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

Anita T. Shaffer @Shaffer1
Published: Friday, Feb 01, 2013
John M. Lambert

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.

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—an antibody, a cytotoxic agent, and a linker that holds the two together—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?

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