White blood cells in the human body produce billions of different soluble proteins that circulate through the blood to react with invading toxins, infectious agents or even other unwanted human proteins. True human therapeutic antibodies, as the name implies, are derived directly from a natural human immune response.
To develop a true human antibody therapy, thousands of human donors may be screened to find an individual that has in their blood a specific antibody that matches the desired characteristics needed to obtain the intended medical benefit. White blood cells from that individual are then obtained, the unique gene that produced the antibody is cloned, and the genetic information is 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 gene sequence engineering technology in the laboratory.
To appreciate the background safety and tolerability of true human antibodies, it is important to consider the fundamental biology of natural antibody production.
Billions of different white blood cells secrete billions of unique antibodies every day into the circulation. The vast number of different antibodies (and cells that produce them) are essential to enable adequate molecular diversity to ward off all potential infectious threats. Since antibodies act to bind and thereby neutralize unwanted agents, any given circulating antibody must be able to react with an almost limitless number of existing and evolving disease entities.
The staggering number of different antibodies needed to achieve this level of preparedness, however, is a daunting concept from a genetics point of view. If an individual antibody gene was needed to encode each of a billion different antibodies, there would be 20,000-times as many genes needed just for antibodies as there would 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 the DNA. Clearly, the system of antibodies could not have evolved to protect us, had not an elegant solution emerged to deal with this genetic conundrum.
Thus a hallmark of the immune physiology of all vertebrates (all have antibodies) is the ability to recombine and selectively mutate a relatively small number of gene segments to create a phenomenal and effectively unlimited number of antibody genes. By rearranging, recombining and mutating the genetic code, specialized white blood cells, or B lymphocytes, are able to create unique antibody genes. Each antibody gene is unique to the individual B lymphocyte that created it, and no copy of the gene exists in the human germline.
The extraordinary process of gene rearrangement and mutation results in a multitude of unique B lymphocytes and consequently an incredibly diverse repertoire of antibodies. A repertoire needed to protect the individual from a myriad of possible 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 the discovery that B lymphocytes made genes unique from the rest of the body raised another problem: 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 other foreign substance such as a virus or bacteria? How could the body distinguish the apparently “foreign” antibody molecules from the bona fide infectious intruders?
Unraveling the genetics of antibody production led to another major advance in medicine: the discovery of how an endless array of antibody proteins could be made in a way that individual molecules were always tolerated by the body.
Extraordinary studies around the early 1990s clearly demonstrated that the growth and expansion of antibody-producing B lymphocytes was not a random process. Rather, it was established that the antibody produced by each and every B lymphocyte (and the cells that produced it) was subject to intense scrutiny. Remarkable studies showed that B lymphocytes, which rearranged genes that produced acceptable antibodies, were stimulated to grow. These cells could proliferate and produce copious amounts of antibody in the event that the particular antibody was needed to ward off a harmful agent. On the other hand, B lymphocytes that rearranged genes to produce antibodies that were ineffective or caused undue reactivity were simply killed off.
The mechanism for creating antibody diversity while protecting the individual from a mass of unwanted or intolerable antibody molecules was exquisite. A marvelous selection process existed. B lymphocytes that produce “good” antibodies were promoted. Those producing “bad” antibodies were destroyed. The fate of B lymphocytes in vertebrates hinged on the ability of the cells to rearrange genes that produced well tolerated, effective antibodies.
This selection process has been elucidated in great detail. In an attempt to survive, B lymphocytes that produce a problematic antibody can even undergo further genetic rearrangement in an attempt to produce an acceptable antibody. If the antibody remains intolerable, however, the cell is stimulated to undergo a process of so called 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 a problematic antibody.
There can be no more important feature of antibody development than the 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 are described as “fully human”, 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. XBiotech’s lead product Xilonix™ is expected to be the only product to be marketed that is a true human antibody.
The misperception in the market place is that so called fully human antibodies are actually derived from humans. The reality is that antibodies marketed as fully human are actually engineered and are not really human antibodies. There is a crucial difference between an engineered antibody and a true human antibody isolated from an immune individual.
In the human body, antibodies are subjected to a process of deletion and selection. This process allows intolerable antibodies to be expunged and the tolerable ones to be produced as part of the body’s immune system (please see detailed discussion above).
The difficulty with respect to the current antibodies being marketed as fully human antibodies is that this descriptive nomenclature suggests that they are the ultimate generation of antibody therapeutics. These so called fully human products are implied to be the final step in the historical development of antibody based therapies that started with the use of 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” (engineered from human germline sequences).
The various stakeholders—including patients, physicians, regulators and investors—are under the impression that the products being sold as fully human antibodies are indeed the same as real human antibodies. This inappropriately suggests that the marketed antibodies are at an apex in terms of safety and tolerability. This assumption is of course not correct.
XBiotech’s development of actual true human antibody therapeutics is therefore particularly disruptive. The concept of a disruptive technology is often made in reference to a quantum advance in a technology. Typically, a next generation, disruptive technology, replaces an existing technology that is recognizably inferior. In the case of antibody therapeutics, however, existing technology is masquerading as the ultimate evolution of the antibody technology platform. An implication is that incumbent stakeholders in the fully human antibody business need not acknowledge, and thus could be expected to be particularly resistant to, the arrival of the displacing technology.
XBiotech is working with the United States Adopted Names Council (USANC) to create a new nomenclature to describe and differentiate true human antibodies from the existing fully human. As an incumbent themselves, not surprisingly there has been reluctance to provide distinguishing nomenclature despite prima facie differentiation between true human antibodies and existing fully human products.
USANC is affiliated with the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), the American Pharmacists Association and works closely and shares members with the Food and Drug Administration (FDA).
In our opinion, the naming of existing products as “fully human” is both inappropriate and even misleading, and that the “fully human” designation serves to underplay the inherent safety risk of infusion or anaphylactic reactions that exists with these antibodies. The key issue surrounding differentiation for XBiotech’s antibody platform is therefore proper disclosure of safety and tolerability expectations. We believe that this crucial differentiation between our products and existing marketed products known as fully human will ultimately move the USANC and other agencies to appropriately address the issue.
To this end, XBiotech will continue to actively pursue with USANC the establishment of a new naming system that identifies true human antibodies and distinguishes them from the so called fully human products already marketed.