Malignant melanoma is diagnosed in an estimated 160,000 new patients each year and, despite being less common than other skin neoplasms, it is responsible for 75% of skin cancer-related deaths. Current available treatment options for melanoma are limited to surgery, chemotherapy, radiotherapy and immunotherapy, although there are a number of targetted agents in the clinical development at the moment. Ipilimumab effect in melanoma is indirect and probably due to enabling a T-cell mediated immune response
In a randomised clinical study that assessed the response of unresectable or metastatic melanoma patients to Ipilimumab, alone and in combination with investigational peptide vaccine adjuvant, gp100, the combination showed increased survival time (median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone) as well as a near doubling of the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%) as compared to the peptide alone.
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 has been issued with a Black Box warning as it can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation, particularly enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.
Ipilimumab is administered intravenously, and the recommended dose is 3 mg/kg administered over 90 minutes every 3 weeks for a total of four doses. The terminal half-life (t1/2) is 14.7 days (30.1%); systemic clearance (CL) is 15.3 mL/h (38.5%); and volume of distribution at steady-state (Vss) is 7.21 L (10.5%).
The full prescribing information can be found here. Yervoy™ is a product of Bristol-Myers Squibb