The next advent in mAb development were humanized mAbs. This may sound similar to chimeric structures when explained, however the key to understanding this difference is as opposed to replacing the Fc region in chimeric mAbs, there is a substitution where rodent sequences are exchanged for human sequences except in the Fab region, specifically the CDR where paratope binding is done.This may seem odd to take these approaches of generating various mAbs degrees of humanization as it would be ideal to develop fully human mAbs. However this was hard to do initially due to challenges related to a lack of a stable human myeloma fusion partner. Though this challenge was eventually overcome due to phage-display platforms, and transgenic mouse platforms. These methods are both extremely versatile. For phage-display platforms it was discovered that foreign DNA sequences could be cloned into bacteriophages such that the cloned sequences would be expressed on the surface of the phage as fusion proteins, in turn they would then be enriched for specific sequences. This was combined with PCR amplification methods for cloning expressed Ig variable region cDNA in order to create a library of phage fusion proteins that could be used rapidly to access target-specific mAbs without hybridoma clones. (Lonberg 2008) Later it was shown that genetically engineered mice were able to express fully human antibodies that could be accessed by conventional hybridoma technology, allowing another technique to produce fully human mAbs. Despite the possibility of using fully human mAbs there are still issues of immunogenicity, which is why the development from murine to fully human mAbs was necessary for the furthering of mAbs as therapeutic agents.
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