Monoclonal Antibodies

Products

The first therapeutic monoclonal antibody was approved in 1986. Muromonab-CD3 (Orthoclone OKT3) binds to the CD3 receptor on T cells and has been used in transplantation medicine. Numerous drugs containing antibodies are now available. A selection of active substances can be found at the end of this article. These are expensive drugs. For example, 1 ml of a TNF-alpha inhibitor costs several hundred francs. Drug development and the complicated manufacturing process account for an important share of the costs. Currently, many drugs are starting to lose their patent protection, and somewhat cheaper biosimilars are entering the market.

Structure and properties

Monoclonal antibodies (mAbs) are glycoproteins and biologics with a high molecular mass of about 150 kDa that belong to the immunoglobulin superfamily. Therapeutic antibodies are usually γ-immunogloblins (IgG, gamma globulins). IgG antibodies are homodimers consisting of two heterodimers with one light and one heavy chain. The subunits are connected by disulfide bridges. A distinction is made between the Fab fragment (fragment antigen binding) and the Fc fragment (fragment constant). The Fab fragment contains the variable regions that bind to the target structure or antigen.

Fabrication

Antibodies are produced by various biotechnological methods. The first murine antibodies (mouse antibodies) had the particular disadvantage that, as foreign molecules, they often triggered an immune response and allergies. Therefore, chimeric, humanized and finally human antibodies were developed. They are less immunogenic and have a longer half-life. The first chimeric antibody was released in the mid-1990s. The origin can be identified by the suffix (commonly: -mab):

  • -ximab: chimeric antibody (murine and human components, about 75% human), 1st representative Abciximab.
  • -zumab: humanized antibodies (85% human), 1st representative daclizumab.
  • -umab: humanized antibodies (100% human), 1st representative adalimumab.

Antibody fragments consisting only of the antigen-binding Fab fragment have also been developed. For example, one such agent is ranibizumab (Lucentis). The fragments spread better because they are smaller. They also interact less with the immune system because the Fc fragment is missing. Incidentally, antibodies for veterinary use end with the following suffix:

  • -vetmab: antibody for veterinary medicine, e.g., locivetmab.

Effects

Antibodies are characterized by specific and high-affinity binding to a molecular target. A common mechanism of action is inactivation of the drug target. For example, omalizumab (Xolair) binds to IgE and exerts antiallergic effects in this manner. Antibodies can also bind to receptors on the cell surface and influence signal transmission. This is true, for example, of cetuximab (Erbitux), which targets the epidermal growth factor receptor (EGFR) and is administered for cancer therapy. Some antibodies interact with the immune system and lead to cell destruction via activation of the complement system or immune cells. This is important in cancer therapy, among other applications:

  • Complement-Dependent Cytotoxicity (CDC) – complement system.
  • Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) – immune cells.

Finally, antibodies are also used to selectively transport other drugs to their site of action (drug targeting).

Indications

The indications for monoclonal antibodies are continuously broadening. Traditionally, antibodies have been administered for cancer and rheumatic diseases, among others. Today, many other indications exist (selection): psoriasis, inflammatory bowel disease, osteoporosis, multiple sclerosis, drug inactivation, macular degeneration, asthma, urticaria, hypercholesterolemia, viral infectious diseases, cancer immunotherapy, and atopic dermatitis.

Dosage

Antibodies generally have a long half-life in the range of approximately 14 to 20 days. Therefore, the dosing interval is much longer than for most oral dosage forms. The drugs are usually injected/infused subcutaneously or intravenously. They can also be injected locally into an organ. How they are used depends on the drug.

Contraindications

For complete precautions, see the drug label.

Interactions

Drug-drug interactions via CYP450, other metabolic enzymes, or transporters are unlikely. Some antibodies may not be combined with live vaccines. In addition, other compound-specific interactions are possible.

Adverse effects

Antibody administration may result in the development of autoantibodies directed against the therapeutic agents that abrogate the effect (immunogenicity). The risk is present with chimeric, humanized, and human antibodies but is much lower compared with murine antibodies.

Agents (selection)

  • Abciximab (ReoPro)
  • Adalimumab (Humira)
  • Alemtuzumab (Lemtrada)
  • Alirocumab (Praluent)
  • Atezolizumab (Tecentriq)
  • Avelumab (Bavencio)
  • Basiliximab (Simulect)
  • Belimumab (Benlysta)
  • Benralizumab (Fasenra)
  • Bevacizumab (Avastin)
  • Bezlotoxumab (Zinplava)
  • Bimagrumab
  • Blinatumomab (Blincyto)
  • Brentuximab vedotin (Adcetris)
  • Canakinumab (Ilaris)
  • Certolizumab (Cimzia)
  • Cetuximab (Erbitux)
  • Daclizumab (Zinbryta, off label).
  • Denosumab (Prolia)
  • Dupilumab (Dupixent)
  • Durvalumab (Imfinzi)
  • Eculizumab (Soliris)
  • Efalizumab (Raptiva, off-label)
  • Elotuzumab (Empliciti)
  • Evolocumab (Repatha)
  • Golimumab (Simponi)
  • Guselkumab (Tremfya)
  • Infliximab (Remicade)
  • Ipilimumab (Yervoy)
  • Ixekizumab (Taltz)
  • Mepolizumab (Nucala)
  • Muromonab-CD3 (Orthoclone OKT 3, off label).
  • Natalizumab (Tysabri)
  • Necitumumab (Portrazza)
  • Nivolumab (Opdivo)
  • Obiltoxaximab (Anthim)
  • Obinutuzumab (Gazyvaro)
  • Ocrelizumab (Ocrevus)
  • Ofatumumab (Arzerra)
  • Olaratumab (Lartruvo)
  • Omalizumab (Xolair)
  • Palivizumab (Synagis)
  • Panitumumab (Vectibix)
  • Pembrolizumab (Keytruda)
  • Pertuzumab (Perjeta)
  • Ramucirumab (Cyramza)
  • Ranibizumab (Lucentis)
  • Reslizumab (Cinqair)
  • Rituximab (MabThera)
  • Romosozumab (Evenity)
  • Secukinumab (Cosentyx)
  • Siltuximab (Sylvant)
  • Tocilizumab (Actemra)
  • Trastuzumab (Herceptin)
  • Ustekinumab (Stelara)
  • Vedolizumab (Entyvio)