This year’s ASCO annual meeting should be a very exciting event for anyone who has been following the field of antibody-drug conjugates (ADCs). During the conference, investigators will present impressive clinical data generated by ADCs powered by Immunogen’s (IMGN) and Seattle Genetics’ (SGEN) technologies. The data includes studies for Genentech’s (DNA) T-DM1, Seattle Genetics’ SGN-35 and Curagen’s (CRGN) CR011-vcMMAE .  These data will put ADCs on the verge of transitioning from a remote niche to one of the hottest areas in oncology.

For more background on ADCs and the tremendous opportunity they represent, start here and here. In the meantime, below is a summary of everything you always wanted to know about ADCs but were afraid to ask: 

1)      Cancer is a disease caused by uncontrolled growth and division of cells in the body. These cells are very similar to healthy cells, which makes developing effective anti-cancer drugs very challenging. Fortunately, cancer cells can often be distinguished from normal cells based on structural elements they present on their outer surface. These cancer specific elements are generally termed tumor-associated antigens or TAAs.

2)      Antibodies are proteins that recognize and bind specific structural elements. These properties can be harnessed for the development of targeted anticancer drugs that affect cancer cells while sparing healthy ones.

3)      In the past decades, technologies that enable the creation, production and evaluation of antibodies against tumor associated antigens, led to the development and commercialization of anti-cancer antibodies. These antibodies, such as Rituxan and Erbitux bind TAAs presented on cancer cells with minimal side effects.

4)      Upon binding cancer cells, antibodies can exert their therapeutic effect via a number of mechanisms such as recruitment of the immune system and disruption of growth signals.

5)      Binding cancer cells does not necessarily lead to an anti-cancer effect, as most cancer-specific antibodies just attach to cancer cells without causing any damage. These antibodies might be useful for diagnosis or imaging purposes but not as drugs. Thus, the approved anti-cancer antibodies represent a tiny fraction of available cancer-specific antibodies.

6)      In addition, even the few effective anti-cancer antibodies typically have a mild effect on the course of the disease, especially in the case of solid tumors such as breast and lung cancers.

7)      This gives rise for the need to boost antibodies’ potency by coupling them with effector molecules such as chemotherapy drugs. An ADC is an antibody that is linked to a toxic payload of chemotherapy drug.

Some like to describe antibodies as guided missiles because they can find and attack specific targets without causing collateral damage to their surroundings. Using the same analogy, although these guided missiles can hit the target, the damage they inflict is limited, so there is a need to arm them with more potent warheads. This is the rationale behind developing ADCs – utilizing antibodies’ ability to identify cancer cells with the ability of chemotherapy drugs to kill them. 

Although the concept of ADCs is very intuitive, the actual development of these agents has been proven to be excruciatingly difficult. As a result, most companies stayed away from this field, focusing on developing “naked” antibodies that are not linked to an effector molecule.  Today, however, technologies for arming antibodies are finally mature enough to allow drug developers to pursue this promising path.

The two most prominent technologies for creating ADCs were developed by Immunogen and Seattle Genetics for over a decade. If proven effective, these platforms can be utilized for developing an unlimited number of drug candidates for a broad spectrum of cancer types. Unlike other emerging fields, the growth and adoption of ADCs may be very rapid thanks to the vast experience and insight gained in the antibody industry. For over 30 years, investigators have identified clinically relevant targets, produced cancer specific antibodies and developed model systems for evaluating efficacy. The big splash ADCs are about to make could not have come at a more opportune time for the pharma industry, which is going through a severe innovation crisis. The company that could benefit the most from ADCs is no other than Genentech, whose antibody pipeline looks like a pale shadow of the great innovative pipeline it had in the 90’s. Genentech has invested a lot of effort and created one of the broadest collection of antibodies against a plethora of well characterized tumor associated antigens, so within several years, Genentech can theoretically have a dozen of ADCs in the clinic at minimal cost.  

Back to this year’s ASCO meeting, positive data from three different clinical programs will be presented. Genentech will present two phase I trials where T-DM1 (which utilizes Immunogen’s technology) was given to breast cancer patients. Seattle Genetics will give an update from the phase I trial of SGN-35 in late stage Hodgkin’s Lymphoma. Curagen will publish results of CR011-VCMMAE in metastatic melanoma patients.

  T-DM1  

Genentech presented results from two dose escalation studies of T-DM1, which is comprised of Genentech’s blockbuster antibody, Herceptin®, and Immunogen’s linker and effector molecules. Of note, the patients enrolled to the trials had previously progressed during treatment with Herceptin in combination with chemotherapy.