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Monoclonal antibody therapy

Monoclonal antibody therapy is the use of monoclonal antibodies (or mAb) to specifically target cells. The main objective is stimulating the patient's immune system to attack the malignant tumor cells and the prevention of tumor growth by blocking specific cell receptors. Variations exist within this treatment, e.g. radioimmunotherapy, where a radioactive dose localizes on target cell line, delivering lethal chemical doses to the target.

Structure and function of human and therapeutic antibodies

Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, approximately 150 kDa and are composed of two different kinds of polypeptide chain, called the heavy (~50kDa) and the light chain (~25kDa). There are two types of light chains, kappa (κ) and lambda (λ). By cleavage with enzyme papain, the Fab (fragment-antigen binding) part can be separated from the Fc (fragment crystalline) part of the molecule (see image). The Fab fragments contain the variable domains, which consist of three hypervariable amino acid domains responsible for the antibody specificity embedded into constant regions. There are four known IgG subclasses all of which are involved in Antibody-dependent cellular cytotoxicity.

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.

Origins of monoclonal antibody therapy

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.

Murine monoclonal antibodies

Initially, murine antibodies were obtained by hybridoma technology, for which Kohler and Milstein received a Nobel prize. However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances. Major problems associated with murine antibodies included reduced stimulation of cytotoxicity and the formation complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock.

Chimeric and humanized monoclonal antibodies

To reduce murine antibody immunogenicity, murine molecules were engineered to remove immunogenic content and to increase their immunologic efficiency. This was initially achieved by the production of chimeric and humanized antibodies. Chimeric antibodies are composed of murine variable regions fused onto human constant regions. Human gene sequences, taken from the kappa light chain and the IgG1 heavy chain, results in antibodies that are approximately 65% human. This reduces immunogenicity, and thus increases serum half-life.

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.

Human monoclonal antibodies

Human monoclonal antibodies are produced using transgenic mice or phage display libraries. Human monoclonal antibodies are produced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of monoclonal antibodies. Phage display libraries allow the transformation of murine antibodies in vitro into fully human antibodies.

FDA approved therapeutic antibodies

The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specific transplant rejection drug, Muromonab (OKT-3), in 1986. This drug found use in solid organ transplant recipients who became steroid resistant. Currently, twenty-one FDA-approved therapies exist, and hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

FDA approved monoclonal antibodies
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
Tositumomab	Bexxar	2003	murine	CD20	Non-Hodgkin lymphoma
Trastuzumab	Herceptin	1998	humanized	ErbB2	Breast cancer

Radioimmunotherapy

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.

Antibody-directed enzyme prodrug therapy (ADEPT)

ADEPT involves the application of cancer associated monoclonal antibodies which are linked to a drug-activating enzyme. Subsequent systemic administration of a non-toxic agent results in its conversion to a toxic drug, and resulting in a cytotoxic effect which can be targeted at malignant cells. The clinical success of ADEPT treatments has been limited to date. However it holds great promise, and recent reports suggest that it will have a role in future oncological treatment.

Drug and gene therapy: Immuno-liposomes

Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells. Although this technique is still in its infancy, significant advances have been made. Immunoliposomes have been successfully used in vivo to achieve targeted delivery of tumour-suppressing genes into tumours, using an antibody fragment against the human transferrin receptor. Tissue-specific gene delivery using immunoliposomes has also been achieved in brain, and breast cancer tissue.