Monoclonal antibodies in therapy

Reading time 4 minutes

Monoclonal antibodies (MAK) were first produced using the so-called hybridoma technique by G. Köhler and C. Milstein and published in the journal Nature in 1975 published.

They are always directed against an epitope (structure against which antibodies or T cell receptors are formed in the course of an adaptive immune response, or molecular structures, molecule sections of an antigen that can trigger an acquired immune response). Or: antibodies formed by identical immune cells that are directed against a specific substance, identify and bind to it.

Manufacturing

They are made from a B cell (B lymphocyte; b derived from Bursa fabricii, an avian organ in which B lymphocytes were first described). They are the only cells in the body that can produce plasma cells that secrete antibodies. This makes them, together with the T lymphocytes, a crucial part of the adaptive immune system.

The first antibody used therapeutically to prevent rejection reactions after kidney, heart and liver transplants was in 1986 Muromonab-CD3 (Mon -Y monoclonal, away -> anti-body). It binds specifically to the CD3 surface antigen of T lymphocytes and thus interrupts the immune response (rejection reaction).

nomenclature

The nomenclature of the drug names, by the WHO in 1950 as part of the system of international non-proprietary names (International Nonproprietary Name – INN) and published in 1953. The root of the word –mab stands for monoclonal anti body and was first proposed in 1990 and the current system was subsequently developed between 1991 and 1993. At the end of 2008, the WHO revised the nomenclature, which since 2009 has also included the area of action and organism of origin of the antibody.

The sequence of syllables is defined as follows: Prefix + Area of Effect + Origin Organism + Word Root

For example, it is derived from the product name Tezepelumab from the word parts –l, –u and -mab from the fact that it is a drug with a range of effects Iimmune system, huone as the place of origin of the antibody and Monoclonal anti body acts. Tezepe represents the freely selectable prefix of the trade name.

Mode of action

The mode of action of all MAKs only differs in the epitope it is directed against. How Muromonab-CD3 the transplant rejection reaction reduced, thus neutralized Tezepelumab as antibodies of the IgG2 type (immunoglobulin G2) the cytokine (cytokines are an inhomogeneous group of regulatory peptides or proteins that are responsible for intercellular signal transmission and control their proliferation (growth) and differentiation. They are produced, among other things, by macrophages, B lymphocytes, T lymphocytes, natural killer cells (NKs), and fibroblasts.) TSLP (Thymic Stromal LymphoPoietin).

TSLP is formed in skin and mucous membrane epithelia (cells of tissue layers of similar structure and function), including in the lung epithelium.

IgG2 deficiency leads to frequent infections with encapsulated bacteria of the upper and deep respiratory tract, as well as autoimmune diseases and thrombocytopenia. Combined IgG2/IgG4 deficiency syndromes have been observed in children. The cause of IgG2 deficiency (norm: serum concentration 14 – 20 %, 115 – 570 mg/dl) can be impaired IFNγ synthesis. IFNγ is antiviral, antitumoral and immunostimulating.

Asthma is caused by allergic and non-allergic trigger factors that trigger the production of TSLP. TSLP serves to trigger an immune reaction by releasing antigen-presenting cells, which subsequently lead to inflammatory reactions.

Tezepelumab intervenes at an early stage in the inflammatory process by neutralizing TSLP and increasing the concentration of eosinophil granulocytes and FeNO (fractionated exhaled nitric oxide (NO); biomarker for the diagnosis and monitoring of bronchial asthma), as well as IL-5, IL-13 permanently reduced for two weeks. Serum IG-E reduction occurred more slowly. After four weeks, submucosa eosinophil counts were reduced by 89%, independent of inflammatory biomarkers.

Pharmacokinetics

Tezepelumab has a bioavailability of approximately 77% regardless of the injection site, a volume of distribution centrally of 3.9, peripherally of 2.2 liters based on a person weighing 70 kg*, and an elimination half-life of 26 days. Metabolism occurs via proteolytic enzymes, not liver enzymes.
The maximum serum concentration is reached after 3 – 10 days.
Clearance occurs at 0.17 liters/day*.

dosage

Tezepelumab is administered subcutaneously (upper arm, abdomen or thigh) at 210 mg every four weeks for one year. A check-up at the end of the cycle decides whether therapy should be continued.

During therapy with Tezepelumab If necessary, ongoing corticosteroid therapy is continued or reduced in a controlled manner. Abrupt discontinuation is contraindicated.

Side effects

(common (≥1/100, <1/10)

Hypersensitivity reactions (occur within hours to a few days after injection):

• Anaphylaxis (discontinuation of therapy)
• Arthralgia (joint pain, 3.8 %)
• Pharyngitis (inflammation of the throat, 4.1 %)
  Pharyngitis, bacterial pharyngitis, streptococcal pharyngitis and viral pharyngitis
• rash
  (rash, erythematous rash, maculopapular rash, macular rash)
• Discomfort at the administration site

source

Studies

Tezepelumab was in the study PATHWAY (02/04/2014, update 12/04/2018) and NAVIGATOR (November 20, 2017, update November 26, 2021) randomized, double-blind, placebo-controlled in parallel groups.

PATHWAY was a 52-week exacerbation study that enrolled 550 patients (aged 18 years and older) with severe, uncontrolled asthma who received treatment with tezepelumab 70 mg subcutaneous Q4W, tezepelumab 210 mg subcutaneous Q4W, tezepelumab 280 mg subcutaneous Q2W, or placebo. Patients were required to have had at least 2 asthma exacerbations requiring treatment with oral or systemic corticosteroids or an asthma exacerbation resulting in hospitalization in the previous 12 months.*

NAVIGATOR was a 52-week exacerbation study involving a total of 1061 patients
(adults and adolescents aged 12 years and over) with severe, uncontrolled asthma included
and who received treatment with tezepelumab 210 mg subcutaneously Q4W or placebo. The
Patients had to have had at least 2 asthma exacerbations in the previous 12 months
have required or resulted in treatment with oral or systemic corticosteroids
led to hospitalization.*

In both the (Phase 3) PATHWAY and NAVIGATOR studies, patients were required to have an ACQ6 (Asthma Control Questionnaire-6) score of at least 1.5 at screening and reduced lung function (predicted one-second capacity [FEV1] before bronchodilation) at baseline under 80 % in adults and under 90 % in adolescents). Patients had to have been regularly treated with medium or high doses of inhaled corticosteroids (ICS) and had received at least one other medication for asthma control, with or without oral corticosteroids (OCS). A high ICS dose was defined as >500 mcg fluticasone propionate or equivalent daily. A median ICS dose was defined as >250 to 500 mcg fluticasone propionate or equivalent daily in PATHWAY and 500 mcg fluticasone propionate or equivalent daily in NAVIGATOR. Patients continued their background asthma therapy throughout the study period.*

*source

Two additional phase 3 studies SOURCE (NCT03406078 – January 23, 2018, update December 9, 2021 and DESTINATION (ID NCT03706079 – October 15, 2018, update June 6, 2023), as well as a phase 2 study CASCADE (NCT03688074 – September 28, 2018, update February 21, 2022) are currently running.