"We are getting a significant number of patients back into remission, and some of them go on to bone marrow transplants. There are some toxicities, but it's much better tolerated than chemotherapy."
"It's a game changer" for these patients, says Luskin, who is educational director of the Adult Leukemia Program at Dana-Farber. "We are getting a significant number of patients back into remission, and some of them
go on to bone marrow transplants. There are some toxicities, but it's much better tolerated than chemotherapy."
Blinatumomab is also approved for patients who are clinically in remission, but have microscopic evidence of residual disease, referred to as minimal residual disease. When used prior to stem cell transplant, the results seem superior to historical standards.
How Antibodies Work
The human immune system creates millions of different antibodies, Y-shaped proteins, each of which is fine-tuned to latch onto one distinctive antigen — a molecule on the surface of a microbe or infected cell or cancer cell — even an antigen the immune
system hasn't encountered previously. Antibodies float through the body keeping a lookout for a unique antigen on the surface of a foreign cell. When an antibody binds to the antigen of a foreign or dangerous cell, it kills the cell or flags it for
destruction by the immune system.
Antibodies are Y-shaped molecules with highly specific binding sites on their tips that recognize a unique antigen, or identifying molecule, on a target cell. Each monoclonal antibody can only recognize one cellular antigen, but a bispecific antibody
can recognize two different cellular antigens.
Monoclonal antibodies made in the laboratory were first created in 1975 and have been used for more than two decades to treat cancer and other diseases. In 1980, a team headed by Dana-Farber's Lee Nadler, MD,
now senior vice-president for experimental medicine, administered the first monoclonal antibody to a human patient with lymphoma. It didn't cure the patient, but showed that treatment with a laboratory-manufactured antibody directed against a lymphoma-associated
antigen was safe and could decrease the amount of antigen in the patient's blood.
This same monoclonal antibody from the Nadler lab led to the discovery of the CD20 antigen, which is abundantly expressed on cancerous B cells in non-Hodgkin lymphoma. The CD20 antigen became the first target for monoclonal
antibody therapy, and in 1997 the anti-CD20 monoclonal antibody rituximab (Rituxan) was the first such antibody to be approved for the treatment of cancer.
Among the many that have subsequently been approved for cancer are: trastuzumab (Herceptin), used to treat HER2-positive metastatic breast cancer; bevacizumab (Avastin), used in treating colorectal cancer,
glioblastoma, and ovarian cancer; and cetuximab (Erbitux), for colorectal and head and neck cancer. Recently, monoclonal antibodies have opened a new era in immunotherapy by targeting and disabling molecular checkpoints that keep the immune system
from responding to cancer cells. Among these revolutionary new antibodies are pembrolizumab (Keytruda) and nivolumab (Opdivo).
Advantages of Bispecific Antibodies
However, despite having two arms with tips that recognize antigens, these monoclonal antibodies can only engage with one type of antigen. A bispecific antibody (BsAb), by contrast, can recognize and bind to two antigens at one time. These may be antigens
on two different cells or two different antigens on the same cell. This opens up a new avenue of therapeutic possibilities; many are in clinical testing, but some have begun to reach the clinic.
Blinatumomab, for example, is an antibody called a bispecific T-cell engager (BiTE) that can use one arm to bind to an antigen on a cancerous B cell, while the other arm latches onto an antigen on an immune T cell. By bridging these two cells, blinatumomab
activates the T cell to attack and destroy the harmful tumor cell.
"With bispecific antibodies, you're bringing the patient's T cells to the game," says Daniel DeAngelo, MD, PhD, chief of the Division of Leukemia at Dana-Farber. "These T-cell engagers bring the patient's
immune cells to target the relapsed cells. The advantages are that you can administer it whenever you want, and you can always turn it off if there is toxicity."