Monoclonal antibodies

Monoclonal antibodies are antibodies, i.e. immunologically active proteins produced by a single cell line (a cell clone) and directed specifically against a single epitope of a defined molecular structure. Monoclonal antibodies represent a therapeutically and diagnostically important subgroup of so-called biologicals.

In contrast to artificial monoclonal antibody production, the physiological immune response of the organism against an invaded antigen is always applied as a polyclonal response. For example, it is always directed against several different epitopes on the surface of a bacterium.

Antibodies (immunoglobulins) are symmetrically structured glycoproteins. They each consist of two identical light (light chain - L) and two heavy (heavy chain - H) peptide chains connected by disulfide bridges. Between the L- and the H- chain lies the antigen binding site (Fab piece = antigen-binding fragment). Due to its symmetrical structure, the antibody has two binding sites. It is therefore also called bivalent. In immunoglobulins of one class and species, the amino acid sequence of the Fc-piece is identical. The Fc-piece is responsible for complement activation. It is not capable of antigen binding.

Naming: The monoclonal antibodies used in therapy are classified according to an international terminology. The individual syllables indicate the target of the antibody, the species from which they originate. They begin with a variable prefix and end with the suffix -mab which stands for "monoclonal antibody". Other terms denote the composition of the antibodies:

prefix: -o(s)-: bone, -vi(r)-: virus, -ba(c)-: bacteria, -li(m)-: immune system, -le(s)-: infectious lesions, -ci(r)-: cardiovascular system, -xi-: chimeric (e.g. mouse-human or hamster-human), -mu(l)-: musculoskeletal system, -ki(n)-: interleukin, -co(l)-: colon tumour, -me(l)-: melanoma, -ma(r)-: breast tumour, -go(t)-: testicular tumour, -go(v)-: ovarian tumour, -pr(o)-: prostate tumour, -tu(m)-: tumour (general), -neu(r)-: nervous system, -tox(a)-: toxin, -fu(ng)-: fungi.

Suffix: murine (the complete antibody consists of mouse proteins (suffix -omab), chimeric (only the variable part of the antibody is composed of mouse protein (suffix -xi-mab, e.g. Rituximab), humanized (only the antigen binding sites of the Fab fragments are made of mouse protein (ending zumab, e.g. Omalizumab), antibody from primate: ending -imab, human (the complete antibody consists of human protein (ending mumab; e.g. adalimumab).

Since monoclonal antibodies with high specificity can bind and neutralize molecules, they play an increasingly important role in both therapy (therapeutic monoclonal antibodies) and diagnostics (diagnostic monoclonal antibodies).

Diagnostic monoclonal antibodies: Antigen-antibody reactions form the basis for numerous experimental and diagnostic procedures (e.g. immunophenotyping, FACS, immunohistology, ELISA, ELISPOT, radioimmunoassay and Western blot).

Therapeutic monoclonal antibodies: these play an increasingly important role in medicine. These are genetically engineered, custom-made proteins that can be used to influence or block a very specific inflammatory response or to inhibit cells at various points in the cell cycle by means of agonist/receptor interactions, thus inhibiting their proliferation. Therapeutic monoclonal antibodies have applications in hematological and oncological diseases, autoimmune diseases, transplant rejection in pain syndromes, metabolic diseases and genetic diseases.

In the production of monoclonal antibodies against a specific antigen, a mouse is first immunized with this antigen. Antigen binding triggers a transmembrane signal for proliferation and terminal differentiation of B cells. After a proliferation phase, numerous plasma cells with identical DNA sequence are present for antibody production. These cloned B-cells thus produce identical antibodies. They are subsequently isolated and fused with plasma cells from a target line derived from a myeloma. This fusion results in a so-called hybridoma cell line which retains the fundamental characteristics of its original cells: the ability to continue producing a predetermined antibody from the B lymphocyte, and the ability to grow indefinitely in vitro from the myeloma cell.

