Nivolumab

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Nivolumab ?
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetProgrammed_cell_death_1
Clinical data
Legal status ?
Identifiers
CAS number946414-94-4
ATC codeNone
Chemical data
FormulaC6362H9862N1712O1995S42 
Mol. mass143.6 kDa
 
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Nivolumab ?
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetProgrammed_cell_death_1
Clinical data
Legal status ?
Identifiers
CAS number946414-94-4
ATC codeNone
Chemical data
FormulaC6362H9862N1712O1995S42 
Mol. mass143.6 kDa

Nivolumab (nye vol' ue mab), a drug in clinical trials also known as BMS-936558 or MDX1106, is a fully human IgG4 monoclonal antibody developed by Bristol-Myers Squibb for the treatment of cancer.[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor on activated T cells.

Non-Technical Overview[edit]

Nivolumab works by blocking a protein called PD-1. Drugs which inhibit PD-1, in fact, may be able to treat a variety of cancers.

PD-1, or programmed cell death 1, is a protein on the surface of activated T cells, the warriors of the immune system. If another molecule, called PD-L1, binds to PD-1, the T cell dies or becomes docile. This is a way that the body regulates the immune system, to avoid an overreaction. Since many cancer cells, however, make PD-L1, the cancer cells can disarm the T cells and inhibit them from attacking the tumor. Nivolumab blocks PD-L1 from binding to PD-1.

PD-1 blockers appear to free up the immune system only around the tumor, rather than more generally, which could mean they can have fewer side effects as well.[2]

Market Watch[edit]

There are several other companies pursuing drugs that block the action of PD-1 including Merck; the Genentech unit of Roche; GlaxoSmithKline, working with a small Maryland company called Amplimmune; and Teva working with an Israeli biotech company, Curetech. Nivolumab, being in Phase III clinical trials, is predicted to hit the markets first.[3]

As of July 2013, nivolumab is predicted to launch in 2015 and become the overall non-small cell lung cancer (NSCLC) market sales leader by 2022, reaching revenues of $1.75 billion in the key global markets of the US, UK, France, Germany, Italy, Spain, Japan, China and India, according to GlobalData.[4]

Technical Summary[edit]

Nivolumab is an antibody that specifically blocks PD-1, which can overcome immune resistance. Specifically, since tumor cells express PD-L1, an immunosuppressive PD-1 ligand, inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity.

A phase I clinical trial [5] tested the safety and efficacy of nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight administered by intravenous infusion every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that "anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use."[6] Common adverse events with nivolumab included fatigue, rash, diarrhea, decreased appetite, nausea, and pruritus. Grades 3-4 toxicity occurred in 41 of 296 patients, with 3 deaths attributed to treatment-related pneumonitis.

This study suggests that manipulation of T-cell activation through blockade of the PD-1 system can produce antitumor responses in non-small-cell lung cancer. A phase I study is currently underway to determine the safety of giving the anti PD-1 antibody nivolumab with platinum doublet therapy in patients with advanced non-small-cell lung cancer (NCT01454102).

Phase III clinical trials of nivolumab are recruiting in the US and EU.[7] Bristol-Myers Squibb is currently enrolling participants in clinical trials for renal cell carcinoma, lung cancer, melanoma, and advanced or metastatic solid tumors.[8]

References[edit]

  1. ^ Statement On A Nonproprietary Name Adopted By The USAN Council - Nivolumab, American Medical Association.
  2. ^ http://www.nytimes.com/2012/06/02/business/drug-helps-immune-system-fight-cancer.html?_r=0
  3. ^ http://shearlingsplowed.blogspot.com/2013/04/merck-oncology-candidate-granted.html
  4. ^ http://www.healthcare.globaldata.com/media-center/press-releases/pharmaceuticals/nivolumab-to-lead-lung-cancer-drug-market-with-sales-of-175-billion-by-2022
  5. ^ A Phase 1b Study of MDX-1106 in Subjects With Advanced or Recurrent Malignancies (MDX1106-03), NIH.
  6. ^ Topalian SL, et al. (June 2012). "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer". New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. Lay summaryNew York Times. 
  7. ^ Nivolumab at ClinicalTrials.gov, A service of the U.S. National Institutes of Health.
  8. ^ http://www.nivolumabdrugresearchstudies.com/about_the_studies.aspx