27 March 2023 | archive-url=https://web.archive.org/web/20230327175925/https://www.fda.gov/drugs/resources-information-approved-drugs/obinutuzumab | url-status=dead }}</ref>

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.<ref>{{cite web | url=https://www.lymphoma.org/newsarchive/fda-approves-ibrutinib-imbruvica-in-combination-with-obinutuzumab-gazyva-for-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll/ | title=FDA Approves Ibrutinib/Obinutuzumab for Treatment-Naive Patients with Chronic Lymphocytic Leukemia | access-date=4 June 2019 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804172601/https://lymphoma.org/newsarchive/fda-approves-ibrutinib-imbruvica-in-combination-with-obinutuzumab-gazyva-for-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll/ | url-status=live }}</ref>

==Research==
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)|CHOP]] chemotherapy as a first line treatment for people with advanced CD20-positive [[diffuse large B-cell lymphoma]].<ref name=2014reviewCameron/> It was called GA101 during research.{{fact|date=March 2025}}

== References ==
{{Reflist}}

== External links ==
* {{cite web | title=Obinutuzumab | work=NCI Dictionary of Cancer Terms | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/obinutuzumab }}
* {{cite web | title=Obinutuzumab | website=National Cancer Institute | date=12 November 2013 | url=https://www.cancer.gov/about-cancer/treatment/drugs/obinutuzumab }}

{{Targeted cancer therapeutic agents}}
{{Monoclonals for tumors}}
{{Immunosuppressants}}
{{Portal bar | Medicine}}
{{Authority control}}

[[Category:Drugs developed by Hoffmann-La Roche]]
[[Category:Drugs developed by Genentech]]
[[Category:Monoclonal antibodies for tumors]]
[[Category:Orphan drugs]]