ADC Technology and Mechanism of Action

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Edward S. Kim, MD, MBA: Good afternoon, everyone. I’m really pleased that you could join us for this OncLive® seminar titled “On the Horizon in NSCLC: Antibody-Drug Conjugates.” We’re excited that you’re able to join us. Hopefully, we’ll be able to share some knowledge regarding this interesting area of therapeutics. I’m Ed Kim. I’m at City of Hope [in Newport Beach, California], where I serve as a physician-in-chief at City of Hope in Orange County and vice physician-in-chief for the [National Medical Center]. I’m joined by my good friend and an old colleague, Dr Alexander Spira. He’s the codirector of the VCS [Virginia Cancer Specialists] Research Institute and the director of the thoracic and phase 1 program. He is a clinical assistant professor at Johns Hopkins [University School of Medicine in Baltimore, Maryland] and also a very experienced lung medical oncologist. Welcome, Alex. It’s great to be with you.

Alexander Spira, MD, PhD, FACP: Thanks for having me. Good to see everybody.

Edward S. Kim, MD, MBA: Let’s jump right in. We know multiple things happening in lung cancer. We’re going to take an in-depth look at what these antibody-drug conjugate [ADC] technologies are and why they’re so impactful in the treatment of non–small cell lung cancer. We’ll also review the strategies for managing the adverse events that can occur. Feel free, at any time, to ask questions. We’ll get to them as we go along. Let’s begin the program.

First, what’s an antibody-drug conjugate? There are 3 components: an antibody, which is the drug delivery portion; the linker, which connects the antibody to the payload; and the drug or the payload that destroys the tumor cells. You want these antibody portions to have a high affinity for their target. That way, you can get the binding done. Of course, delivering this drug or payload is an effective way to kill cancer cells.

When we look at the overall mechanism of action of an ADC, you can see that you start with binding to the cell surface. You want that high affinity and avidity. You get endocytosis of the ADC, which leads to lysosomal degradation. You get cleavage of this payload and release of it, which causes DNA or microtubule damage. That leads to a programmed cell death. You can also get this bystander effect as you have seepage into other nearby environmental areas that could kill other cells with the effect that occurs within the cell. We see that bystander effect occurring with neighboring cells in the vicinity.

There have been a lot of key milestones in ADC clinical development. Everyone talked about the magic bullet concept [in the early 1900s]. That was very different from what we’re seeing with some of the targeted agents or precision medicine, but they’re a variation of it. In the 1980s we had first ADC human clinical trials using an anti–CEA [carcinoembryonic antigen] antibody, a vindesine conjugate. Then there was the first approval of a monoclonal antibody preventing the rejection of kidney transplants. Gemtuzumab ozogamicin for recurrent refractory AML [acute myeloid leukemia]was approved in 2000. We’ve seen additional approvals in 2013 and 2019 of drugs with trastuzumab-based, HER2 [human epidermal growth factor receptor 2]–based ADCs with emtansine, deruxtecan, and brentuximab vedotin. There’s a lot of acceleration, as you can see. In 2022, we have 12 approved ADCs for cancer. The technology, as well as the specificity of how we’ve been developing these with the minimization of adverse effects, has led to a lot of different approvals.

Here’s the list of FDA-approved ADCs. It’s an expansive list. I’m not going to go through each 1, but they should look familiar. You can see where their target is and the diseases with these HER2 or hematology-related malignancies. We’re seeing more of them expand, especially in areas like solid tumors that are outside breast cancer. We’re hopeful that that can continue.

First polling question is, do you have experience with ADCs in your clinical practice? Please answer yes or no. I don’t think we have any Jeopardy music on this.

Alexander Spira, MD, PhD, FACP: You can sing.

Edward S. Kim, MD, MBA: We don’t want to disengage the audience this quickly. I’ll have my daughter sing. She’s a good singer. Let’s see what we’ve got, and what the results are. We’ll send them out so everyone can see them. You can see here that the majority of folks have experience, but we still have a high number of folks who do not. It’s a no that we have some experience there.

Transcript edited for clarity.