To be effective, antibodies must bind to their intended target in the body with a high degree of specificity and with very high affinity. Genes for these specific, high affinity antibodies are not, however, present in the human genome. There is a good reason for this: to have genes for high affinity antibodies specific to all the possible variations of all the possible infectious agents and toxins in the world would require billions of individual genes. Since the human genome is made up of only 50,000 genes or so, packing this array of antibody genes into our body is not feasible. Through a remarkable process of genetic engineering that occurs inside specialized cells of the immune system, segments of DNA present in our cells is shuffled and recombined, and then mutated to produce billions of possible antibody genes. Gene rearrangement and so-called somatic hypermutation creates antibodies with protein sequences unique only to the cell that performed the engineering. Since this process is somewhat random, selection and deletion of the antibody producing cells is necessary to ensure that antibodies bind their target with high affinity on the one hand, but are not otherwise incompatible, or cause harm, to the body. Cells producing good antibodies are selected, while those producing bad antibodies are deleted. The vast majority of cells that produce new antibodies within the body are in fact deleted.
There is no system or means to reproduce the natural selection and deletion conditions outside the human body. Yet this hallmark of the immune system is essential to produce safe and effective antibodies.
All of the technologies developed to date to produce humanized or fully human antibody therapeutics have generated high affinity antibodies by modification of the gene sequences in the test tube, skipping the crucial selection process that takes place in the body. While therapeutic antibody products are marketed as "fully human," the sequences of these antibodies are in fact not derived from a human gene nor have they undergone selection for tolerability in humans.
There are significant technical and practical challenges in identifying and cloning genes for True Human™ antibodies.
A key problem to overcome is to identify highly specific, and high affinity antibodies present in human blood. Thousands of human blood samples may need to be screened before the right antibodies are identified. Then an individual source of the blood must be located and a tissue sample obtained. Once obtaining cells from the individual, the specific antibody gene present in the exceedingly rare cell that engineered this gene must be faithfully cloned.
The Company has indeed screened thousands of donors using a Super High Stringency Antibody Mining technology (SHSAM™). SHSAM™ has enabled us to identify clinically relevant antibodies-discovered from literally trillions of irrelevant background antibody molecules in the blood of donors. Novel cloning technologies developed at XBiotech have also enabled our scientists to capture an accurate copy of the gene from these donors in order to reproduce a True Human™ antibody for use in clinical therapy.