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 continuing to be developed. A number of different classes of immunotherapeutic agents have been developed (see also table Some Immunotherapeutic Agents in Clinical Use):
Monoclonal antibodies
Fusion proteins
Soluble cytokine receptors
Recombinant cytokines
Small-molecule mimetics
Cellular therapies
Деякі імунотерапевтичні засоби, що застосовуються в клінічній практиці
Agent | Effects | Some Indications* |
|---|---|---|
Monoclonal antibodies† | ||
Abciximab | Platelet antiglycoprotein IIb/IIIa receptor | Prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention or in high-risk patients with acute coronary syndrome |
Adalimumab | Anti–TNF-alpha | Polyarticular juvenile idiopathic arthritis Non-infectious uveitis Chronic plaque psoriasis |
Alemtuzumab | Anti–B cell (CD52) | B-cell CLL Relapsing multiple sclerosis |
Alirocumab | Anti-proprotein convertase subtilisin kexin type 9 | Lowering of LDL cholesterol, as an adjunct to diet and statins, in adults with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease |
Atezolizumab | Anti–PD-L1 | Transitional cell (urothelial) carcinoma Triple-negative breast cancer BRAF V600 mutation positive melanoma Alveolar soft part sarcoma |
Avelumab | Anti-PD-L1 | |
Basiliximab | Anti–IL-2 receptor | |
Belimumab | Anti–B-lymphocyte stimulator protein (anti-BLyS) | |
Benralizumab | Anti-IL-5 receptor alpha | Eosinophilic asthma |
Bevacizumab | Anti–VEGF-A | Epithelial ovarian, fallopian tube, or primary peritoneal cancer HER2-negative breast cancer Nonsquamous NSCLC |
Bezlotoxumab | Anti-Clostridioides (formerly, Clostridium) difficile toxin B | C. difficile infection |
Blinatumomab | Bispecific: Anti-CD19 and anti-CD3c | B-cell precursor ALL |
Brentuximab vedotin | Anti-CD30 (linked to the antimitotic agent monomethyl auristatin E) | ALCL or other CD30-expressing T cell lymphomas |
Brodalumab | Anti-IL-17 receptor A | |
Brolucizumab | Anti-VEGF-A | Neovascular (wet) age-related macular degeneration |
Burosumab | Anti-fibroblast growth factor 23 | X-linked hypophosphatemia |
Canakinumab | Anti–IL-1 beta | Periodic fever syndromes: |
Caplacizumab | Anti-von Willebrand factor | Acquired thrombotic thrombocytopenic purpura |
Cemiplimab | Anti-PD-1 | Cutaneous squamous cell carcinoma NSCLC |
Certolizumab (pegylated Fab’ fragment) | Anti–TNF-alpha | Nonradiographic axial spondyloarthritis |
Cetuximab | Anti-EGFR | |
Crizanlizumab | Anti-P-selectin | |
Daratumumab | Anti-CD38 | |
Denosumab | Anti-RANKL | Giant cell tumor of bone Prevention of skeletal-related events (eg, fractures, bone pain) in patients with multiple myeloma or bone metastases from solid tumors To increase bone mass in males receiving androgen deprivation therapy for prostate cancer and in females receiving adjuvant aromatase inhibitor therapy for breast cancer |
Dinutuximab | Anti-GD2 glycolipid | Pediatric neuroblastoma |
Dupilumab | Anti-IL-4 receptor alpha | Atopic asthma Chronic rhinosinusitis with nasal polyposis |
Durvalumab | Anti-PD-L1 | |
Eculizumab | Anti–complement component C5 | Atypical hemolytic uremic syndrome |
Elotuzumab | Anti-SLAMF7 | |
Emapalumab | Anti-IFN-gamma | |
Emicizumab | Bispecific anti-factor IXa and anti-factor X | Prevention or reduction of bleeding episodes in patients with hemophilia A |
Enfortumab vedotin | Anti-Nectin-4 linked to the antimitotic drug monomethyl auristatin E | Urothelial cancer |
Erenumab | Anti-calcitonin gene-related peptide receptor | Migraine prevention |
Evolocumab | Anti-proprotein convertase subtilisin kexin type 9 | Cardiovascular risk reduction in patients with coronary artery disease Lowering of LDL-cholesterol in familial hypercholesterolemia or atherosclerotic cardiovascular disease |
Fremanezumab | Anti-calcitonin gene-related peptide receptor | Migraine prevention |
Galcanezumab | Anti-calcitonin gene-related peptide receptor | Migraine prevention |
Gemtuzumab | Anti-CD33 ozogamicin conjugate | CD33+ acute myeloid leukemia |
Golimumab | Anti–TNF-alpha | |
Guselkumab | Anti-IL-23 | |
Ibalizumab | Anti-CD4 | |
Ibritumomab tiuxetan | Anti–CD20 linked to the radioactive agent yttrium 90 | B-cell non-Hodgkin lymphoma |
Idarucizumab | Anti-dabigatran | Reversal of the anticoagulant effects of dabigatran when needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding |
Infliximab | Anti–TNF-alpha | |
Inotuzumab | Anti-CD22-ozogamicin conjugate | B-cell precursor ALL |
Ipilimumab | Anti–CTLA-4 | |
Isatuximab | Anti-CD38 | |
Ixekizumab | Anti-IL17A | |
Lanadelumab | Anti-plasma kallikrein | |
Mepolizumab | Anti-IL-5 | Eosinophilic asthma Chronic rhinosinusitis with nasal polyps |
Mogamulizumab | Anti-CCR4 | |
Moxetumomab pasudotox | Anti-CD22 linked to a truncated form of Pseudomonas exotoxin PE38 | Hairy cell leukemia |
