True human antibodies as the name implies are literally cloned directly from a natural human immune response. Thousands of human donors are screened to find an individual with a specific antibody with the desired characteristics for use as a therapeutic agent. The unique gene from that individual is cloned, and the genetic information used to produce an exact replica of the antibody sequence. A true human antibody is therefore not to be confused with other marketed antibodies, such as so-called fully human antibodies which are, without exception, created through engineering technology in the laboratory.
To appreciate the background safety and tolerability of antibody therapy—that is intrinsic to the molecule and not what it is designed to target—it is critical to understand the fundamental difference between those that are engineered with that of true human antibodies.
Literally billions of unique antibodies are produced every day in an individual human immune system. The massive diversity is necessary to enable these molecules to potentially bind and protect us against what is essentially a limitless number of possible disease threats. However, if unique antibody genes were needed to encode only a billion different antibodies, there would be 20,000-times as many genes needed to encode antibodies as there would be needed to encode the rest of the entire human genome! Individual cells would need to be gigantic, and monumental resources would be required to make, copy and maintain all of that DNA.
A hallmark of the immune physiology of all vertebrates is the ability to recombine and selectively mutate a relatively small number of genes to create a phenomenal and essentially unlimited number of antibody genes. By this process a single specialized cell, or B lymphocyte, is able to create a unique antibody gene, for which no other copy exists in any other somatic cell or in the human germline. From a remarkable process of gene rearrangement and mutation, within the nucleus of individual B lymphocytes, unique antibody genes are born. So for the multitude of B lymphocytes that are produced each day from the bone marrow of an individual, there is the ability to assemble and manufacture an incredibly diverse repertoire of antibodies, that are able to protect the individual from a myriad of diseases.
Elucidating the mechanisms behind the ability to shuffle germline genetic sequence to produce unique antibody genes must be considered one of the major achievements of medical research in the 20th century. But this discovery also raised another fundamental question: If antibodies were not produced from genes encoded in the human genome and the products of these genes were new to the body, why were these antibody molecules not recognized by the immune system as foreign substances—like any foreign substance such as a virus or bacteria?
Another major advance in medicine during the 20th century was thus unraveling the mystery of how B lymphocytes could produce an endless array of antibody proteins that were always tolerated by the body.
Extraordinary studies around the early1990s clearly demonstrated that the growth and expansion in the bone marrow of individual antibody-producing B lymphocytes was not a random process. Rather, it was established that the antibody produced by each and every B lymphocyte was subject to precise scrutiny. It was clear that B lymphocytes that produced tolerable antibodies were stimulated to grow while those with intolerable antibodies were killed off. It emerged that a marvelous selection process of promoting or destroying antibody producing cells took place based on the tolerability of the antibody they produced.
The selection process was described in exquisite detail. A unique antibody made from a B lymphocyte is first displayed on the cell’s surface and a series of events that happens next decides the fate of that cell harboring the unique antibody gene. If the antibody produced is too reactive with substances or tissue in the surrounding environment, the cell is signaled to undergo further genetic rearrangement in an attempt to produce an acceptably tolerated antibody. If the antibody remains intolerable, however, the cell is stimulated to undergo a process of programmed cell death. Since a single B lymphocyte harbors a single, unique antibody, once the cell is destroyed the gene and the problematic antibody no longer exist in the body. The vast majority of B lymphocytes (billions in an individual each day) are known to be destroyed because they produce antibodies that are intolerable. Hence, there can be no more important feature of antibody development than this process of selection. Selection is a fundamental step to enable the body to produce an extremely diverse set of antibody molecules without producing any that cause harm.
Until now each and every therapeutic antibody on the market has been derived through gene sequence modification in the laboratory to produce the desired antibody product. Marketed antibodies to date, described as fully human, are not derived from human gene sequences that have undergone the crucial process of selection in a human. Without exception, all marketed products to date that use the term fully human to describe the product are in fact engineered and are not selected based on natural tolerance in the human body. The use of the term fully human to describe these products has thus created considerable confusion. There are at present no true human antibodies currently marketed.
The misperception in the market place is that so called fully human antibodies are actually derived from humans. The reality is that antibodies marketed with this nomenclature are engineered and are not actually human antibodies, ie. they have not undergone the crucial process of selection and development in a human. The difficulty is that fully human antibodies were introduced as the ultimate generation of these therapeutics, as the final step in a development process that started with simple mouse antibodies, then mouse-human fusion products (known as “chimeric”), followed by mouse-human fusion antibodies with further modifications (known as “humanized”), and finally “fully human”.
The technical challenge has been to progress towards a tolerability, safety and efficacy that could only be achieved with actual human antibodies. Somehow, though, the introduction of antibodies derived from clever engineering technologies that used a starting material of antibodies from “humanized mice” or other sources were granted the nomenclature “fully human” in the market place.
The various therapeutic antibody stakeholders—including patients, physicians and those in the public markets investing in antibody companies—are under the impression that the products being sold as fully human antibodies are indeed the same as real human antibodies—in other words that safety, tolerability and development of these products are at an apex. This assumption by the stakeholders is of course incorrect.
XBiotech’s development of actual true human antibody therapeutics are therefore particularly disruptive. While the concept of a disruptive technology is often cited by companies to highlight novelty and importance of their product, there can be few examples where the concept takes on such importance as with true human antibodies. Typically, a next generation, disruptive technology, replaces an existing technology that is recognizably inferior. In the case of antibody therapeutics, existing technology is masquerading as the next or ultimate generation. The implication is that those entrenched and profiting from the misconception in the therapeutic antibody business are particularly reluctant to acknowledge the arrival of the displacing technology, since they de facto already have it.
XBiotech therapeutic antibody products are derived from a natural antibody produced within the human body. XBiotech’s true human antibody products in the pipeline are thus expected to be the best tolerated therapeutic antibodies ever developed for treating human disease. The Company’s lead product candidate has now been in multiple clinical trials where it has indeed shown unprecedented safety and tolerability. XBiotech is seeking to establish a new naming system for antibodies that identifies true human antibodies and distinguishes them from the so called fully human products already marketed. To date, the provision of such nomenclature by the relevant authorities has been refused. However, the Company will continue to pursue a revision of therapeutic antibody nomenclature to distinguish true human antibodies from all other products currently on the market.