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Immunotherapeutics

by Peter J. Delves, PhD

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*):

  • Monoclonal antibodies

  • Fusion proteins

  • Soluble cytokine receptors

  • Recombinant cytokines

  • Small-molecule mimetics

  • Cellular therapies

Some Immunotherapeutic Agents in Clinical Use*

Agent

Effects

Indications

Monoclonal antibodies

Adalimumab

Anti–TNF-α

Moderate to severe RA

Plaque psoriasis

Moderate to severe Crohn disease refractory to standard treatments

Ulcerative colitis

Ankylosing spondylitis

Psoriatic arthritis

Moderate to severe polyarticular juvenile idiopathic arthritis

Alemtuzumab

Anti–B cell (CD52)

B-cell chronic lymphocytic leukemia refractory to standard treatments

Basiliximab

Anti–IL-2 receptor

Prevention of acute kidney rejection

Belimumab

Anti–B-lymphocyte stimulator protein (anti-BLyS)

Autoantibody-positive SLE in adults receiving standard treatment

Brentuximab vedotin

Anti-CD30 (linked to the antimitotic agent monomethyl auristatin E)

Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least 2 multidrug chemotherapy regimens in patients who are not candidates for ASCT

Systemic anaplastic large cell lymphoma after failure of at least one multidrug chemotherapy regimen

Canakinumab

Anti–IL-1β

Cryopyrin-associated periodic syndromes (cryopyrinopathies) in patients ≥ 4 yr

Juvenile idiopathic arthritis in patients ≥ 2 yr

Certolizumab (pegylated Fab’ fragment)

Anti–TNF-α

Moderate to severe RA in adults

Moderate to severe Crohn disease if response to conventional treatments is inadequate

Psoriatic arthritis

Ankylosing spondylitis

Daclizumab

Anti–IL-2 receptor

Prevention of acute kidney rejection

Eculizumab

Anti–complement component C5

Paroxysmal nocturnal hemoglobinuria

Atypical hemolytic uremic syndrome

Golimumab

Anti–TNF-α

Moderate to severe RA (used with methotrexate)

Psoriatic arthritis

Ankylosing spondylitis

Moderate to severe ulcerative colitis if patients have an inadequate response to or are intolerant of prior treatments or if they require continuous corticosteroid therapy

Ibritumomab

Anti–B cell (CD20; linked to the radioactive agent yttrium 90)

Relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin lymphoma

Infliximab

Anti–TNF-α

Moderate to severe Crohn disease or ulcerative colitis if response to conventional treatments is inadequate

Moderate to severe RA (used with methotrexate)

Active ankylosing spondylitis

Active psoriatic arthritis

Chronic severe plaque psoriasis when other treatments are less appropriate

Ipilimumab

Anti–CTLA-4

Inoperable or metastatic advanced melanoma

Natalizumab

Anti–α 4 -integrin subunit

Relapsing multiple sclerosis or Crohn disease when other treatments are inadequate

Ofatumumab

Anti‒B cell (CD20)

CLL refractory to fludarabine and alemtuzumab

Omalizumab

Anti-IgE

Moderate to severe asthma in patients > 12 yr with documented allergic disorders inadequately controlled by inhaled corticosteroids

Chronic idiopathic urticaria in patients ≥ 12 yr who remain symptomatic despite H 1 antihistamine treatment

Rituximab

Anti–B cell (CD20)

Relapsed or refractory CD20+, low-grade or follicular B-cell non-Hodgkin lymphoma

CD20+ CLL (used with fludarabine and cyclophosphamide)

Moderate to severe RA (used with methotrexate) when response to TNF-antagonists is inadequate

Granulomatosis with polyangiitis (Wegener granulomatosis)

Microscopic polyangiitis

Siltuximab

Anti–IL-6

Multicentric Castleman disease in patients who are HIV- and HHV-8–negative

Tocilizumab

Anti–IL-6 receptor (anti–IL-6R)

