ADCs Are Poised to "Blossom" as a New Category of Therapy: An Interview With John M. Lambert, PhD

John M. Lambert, PhD,

executive vice president of Research and Development and chief scientific officer,

ImmunoGen, Inc

Like many anticancer therapies, antibody-drug conjugates (ADCs) have traveled a long and sometimes rocky road. These days, however, the compounds are a robust area of oncology exploration, with an estimated 25 ADCs under study in clinical trials, up from six less than a decade ago.¹

One of the major developers of ADC technology is ImmunoGen, Inc, where researchers have believed in the potential of the underlying therapeutic strategy since the Waltham, Massachusetts-based company was founded in 1981. Now, the company’s Targeted Antibody Payload (TAP) technology forms the basis of a promising new breast cancer therapy and is helping to build a portfolio of compounds in several tumor types.

The company developed the DM1 cell-killing agent and the linker mechanism that transforms Genentech’s trastuzumab (the active component of Herceptin) into trastuzumab emtansine (T-DM1). Updated data from the EMILIA trial, presented at the European Society for Medical Oncology (ESMO) 2012 Congress in October, indicate that T-DM1 improved overall survival in patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer when compared with a combination of capecitabine and lapatinib (XL).² Median overall survival was 30.9 months for T-DM1 versus 25.1 months for the XL regimen, representing a 32% reduction in the mortality risk (HR = 0.68; 95% CI, 0.55-0.85; P <.001). The safety data indicated that T-DM1 was better tolerated than the XL doublet, with fewer treatment-related toxicities and discontinuations.

The FDA is evaluating a Biologics License Application for T-DM1 under its priority review program and is expected to make a decision by February 26, 2013, according to Genentech.

For ImmunoGen, T-DM1 is important but not the only ADC in development with its technology. In all, 10 TAP compounds are in clinical testing, with more compounds in earlier stages behind these. These compounds use one of four different cell-killing agent/linker combinations, and are being developed by ImmunoGen alone or in collaboration with pharmaceutical companies. In December, ImmunoGen announced that Amgen has licensed the rights to use the TAP technology for a third therapeutic target. In addition to Genentech, ImmunoGen’s other collaborative partners include Bayer HealthCare, Biotest, Lilly, Novartis, and Sanofi.

Tumor types for which the compounds are being developed include breast cancer, small-cell lung cancer, gastric cancer, and diffuse large B-cell lymphoma and other hematologic malignancies.

“In the next several years, we expect a blossoming of compounds being evaluated in the clinic,” said John M. Lambert, PhD, executive vice president of Research and Development and chief scientific officer at Immuno- Gen. “The technology is established. It’s a question now of exploiting it in the right setting, the right disease, and the right target. It is, in a way, the beginning. T-DM1 has been the flagship, the one that’s broken the ice, but the activity behind it is very exciting.”

In an interview with OncologyLive, Lambert discussed ADCs and ImmunoGen’s arduous and painstaking journey in developing the compounds.

OncologyLive: Please describe the TAP technology and the role it plays in an ADC.Lambert: Our TAP technology consists of our highly potent cytotoxic agents, which we developed specifically for targeted delivery to cancer cells using antibodies. It also includes our portfolio of engineered linkers, which are designed to keep the payload⎯the cytotoxic agent—attached to the antibody in circulation and control its release and activation inside a cancer cell. So if you think of an ADC as having three components&mdash;an antibody, a cytotoxic agent, and a linker that holds the two together&mdash;the latter two are our TAP technology.

Why the interest in ADCs?

The goal with creating an ADC is to combine the targeting ability of an antibody with the cell-killing potency of a cytotoxic small molecule, in essence combining the best property of each entity in one molecule. The rationale is that, by targeting the cytotoxic small molecule, you can get an anticancer therapy with a better efficacy/tolerability profile.

What is the adverse-event profile of ADCs?

As with other antibody-containing therapies, ADCs have the potential for infusion-related adverse events. Beyond that, the adverse-event profile of each individual ADC can be very different⎯depending on the antibody target, the cell-killing agent, and the linker used. It could be best to think of ADCs as a category of therapy, rather than as a specific class of drugs. So one shouldn’t assume from one ADC to another that the adverse-event profile would be the same. From the clinical experience to date—it’s early days now in this field&mdash;it seems be they’re not the same.

How is TAP technology being used as part of T-DM1?

In T-DM1, our technology is the DM1 cytotoxic agent and the engineered linker that joins the DM1 to the trastuzumab antibody. In the mid-1990s, we identified that HER2 would be a good target for this type of therapeutic, and we thought that if trastuzumab were armed with our TAP technology, it could turn it into a really good therapeutic compound.

The next most-developed compound in ImmunoGen’s pipeline is IMGN901. Please discuss this agent.

IMGN901 is a TAP compound that contains DM1 as the payload, which is the same payload as in T-DM1, but it is attached with another of our engineered linkers. IMGN901 is also called lorvotuzumab mertansine⎯lorvotuzumab is its antibody component, mertansine is the INN [International Nonproprietary Name] for DM1 attached using our SPP engineered linker.

