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Second generation monoclonal antibody provides benefit for patients with follicular lymphoma

A second generation, highly targeted monoclonal antibody appears to provide benefit for some patients with follicular lymphoma for whom other treatments have failed, according to results of a phase I clinical trial.

In the 16 patients evaluated so far, four have achieved either a partial or complete response with use of the novel agent AME-133v, said the study’s lead investigator, Andres Forero, M.D., associate scientist at the University of Alabama, Birmingham, Comprehensive Cancer Center.

“These first results suggest that AME-133v provides a mechanism of action that may be more potent and ultimately more effective than the treatments we have on hand for a subset of patients with this cancer,” Forero said. “Given these encouraging results, patients are currently being enrolled in a phase II study.”

The majority of patients in this study either did not initially respond or relapsed after use of Rituximab, the first monoclonal antibody therapy approved for use in lymphoma treatment. AME-133v is a second-generation therapy that is believed to be a more specific treatment for follicular lymphoma in general, compared to Rituximab, but is also thought to offer particular benefits for those patients who have a variant in the immune cells needed to attack the cancer, Forero says.

“Monoclonal antibodies were the first successful targeted therapy for cancer, and we have now moved on to a whole new class of second generation antibodies for the treatment of many different lymphomas,” Forero said. “This is an exciting time.”

Follicular lymphoma is a particularly difficult to treat subtype of non-Hodgkin lymphoma, which is a cancer that arises from white blood immune cells known as lymphocytes. Rituximab binds to CD20, a cell surface antigen expressed on almost all B-cell lymphomas as well as on normal B cells, and works to kill the cancer cell via a mechanism that is not yet understood.

Although treatment with Rituximab as a single agent has resulted in significant responses in patients with almost every subtype of B-cell lymphoma, including follicular lymphoma, recent evidence has shown that some patients with effector immune cells that carry a mutation in the receptor protein Fc?RIIIa 158-F do not have the same response, Forero says. This is an issue that is related to the patient’s own biological makeup, not to the cancer cells themselves, he adds. There are three different classes of Fc? receptors to which the monoclonal antibody binds on leukocyte effector cells – T helper cells -- that direct other immune cells to the antigen. Response to Rituximab depends on variants in the receptors these helper cells use.

AME-133v is an anti-CD20 antibody engineered to bind more strongly to these variant receptors. In preclinical studies, it demonstrated a 10-fold improved killing power of human B cells, compared with Rituximab, researchers report.

Of the 22 patients treated with AME-133v in this study, 20 had been treated with Rituximab and 18 also had chemotherapy. All were Fc?RIIIa 158-F carriers. This was a dose escalation study, and researchers report that the agent was well tolerated at all doses – 90 percent of patients experienced only grade I adverse events.

“AME-133v appears to be capable of binding with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity,” Forero said.

Source: American Association for Cancer Research, 2008