Hematology, Oncology

• Alemtuzumab: humanized antibody, ► CD52 on lymphocytes. Indication: chronic lymphocytic leukemia, T-cell lymphomas2, acute lymphoblastic leukemia.
• Apolizumab: humanized antibody, ► HLA-DR antigen on B lymphocytes. Indication: solid tumors, acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma.
• Atezolizumab: humanized antibody, ► PD-L1. Indication: bladder cancer.
• Avelumab: humanized antibody ► PD-L1. Indication: bladder cancer, non-small cell lung cancer (NSCLC), Merkel cell carcinoma.
• Bevacizumab: humanized antibody ► VEGF (vascular endothelial growth factor). Indication: colorectal cancer, breast cancer, non-small cell lung cancer, wet age-related macular degeneration (off-label use).
• Blinatumomab: murine antibody ►bispecific CD-19. indication: ALL
• Catumaxomab: murine antibody (rat/mouse): ► trifunctional EpCAM antigen on tumor cells, CD3 receptor on T lymphocytes. Indication: malignant ascites due to EpCAM-positive carcinoma.
• Cemiplimab: primate-derived antibody ► PD-1. Indication: squamous cell carcinoma.
• Cetuximab: chimeric antibody ► epidermal growth factor receptor (EGF). Indication: colorectal cancer, head and neck tumors.
• Claudiximab (experimental): chimeric monoclonal antibody ► GC182 (claudin 18.2). Indication: adenocarcinomas of the gastrointestinal tract and pancreatic tumors used.
• Daratumumab: human antibody ► CD38. Indication: multiple myeloma, approved in the U.S. and EU.
• Durvalumab: human antibody ► PD-L1. Indication: bronchial carcinoma.
• Eculizumab: humanized antibody ► C5 complement factor. Indication: paroxysmal nocturnal hemoglobinuria (PNH).
• Elotuzumab: humanized antibody ► Signaling Lymphocyte Activation Molecule (SLAMF7; CS1). Indication: multiple myeloma
• Emicizumab: humanized antibody ► bispecific factor IXa and X. Indication: inhibitor hemophilia.
• Epratuzumab: humanized antibody ► CD22 antigen. Indication: non-Hodgkin's lymphoma, autoimmune diseases, acute lymphoblastic leukemia.
• Gemtuzumab ozogamicin: humanized antibody ► calicheamicin-loaded CD33 antigen acute myeloid leukemia.
• Ibritumomab-tiuxetan: murine antibody ► 90Y-labeled CD20 antigen on B lymphocytes Non-Hodgkin's lymphoma (radioimmunotherapy)
• Inotuzumab ozogamicin (as conjugate): humanized antibody ► humanized CD22 antigen. Indication: acute lymphoblastic leukemia.
• Ipilimumab: humanized antibody ► CTLA-4. Indication: malignant melanoma.
• Mogamulizumab: humanized antibody ► CCR4. Indication: adult T-cell leukemia, various non-Hodgkin lymphomas.
• Moxetumomab pasudotox-tdfk: murine antibody ► CD22 antigen. Indication: hairy cell leukemia.
• Necitumumab: human antibody ► epidermal growth factor receptor (EGF). Indication: bronchial carcinoma, gastric carcinoma.
• Nivolumab: human antibody ► PD-1. Indication: malignant melanoma, non-small cell lung cancer.
• Obinutuzumab: humanized antibody ► CD20 antigen on B lymphocytes. Indication: chronic lymphocytic leukemia, follicular lymphoma.
• Ofatumumab: human antibody ►CD20 antigen on B lymphocytes. Indication: chronic lymphocytic leukemia.
• Olaratumab: human antibody ►IgG1 to PDGF receptor-α (platelet-derived growth factor receptor α). Indication: sarcoma (approval revoked).
• Oregovomab: murine antibody ► CA-125. indication: ovarian cancer.
• Panitumumab: human antibody ► epidermal growth factor receptor (EGF). Indication: EGF receptor-expressing tumors, esp. metastatic colorectal carcinoma.
• Pembrolizumab (MK-3475): humanized antibody ► PD-1 melanoma, mesothelioma, NSCLC.
• Pertuzumab: humanized antibody ► HER2, HER2 receptor (inhibits dimerization of target as well as its heterodimerization with other HER receptors, e.g. EGF receptor, slowing tumor growth. Indication: breast carcinoma. Experimental: ovarian carcinoma, bronchial carcinoma and prostate carcinoma.
• Ramucirumab: human antibody ► VEGF receptor. Indication: bronchial carcinoma, gastric carcinoma.
• Rituximab: chimeric antibody ► CD20 antigen on B lymphocytes. Indication: non-Hodgkin's lymphoma.
• Rovalpituzumab tesirine: humanized antibody ► delta-like protein 3 (DLL3). Indication: small cell lung cancer (SCLC).
• Siltuximab: chimeric antibody ► binds human IL-6. Indication: Castleman's disease (MCD), multiple myeloma.
• Tremelimumab: human antibody ► CTLA-4. indication: bronchial carcinoma, mesothelioma.
• Tositumomab: marine antibody ►131I-labeled CD20 antigen on B lymphocytes. Indication: non-Hodgkin's lymphoma (radioimmunotherapy).
• Trastuzumab: humanized antibody ► HER2/neu receptor. Indication: breast cancer, gastric cancer.
• Zanolimumab: humanized antibody ► CD4 antigen on T lymphocytes. Indication: T-cell lymphoma.

Immunological targets (autoimmune diseases,graft rejection, pain).

