Biopharmaceuticals: Approval Trends in 2007 - More than 70% of the products were produced in mammalian cells. - BioPharm International


Biopharmaceuticals: Approval Trends in 2007
More than 70% of the products were produced in mammalian cells.

BioPharm International
Volume 21, Issue 10

Soliris (eculizumab) is a 148 kDa humanized IgG2/4 kappa antibody produced by recombinant means in an NS0 murine myeloma cell line. The antibody is composed of two 448 amino acid heavy chains and two 214 amino acid light chains, and displays a characteristic IgG oligosaccharide attached to Asn 298 of the heavy antibody chains. The product, which binds to the human C5 complement protein, was approved in 2007, both in the EU and the US, and is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), to reduce hemolysis. It has orphan status.

PNH is a rare genetic condition in which patients harbour a mutant gene coding for CD 59, a complement inhibitory protein normally found on the surface of red blood cells. As its name suggests, this protein serves to inhibit the formation of a complement complex (i.e., the membrane attack complex) on the red blood cell (RBC) surface, thereby preventing RBC destruction (hemolysis). This RBC protective mechanism is absent in PNH sufferers and the predominant clinical manifestation of the condition is intravascular hemolysis. Patients typically have a 15-year median survival period from diagnosis. The treatment approaches are largely palliative, with transfusion therapy often used to maintain RBC levels. By binding to the C5 complement protein, the antibody effectively inhibits final activation of the complement system, hence preventing complement-mediated hemolysis.

Antibody manufacture entails an initial cell-culture step using a 5,000-L bioreactor. The product is subsequently purified by a combination of chromatographic steps, and downstream processing also incorporates viral inactivation (low pH) and virus-removal (nanofiltration) steps. The excipients added include phosphate buffer components, sodium chloride, and polysorbate 80. The final product is filter sterilized and presented in vials as a concentrate (30 mL of a 10 mg/mL solution) destined for IV infusion after dilution to 5 mg/mL. A typical dosage regime entails initial infusion of 600 mg of product weekly for four weeks, a 900-mg infusion at week five, followed by 900-mg infusions every second week thereafter.

Product safety and efficacy were primarily investigated by one main study involving 87 PNH patients. All had received at least four blood transfusions for anemia in the previous year. By the 26-week endpoint, 49% of treated patients displayed stabilized hemoglobin levels, as opposed to none in the untreated group. Likewise, 51% of the treated group had avoided the necessity for a blood transfusion while all of the nontreated group required transfusions. The most commonly reported side effects included headaches, urinary tract infections, and nasopharyngitis. The most significant adverse reaction experienced was meningococcal infections. As a result, patients should be vaccinated against meningitis caused by Neisseria meningitides before product administration.

The active ingredient in Soliris is manufactured by Lonza Biologics (Newington, New Hampshire). The product is marketed in the United States and EU by Alexion (Cheshire, CT).

Gary Walsh, PhD, is an associate professor in the Industrial Biochemistry Program at the University of Limerick, Limerick City, Ireland, +353.61.202664,
He is also a member of BioPharm International's Editorial Advisory Board.


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