12:00 AM
Dec 20, 2010
 |  BioCentury  |  Strategy

TAP's Big Finish

After nearly 30 years, ImmunoGen's TAP antibody technology turns a corner

It has taken nearly three decades, but ImmunoGen Inc. is finally getting some traction with its TAP targeted antibody payload platform. The company has closed out 2010 with a rush of news, and now intends to get down to the business of developing its internal pipeline, which President and CEO Daniel Junius sees as the company's real growth driver.

In October, the company announced its largest deal yet for the TAP technology - with Novartis AG - as well as positive clinical data for its lead in-house candidate, lorvotuzumab mertansine (IMGN901).

These announcements came just days after partner Genentech Inc. announced positive data in a second breast cancer indication for the most advanced TAP compound - T-DM1, which consists of the big biotech's trastuzumab antibody against HER2 conjugated to ImmunoGen's DM1 toxin.

According to Junius, these successes were made possible by a series of lessons learned in the clinic, including failures of compounds designed using different iterations of the technology.

Now, having worked its way through three iterations of TAP that are differentiated mainly by improvements to the cytotoxic payload, ImmunoGen is looking to move beyond its heavily partnered business model.

This month, the company started a Phase I/II trial of lorvotuzumab in small cell lung cancer (SCLC) and anticipates making a decision by year end on whether to enter pivotal trials of the candidate in Merkel cell carcinoma (MCC).

By the end of 2011, ImmunoGen expects its internal pipeline plus its partnerships to account for about a dozen compounds in the clinic.

To advance its ambitions, the company had almost $95 million in its coffers at Sept. 30, bolstered by an $83 million follow-on in May. Including partnership income, it is guiding for its cash to grow to as much as $110 million by the end of its fiscal year next June 30.

Tweaking TAP

ImmunoGen has been using antibodies as targeting vehicles to deliver cytotoxic compounds since it was founded in 1981. It started with antibodies conjugated to traditional chemotherapeutics.

"The idea was that there was already something you knew would kill cancer cells," Junius told BioCentury. "The hope was that you could maintain the potency while targeting the chemotherapeutic to the tumor cells," thus sparing healthy cells.

But when it took these early antibody-drug conjugates (ADCs) into the clinic, ImmunoGen found the potency of the combination was lower than when the chemotherapeutic was given alone.

The next iteration of TAP used ricin as the payload. Ricin, a plant-derived class II ribosome-inactivating protein, was selected because it was more potent than traditional chemotherapeutics.

Oncolysin B, an immunotoxin consisting of a mAb linked to ricin, made it into a Phase III trial for lymphoma. But in that study, the company saw an immune response to the ricin protein, which caused it to discontinue the program.

"We showed with the ricin ADC that there was potential to the TAP technology," Junius said. "But next, we had to find an agent lacking the immune response while maintaining the potency."

That drove ImmunoGen to switch from protein to small molecule toxins. The third iteration of TAP thus linked a targeting mAb to maytansinoid DM1, a bacterial toxin that disrupts the mitotic process in dividing cells. According to Junius, it is up to 1,000 times more potent than traditional chemotherapies.

Clinical trials also have confirmed the lack of an immune response.

Another problem the company had to solve was how to effectively release the toxin from the antibody.

"In the early days of the maytansinoid toxin, we realized that the toxin had to be released from the antibody to be effective," noted EVP of R&D and CSO John Lambert.

The earliest versions of TAP DM1 used a cleavable disulfide linker, SPP.

For lorvotuzumab (formerly huN901-DM1), one of the early molecules out of this program, Immunogen used DM1 linked via SPP to a CD56-targeting antibody.

While the company continued to look at additional linker technologies, it also was busy building partnerships on top of a 1999 deal with GlaxoSmithKline plc. It partnered the TAP technology in deals with sanofi-aventis Group; Boehringer Ingelheim GmbH; Genentech, now a unit of Roche; Millennium Pharmaceuticals Inc., now part of Takeda Pharmaceutical Co. Ltd.; and Centocor Inc., a unit of Johnson & Johnson.

As part of its partnership with Genentech, ImmunoGen tested a noncleavable thioether linker called SMCC.

The companies tested Genentech's trastuzumab using both SMCC and SPP attached to DM1. Genentech also tried Seattle Genetics Inc.'s ADC technology with trastuzumab.

The Seattle Genetics technology uses auristatin as the payload. Like maytansinoid, auristatin disrupts the mitotic process. And instead of using lysine as the linker, Seattle Genetics uses structural cysteines.

In animal models, SMCC performed best with trastuzumab.

Genentech spokesperson Krysta Pellegrino told BioCentury that Genentech decided to focus on T-DM1 based on its "promising early stage efficacy and safety profile."

This past October, Genentech and ImmunoGen announced positive results from the open-label, international Phase II TDM4450 trial in 137 treatment-naïve patients with HER2-positive metastatic breast cancer. Patients receiving 3.6 mg/kg IV T-DM1 every three weeks had an overall response rate of 48%, including 3 complete responses (CRs) and 29 partial responses (PRs), plus 22 cases of stable disease (SD).

The active-control arm consisting of...

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