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How Do FDA-Approved Antibody-Drug Conjugates Work for DLBCL?

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Published on May 10, 2021

Expert Explains Antibody-Drug Conjugate Treatment for DLBCL

The FDA has approved the drug polatuzumab vedotin-piiq (Polivy) in combination with bendamustine and rituximab (Rituxan) for the treatment of diffuse large B-cell lymphoma (DLBCL) in individuals with at least two prior lines of therapy. This is one of many new antibody-drug conjugates (ADCs) approved for treating DLBCL. Follow along as Dr. Peter Martin, MD, Chief of the Lymphoma Program at Weill Cornell Medicine, explains exactly how this type of treatment works. Dr. Martin also discusses the potential side effects and strategies for managing them.

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Transcript | How Do FDA-Approved Antibody-Drug Conjugates Work for DLBCL?

What Are the FDA-Approved Antibody-Drug Conjugates for DLBCL?

Dr. Martin: The drug polatuzumab vedotin (Polivy) was approved fairly recently in combination with bendamustine (Bendeka) and rituximab (Rituxan) for treatment of diffuse large B-cell lymphoma after at least two prior lines of therapy. The concept of polatuzumab vedotin, or indeed all antibody-drug conjugates, is not new. In another lymphoma called Hodgkin lymphoma we've had the drug brentuximab vedotin (Adcetris) approved for a long time. The idea is that there is a monoclonal antibody—in this case polatuzumab. Polatuzumab binds to a protein called CD79B on the surface of lymphoma cells, and that polatuzumab antibody is linked by a special protein called the linker protein, creatively, to a toxin called vedotin which is essentially a sophisticated form of chemotherapy.

How Do Antibody-Drug Conjugates Work to Treat Diffuse Large B-Cell Lymphoma?

When the polatuzumab vedotin is bound to the lymphoma cell it gets internalized, and inside the lymphoma cell there are chemical changes that digest the linker protein. The vedotin toxin, also called monomethyl auristatin, dissolves into the cytoplasm of the cell, where it interacts with microtubules, which are used essentially to split the cell or used to direct the cell as it divides from one into two.

So in other words, the polatuzumab vedotin prevents the cell from being able to divide from one into two cells, among other things. It's a very sophisticated way of delivering a highly toxic chemotherapy drug to the inside of a cell that is trying to divide from one into two. And it is a remarkably effective drug, and I think I've said this many times, any option we have for the treatment of lymphoma is always going to improve our ability to take care of people.

What Are the Side Effects of This Type of Treatment?

It's not without side effects, although it is targeted very specifically to the lymphoma cells. We do see that some other cells are impacted by the vedotin toxin. In particular, we see what we call myelosuppression or reduction in other blood cell counts, including platelets and neutrophils, most significantly. This is compounded when it's given in combination with bendamustine and rituximab. We also see what's called neuropathy, which essentially results in numbness and tingling in the fingers and toes.

Both of those side effects are reversible, and so we learn to try to deal with the good and the bad of each medication. I mentioned that it's great to have new drugs available and there are indeed multiple treatments that are available in the same space. We also have the combination of lenalidomide (Revlimid) plus an anti-CD19 antibody, tafasitamab (Monjuvi). We also have an oral medication called selinexor (Xpovio), which inhibits a protein called XPO1 inside cancer cells. And then there are also CAR T-cells as well. There are a lot of other promising targets and drugs that are targeting those targets. And we're going to see new drugs approved in the near future, probably most immediately the bi-specific antibodies that target the lymphoma cells plus other immune system cells like T-cells. So, lots of room to grow in diffuse large B-cell lymphoma and lots of expected exciting developments in the near future.

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