New Partners to Develop Immune Engagers

In a deal that could be worth up to $5 billion, Genentech and the German biotech firm Affimed will partner to drive development of T-cell and natural killer (NK) cell engagers. These immunotherapies, which spur immune cells to kill cancer cells, are under study for a variety of cancers, but so far only one has received FDA approval.

Although patients can produce T cells that recognize antigens on their cancer, these cells are usually rare. Immune-cell engagers can overcome the lack of antigen-specific cells: They are composed of two or more linked antibody fragments that bridge immune cells and cancer cells—and stimulate the immune cells' cytotoxic activity. For example, the engager blinatumomab (Blincyto; Amgen) consists of an antibody fragment that binds the CD3 receptor on T cells, and a fragment that attaches to the CD19 protein on malignant B cells, making more immune cells able to attack tumor cells. “It solves the numbers problem,” says Charles Sentman, PhD, of the Dartmouth Geisel School of Medicine in Lebanon, NH, who isn't connected to the deal.

More than 20 engagers designed for T cells or NK cells are in development, but blinatumomab is the only one approved in the United States. The FDA gave it accelerated approval in 2014 for Philadelphia chromosome–negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Last year, the agency granted final approval for the drug and expanded its use to patients with Philadelphia chromosome–positive disease. That decision was based on the phase III TOWER trial, in which median overall survival for patients who received blinatumomab was 7.7 months, versus 4 months for those treated with standard chemotherapy.

The deal between Affimed and Genentech is intended to speed new drugs to the clinic. Affimed will contribute its expertise in creating T-cell and NK-cell engagers—two of its engagers are in clinical trials. Genentech will contribute financing and oversee clinical development and commercialization.

T-cell engagers have a head start, but using NK-cell engagers to fight cancer makes sense, says Daniel Vallera, PhD, of the University of Minnesota Masonic Cancer Center in Minneapolis, because NK cells “evolved basically to kill tumors.” The T-cell engagers under development link to CD3 and target a variety of antigens and cancer types. The first of Affimed's NK-cell engagers to reach clinical trials, AFM13, instead binds to CD30 on cancer cells and stimulates CD16, the activating receptors on NK cells. The trials are testing the drug against Hodgkin and CD30-positive lymphomas.

Vallera, who is not involved with Affimed, and his colleagues have designed a slightly different NK-cell engager. It binds to CD16 and targets CD33. To boost the drug's anticancer effect, the researchers also added IL15, which activates NK cells and prompts them to divide. The researchers have requested go-ahead from the FDA to begin a phase I trial of the drug in patients with acute myeloid leukemia.

The clinical promise of engagers is “very exciting,” but where the drugs would fit into patients' treatment plans remains unclear, says Sentman. Whether they will be more effective alone or in combination with other drugs, such as checkpoint inhibitors, is unknown. However, one of Affimed's NK-cell engager trials is testing AFM13 with the PD-1 inhibitor pembrolizumab (Keytruda; Merck). “The potential is there, if we can learn how best to use them,” he says. –Mitch Leslie

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