• Adalimumab: human antibody ► TNF-α (tumor necrosis factor α). Indication: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease.
• Alemtuzumab: humanized antibody ► CD52 antigen on lymphocytes. Indication: multiple sclerosis
• Anifrolumab: humanized antibody ► anti-type-I IFN. Indication: lupus erythematosus.
• Basiliximab: chimeric antibody ► CD25 antigen (interleukin-2 receptor). Indication: prophylaxis of acute rejection in renal transplantation.
• Anifrolumab: Fully human, IgG1κ monoclonal antibody (mAb), ► binds to interferon (IFN) alpha receptor 1 (IFNAR1), thereby blocking type I IFN signaling. Indication: systemic lupus erythematosus.
• Belimumab: human antibody ► BLys (B lymphocyte stimulator, a cytokine of the TNF superfamily). Indication: lupus erythematosus.
• Brodalumab: human antibody ► interleukin-17 receptor. Indication: psoriasis, psoriatic arthritis, asthma.
• Canakinumab: human antibody ► interleukin-1 beta receptor. Indication: periodic fever syndromes (CAPS, TRAPS, HIDS/MKD, FMF), systemic juvenile idiopathic arthritis (SJIA), gouty arthritis.
• Certolizumab: humanized antibody ► TNF-α (tumor necrosis factor α). Indication: rheumatoid arthritis, axial spondolyarthritis, psoriatic arthritis, psoriasis, Crohn's disease.
• Clazakizumab: humanized antibody ► interleukin-6 receptor. Indication: rheumatoid arthritis.
• Daclizumab: humanized antibody ► CD25 antigen (interleukin-2 receptor). Indication: multiple sclerosis(has been withdrawn from the market).
• Epratuzumab: humanized antibody ► CD22 antigen. Indication: autoimmune diseases, non-Hodgkin's lymphoma.
• Fasinumab: humanized antibody ► nerve growth factor (NGF). Indication: pain in osteoarthritis.
• Guselkumab: human antibody ► anti-interleukin-23. Indication: psoriasis, rheumatoid arthritis.
• Golimumab: human antibody ► TNF-α (tumor necrosis factor α). Indication: ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.
• Infliximab: chimeric antibody ► TNF-α (tumor necrosis factor α). Indication: Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis.
• Ixekizumab: humanized antibody ► interleukin-17A receptor (IL-17A). Indication: psoriasis, psoriatic arthritis.
• Mavrilimumab: (CAM-3001) humanized antibody ► rheumatoid arthritis.
• Muromonab-CD3: murine antibody ► CD3 receptor on T lymphocytes. Indication: treatment of acute rejection in kidney, heart and liver transplantation.
• Natalizumab: humanized antibody ► CD49d (α4-integrin). Indication: multiple sclerosis.
• Risankizumab: humanized antibody ► interleukin-23 receptor. Indication: psoriasis, psoriatic arthritis, Crohn's disease.
• Rituximab: chimeric antibody ► CD20 antigen on B lymphocytes. Indication: rheumatoid arthritis.
• Sarilumab: human antibody ► interleukin-6 receptor (IL-6R). Indication: rheumatoid arthritis.
• Secukinumab: human antibody ► interleukin-17A receptor. Indication: psoriasis, psoriatic arthritis, ankylosing spondylitis.
• Sifalimumab: (MEDI-545): human antibody ► Indication: lupus erythematosus.
• Sirukumab: human antibody ► interleukin-6 receptor. Indication: rheumatoid arthritis, but negative recommendation on the part of the FDA .
• Tanezumab: humanized antibody ► NGF (nerve growth factor). Osteoarthritis pain (2020: compound not yet approved).
• Tocilizumab: humanized antibody ► interleukin-6 receptor. Indication: rheumatoid arthritis, cytokine storm after treatment with CART cells, giant cell arteritis.
• Ustekinumab: human antibody ► interleukin 12/23. indication: plaque psoriasis.
• Vedolizumab: humanized antibody ► IgG1. Indication: Crohn's disease and ulcerative colitis , hypercholesterolemia.
• Alirocumab: humanized antibody ► PCSK9 (via indirectly: LDL receptor). Indication: hypercholesterolemia (prevention of cardiovascular events including stroke).
• Evinacumab (REGN1500): human antibody ► PCSK9. Indication: homozygous familial hypercholesterolemia.
• Evolocumab (AMG-145): human antibody ► PCSK9 (via indirectly: LDL receptor) hypercholesterolemia (prevention of cardiovascular events including stroke).

Cardiovascular diseases

• Abciximab ReoPro: chimeric antibody ► Fab fragment GPIIb/IIIa on platelets. Indication: prevention of vascular occlusion after PTCA (Note: sales discontinued).