Moderate to severe RA when response to TNF-antagonists is inadequate

Polyarticular or systemic juvenile idiopathic arthritis in patients ≥ 2 yr

Tositumomab

Anti–B cell (CD20; linked to radioactive iodine [ 131 I])

Refractory and relapsed CD20+ low-grade follicular or transformed non-Hodgkin lymphoma

Ustekinumab

Anti-IL-12 and -IL-23

Moderate to severe plaque psoriasis

Psoriatic arthritis

Vedolizumab

Anti-α 4 β 7 integrin

Moderate to severe active ulcerative colitis if response to conventional therapy or TNF-antagonists is inadequate

Moderate to severe Crohn disease if response to conventional therapy or TNF-antagonists is inadequate

Fusion proteins

Abatacept (CTLA-4 extracellular domain fused to the Fc region of IgG1)

Inhibition of T-cell activation

Moderate to severe RA

Denileukin diftitox (fusion of IL-2 to diphtheria toxin)

Delivery of toxin to CD25 component of IL-2 receptor

CD25+ cutaneous T-cell lymphoma

Etanercept (fusion of 2 CD120b TNF-α receptors to Fc region of IgG1)

Decrease in TNF levels

RA

Polyarticular juvenile idiopathic arthritis in patients ≥ 2 yr

Psoriatic arthritis

Ankylosing spondylitis

Plaque psoriasis

Soluble cytokine receptor

Anakinra (IL-1 receptor antagonist, sometimes pegylated for longer half-life)

Competitive inhibition of IL-1α and IL-1βactivities

In patients 18 yr: Moderate to severe RA, cryopyrin-associated periodic syndromes

Cytokines

IFN-α

Antiproliferative and antiviral

In patients 18 yr: Chronic hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia, metastatic melanoma

IFN-β

Antiproliferative and antiviral

Reduction of number of flare-ups in relapsing multiple sclerosis

IFN-γ

Immunostimulatory and antiviral

Control of infection in chronic granulomatous disease, delay of progression in severe malignant osteopetrosis

IL-2

Immunostimulatory

Metastatic renal cell carcinoma and metastatic melanoma

IL-11

Thrombopoietic growth factor

Prevention of thrombocytopenia after myelosuppressive chemotherapy

G-CSF

Stimulation of granulocyte production

Reversal of neutropenia after chemotherapy, radiation therapy, or both

GM-CSF

Stimulation of granulocyte and monocyte/macrophage production

Reversal of neutropenia after chemotherapy, radiation therapy, or both

Cellular therapy

Sipuleucel-T

Autologous circulating ICAM-1+ peripheral blood mononuclear cells activated with prostatic acid phosphatase and GM-CSF

Asymptomatic or minimally symptomatic metastatic prostate cancer refractory to castration (hormone therapy)

*mAbs used for diagnostic testing and radiologic imaging are not included.

ANCA = antineutrophil cytoplasmic antibodies; CD = cluster of differentiation; CLL = chronic lymphocytic leukemia; CTLA =cytotoxic T-lymphocyte antigen; Fc =crystallizable fragment; G-CSF = granulocyte colony-stimulating factor; GM-CSF =granulocyte-macrophage colony-stimulating factor; HHV-8 = human herpesvirus 8; ICAM = intercellular adhesion molecule; IFN = interferon; mAb =monoclonal antibody; TNF = tumor necrosis factor.

Monoclonal antibodies

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

  • Chimeric

  • Humanized

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 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:

  • Chimeric

  • Humanized

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.

Fusion proteins

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 cytokine receptors

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.

Recombinant cytokines

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-molecule mimetics

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).

Cellular therapies

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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • SIMULECT
  • ORENCIA
  • TYSABRI
  • KINERET
  • No US brand name
  • XOLAIR
  • ENBREL
  • SOLIRIS
  • SIMPONI
  • RITUXAN
  • REMICADE
  • OTREXUP
  • HUMIRA
  • CAMPATH
  • ACTEMRA
  • ZEVALIN

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