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Nivolumab

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Nivolumab

Nivolumab?
Monoclonal antibody
Type Whole antibody
Source Human
Target PD-1
Clinical data
Legal status
?
Identifiers
CAS number
ATC code None
Chemical data
Formula C6362H9862N1712O1995S42 
Mol. mass 143.6 kDa

Nivolumab (nye vol' ue mab), a drug in clinical trials also known as ONO-4538/BMS-936558 or MDX1106, is a fully human IgG4 monoclonal antibody developed by Ono Pharmaceutical and Medarex (Medarex was later acquired 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 (PD-1) receptor on activated T cells.

Non-technical overview

Nivolumab works by blocking a protein called programmed cell death 1 (PD-1). Drugs which inhibit PD-1 may be able to treat a variety of cancers.

PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1 (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 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

There are several other companies pursuing drugs that block the action of PD-1 including Merck;GlaxoSmithKline, working with a small Maryland company called Amplimmune; and Teva working with an Israeli biotech company, Curetech.

Technical summary

Nivolumab is an antibody that specifically blocks PD-1, thereby overcoming 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[3] 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."[4] 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.[5]

Phase III clinical trials of nivolumab are recruiting in the US and EU.[6] Bristol-Myers Squibb is currently enrolling participants in clinical trials for renal cell carcinoma, lung cancer, melanoma, and advanced or metastatic solid tumors.[7]

References

  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. ^ A Phase 1b Study of MDX-1106 in Subjects With Advanced or Recurrent Malignancies (MDX1106-03), NIH.
  4. ^ Topalian SL, et al. (June 2012). "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer". New England Journal of Medicine 366.  
  5. ^ ClinicalTrials.gov NCT01454102 Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, Pemetrexed/Cisplatin, Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib, Ipilimumab or as Monotherapy in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer (NSCLC) (CheckMate 012)
  6. ^ Nivolumab at ClinicalTrials.gov, A service of the U.S. National Institutes of Health.
  7. ^ http://www.nivolumabdrugresearchstudies.com/about_the_studies.aspx
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