Angiological diseases

• Idarucizumab: humanized antibody fragment (Fab). ► binds with very high affinity to dabigatran. Antidote for rapid and specific reversal of dabigatran-induced anticoagulation.

Infectious diseases

• Bezlotoxumab: human antibody ► Clostridium difficile toxin B. Indication: Clostridium difficile infection (CDI).
• Motavizumab: chimeric antibody ► component of respiratory syncytial virus (RSV). Indication: prophylaxis of respiratory syncytial virus (RSV) pneumonia in preterm infants, Extremely Low Birth Weight Preterm (ELBW) and Very Low Birth Weight Preterm (VLBW) infants.
• Palivizumab: humanized antibody ► component of respiratory syncytial virus (RSV) prophylaxis for RSV pneumonia in preterm infants
• Ibalizumab-uiyk: humanized antibody ► CD4 T-cell receptor. Indication: AIDS

Neurological diseases

• Aducanumab: humanized antibody ► tbd. indication: Alzheimer's disease.
• Eptinezumab: humanized antibody ► calcitonin gene-related peptide (CGRP). Indication: migraine
• Erenumab: humanized antibody ► Calcitonin Gene-Related Peptide (CGRP) receptor. Indication: migraine
• Fremanezumab: humanized antibody ► Calcitonin Gene-Related Peptide (CGRP). Indication: migraine, cluster headache.
• Galcanezumab: humanized antibody ► Calcitonin Gene-Related Peptide (CGRP) Migraine, cluster headache.
• Ocrelizumab: humanized antibody ► CD20 antigen. Indication: multiple sclerosis
• Solanezumab: humanized antibody ► tbd. indication: Alzheimer's disease.
• Ublituximab: chimeric (mouse/human) antibody ► CD20 antigen on B lymphocytes. Indication: multiple sclerosis

Ophthalmology

• Ranibizumab: humanized antibody ►Fab fragment VEGF-A (vascular endothelial growth factor A) Wet macular degeneration.
• Brolucizumab ►Fv fragment of vascular endothelial growth factor A. Indication: macular degeneration
• Aflibercept ►false receptor, vascular endothelial growth factor A (VEFG) trap. Indication: macular degeneration.

Dermatology/Pulmonology

• Adalimumab: human antibody ► TNF-α (tumor necrosis factor α). Indication: psoriasis
• Dupilumab: human antibody ► interleukin 4/13 atopic dermatitis; sinusitis.
• Efalizumab: humanized antibody ► CD11a antigen. Indication: psoriasis
• Infliximab: chimeric antibody ► TNF-α (tumor necrosis factor α). Indication: psoriasis
• Nemolizumab: humanized antibody ► interleukin-31. indication: atopic dermatitis/prurigonodularis.
• Tildrakizumab: humanized antibody ► interleukin-23. Indication: moderate-to-severe plaque psoriasis.
• Ustekinumab: human antibody ► interleukin-12/23. Indication: plaque psoriasis, allergic diseases.
• Asthma/COPD
• Benralizumab: humanized antibody ► alpha subunit of IL-5 receptor (IL-5Rα). Indication: asthma; COPD?
• Mepolizumab: humanized antibody ► interleukin-5. Indication: asthma, COPD, hypereosinophilia syndrome, eosinophilic granulomatosis with polyangiitis.
• Omalizumab: humanized antibody ► IgE (Fc part). Indication: severe bronchial asthma, chronic idiopathic urticaria.
• Reslizumab: humanized antibody ► interleukin-5. indication: asthma.
• Tralokinumab: humanized antibody ► interleukin-13. Indication: atopic dermatitis(not yet approved).

Dentistry

• (plantibody): recombinantly produced in plants ("plantibody"). Specific binding to Streptococcus mutans (leading germ of dental caries) as mouth rinse against dental caries. Indication: elimination of S. mutans from oral flora[41].

Osteology

• Denosumab: humanized antibody ► RANK ligand (receptor activator of NF-κB ligand, RANKL) osteoporosis; bone metastases.
• Romosozumab: humanized antibody ► sclerostin. Indication: postmenopausal osteoporosis.
• Sulesomab: murine antibody ► 99mTc-labeled IMMU-MN3 Fab'-SH fragment against granulocytes osteomyelitis.
• Arcitumomab: murine antibody ►99mTc-labeled IMMU-4 F(ab')2 against CEA colorectal carcinoma

The principle of the production of monoclonal antibodies was published in 1975 by César Milstein, Georges Köhler and Niels Jerne, who received the Nobel Prize for Medicine in 1984. The technique is based on the fusion of antibody-producing B cells with cells of a myeloma cell line, resulting in hybrid cells that produce unlimited amounts of antibodies of a certain specificity (hybridoma technique).