Ipilimumab

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Ipilimumab’s molecular target is CTLA-4 (Uniprot: P16410; canSAR ; PFAM: P16410), a negative regulator of T-cell activation. Ipilimumab augments T-cell activation and proliferation by binding to CTLA-4 and preventing its interaction with its ligands (CD80 and CD86). CTLA-4 is a membrane-bound, 223 amino acid long, T-cell protein. It contains an immunoglobulin V-type domain (PFAM:PF07686). The structure of CTLA-4 is determined (see e.g. PDBe:3osk)

Ipilimumab (i pi lim′ ue mab; also known as MDX-010 and MDX-101), marketed asYervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S. Food and Drug Administration (FDA) approved human monoclonal antibody developed byBristol-Myers Squibb, and works by activating the immune system by targeting CTLA-4.

Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy cancer cells.

In addition to melanoma, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer.

Yervoy is a monoclonal antibody drug indicated for treating metastatic melanoma. The drug was developed by Bristol-Myers Squibb.

In March 2011, The US Food and Drug Administration (FDA) approved Yervoy to treat patients with newly diagnosed or previously-treated unresectable or metastatic melanoma. Yervoy is the first drug approved vor the treatment of metastatic melanoma in the US.

Bristol-Myers Squibb submitted a marketing authorisation application to the European Medicines Agency in May 2010. The drug received approval from the European Commission in July 2011.

Approval from Australia’s Therapeutic Goods Association was received in July 2011. The drug is currently being reviewed by Health Canada.

Metastatic melanoma

Melanoma responsible for majority of skin cancer deaths in the US. In metastatic melanoma the cancer spreads to other parts of the body from its starting point. It becomes difficult to treat the disease once it spreads beyond the skin to other parts of the body. The disease is also known as stage IV melanoma.

If the melanoma spreads to the lungs then the patient faces breathing problems. The patients with metastatic melanoma may feel symptoms of fatigue, loss of weight, and appetite and bowel problems.

The incidence of the disease has increased steadily in the US after 1970s. The American Cancer Society (ACS) estimated that more than 68,000 new cases of melanoma were registered in the US in 2009. The ACS estimated that the number of deaths occurred due to melanoma in 2010 was more than 8,700.

Yervoy mechanism

Yervoy treats metastatic melanoma by activating the immune system. The drug works by binding or inhibiting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule that plays vital role in relating natural immune responses. The presence or absence of CTLA-4 can curb or increase the immune system’s T-cell response in fighting disease.

The drug also works by blocking a complex set of interactions in the immune system. It is designed to inhibit the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.

Approvals and indications

Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. 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.” Additionally Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma, November 2012