Glycoengineered Antibodies Show Promise

The use of glycoengineered monoclonal antibodies to attack cancer seems promising, given some recent successes—including early results from a randomized phase III trial of one such antibody to treat patients with chronic lymphocytic leukemia (CLL).

In January, Genentech disclosed positive but unspecific results in progression-free survival in a trial examining treatment with obinutuzumab, a glycoengineered anti-CD20 antibody also known as GA101, plus chlorambucil. The 3-arm study is comparing that combination to the anti-CD20 antibody rituximab (Rituxan; Biogen IDEC and Genentech) plus chlorambucil, and to chlorambucil alone, in nearly 800 previously untreated people with CLL.

GA101 is said to be the first glycoengineered, type 2 anti-CD20 monoclonal antibody in human tests for B-cell malignancies. Nancy Valente, MD, vice president for global hematology development for Genentech, says the final results of the comparison of GA101 plus chlorambucil versus chlorambucil alone met the primary endpoint of improved progression-free survival. In addition, a progression-free survival futility analysis comparing the GA101-chlorambucil combination to the rituximab-chlorambucil combination concluded that those study arms should continue and, says Valente, is reason to be “cautiously optimistic” that GA101 could be superior to rituximab.

Physicians have long been interested in the sugars on the surface of cancer cells because they seem to play a critical role in the cells' ability to invade tissue and metastasize, says Jay Listinsky, MD, PhD, a pathology researcher at the University of Alabama at Birmingham. Glycoengineering, which alters protein-associated sugars in an attempt to boost the protein's pharmacokinetic properties, has been “kind of a Rodney Dangerfield of biological science” that is now gaining some respect, Listinsky says.

The glycoengineering of monoclonal antibodies involves generating antibodies with modified fragment crystallizable (Fc) regions so that fucose-containing glycans are markedly reduced or absent. With fucose out of the way, immune cells with FcγRIIIa receptors, including natural killer cells and macrophages, bind much more effectively to the antibody. That increases antibody-dependent cellular cytotoxicity—the elimination of cancer cells by immune system effector cells.

“Fucose, in general, seems to be part of interaction domains,” says Listinsky. “It is typically located at the ‘business ends' of biological carbohydrate molecules, doing something important.” But in the case of antibodies, he says, fucose is a barrier that keeps natural killer cells and other immune cells at bay.

At least 15 glycoengineered monoclonal antibodies are at some stage of development for treating cancer, according to a 2012 editorial in the journal mAbs. For example, the anti-CCR4 antibody mogamulizumab (Poteligeo; Kyowa Hakko Kirin) became the first glycoengineered monoclonal antibody to reach the market last year, after Japanese regulators approved it as a treatment for relapsed or refractory adult T-cell leukemia or lymphoma.

More recently, in December researchers at Roche Glycart reported in vitro and mouse xenograft results for GA201, a glycoengineered epidermal growth factor receptor (EGFR)-targeted monoclonal antibody. They say their findings suggest that GA201 might prove more effective than cetuximab (Erbitux; Bristol-Myers Squibb, Eli Lilly) in patients with EGFR-positive solid tumors and might become a first-in-class treatment for KRAS-mutated tumors.