Unlocking the potential of monoclonal antibodies
Lab-made antibodies are increasingly important in the fight against Alzheimers, COVID and other diseases
An experimental Alzheimers drug, hailed as a breakthrough, slowed cognition decline in people with early-stage disease, according to a new study in the New England Journal of Medicine. The drug, lecanemab, is a monoclonal antibody or mAb for short designed to clear amyloid plaques in the brain that many think are a root cause of Alzheimers disease.
This is the first time weve been able to prove that we can slow the progression of Alzheimers, said Paul Aisen, director of the Alzheimers Therapeutic Research Institute at the Keck School of Medicine of USC and a co-author on the study. Its now clear that removing amyloid can slow disease progression.
Monoclonal antibodies are an increasingly important tool in our arsenal to fight disease. FDA-approved monoclonal antibodies treat COVID-19, certain types of cancer and even asthma. When combined with radioactive particles, mAbs can home in on prostate cancer cells to show where the disease has spread.
But what are monoclonal antibodies exactly and how do they work? To learn more, USC News sat down with Aisen and Paula Cannon, a Distinguished Professor in the department of molecular microbiology and immunology at the Keck School.
Dr. Cannon, can you begin by explaining how we make our own antibodies?
CANNON: Antibodies are one of the many weapons our immune system has, made by a type of white blood cell we have whizzing around in our body called B cells. The cool thing about antibodies is they are these little Y-shaped molecules, and the tips of the Y in every antibody have a slightly different, unique shape.
Our bodies make an estimated 50 trillion different antibodies, and all these different shapes are displayed on their own host B cell. When you get infected by a virus or a bacterium, the very rare antibody that happens to have the right shape on the tips of its Y binds to the virus when it touches it.
The antibody initially sits on the outside of the B cell, and this contact with the invader triggers the B cell. It starts to grow and divide and make lots and lots of B cells and theyre all now spewing out these specific antibodies into the blood, to go hunt for more of their target.
Monoclonal antibodies are laboratory-made versions of that, correct?
CANNON: Thats right. When we talk about monoclonal antibodies, its just an unnecessarily long-winded way of saying an antibody with a single or mono shape. Youre giving people antibodies they havent already made, doing an end run around nature. COVID is a great example. Antibodies against COVID bind to the viruss spike protein, preventing it from infecting healthy cells.
Monoclonal antibodies the manmade version are good for people who are older, sicker, immune deficient and arent having a good response to the vaccine or making their own antibodies.
In addition to blocking or neutralizing a virus, antibodies both natural and lab-made work in other ways, right?
CANNON: Another thing that antibodies can do is stick onto the surface of, say, a cancer cell. And remember, antibodies are Y-shaped. The tips dock onto the cancer cell but the tail also does some work it can beckon over other components of the immune system to engulf or kill those cancer cells.
Dr. Aisen, what is the mechanism behind monoclonal antibodies for Alzheimers? How do those work?
AISEN: There are many different antibodies being developed for Alzheimers. The common feature of antibodies that remove amyloid plaques is they bind tightly to amyloid plaques in the brain in a way that enables microglial cells which are the brains waste collectors to chew up plaques.
Normally, plaques are resistant to microglial clearance, but the binding of the antibodies facilitates microglial binding and digestion of plaques. Evidence suggests the amyloid fragments are leaving through the microvasculature, tiny blood vessels in the brain, in a process that can damage vessel walls. Thats the reason, we think, that these antibody treatments can cause adverse effects such as tiny hemorrhages and areas of brain swelling.
Whats the next step for mAbs as an Alzheimers treatment?
AISEN: We think the benefit will be greater if we treat earlier. Amyloid accumulates for 10 to 15 years before the onset of symptoms. We should remove the amyloid before symptoms start, that is, while brain function is still pretty normal.
In Alzheimers, different forms of amyloid accumulate in the brain, including monomers, small aggregates called oligomers, protofibrils, fibrils and plaques. Some people believe its the smaller forms of amyloid that do more damage than the plaques themselves. Thats still a matter of debate.
There is one antibody that only binds to monomers, which are single, tiny pieces of amyloid. This antibody is called solanezumab. Since it has a limited effect on plaques, it does not cause microhemorrhages or brain swelling. And our hope is that at an early stage this will be effective.