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Antibody Generation Technologies
Currently two major technology platforms have been used routinely in therapeutic antibody generation: hybridoma and phage display technology. Hybridoma technology is used most due to its maturity, low cost, and the antibodies generated usually have very high affinity.  These antibodies could be mouse or fully human origin.  Phage display generation antibody usually provides an fully human antibody but the affinity of obtained antibody is usually low, requiring further affinity maturation and in many cases the antibodies obtained has poor manufacturability.  Thus hybridoma technology is still most often used technology.
 
Limitation of Hybridoma Technology
However, because the generation of antibody using hybridoma technology is relied on the recognition of foreign antigen sequences by the mouse or rat, the antibodies obtained usually only recognize those sequences of the antigen that are not conserved between human and rodent .  Thus the epitope coverage of these hybridoma derived antibodies may be limited.  Those antibodies that can recognize epitope sequence shared between human and rodents are usually not generated and thus not protected. Furthermore, because many evolutionary important proteins have high degree of sequence conservation between human and rodents and it has been very difficult to generate antibodies against these targets, major gaps in the antibody patent space exist.
 
 
                                                 Janeway C.PNAS 98:7461-7468
 
 
Immune Tolerance
In order to generate antibody against a target antigen, mouse or rat needs to have T cells which can recognize antigen fragment produced by antigen presentation cells.  However, during development, many T cells recognizing self-antigens have been eliminated, only those recognizing foreign sequences can survive.  This process is known as immune tolerance.  Thus for any antigen sequence, the higher degree of conservation between human and rodent sequences, the lesser it will likely generate peptide fragments to activate T cells.  Without activated T cells, antibody producing B cells will not receive co-stimulation signals and thus immature B cells will not differentiate into mature B cells and plasma cells, which is required for antibody generation.  In order for rodents to generate antibodies against this type of antigen, one must activate T cells.  For the same reason, for those proteins with low degree of sequence conservation most antibodies generated using hybridoma approach will mainly recognize those regions of the antigen sequence which are different between human and rodent sequences, but not those shared between human and rodents.  Because those regions highly conserved between human and rodent are usually evolutionally important for structure or function of the protein, antibodies targeting those epitopes may have higher activities. Unfortunately those antibodies are usually not generated and protected for many well validated disease target proteins.
 
Commonly used adjuvant such as complete freund’s adjuvant (CFA) or incomplete freund’s adjuvant (IFA) are usually used during immunization to stimulate the expression of costimulation T cell factors such as B7 to increase immune response.  However this is not enough to activate T cells and another important signal is the formation of complex between MHC-II presented antigen peptides with corresponding T cell receptors.  What MabSpace provides is a technology that can enable any antigen to activate T cells, and thus antibody generation. 
 
Advantage of Immune Tolerance Breaking Technology
The advantage of MabSpace’s technology is that it enables one to obtain antibodies with diverse binding epoitopes including cross-reactive antigen binding antibodies efficiently.  The antibodies obtained will have distinct epitopes and likely not covered by existing patents from those of competitor's program, thus enabling one to obtain antibodies with potentially better drug-like properties and freedom to operate. 

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