IMGN901 binds to a target that is found on essentially 100% of small-cell lung cancer tumors. IMGN901 is now being evaluated for first-line treatment of extensive-disease small-cell lung cancer in our NORTH phase II trial—a two-arm trial testing the impact of adding IMGN901 to etoposide plus carboplatin.³ Thus, we’re taking advantage of the relatively benign side-effect profile of IMGN901 by assessing it added to standard chemotherapy to improve outcome.

What does the future hold for the TAP platform?

Today our TAP platform consists of several different maytansinoid derivatives, including DM1, and a portfolio of linkers we’ve engineered to impart specific properties to the TAP compound. We think this platform is already quite developed, although we do keep having new insights for additional engineered linkers.

For example, we’ve developed linkers that extend the utility of the ADCs to counter multidrug resistance in cancer cells. One way that cancer cells evade being killed is by pumping out toxic drugs very quickly⎯essentially spitting them out before they can kill the cell. We’ve designed linkers that help keep our cytotoxic agents inside a cancer cell until the cell is killed.

Our IMGN853 TAP compound utilizes one of the linkers we developed to counter multidrug resistance. IMGN853 targets the folate receptor 1, which is an antigen abundant on many ovarian cancer cells and on a good proportion of lung cancer cells. It is now in clinical testing.⁴

We’re also working on developing other types of payload agents so we can have ADCs that kill cancer cells using mechanisms of action other than tubulin inhibition. The most advanced ADCs to date, such as T-DM1, all contain tubulin-acting agents. However, just as with chemotherapy, one mechanism of action doesn’t work for all cancers. There are chemotherapeutic drugs that target DNA, there are others that target tubulin, there are others that target other elements to cause cell death. I think there will ultimately be ADCs available for all of these different types of payloads.

This illustration depicts the mechanism of action of an antibody-drug conjugate using the Targeted Antibody Payload (TAP) technology. ImmunoGen, Inc developed the TAP technology, which is used in T-DM1 and other compounds currently in clinical testing.

Illustration courtesy of ImmunoGen, Inc

What scientific advances enabled ImmunoGen to move the TAP technology forward?

They’re not so much technological advances as an understanding of the clinical behavior of antibodies that led to an understanding of the requirements for the payload and linker designs. It’s the clinical pharmacology of antibody distribution in the body, such as how antibodies penetrate tumors and how much gets retained in the tumors. This is what you could broadly call the pharmacodynamics of antibody behavior clinically and preclinically. It was this that led to understanding the requirements of the payload and linker, which then led to the designs we ultimately have developed.

Of course, there is one technology that underlies everything. In the early 1980s, we and others worked with murine antibodies derived from mouse hybridoma work. As it turned out, we learned that these are not nonimmunogenic in humans⎯you can’t really evade the human immune response to this foreign protein, the mouse antibody. The technologies to make nonimmunogenic antibodies⎯that is, humanization⎯led to the first successful naked antibody products, and ultimately underlie ADC development.

How did this understanding unfold over the years?

The two key founders or members of the scientific advisory board were the late Baruj Benacerraf, MD, who, at the time, was the head of the Dana-Farber Cancer Institute, and in 1980 won the Nobel Prize for immunology, and then Stuart F. Schlossman, MD, MPP, who was, at the time, head of the Division of Tumor Immunology. They were among the leading immunologists of the day, and immunologists were, of course, the group of people who immediately saw the power of monoclonal antibody technology.

But their view right from the beginning was that, in the end, naked antibodies probably were not going to be particularly active because by the time you have a solid tumor, it had already evaded the immune system.

So at ImmunoGen, right from the beginning, the concept was that antibodies probably were not going to be effective enough, and so we needed to arm them with something potent.

Broadly speaking, the 1980s were spent learning the pharmacodynamics and understanding what was needed for an ADC technology to work, what the characteristics of the payload and linker needed to be. Then in the 1990s, we developed that. In the 2000s, we’re developing ADCs in the clinic.

As we started our research and kept on learning in the field, we just never ran out of ideas of how to jump the next hurdle that we faced. That’s a little bit how science is. When you’ve exhausted all your ideas about how to jump the next hurdle, you move on to another project. But we never ran out of ideas.

References

1. Tuma RS. Enthusiasm for antibody-drug conjugates. J Natl Cancer Inst. 2011;103:1493-1494.
2. Verma S, Miles D, Gianni L. Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA12.
3. ImmunoGen, Inc. A study to test safety and efficacy of IMGN901 in combination with carboplatin/etoposide in patients with advanced solid tumors and extensive stage small cell lung cancer. ClinicalTrials.gov website, NCT01237678. www.ClinicalTrials.gov. Updated August 28, 2012. Accessed November 20, 2012.
4. ImmunoGen, Inc. First-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of IMGN853 in adults with ovarian cancer and other FOLR-1-positive solid tumors (IMGN-0401). ClinicalTrials.gov website, NCT01609556. www.ClinicalTrials.gov. Updated May 31, 2012. Accessed November 20, 2012.