Targeted therapies such as monocolonal antibodies are an important part of anticancer drug development. Humanized antibodies may be used either alone in unlabeled or naked form or conjugated with radioactive isotopes, chemotherapeutics, or toxins to create highly targeted agents. Antibody drug conjugates (ADCs), or monoclonal antibodies linked to a cytotoxic small molecule, provide a niche opportunity for biopharmaceutical companies and contract manufacturers.
Patricia Van Arnum
Monclonal antibodies target cancer
Six engineered monoclonal antibodies ["Rituxan" (rituximab), "Herceptin" (trastuzumab), "Campath" (alemtuzumab), "Avastin" (bevacizumab), "Erbitux" (cetuximab), and "Vectibix" (panitumumab)], two radionuclide-conjugated monoclonal antibodies ["Zevalin" (ibritumomab tiuxetan) and "Bexxar" (tositumomab; iodine I 131 tositumomab)], and one ADC ["Mylotarg" (gemtuzumab ozogamicin)] have been approved to treat cancer (1).
Wyeth's (Madison, NJ) Mylotarg is the only ADC approved by the US Food and Drug Administration. The drug was approved in 2000. Mylotarg consists of a recombinant humanized IgG4 kappa antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora subspecies calichensis (see Figure 1). The antibody portion of Mylotarg binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells. The anti-CD33 hP67.6 antibody is produced by mammalian cell suspension culture using a myeloma NS0 cell line and is purified under conditions which remove or inactivate viruses. Three separate and independent steps in the hP67.6 antibody purification process achieves retrovirus inactivation and removal. These include low pH treatment, diethylaminoethyl (DEAE)-"Sepharose" chromatography, and viral filtration. Mylotarg's amino-acid sequences are 98.3% of human origin. The constant and framework regions contain human sequences. The complementarity-determining regions are derived from a murine antibody (p67.6) that binds CD33. This antibody is linked to N-acetyl-gamma calicheamicin via a bifunctional linker. Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with four to six moles calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to the calicheamicin derivative (2).
Figure 1: "Mylotarg" (gemtuzumab ozogamicin) is an antibody drug conjugate. It is composed of a recombinant humanized IgG4 kappa antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora subspecies calichensis.