Natalizumab | Anti–alpha-4 integrin subunit | |
Necitumumab | EGFR1 | Squamous NSCLC |
Nivolumab | Anti–PD-1 | Esophageal cancers and gastroesophageal cancers |
Obiltoxaximab | Anti-protective antigen of Bacillus anthracis | Inhalational anthrax (used with antibiotics) |
Obinutuzumab | Anti-CD20 | Follicular lymphoma |
Ocrelizumab | Anti-CD20 | |
Ofatumumab | Anti‒CD20 | |
Omalizumab | Anti-IgE | |
Palivizumab | Anti-respiratory syncytial virus (RSV) F protein | Prevention of serious lower respiratory tract RSV disease |
Panitumumab | Anti-EGFR | |
Pembrolizumab | Anti–PD-1 | B-cell lymphoma Gastric or gastroesophageal junction adenocarcinoma Squamous cell carcinoma of the esophagus |
Pertuzumab | Anti-HER2 | |
Polatuzumab | Anti-CD79b | B-cell lymphoma |
Ramucirumab | Anti–VEGFR-2 | Gastric or gastroesophageal junction adenocarcinoma |
Ranibizumab | Anti-VEGF | Neovascular (wet) age-related macular degeneration Macular edema after retinal vein occlusion Diabetic macular edema Myopic choroidal neovascularization |
Ravulizumab | Anti-C5 | Paroxysmal nocturnal hemoglobinuria Atypical hemolytic uremic syndrome |
Raxibacumab | Anti-protective antigen of Bacillus anthracis | Inhalational anthrax |
Reslizumab | Anti-IL-5 | Eosinophilic asthma |
Risankizumab | Anti-IL-23p19 | |
Rituximab | Anti–CD20 | CD20+ B-cell lymphomas Leukemias |
Romosozumab | Anti-sclerostin | |
Sarilumab | Anti-IL-6 receptor | |
Secukinumab | Anti–IL-17A | Non-radiographic axial spondyloarthritis |
Siltuximab | Anti–IL-6 | Multicentric Castleman disease |
Sotrovimab | Anti-SARS-Cov-2 conserved spike epitope | |
Teprotumumab | Anti-IGF-1 receptor | |
Tildrakizumab | Anti-IL-23 | |
Tocilizumab | Anti–IL-6 receptor | Cytokine release syndrome following CAR T cell treatment |
Tositumomab | Anti–CD20 linked to radioactive iodine [131I] | CD20+non-Hodgkin lymphoma |
Trastuzumab | Anti–HER2 | HER2+ breast cancer HER2+ stomach or gastroesophageal junction adenocarcinoma |
Ustekinumab | Anti–IL-12 and –IL-23 | |
Vedolizumab | Anti–alpha-4 beta-7 integrin | |
Fusion proteins | ||
Abatacept (CTLA-4 extracellular domain fused to the Fc region of IgG1) | Inhibition of T-cell activation | |
Aflibercept (portions of VEGF extracellular domains fused to the Fc region of IgG1 | Inhibition of neovascularization and vascular permeability | Neovascular (wet) age-related macular degeneration |
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-alpha receptors to Fc region of IgG1) | Decrease in TNF levels | |
Soluble cytokine receptor | ||
Anakinra (IL-1 receptor antagonist, sometimes pegylated for longer half-life) | Competitive inhibition of IL-1 alpha and IL-1 beta activities | Neonatal-onset multisystem inflammatory disease (NOMID) Deficiency of IL-1 receptor antagonist (DIRA) Calcium pyrophosphate arthritis (pseudogout) |
Cytokines | ||
IFN-alpha | Antiproliferative and antiviral | AIDS-related Kaposi sarcoma Hairy cell leukemia |
IFN-beta | Antiproliferative and antiviral | |
IFN-gamma | Immunostimulatory and antiviral | Control of infection in chronic granulomatous disease Malignant osteopetrosis |
IL-2 | Immunostimulatory | |
IL-11 | Thrombopoietic growth factor | |
G-CSF | Stimulation of granulocyte production | Neutropenia |
GM-CSF | Stimulation of granulocyte and monocyte/macrophage production | Neutropenia |
Cellular therapy | ||
Axicabtagene ciloleucel (CAR T) | CD19-directed genetically modified autologous T-cell | B-cell lymphoma |
Sipuleucel-T | Autologous circulating ICAM-1+ peripheral blood mononuclear cells activated with prostatic acid phosphatase and GM-CSF | |
Tisagenlecleucel (CAR T) | CD19-directed genetically modified autologous T-cell | B-cell precursor ALL B-cell lymphoma |
* Many immunotherapeutic agents are only approved for use in certain subgroups of patients (eg, based on age, subtype and stage of disease, previous treatment, etc). They are often used in conjunction with other medications. Refer to prescribing information for more details. | ||
† mAbs used for diagnostic testing and radiologic imaging are not included. The Antibody Society maintains a comprehensive list of approved antibody therapeutics and those in regulatory review in the United States and the European Union. | ||
ALCL = anaplastic large cell lymphoma; ALL = acute lymphoblastic leukemia; ANCA = antineutrophil cytoplasmic antibodies; CAR = chimeric antigen receptor; CD = cluster of differentiation; CLL = chronic lymphocytic leukemia; CTLA = cytotoxic T-lymphocyte antigen; EGFR = epidermal growth factor receptor; Fc = crystallizable fragment; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; HER2 = human epidermal growth factor receptor 2; HNSCC = head and neck squamous cell carcinoma; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; LDL = low density lipoprotein; mAb = monoclonal antibody; MRD = minimal residual disease; NSCLC = non small cell lung cancer; PD-L1 = programmed death–ligand 1; RANKL = receptor activator of nuclear factor kappa beta ligand; SLAMF7 = signaling lymphocyte activation molecule family member 7; TNF = tumor necrosis factor; VEGF-A = vascular endothelial growth factor A; VEGFR = VEGF receptor. | ||
