Products

Erythropoietin Alfa111-113

Erythropoietin alfa, recombinant Epoetin Alfa, Epogen, Procrit, is a glycoprotein that stimulates red blood cell production. It is produced in the kidney, and it activates the proliferation and differentiation of specially committed ery-throid progenitors in the bone marrow. Epoetin alfa (Epogen) is a 165-amino acid glycoprotein that is manufactured in mammalian cells by rDNA technology. The protein is heav ily glycosylated and has a molecular mass of approximately 30,400 Da. Erythropoietin is composed of four antiparallel a-helices. The rDNA protein has the same amino acid sequence as natural erythropoietin.

Epoetin is indicated to treat anemia of chronic renal failure patients, anemia in zidovudine-treated HIV-infected patients, and in cancer patients taking chemotherapy. The results in these cases have been dramatic; most patients respond with a clinically significant increase in hematocrit.

Filgrastim114115

Filgrastim, G-CSF, Neupogen, stimulates the proliferation of granulocytes (especially neutrophils) by mobilizing hematopoietic stem cells in the bone marrow. Endogenous G-CSF is a glycoprotein produced by monocytes, fibro-blasts, and endothelial cells. G-CSF is a protein of 174 amino acids, with a molecular mass of approximately 18,800 Da. The native protein is glycosylated.

Filgrastim selectively stimulates proliferation and differentiation of neutrophil precursors in the bone marrow. This leads to the release of mature neutrophils into the circulation from the bone marrow. Filgrastim also affects mature neutrophils by enhancing phagocytic activity, priming the cellular metabolic pathways associated with the respiratory burst, enhancing antibody-dependent killing, and increasing the expression of some functions associated with cell surface antigens.

In patients receiving chemotherapy with drugs such as cyclophosphamide, doxorubicin, and etoposide, the incidence of neutropenia accompanied by fever is rather high. Administration of G-CSF reduces the time of neutrophil recovery and duration of fever in adults with acute mye-logenous leukemia. The number of infections, days that antibiotics are required, and duration of hospitalization are also reduced.

Filgrastim116 is identical with G-CSF in its amino acid sequence, except that it contains an N-terminal methionine that is necessary for expression of the vector in E. coli. The protein is not glycosylated. Filgrastim is supplied in a 0.01 M sodium acetate buffer containing 5% sorbitol and 0.004% polysorbate 80. It should be stored at 2°C to 8°C without freezing. Under these conditions, the shelf life is 24 months. Avoid shaking when reconstituting; although the foaming will not harm the product, it may alter the amount of drug that is drawn into a syringe.

Sargramostim117,118

Sargramostim, granulocyte-macrophage colony-stimulating factor (GM-CSF), Leukine, is a glycoprotein of 127 amino acids, consisting of three molecular subunits of 19,500, 16,800, and 15,500 Da. The endogenous form of GM-CSF is produced by T lymphocytes, endothelial fibroblasts, and macrophages. Recombinant GM-CSF, produced in S. cere-visiae, differs from native human GM-CSF only by substitution of a leucine for an arginine at position 23. This substitution facilitates expression of the gene in the yeast. The site of glycosylation in the recombinant molecule may possibly differ from that of the native protein.

Sargramostim binds to specific receptors on target cells and induces proliferation, activation, and maturation. Administration to patients causes a dose-related increase in the peripheral white blood cell count. Unlike G-CSF, GM-CSF is a multilineage hematopoietic growth factor that induces partially committed progenitor cells to proliferate and differentiate along the granulocyte and the macrophage pathways. It also enhances the function of mature granulocytes and macrophages/monocytes. GM-CSF increases the chemo-tactic, antifungal, and antiparasitic activities of granulocytes and monocytes. It also increases the cytotoxicity of mono-cytes toward neoplastic cell lines and activates polymor-phonuclear leukocytes to inhibit the growth of tumor cells.

Sargramostim is used to reconstitute the myeloid tissue after autologous bone marrow transplant and following chemotherapy in acute myelogenous leukemia. The preparation decreases the incidence of infection, decreases the number of days that antibiotics are required, and decreases the duration of hospital stays.

Sargramostim is supplied as a solution or powder (for solution). Both forms should be stored at 2°C to 8°C without freezing. The liquid and powder have expiration dates of 24 months. The reconstituted powder and the aqueous solution should not be shaken.

Becaplermin119

Becaplermin, Regranex Gel, an endogenous polypeptide that is released from cells that are involved in the healing process, is a recombinant human platelet-derived growth factor (rhPDGF-BB). The "BB" signifies that becaplermin is the homodimer of the B chain. Becaplermin is produced by a recombinant strain of S. cerevisiae containing the gene for the B chain of PDGF. The protein has a molecular mass of approximately 25 kDa and is a homodimer composed of two identical polypeptide chains that are linked by disulfide bonds. It is a growth factor that activates cell proliferation, differentiation, and function, and it is released from cells involved in the healing process.

Becaplermin is formulated as a gel recommended for topical use in the treatment of ulcerations of the skin secondary to diabetes.

Interferons

The interferons are a family of small proteins or glycoproteins of molecular masses ranging from 15,000 to 25,000 Da and 145 to 166 amino acids long. Eukaryotic cells secrete interferons in response to viral infection. Their mechanism of action is bimodal. The immediate effect is the recruitment of natural killer (NK) cells to kill the host cell harboring the virus (Fig. 4.13). Interferons then induce a state of viral resistance in cells in the immediate vicinity, preventing spread of the virus. Additionally, interferons induce a cascade of antiviral proteins from the target cell, one of which is 2',5'-oligoadenylate synthetase. This enzyme catalyzes the conversion of ATP into 2',5'-oligoadenylate, which activates ribonuclease R, hydrolyzing viral RNA. Interferons can be defined as cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities.

Three classes of interferon (IFN) have been characterized: a (alpha), S (beta), and y (gamma) (see Table 4.6). ^-Interferons are glycoproteins derived from human leukocytes. S-Interferons are glycoproteins derived from fibroblasts and macrophages. They share a receptor with ainterferons. y-Interferons are glycoproteins derived from human T lymphocytes and NK cells. These interferons are acid labile and used to be called "type 2 interferon." The receptor for IFN-y is smaller than that for IFN-a and IFN-jS, 90 to 95 kDa versus 95 to 110 kDa, respectively. The three classes are not homogeneous, and each may contain several different molecular species. For example, at least 18 genetically and molecularly distinct human a-interferons have

Natural Killer Infected Host Neighboring

Cell Cell Cell

Figure 4.13 • Antiviral mechanism of action of the interferons.

Natural Killer Infected Host Neighboring

Cell Cell Cell

Figure 4.13 • Antiviral mechanism of action of the interferons.

TABLE 4.6 Interferons Used Therapeutically

Interferon

Endogenous

Available

Type

Source

Drug Products

Alpha

Leukocytes

Interferon alfa-2a

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