Today it is clear that treating cancer with monoclonal antibodies is one of the greatest advancements in oncology. Just over a decade ago, the approval of Rituxan marked the birth of a multi-billion dollar market, as 8 additional antibodies have since joined Rituxan. The market is currently dominated by a specific flavor of antibodies termed “naked” antibodies, which represent a fraction of the large amount of different antibody flavors. In contrast to naked antibodies, other flavors have yet to reach maturity, although some of these are making their way steadily to the center stage. All these approaches have one thing in common: They rely on antibodies’ exquisite ability to recognize and bind a target in a very specific manner. One of these approaches, represented by Immunogen (IMGN) and Seattle Genetics (SGEN), deals with Antibody-drug conjugates (ADCs), which are constructed by linking antibodies to a drug-payload. The antibody serves as a guiding system by guiding the drug to tumors, and releases it inside cancer cells. In addition, there is a lot of activity in developing additional antibody-based therapies that involve linking other types of substances to antibodies. For example, one possibility for boosting an antibody’s potency is linking it to a radioactive molecule like in GlaxoSmithKline’s (GSK) Bexxar case.
In biotech, just like in other investment fields, it is important to recognize market trends, and identify emerging technologies and concepts. The problem with such cutting-edge technologies is that, regardless of how promising they seem, there is always an unknown period of incubation, in which the technology migrates from basic research to the industry. If we take the whole antibody industry as an example, it took almost a quarter of a century from the scientific breakthrough that gave rise to monoclonal antibodies, to the approval of Rituxan. In the case of ADCs, several encouraging results may imply that the incubation period is finally over, although drug development is always characterized with a high level of uncertainty. As someone who has been following the antibody market for quite some time now, I assumed that ADCs such as T-DM1 will represent the majority of clinical breakthroughs in the coming years. However, preliminary results from a small clinical trial that were published in ASH three months ago, showed that there is a unique platform which can generate highly potent antibodies, without even linking them to drugs or other effector molecules. In fact, this platform gave rise to one of the most potent antibodies ever tried on human beings – Micromet’s (MITI) MT103.
Micromet is a German-based company that developed a unique antibody-based platform termed BiTE® (Bispecific T Cell Engagers). BiTE antibodies are unique in the sense that they combine two approaches that have been investigated for years without any meaningful success. I discussed the clinical activity of MT103 in brief here and intend to do so more thoroughly in the second part of this article. But first, let’s look at the two approaches which are represented by BiTE antibodies.
First and foremost BiTE antibodies are bi-specific antibodies (bsAbs). Unlike standard antibodies, which have identical structure and function to naturally occurring antibodies, bsAbs are not something that can be usually seen in nature. A “normal” antibody is commonly represented as a “Y” shaped molecule (see picture). It has two identical “arms”, each can bind exactly the same target. Therefore, such antibodies are considered mono-specific. A bi-specific antibody can also be represented as a “Y” shaped molecule, but it has two different arms, each one capable of binding a different target. Hence, a bispecific antibody can simultaneously bind two different and unrelated targets. It doesn’t take too much imagination to understand that this type of antibodies theoretically opens new and exciting perspectives for antibody-based therapy.
In the context of cancer therapy, bispecific antibodies are usually designed to redirect immune cells to tumor cells, in a way that will lead to the attack of the tumor. One arm is directed against a target on a cancer cell while the other arm is directed against a target on the immune cell. In most cases, bispecific antibodies must not only bring the immune cell closer to cancer cells but also activate it to attack the tumor. In order to achieve both of these tasks, there is a need to identify specific targets on immune cells that can be activated by antibody binding, or find supplementary ways to achieve this activation. Naturally, there is a large number of options when designing a bsAb. One variable is the target on the cancer cells, another variable is the type of immune cell to be recruited, while a third variable is which structural element (antigen) on that specific immune cell should be targeted. This is much more complicated than designing mono-specific antibodies, in which only the target on the cancer cells should be chosen.
Cancer cells are constantly created in our body but in the vast majority of cases, our immune system identifies and exterminates them. In some cases, however, a cancer cell manages to evade or suppress the immune response, thus enabling itself to multiply and spread throughout the body. BsAbs are similar to cancer vaccines such as Cell Genesys’ GVAX in their intent to promote an immune response against cancer. This approach holds that there is an immense potential in our immune system that can be unleashed upon cancer since our immune system commands a very potent and diverse arsenal of anti-cancer weapons. In both cases, the challenge is activating these weapons effectively and safely, with an emphasis on “safely”.
Manipulating our immune system is not something to be taken lightly, as it is compiled of many players and interactions, that are elegantly orchestrated. Because our immune system is so potent, it is also heavily regulated in order to keep things from getting out of hand. Auto-immune diseases, such as Rheumatoid arthritis and Multiple sclerosis, where the immune system attacks the body’s healthy tissues are one example for what happens when this control is lost.
The phase I trial of TGN1412 in 2006 should serve as reminder for the explosive and dangerous potential immune modulating antibodies have. TGN1412 is an antibody that binds CD28, a receptor on T cells that can strongly activate them, upon antibody binding. This antibody was evaluated for safety in a phase I study that turned into one of the most notorious clinical trials in recent years. Apparently, TGN1412 led to a strong immune response that simply got out of control, sending immune cells rampaging through the patients’ bodies, destroying healthy tissues. All 6 patients who received this antibody were rushed to the ER in critical state with severe side effects that included severe pains, convulsing, and failure of the liver, heart and lungs.
Bispecific antibodies may prove to be safer than antibodies such as TGN1412 since they redirect the immune cells to respond specifically against cancer cells that express a specific target. Nevertheless, immune cells can communicate with each other to create a systemic response. This might be very positive when the systemic response is controlled and channeled against cancer, as it might overcome the immunosuppressant nature of tumors. Nevertheless, this might also lead to devastating results if the immune response is turned against normal tissues.
Bispecific antibodies are still a minor niche among the industry and as such, are ignored by most pharma companies, due to a history of technical difficulties and poor evidence of clinical activity. Will we ever see commercial drugs based bsAbs? Nobody knows, but Micromet is getting closer than any company has ever gotten to realizing the potential of bispecific antibodies.
The second structural feature of BiTE antibodies is their small size, about one third of normal antibodies like Rituxan and Herceptin. Small antibodies, generally referred to as scFv (Single Chain Variable Fragment) antibodies, are constructed by taking only the tips of the antibodies’ binding arms, which are the regions through which any antibody binds its target. The best analogy I could find in order to explain the difference between small antibodies and regular ones, is comparing antibodies to a human arm. An antibody can be described as two whole arms while a small antibody can be descried as just the palms.
Smaller antibodies have some flaws that hampered most efforts to develop drugs based on this antibody type. First, their small size leads to very fast clearance from the patient’s body, so it is very difficult to maintain a sufficient level of the antibody in the bloodstream over time. Second, most small antibodies have only one arm, which decreases their binding abilities. One significant advantage of small antibodies is their ability to penetrate tissues more efficiently. The tissue penetration factor is regarded as very important in the case of solid tumors, where tumors are typically a dense mass of cells that is very hard to penetrate, as opposed to blood cancers, where tumors are much more accessible. Moreover, in advanced cancers, tumors often metastasize by sending cancer cells that penetrate into the patient’s organs. These metastatic lesions are less approachable to conventional antibodies. Until now, the disadvantages in small antibodies outdid the advantages, but ironically, this feature has been crucial for the success of BiTE antibodies.