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Immunotherapeutic agents use or modify immune mechanisms. Use of these agents is rapidly evolving; new classes, new agents, and new uses of current agents are certain to be developed. A number of different classes of immunotherapeutic agents have been developed (see Table: Some Immunotherapeutic Agents in Clinical Use*):
Some Immunotherapeutic Agents in Clinical Use*
Monoclonal antibodies (mAbs) are manufactured in vitro to recognize specific targeted Ags; they are used to treat solid and hematopoietic tumors and inflammatory disorders. The mAbs that are currently in clinical use include
Murine mAbs are produced by injecting a mouse with an Ag, harvesting its spleen to obtain plasma cells that are producing Ab specific to that Ag, fusing those cells with immortal mouse myeloma cells, growing these hybridoma cells (eg, in cell culture), and harvesting the Ab. Although mouse antibodies are similar to human antibodies, clinical use of murine mAbs is limited because they induce human anti-mouse Ab production, can cause immune complex serum sickness (a type III hypersensitivity reaction), and are rapidly cleared. An exception is muromonab-CD3 (OKT3), which effectively prevents acute rejection of solid organ transplants; it is typically given only once or twice to a patient receiving other immunosuppressants (see Overview of Transplantation : Monoclonal antibodies (mAbs)).
To minimize the problems due to use of pure mouse Ab, researchers have used recombinant DNA techniques to create monoclonal Abs that are part human and part mouse. Depending on the proportion of the Ab molecule that is human, the resultant product is termed one of the following:
In both cases, the process usually begins as above with production of mouse hybridoma cells that make Ab to the desired Ag. Then the DNA for some or all of the variable portion of the mouse Ab is merged with DNA for human immunoglobulin. The resultant DNA is placed in a mammalian cell culture, which then expresses the resultant gene, producing the desired Ab. If the mouse gene for the whole variable region is spliced next to the human constant region, the product is termed "chimeric." If the mouse gene for only the Ag-binding hypervariable regions of the variable region is used, the product, termed "humanized," is even more human.
Chimeric mAbs activate Ag-presenting cells (APCs) and T cells more effectively than murine mAbs but can still induce production of human anti-chimeric Ab.
Humanized mAbs against various antigens (Ags) have been approved for the treatment of colorectal and breast cancer, leukemia, allergy, autoimmune disease, transplant rejection, and respiratory syncytial virus infection.
These hybrid proteins are created by linking together the gene sequences encoding all or part of 2 different proteins to generate a chimeric polypeptide that incorporates desirable attributes from the parent molecules (eg, a cell-targeting component combined with a cell toxin). The circulating half-life of therapeutic proteins can also often be improved by fusing them to another protein that naturally has a longer serum half-life (eg, the Fc region of IgG).
Soluble versions of cytokine receptors are used as therapeutic reagents. They can block the action of cytokines by binding with them before they attach to their normal cell surface receptor.
Etanercept, a fusion protein, consists of 2 identical chains from the CD120b receptor for tumor necrosis factor (TNF)-α. This agent thus blocks TNF-α and is used to treat RA refractory to other treatments, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
Soluble IL receptors (eg, those for IL-1, IL-2, IL-4, IL-5, and IL-6) are being developed for treatment of inflammatory and allergic disorders and cancer.
Colony-stimulating factors (CSF), such as erythropoietin, granulocyte CSF (G-CSF), and granulocyte-macrophage CSF (GM-CSF), are used in patients undergoing chemotherapy or transplantation for hematologic disorders and cancers (see Table: Some Immunotherapeutic Agents in Clinical Use*). Interferon-α (IFN-α) and IFN-γ are used to treat cancer, immunodeficiency disorders, and viral infections; IFN-β is used to treat relapsing multiple sclerosis. Many other cytokines are being studied.
Anakinra, used to treat RA, is a recombinant, slightly modified form of the naturally occurring IL-1R antagonist; this drug attaches to the IL-1 receptor and thus prevents binding of IL-1, but unlike IL-1, it does not activate the receptor.
Cells expressing cytokine receptors can be targeted by modified versions of the relevant cytokine (eg, denileukin diftitox, which is a fusion protein containing sequences from IL-2 and from diphtheria toxin). Denileukin is used in cutaneous T-cell lymphoma to target the toxin to cells expressing the CD25 component of the IL-2 receptor.
Small linear peptides, cyclicized peptides, and small organic molecules are being developed as agonists or antagonists for various applications. Screening libraries of peptides and organic compounds can identify potential mimetics (eg, agonists for receptors for erythropoietin, thrombopoietin, and G-CSF).
Immune system cells are harvested (eg, by leukapheresis) and activated in vitro before they are returned to the patient. The aim is to amplify the normally inadequate natural immune response to prostate cancer. Methods of activating immune cells include using cytokines to stimulate and increase numbers of antitumor cytotoxic T cells and using pulsed exposure to antigen-presenting cells such as dendritic cells with tumor antigens.
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