Erbitux manufacture is initiated by batch culturing the producing cell line in serum-free media in 10,000-L and 12,000-L
bioreactors. Multistep chromatographic purification is undertaken following initial recovery and concentration. Downstream
processing also incorporates two specific viral inactivation and removal steps, and the final product is formulated as a sterile,
2-mg/mL-cetuximab solution, intended for administration via infusion.
Both in vitro and animal studies confirmed that Erbitux inhibits the growth and survival of tumor cells over-expressing EGFR. Clinical
trials also showed that a combination of Erbitux and irinoectan outperformed Erbitux monotherpay in terms of objective response
rate, disease control rate, and progression-free survival. Reported adverse events include severe infusion-related reactions,
pulmonary complications, dermatological toxicity, and gastrointestinal disturbances.
Avastin (bevacizumab) is a humanized monoclonal antibody produced in an engineered CHO cell line. It binds specifically to human vascular
endothelial growth factor (VEGF). Avastin brings about its therapeutic effect by inhibiting angiogenesis (the formation of
new blood vessels), a process required to support tumor growth. Binding to VEGF prevents VEGF interaction with its cell surface
receptor, a process central to the triggering of new blood vessel growth in both normal and diseased tissue.
FDA approved Avastin in 2004. It is indicated for first line of treatment for patients with metastatic carcinoma of the colon
or rectum, in conjunction with specified small molecule chemotherapeutic agents (5 fluorouricil, folinic acid, and irinotecan).
The product has subsequently also gained marketing approval in the EU (in January, 2005). It is manufactured by Genentech
and marketed in the EU by Roche.
Production-scale manufacture entails culture of the CHO producer-cell line in 12,000-L fermentors using a serum-free growth
media. Product purification is achieved via protein A affinity chromatography followed by sequential anion and cation exchange
steps. Two viral inactivation steps are also included in the downstream processing protocol. The final product is concentrated
via ultrafiltration and is formulated as a sterile solution for intravenous infusion.
Clinical trials confirmed the product's efficacy, with Avastin administration (in conjunction with the specified small molecule
chemotherapeutics) resulting in a statistically significant increase in overall survival, higher objective response rates,
and longer progression-free survival. Adverse effects that were noted included gastrointestinal perforations, hemorrhage and
Raptiva (efalizumab) is a humanized monoclonal antibody produced in an engineered CHO cell line. Approval by the European Commission
was in September 2004 (and by FDA in 2003) for the treatment of adult patients with moderate to severe chronic plaque psoriasis
who failed to respond to or were intolerant of other specified systemic therapies. Genentech manufactures the product but
Serono markets it.
Psoriasis is a chronic inflammatory skin disorder caused by T-lymphocyte mediated stimulation of keratinocyte hyperproliferation.
By preventing LFA-1/ICAM binding, the product inhibits several stages of this immunological disorder. Raptiva specifically
binds lymphocyte function-associated antigen 1 (LFA-1), a leukocyte cell surface protein. Binding inhibits interaction of
LFA-1 with intercellular adhesion molecules 1, 2 and 3 (ICAM-1, -2 and -3). LFA-1 is present on activated T lymphocytes, and
ICAM-1 is up-regulated on endothelial cells and keratinocytes in psoriasis plaques.
Manufacture entails initial culture of producer CHO cells in suspension, followed by multiple chromatographic purification
and viral inactivation/removal steps. The final product is presented in lyophilized form, intended for subcutaneous (SC) administration
subsequent to reconstitution in water for injections (WFI).
Clinical trials confirmed that 12 weeks of treatment with Raptiva significantly improved the severity and area of psoriatic
lesions. As an immunosuppressive agent however, the product has the potential to increase the risk of serious infections and
Levemir (insulin detemir) is a long-acting insulin analogue produced in an engineered Saccharomyces cerevisiae cell line. The product differs from native human insulin in that the theronine residue at position 30 of the insulin B chain
(B30) has been omitted and a myristic fatty acid (a C14 saturated fatty acid) has been attached (acylated) to the amino group
of the lysine residue found at position B29. Albumin harbors three high-affinity, fatty-acid, binding sites and, as such,
Levemir binds tightly but reversibly to albumin, both at the site of injection and in the blood. This in turn ensures a constant
and prolonged release of free insulin, bestowing upon it an extended duration of action of up to 24 hours.