Hammer Stock Blog

CD70 program

CD70 is a receptor expressed on many types of blood cancers as well as the majority of renal cancer cases. The expression profile of this target is highly restricted to cancer cells, which, combined with its ability to internalize antibodies, makes it a desirable target for ADCs. Seattle Genetics is evaluating a naked antibody as well as an ADC that target CD70, both candidates are based on the same antibody, which was licensed from CLB-Research and Development. The naked antibody, SGN-70, is evaluated for certain blood cancers and is expected to enter phase I during 2008. Another possible use for SGN-70 is for autoimmune diseases, as it is expressed on white blood cells that are involved in the disease, but not on “resting” cells.

SGN-75 is an ADC based on SGN-70, which is currently evaluated pre-clinically for Renal cell carcinoma. This disease, although not as common as prostate and lung cancers, represents a large market opportunity with over 43,000 new cases and almost 13,000 deaths expected in 2007 in the US alone. Although surgical resection of the kidney has high chances to prevent the disease from spreading, nearly one third of patients are diagnosed at advanced stage, where the cancer has spread to additional organs. In addition, more than 30% of patients who undergo resection will eventually develop metastatic disease, for which very few therapeutic options exist. SGN-75 is expected to enter the clinic only in 2009.

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The partnership with MedImmune, which dates back to 2005, is probably Seattle Genetics’ second most important partnership. On the scientific side, now that MedImmune has been merged with Cambridge Antibody Technology [CAT] to form AstraZeneca’s (AZN) biologics division, Seattle Genetics has a real antibody powerhouse on its side. On the financial side, Seattle Genetics could benefit from another pharma giant on its partner list, equipped with the 8th largest R&D budget in the industry and consequently the ability to support multiple clinical programs simultaneously. Looking at Immunogen’s partnership with Sanofi-Aventis, which has thus far led to 3 clinical programs, is making us hope that AstraZeneca will be to Seattle Genetics, what Sanofi is to Immunogen.

The cooperation with MedImmune originally revolved around one target – EphA2. This intriguing target is highly expressed in numerous solid cancers including breast, prostate and colorectal, which makes the potential opportunity immense. In addition, there is a growing body of scientific evidence that expression of EphA2 is associated with aggressiveness and poor survival, which makes its targeting very reasonable in advanced stages of the disease. The specific targeting of EphA2 looks particularly promising since MedImmune’s scientists discovered that there are several regions within EphA2 which become exposed and consequently accessible for antibodies only on cancer cells.

MedImmune views Epha2 as a very important target. In fact, it has such high hopes for it, that there it is currently evaluating multiple approaches to targeting this promising antigen. One of these approaches is Micromet’s (MITI) Bite (stands for: Bi-Specific T cell Engager) platform, which is being co-developed with Medimmune for several targets, one of which is EphA2. The Bite Platform, a very interesting technology (that deserves an article of its own being so different from other antibody-based platforms) consists of two small antibodies that link between a tumor and specific immune cells in order to manipulate them to attack the tumor. It has demonstrated very impressive potency in mice, and even more impressive results among heavily pre-treated NHL patients, mainly due to the very low doses that showed a clinical effect. The Bite platform hasn’t been evaluated in solid tumors yet, but clinical trials are expected to be announced in the future, one of them is for a Bite agent that targets Epha2. Due to its unique characteristics that present both advantages and disadvantages, it is very hard to predict Bite’s efficacy in these settings. Although some consider Bite an immunotoxin, it differs from immunoconjugates in that it does not contain any drug or toxin payload, so it is reasonable to expect that MedImmune will explore it in parallel to Seattle Genetics’ platform. Although Bite is not necessarily a direct competitor, I bet the folks at Seattle Genetics are following that program closely. Nevertheless, MedImmune seems pretty happy with Seattle Genetics’ platforms, as it has recently licensed Seattle Genetics’ ADC technology for a second undisclosed target.

Author is long SGEN

CR011-vcMMAE is an ADC currently being developed by Curagen (CRGN), based on Seattle Genetics’ ADC technology. The ADC comprises of an antibody against GPNMB, a protein on the surface of melanoma cells linked to a drug payload. Both the drug and the linker in this case are identical to those used by Seattle Genetics in SGN-35. The story behind this agent demonstrates the need of ADC technology and the high value it has in today’s drug development market. It also demonstrates that going after one of the most challenging indication with a relatively new platform, may not be the best way to validate it.

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SGN-35, which is Seattle Genetics’ lead ADC, is comprised of SGN-30 and Seattle Genetics’ highly toxic chemo drug – MMAE. SGN-35 is, in fact, the company’s flagship ADC candidate, since it was its first wholly owned ADC to utilize the company’s new ADC technology, including its peptide-based linker and auristatin-based drug. Having both a naked antibody and an ADC based on the same antibody simultaneously in the clinic is quite unusual, but more than anything, this situation is fascinating because it can clearly exhibit the advantages ADCs have over naked antibodies. In that sense, SGN-35 is similar to Genentech’s Herceptin-DM1, which is currently being developed with Immunogen (IMGN). Herceptin-DM1 served as a validation for Immunogen’s ADC technology since it showed very encouraging results among breast cancer patients, who do not respond to naked Herceptin. Hence, if Seattle Genetics can show that SGN-35 succeeds where SGN-30 fails (hint- Hodgkin’s Lymphoma), without causing substantial side-effects, it should be a very strong proof-of-concept.

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The market of monoclonal antibodies for cancer is one of the fastest growing segments in the pharmaceutical industry, with several blockbuster drugs such as Rituxan and Herceptin. Although over a year has passed since the FDA last approved an antibody for the treatment of cancer, the extensive activity in the field will surely lead to a substantial addition of antibodies in the coming years. (more…)

Metaphorically, antibodies can be described as unarmed guided missiles, which have extraordinary precision and targeting abilities, but once they hit the target, they inflict minimal damage. Chemotherapy and radiotherapy can be described as artillery, very powerful, but unguided. In order to optimally use the two, the most logical step is arming those unarmed missiles with a variety of explosives. Using the same reasoning, there is a true need to develop anti-cancer therapies which have an antibody-like specificity as well as chemo/radio-therapy-like potency. Doing so enables us to take advantage of the selectivity of antibodies and the potent toxic activity of chemo/radio-therapy, thus creating superior cancer treatments. The antibody binds the target on the tumor, delivers its payload and kills the cell. Arming antibodies with effector molecules like chemotherapy agents and radio-isotopes results in a hybrid agent referred to as an Immunoconjugate. An antibody which is not conjugated to an effector is referred to as “naked” antibody.

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