Antibody, fully human

Originator First Introduction Novartis US Type monoclonal antibody Fully human IgGl,... 

Monoclonal antibodies (mAh) are molecules that recognize and bind a specific foreign substance called an antigen. They are produced from a single clone of B lymphocytes. Conventionally, mouse mAh have been generated for experimental and diagnostic use. Techniques have been developed to humanize mouse mAh to facilitate their therapeutic use in humans. It is also now possible to make mAh which are fully human. 

ADCC. Cetuximab is approved for treatment of metastatic colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN). Interestingly, an adverse event, acneiform rash seems to correlate with a better response to cetuximab, while there is no such correlation with expression levels of EGFR assessed by immunohistochemistry. Further side effects are rare infusion reactions and hypomagnesia. Two other anti-EGFR antibodies approved for clinical use are the fully human antibody panitumumab (Vectibix)... 

Panitumumab (Vectibix) Fully human antibody, lgG2 EGFR Ligand competition CRC... 

The most promising types of biologic response modifiers are monoclonal antibodies, cytokines, and fusion proteins.1 Monoclonal antibodies may be chimeric (fused mouse and human segments designated -ximab ), humanized with intermittent murine sequences (designated -zumab ), human backbone with monkey sequences, or fully human.40... 

Weiner, L. 2006. Fully human therapeutic monoclonal antibodies. Journal of Immunotherapy 29(1), 1-9. 

Fuii Human Antibody Full human antibodies are the current engineered antibodies. Several techniques are used to construct these antibodies. One method is to fuse human B cells to myeloma cells. These hybridomas will produce fully human MAbs. Another method is to genetically alter mice in the laboratory to contain human antibody producing genes. In response to antigens, antibodies resembling the human antibodies are produced. 

Three TNF antagonists are currently approved for the treatment of RA etaner-cept (ETN), infliximab (INF), and adalimumab. ETN a fusion protein of two identical chains of the recombinant human TNF receptor, p75, fused with the Fc portion of human immunoglobulin (Ig) G1 binds to soluble TNF-a in vivo. INF and adalimumab are both monoclonal antibodies to TNF-a INF is chimeric, and adalimumab is fully humanized. Both bind to soluble TNF-a, preventing TNF-a from binding to its receptors on cell surfaces. INF can also bind transmembrane TNF-a, fix complement, and cause cell lysis. 

Barrera, P., Joosten, L. A., den Broeder, A. A., van de Putte, L. B., van Riel, P. L., and van den Berg, W. B. (2001) Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 60, 660-669. 

Numerous problems in the construction of chnically applicable drug targeting moieties still need to be solved. Of these issues, immunogenicity after repeated administration, counterproductive hver clearance, and production 5delds are the most important. Although the problem of immunogenicity is beheved to have been solved for monoclonal antibody therapy by the development of humanized and fully human antibodies [110], for other carrier systems such as modified plasma proteins and peptide modified polymers, this remains an important issue. 

Adalimumab is a recombinant, fully human antitumor necrosis factor monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe, active rheumatoid arthritis. It has to be injected subcutaneously. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. Rare side effects include worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis like neurological disease. 

Adalimumab is a fully human IgGi anti-TNF monoclonal antibody. This compound complexes with soluble TNF-ct and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T cell function. 

Lonberg N Fully human antibodies from transgenic mouse and phage display platforms. Curr Opin Immunol 2008 20 450. [PMID 18606226]... 

Three monoclonal antibodies to human TNF are approved for the treatment of inflammatory bowel disease infliximab, adalimumab, and certolizumab (Table 62-3). Infliximab and adalimumab are antibodies of the IgGi subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portions of infliximab and certolizumab are chimeric mouse-human antibodies but adalimumab is fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5-10 mg/kg, the half-life of infliximab is approximately 8-10 days, resulting in plasma disappearance of antibodies over 8-12 weeks. Adalimumab and certolizumab are administered by subcutaneous injection. The half-life for both is approximately 2 weeks. 

The use of specific and nonspecific antisera in human medicine is well established and dates back to 1891 when Emil von Behring developed the first diphtheria antitoxin, but their use carries associated risks such as fluid overload and transmission of disease. The potential for MABs as therapeutic agents was quickly recognized and the first MAB was approved for therapeutic use in 1986 (Ortho Biotech s OKT3, a mouse MAB to CD3, for the reversal of transplant rejection). It became clear early on that the presence of, or appearance of, human antimouse antibodies (HAMA) in the patient, which neutralized subsequent treatments, often limited the efficacy of mouse MABs. More recently, chimeric, deimmunized, or fully human MABs have been developed. 

To circumvent some of the limitations of direct immunization, phage display technology has been applied to the preparation of fully human MABs. Gene libraries of cDNA from nonimmune or immunized donor lymphocytes are expressed in bacteriophages. The bacteriophages display functional antibody fragments and can... 

Chen B, Bautista R, Yu K, Zapata GA, Mulkerrin MG, Chamow SM. Influence of histidine on the stability and physical properties of a fully human antibody in aqueous and solid forms. Pharm Res 2003 20(12) 1952-1960. 

Jakobovits, A. (1995) Production of fully human antibodies by transgenic mice. Curr. Opin. Biotechnol. 6, 561-566. 

Jakobovits, A., Amado, 1C G., Yang, X., Roskos, L. and Schwab, G. (2007) From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice. Nat Biotechnol 25, 1134-1143. 

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