Monoclonal antibodies

Unlocking the potential of monoclonal antibodies

An experimental Alzheimer’s drug hailed as a breakthrough has slowed cognitive decline in people with the disease at an early stage, according to a new study published in the New England Journal of Medicine. The drug, lecanemab, is a monoclonal antibody – or mAb for short – designed to eliminate amyloid plaques in the brain that many believe cause Alzheimer’s disease.

“This is the first time we’ve been able to prove that we can slow the progression of Alzheimer’s disease,” said Paul Aisen, director of the Alzheimer’s Therapeutics Research Institute at Keck School of Medicine. USC and co-author of the study. . “It is 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 focus on prostate cancer cells to show where the disease has spread.

But what exactly are monoclonal antibodies and how do they work? To learn more, USC News spoke with Aisen and Paula Cannon, professor emeritus in the Department of Molecular Microbiology and Immunology at the Keck School.

Dr. Cannon, can you start by explaining how we make our own antibodies?

CANNON: Antibodies are one of the many weapons our immune system has at its disposal, made by a type of white blood cells we have in our bodies called B cells. The cool thing about antibodies is that it’s these little molecules Y-shaped, and the tips of the Y in each antibody have a slightly different and unique shape.

Our body makes about 50 trillion different antibodies, and all of these different forms are displayed on their own host B cell. When you are infected with a virus or bacteria, the very rare antibody that happens to have the correct shape on the tips of its Y binds to the virus when it touches it.

The antibody is initially on the outside of the B cell, and this contact with the invader triggers the B cell. It begins to grow and divide and make piles and piles of B cells and they spit out all now these specific antibodies in the blood, to fetch more of their target.

Monoclonal antibodies are lab-made versions of that, right?

CANNON: It’s true. When we talk about monoclonal antibodies, it’s just an unnecessarily long way of saying an antibody with a unique or “mono” shape. You give people antibodies they haven’t made yet, by running a race in the wild. COVID is a prime example. Antibodies against COVID bind to the spike protein of the virus, preventing it from infecting healthy cells.

Monoclonal antibodies — the artificial version — are good for older people who are sicker, immunocompromised and don’t respond well to the vaccine or make 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 to the surface of, say, a cancer cell. And remember, antibodies are Y-shaped. The spikes latch onto the cancer cell, but the tail also does some work – it can signal other components of the immune system to engulf or kill those cancer cells.

Dr. Aisen, what is the mechanism behind monoclonal antibodies for Alzheimer’s disease? How it works ?

AISIN: There are many different antibodies being developed for Alzheimer’s disease. The common feature of antibodies that clear amyloid plaques is that they bind tightly to amyloid plaques in the brain in a way that allows microglial cells – which are the brain’s waste collectors – to chew up the plaques.

Normally, plaques are resistant to microglial clearance, but antibody binding facilitates microglial binding and plaque digestion. Evidence suggests that amyloid fragments exit through the microvasculature, tiny blood vessels in the brain, in a process that can damage vessel walls. This is why, in our opinion, these antibody treatments can cause side effects such as tiny hemorrhages and swollen areas of the brain.

What’s next for mAbs as a treatment for Alzheimer’s disease?

AISIN: We think the profit will be bigger if we trade earlier. Amyloid accumulates for 10 to 15 years before symptoms appear. We should remove the amyloid before the onset of symptoms, that is, while brain function is still fairly normal.

In Alzheimer’s disease, different forms of amyloid accumulate in the brain, including monomers, small aggregates called oligomers, protofibrils, fibrils, and plaques. Some people think it’s the smaller forms of amyloid that do more damage than the plaques themselves. This is still a subject of debate.

There is an antibody that only binds to monomers, which are 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 we hope that at an early stage it will be effective.

More stories on: Alzheimer’s disease, Cancer, Medicine, Research

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