Obinutuzumab

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Obinutuzumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target CD20
Clinical data
Trade names Gazyva, Gazyvaro
Other namesafutuzumab, [1] GA101
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 28.4 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6512H10060N1712O2020S44
Molar mass 146064.72 g·mol−1
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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. [5] [6] It was originated by GlycArt Biotechnology AG and developed by Roche.[ citation needed ]

Contents

Medical uses

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

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

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

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

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

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.

Related Research Articles

Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within Roche. Historically, the company is regarded as the world's first biotechnology company.

<span class="mw-page-title-main">Chronic lymphocytic leukemia</span> Bone marrow cancer in which lymphocytes are overproduced

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

Lumiliximab is an IgG1k monoclonal antibody that targets CD23. It acts as an immunomodulator and was awarded orphan drug status and fast track designation by the FDA.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund. The company is based in Copenhagen, Denmark – internationally, it operates through the subsidiaries Genmab B.V. in Utrecht, The Netherlands, Genmab U.S., Inc. in Princeton, USA, and Genmab K.K. in Tokyo, Japan. Genmab is a dual-listed company with shares traded on both the Copenhagen Stock Exchange in Denmark and the NASDAQ Global Select Market in the US.

<span class="mw-page-title-main">Bendamustine</span> Chemical compound

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.

Milatuzumab is an anti-CD74 humanized monoclonal antibody for the treatment of multiple myeloma non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Idelalisib</span> Chemical compound

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. It was developed by Gilead Sciences. It is taken orally.

ImmunoGen, Inc. was a biotechnology company focused on the development of antibody-drug conjugate (ADC) therapeutics for the treatment of cancer. ImmunoGen was founded in 1981 and was headquartered in Waltham, Massachusetts.

FCM, or FMC in the context of chemotherapy is an acronym for a chemotherapy regimen that is used in the treatment of indolent B cell non-Hodgkin's lymphomas. In combination with Rituximab, this regimen is called R-FCM or R-FMC, or FCM-R, FMC-R.

Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. When antibodies are afucosylated, antibody-dependent cellular cytotoxicity (ADCC) is increased.

Polatuzumab vedotin, sold under the brand name Polivy, is a CD79b-directed antibody-drug conjugate medication used for the treatment of diffuse large B-cell lymphoma (cancer). It was developed by the Genentech subsidiary of Roche.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Acalabrutinib</span> Chemical compound

Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic Lymphoma (CLL/SLL). It may be used both in relapsed as well as in treatment-naive settings.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

References

  1. ↑ WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101 Archived 3 March 2016 at the Wayback Machine , p 176
  2. 1 2 "Australian Product Information - Gazyva® (obinutuzumab)". Archived from the original on 8 January 2023.
  3. ↑ "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.
  4. ↑ "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.
  5. 1 2 3 4 5 6 "Gazyva- obinutuzumab injection, solution, concentrate". DailyMed. 7 April 2020. Archived from the original on 24 January 2021. Retrieved 16 September 2020.
  6. 1 2 "Gazyvaro EPAR". European Medicines Agency. 5 October 2023. Archived from the original on 2 March 2021. Retrieved 5 October 2023.
  7. 1 2 3 4 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. 1 2 "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. 1 2 3 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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