Моноклональні антитіла
Monoclonal antibodies (mAbs) are manufactured in vitro to recognize specific targeted antigens (Ags); they are used to treat solid and hematopoietic tumors, inflammatory disorders, and infections. Most mAbs in clinical use target a single Ag, but a few are engineered to be bispecific. The monoclonal antibodies that are currently in clinical use include
Murine
Chimeric
Humanized
Fully human
Murine monoclonal antibodies are produced by injecting a mouse with an antigen, harvesting its spleen to obtain B cells that are producing antibody specific to that antigen, fusing those cells with immortal mouse myeloma cells, growing these hybridoma cells (eg, in cell culture), and harvesting the antibody. Although mouse antibodies are similar to human antibodies, clinical use of murine monoclonal antibodies is limited because they induce human anti-mouse antibody production, can cause immune complex serum sickness (a type III hypersensitivity reaction), and are rapidly cleared.
To minimize the problems due to use of pure mouse antibody, researchers have used recombinant DNA techniques to create monoclonal antibodies that are part human and part mouse. Depending on the proportion of the antibody molecule that is human, the resultant product is termed one of the following:
Chimeric
Humanized
In both chimeric and humanized monoclonal antibodies, the process usually begins as above with production of mouse hybridoma cells that make antibody to the desired antigen. Then the DNA for some or all of the variable portion of the mouse antibody 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 antibody. 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 antigen-binding hypervariable regions of the variable region is used, the product is termed "humanized."
Chimeric monoclonal antibodies activate antigen-presenting cells (APCs) and T cells more effectively than murine monoclonal antibodies but can still induce production of human anti-chimeric antibodies.
Humanized monoclonal antibodies against various antigens are available for the treatment of colorectal cancer, breast cancer, leukemia, allergy, autoimmune disease, transplant rejection, and respiratory syncytial virus infection.
Fully human monoclonal antibodies are produced using transgenic mice that contain human immunoglobulin genes or using phage display (ie, a bacteriophage-based cloning method) of immunoglobulin genes isolated from human B cells. Fully human monoclonal antibodies have decreased immunogenicity and therefore may have fewer adverse effects.
Monoclonal antibodies that target checkpoint molecules on either T cells or tumor cells (termed checkpoint inhibitors—see table Some Immunotherapeutic Agents in Clinical Use) are used to prevent downregulation of antitumor responses and effectively treat some heretofore resistant cancers. However, because checkpoint molecules are also involved in other types of immune response, checkpoint inhibitors can cause severe immune-related inflammatory and autoimmune reactions (both systemic and organ specific).
Химерні білки
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).
Розчинні цитокінові рецептори
Soluble versions of cytokine receptors 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)-alpha. This agent thus blocks TNF-alpha and is used to treat rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
Рекомбінантні цитокіни
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 and in patients with severe chronic neutropenia (see table Some Immunotherapeutic Agents in Clinical Use). Interferon-alpha (IFN-alpha) and IFN-gamma are used to treat cancer, immunodeficiency disorders, and viral infections. IFN-beta is used to treat relapsing multiple sclerosis.
Anakinra, used to treat rheumatoid arthritis, is a recombinant, slightly modified form of the naturally occurring IL-1R antagonist; this agent 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.
Низькомолекулярні міметики
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).
Клітинна терапія
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 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. Before being returned to the patient, T cells can be genetically engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) capable of recognizing tumor antigens, an approach that has shown efficacy in patients with leukemia and lymphoma.
