Introduction of Ipilimumab

Ipilimumab (formerly MDX-010) is a fully human IgG1 monoclonal antibody and has a half-life of 12–14 days, that works to activate the immune system by targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a protein receptor that downregulates the immune system. Ipilimumab is indicated for the treatment of unresectable or metastatic melanoma in adults. It is also used to reduce the risk of the deadly skin cancer returning after surgery. Developed by Medarex, Inc., Bloomsburg, NJ, and codeveloped with Bristol-Myers Squibb, Princeton, NJ, ipilimumab (trade name Yervoy) was approved by US FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. It was later approved by the US FDA on October 28, 2015 for stage 3 patients as adjuvant therapy. On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease. Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma in November 2012. It is also undergoing clinical trials for the treatment of other solid tumors, including non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer and metastatic hormone-refractory prostate cancer.

Mechanism of Action of Ipilimumab

T lymphocytes can recognize and destroy tumor cells. Full T cell activation requires engagement of T cell receptor(TCR) to antigen-bound major histocompatibility complex(MHC) on antigen presenting cells (APCs) as well as engagement of CD28 on the T cell surface by members of the B7 family (e.g., B7.1/CD80, B7.2/CD86, B7-H3, B7-H4) on APCs. However, an inhibitory mechanism interrupts this destruction. CTLA-4, a homology of CD28, is an activation-induced, type I transmembrane protein of the Ig superfamily, expressed by T lymphocytes as a covalent homodimer that has a higher binding affinity than CD28 for B7. Crosslinking of CTLA-4 by B7 in the context of T-cell antigen receptor (TCR) engagement inhibits T-cell activation, IL-2 gene transcription, and T-cell proliferation by directly inhibiting TCR signal transduction. Thus, CD28-B7 singnal pathway, the second activating signal, is blocked and results in overall downregulation of T cell activation. Immunotherapy is an emerging therapy that has acquired clinical interest in cancer treatment. The use of monoclonal antibodies (mAbs) in cancer has shown good promise. MAbs interfere with a single target molecule, with high selectivity due to their specifcity. Ipilimumab, a fully human IgG1 monoclonal antibody, was designed to bind CTLA4 and blocked its interaction with B7 on APCs, which can prevent CD28-B7 down regulatory signal. Without the CTLA4-B7 down regulatory signal, T cell function is enhanced and prolonged, as measured by increased production of IL-2, IFN-γ, IL-3, IL-4, IL-5 and IL-10, thus allows the lymphocytes to continue to destroy cancer cells. Generally, ipilimumab binds to CTLA-4, blocking the inhibitory signal, which prolongs T-cell activation and allows the T cells to destroy the tumor cells.

Figure 1 Mechanism of Action of Ipilimumab

Clinical Projects of Ipilimumab *

Approved Drugs of Ipilimumab **

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* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Ipilimumab&Search=Apply&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=&rslt=

** Information presented in the table was collected from the following websites:
https://search.tga.gov.au/s/search.html?collection=tga-websites-web&query=Ipilimumab&op=Search
http://www.ema.europa.eu/ema/index.jsp?curl=search.jsp&q=Ipilimumab&btnG=Search&mid=
https://www.drugbank.ca/drugs/DB06186

For research use only. Not intended for any clinical use.