Know All About: Clinically useful monoclonal antibodies in treatment

GASTROENTEROLOGY

Crohn’s disease is a relapsing condition characterised by transmural inflammation in the gastrointestinal tract. The cytokine tumour necrosis factor α (TNF-α) appears to be central to the immunopathogenesis, and during active disease the intestinal mucosa contains increased amounts of TNF-α.Infliximab (Remicade), a human–mouse chimaeric IgG1 antibody that binds to free and membrane bound TNF-α, is licensed for use in both resistant and fistularising Crohn’s disease.

RHEUMATOLOGY

TNF-α is produced in the rheumatoid synovium and through its numerous proinflammatory actions is central to the pathological process. Infliximab (in combination with methotrexate) is licensed in the UK for treating refractory rheumatoid arthritis (RA).
Etanercept is another anti-TNF agent licensed and effective for the treatment of refractory RA. Etanercept is a recombinant IgG1 Fc fragment fused to two p75 TNF receptors, as opposed to a monoclonal antibody. Etanercept has also been used as monotherapy in early RA, where it has comparable efficacy to methotrexate alone. It is given as a twice weekly subcutaneous injection. Both Etanercept and Infliximab appear to reduce radiographical joint disease progression.
Etanercept has also been studied in psoriatic arthritis, where improvements in both joint pain and swelling and skin lesions have been demonstrated.
Monoclonal antibodies to interleukin 12 (IL-12), and antagonists to IL-1 and costimulatory molecules are under development for arthritis.

INFECTION

Anti-endotoxin and anti-TNF-α monoclonal antibodies proved disappointing in sepsis trials, but monoclonal antibodies are currently being developed against certain infectious agents, including cytomegalovirus and human immunodeficiency virus.
Palivizumab (Synagis) is licensed for respiratory syncitial virus (RSV) prophylaxis. RSV is the most important respiratory pathogen in infants and approximately 1% of infections require hospitalisation.

CARDIOLOGY

Platelet activation at the site of damaged coronary vessels produces a prothrombotic state during acute coronary syndromes and after percutaneous coronary revascularisation.
Abciximab (ReoPro) is a Fab human murine chimaeric monoclonal antibody, which blocks the platelet membrane glycoprotein IIb/IIIa receptor. This interaction antagonises receptor binding to circulating fibrinogen/VonWillebrand factor, inhibiting platelet crosslinking and aggregation.

HAEMATOLOGY/ONCOLOGY

Appropriately selected monoclonal antibodies may have antitumour effects via direct antibody mediated cell death or inhibition of cell growth. The conjugation of drugs, toxins, or radioisotopes to tumour specific monoclonal antibodies can also be of therapeutic benefit .
Rituximab is licensed for use in chemotherapy resistant advanced B cell follicular lymphoma. Most patients with low grade or follicular lymphoma relapse with current treatments. Rituximab is a mouse human chimaeric IgG1 antibody that recognises the transmembrane phosphoprotein CD20 expressed by B cells and their related lymphomas. An infusion of Rituximab dramatically reduces circulating B cell numbers, through antibody dependent cellular cytoxicity or apoptosis.
Targeting protooncogene products offers an alternative antiproliferative strategy, and potential targets include the HER2 gene, the overexpression of which predicts a worse prognosis in breast cancer.Trastuzumab (Herceptin) is a humanised IgG1 antibody that targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity. Trastuzumab has recently been licensed in the UK for patients with relapsed HER2 highly expressing breast malignancies.

TRANSPLANTATION

Successful solid organ transplantation requires selective immunosuppression to prevent organ rejection while avoiding infection.
OKT3 is a murine monoclonal antibody used particularly in renal transplantation, which binds to the pan-T cell marker CD3, and therefore exerts its action on both resting and activated T cells.
Two new monoclonal antibodies have recently been licensed in the UK for the prophylaxis of acute rejection in allogeneic renal transplantation in conjunction with steroids and cyclosporine. Basiliximab (Simulect) is an IgG1κ chimaeric antibody given as two infusions and Daclizumab (Zenapex) is a humanised IgG1 construct administered in five doses over eight weeks. Both these antibodies target CD25 (IL-2 receptor α chain), the expression of which increases in early T cell activation. Interference with the association of the α chain with the β and γ chains of the IL-2 receptor prevents assembly of the functional receptor.
Campath is a monoclonal antibody recognising CD52, a highly glycosylated molecule on lymphocytes and monocytes. Although initially explored in RA and multiple sclerosis,Campath now appears to be emerging as a successful treatment for some B cell chronic lymphatic leukaemias, in addition having to a role in haemopoietic transplantation.