The immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self. Tumor cells are not specifically targeted by one's immune system since tumor cells are the patient's own cells. Tumor cells, however are highly abnormal, and many display unusual antigens that are either inappropriate for the cell type, its environment, or are only normally present during the organisms' development (e.g. fetal antigens).
Other tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of approximately 30% of breast cancer tumor cells. Such breast cancer is known a HER2 positive breast cancer.
Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens presented on the surfaces of tumors.
Immunotherapy developed as a technique with the discovery of the structure of antibodies and the development of hybridoma technology, which provided the first reliable source of monoclonal antibodies. These advances allowed for the specific targeting of tumors both in vitro and in vivo. Initial research on malignant neoplasms found MAb therapy of limited and generally short-lived success with malignancies of the blood. Furthermore treatment had to be specifically tailored to each individual patient, thus proving to be impracticable for the routine clinical setting.
Throughout the progression of monoclonal drug development there have been four major antibody types developed: murine, chimeric, humanised and human. Initial therapeutic antibodies were simple murine analogues, which contributed to the early lack of success. It has since been shown that these antibodies have: a short half-life in vivo (due to immune complex formation), limited penetration into tumour sites, and that they inadequately recruit host effector functions.To overcome these difficulties the technical issues initially experienced had to be surpassed. Chimeric and humanized antibodies have generally replaced murine antibodies in modern therapeutic antibody applications. Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display. Understanding of proteomics has proven essential in identifying novel tumour targets.
Humanised antibodies are produced by grafting murine hypervariable amino acid domains into human antibodies. This results in a molecule of approximately 95% human origin. However it has been shown in several studies that humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold. Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR), using techniques such as chain-shuffling, randomization of complementarity determining regions and generation of antibody libraries with mutations within the variable regions by error-prone PCR, E-coli mutator strains, and site-specific mutagenesis.
|Antibody||Brand name||Approval date||Type||Target||Approved treatment(s)|
|Abciximab||ReoPro||1994||chimeric||inhibition of glycoprotein IIb/IIIa||Cardiovascular disease|
|Adalimumab||Humira||2002||human||inhibition of TNF-a signalling||Inflammatory diseases (mostly auto-immune disorders)|
|Alemtuzumab||Campath||2001||humanized||CD52||Chronic lymphocytic leukemia|
|Basiliximab||Simulect||1998||chimeric||IL-2 receptor a||Transplant rejection|
|Bevacizumab||Avastin||2004||humanized||vascular endothelial growth factor||Colorectal cancer|
|Cetuximab||Erbitux||2004||chimeric||epidermal growth factor receptor||Colorectal cancer|
|Daclizumab||Zenapax||1997||humanized||IL-2 receptor a||Transplant rejection|
|Eculizumab||Soliris||2007||humanized||complement system protein C5||Inflammatory diseases including paroxysmal nocturnal hemoglobinuria|
|Efalizumab||Raptiva||2002||humanized||CD11a||Inflammatory diseases (psoriasis)|
|Ibritumomab tiuxetan||Zevalin||2002||murine||CD20||Non-Hodgkin lymphoma (with yttrium-90 or indium-111)|
|Infliximab||Remicade||1998||chimeric||inhibition of TNF-a signalling||Inflammatory diseases (mostly auto-immune disorders)|
|Muromonab-CD3||Orthoclone OKT3||1986||murine||T cell CD3 Receptor||Transplant rejection|
|Natalizumab||Tysabri||2006||humanized||T cell VLA4 receptor||Inflammatory diseases (mainly autoimmune-related multiple sclerosis therapy)|
|Omalizumab||Xolair||2004||humanized||immunoglobulin E (IgE)||Inflammatory diseases (mainly allergy-related asthma therapy)|
|Palivizumab||Synagis||1998||humanized||an epitope of the F protein of RSV||Viral infection (especially Respiratory Syncytial Virus (RSV)|
|Panitumumab||Vectibix||2006||human||epidermal growth factor receptor||Colorectal cancer|
|Ranibizumab||Lucentis||2006||humanized||vascular endothelial growth factor||Macular degeneration|
|Gemtuzumab ozogamicin||Mylotarg||2000||humanized||CD33||Acute myelogenous leukemia (with calicheamicin)|
|Rituximab||Rituxan, Mabthera||1997||chimeric||CD20||Non-Hodgkin lymphoma|
Radioimmunotherapy involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body. Tositumomab is an exemplar used for non-Hodgkins lymphoma.