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Igenica Follows Genentech Into Antibody-Linked Cancer Drugs

Squint a little, and it’s easy to see the first five years of Burlingame, CA-based Igenica Biotherapeutics as a speeded-up version of the evolution of biotech pioneer Genentech.

Igenica’s leadership ranks are studded with Genentech alumni, including its board chair David Goeddel, a pioneer in gene expression research who was the first scientist Genentech hired. Igenica has just started its first clinical trial on an anti-cancer antibody—-following in the footsteps of Genentech, which developed groundbreaking antibody drugs such as Rituxan, a blockbuster treatment for the blood cancer non-Hodgkin’s lymphoma approved in 1997.

Igenica’s first clinical stage drug, IGN523, is an experimental remedy for acute myeloid leukemia (AML), another cancer that affects white blood cells.

“If we’re wildly successful, IGN523 has the potential to be the Rituxan of AML,” says Igenica CEO Mary Haak-Frendscho.

While Haak-Frendscho is shepherding development of the antibodies like IGN523 that Igenica was founded to develop in 2009, she is also managing the company’s “pivot” to antibody-drug conjugates. These are the double-threat anti-cancer drugs that South San Francisco,CA-based Genentech, now a member of the Roche group, was one of the first to market.

Antibody-drug conjugates have two parts: an antibody that selectively binds to cancer cells, and a toxic drug that can kill those cells. The FDA approved Genentech/Roche/Immunogen’s antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) for patients with HER2-positive, late-stage breast cancer in early 2013.

This year, Igenica plans to choose two of its own antibody-drug conjugates to prepare for clinical trials. Haak-Frendscho sees no latecomer’s disadvantage for Igenica in the hot space. Asked how she sells new investors on the company, she casts Igenica like an observant younger child who watched the older kids crash through the barriers first.

“We let the pioneers spend decades beating the path, and we learned the lessons from them,” Haak-Frendscho says. “We’re not wedded to old technologies.”

One of Igenica’s biggest competitors, however, could be Genentech/Roche, which has a stable of new antibody-drug conjugates already in clinical trials.

Igenica’s bid to produce next-generation antibody-drug conjugates is grounded in the do-it-yourself credo it established from its beginnings as a pure-play developer of “naked antibodies”—those not connected to a toxin. As a first step, the company devised its own method to discover novel molecular targets for drugs. The discovery platform, called sTAg, identified a cell surface protein, CD98, that appears at increased levels on the fast-growing abnormal cells seen in acute myeloid leukemia. CD98, which is also found on other types of cancer cells, helps tumor cells absorb lots of amino acids to feed their rapid growth.

Igenica used its own antibody discovery platform, iTAb, to produce IGN523, which blocks CD98’s ability to serve as an amino acid portal into the cell. As it turns out, crippling CD98 also tips the cancer cell toward apoptosis—a programmed process of cell death—and makes the cell more vulnerable to destruction by the natural killer cells of the immune system, Haak-Frendscho says.

About 90 percent of acute myeloid leukemia cells bear high levels of the CD98 protein, she says. “Most patients have the potential to benefit,” Haak-Frendscho says. “We’re not just addressing a small sub-population here.”

Big pharmaceutical companies including Boehringer Ingelheim and Novartis are also testing drug candidates for acute myeloid leukemia that could some day compete with IGN523.

The first trial participant was dosed with IGN523 in March, under a Phase I trial design developed in discussions with the FDA by Igenica’s vice president of clinical development William Ho. He joined the company in 2012 after leading clinical programs for antibodies and antibody-drug conjugates at Genentech. Although the 33-participant trial is geared toward assessing the safety of varied doses of IGN523, it will also give Igenica a peek at its possible efficacy, and may encourage the company to tackle another cancer type, Haak-Frendscho says.

“Success there would drive us into lung cancer,” she says. Specifically the company would like to test IGN523 against squamous cell carcinoma, a common type of non-small cell lung cancer.

But when Igenica chooses a second clinical stage program, its newer antibody-drug conjugate candidates might leapfrog ahead of IGN523 in lung cancer. The company started building an antibody-drug conjugate research unit about three years ago, when then-CEO Mike Rothe hired some chemists from Genentech who had worked on ado-trastuzumab emtansine.

However, Igenica decided to invent its own technology to link targeted antibodies to payloads of toxic drug molecules, rather than striking a deal as Genentech did to license “linker” compounds from another company. Genentech has made a series of deals Immunogen (NASDAQ: IMGN) and Seattle Genetics (NASDAQ: SGEN), both pioneers of linker development and antibody-drug conjugates. Seattle Genetics marketed the first successful conjugate, brentuximab vedotin (Adcetris), which was approved in 2011 to treat two types of lymphoma, Hodgkin’s disease and anaplastic large-cell lymphoma.

Haak-Frendscho, who was appointed Igenica’s CEO in September of 2012, says the company wanted a full suite of technology platforms so it wouldn’t have to work around the intellectual property rights of other companies when designing products and setting strategies. The company’s proprietary linker compounds are part of its antibody-drug conjugate platform called SNAP, which can make use of antibodies developed with Igenica’s sTAg and iTAb discovery systems.

“Now we have this kind of trifecta of enablement,” Haak-Frendscho says.

The key goal for many developers of next-generation antibody-drug conjugates is to make a more uniform product than the initial drugs in this class. In the earlier drugs, it was hard to control the number of toxins connected to each antibody.

“Some have none, and some have, quite frankly, too many,” Haak-Frendscho says. This can reduce the effectiveness of the drug.

An antibody crowded with too many toxins may be unable to fit into the binding site on the cancer cell. An antibody with no connected toxins takes up a binding site on the cancer cell, edging out other antibodies that could have delivered the toxic payload.

Drug developers have tried a range of new methods to insure pinpoint placement of a set number of toxins on antibodies. Igenica’s fellow Bay area company, South San Francisco-based Sutro Biopharma, has re-engineered its antibodies to contain specific spots where toxins can be linked. These spots are created by incorporating non-natural amino acids into the antibodies.

Igenica has created its antibody-drug linkages through chemistry rather than genetic engineering, Haak-Frendscho says. The company has developed a bifunctional linker like a two-pronged fork. Each prong forms a bond with a specific amino acid on the antibody, creating a chemical bridge to which a toxin can be attached.

Igenica has raised $70 million since its inception. Its latest fundraising round was a $14 million extension in January of a $33 million Series C round initiated in 2012. That round was led by new investor Third Rock Ventures with participation by prior investors 5AM Ventures, OrbiMed, and The Column Group. The new money raised in January will help support Igenica’s operations through early next year, Haak-Frendscho says.

Most of Igenica’s 42 employees are research scientists. The company also works with contractors and “a constellation of consultants,” Haak-Frendscho says. Before considering any moves to go public, Igenica will try to put a number of drug candidates in play, she says.

The company is actively looking for partners to license its technology or to form a broad R&D collaboration to discover new drug targets and develop antibodies and antibody-drug conjugates for specific disease areas, says Igenica’s chief business officer John Celebi.

“We expect a deal in one of these areas this year,” Celebi says “We’ve got multiple irons in the fire.”