Podcast: What’s the next frontier in the fight against cancer?
Listen in as leaders from our research and oncology divisions discuss the potential of antibody drug conjugates
September 22, 2021
Innovation is at the heart of our work, unlocking new scientific discoveries to invent better and more effective treatments for patients around the world.
One of the areas of research we’re particularly excited about is antibody drug conjugates, or ADCs — a means by which therapies may be delivered in a more targeted manner. ADCs are complex molecules composed of an anticancer agent joined to an antibody via a linker. The ADC is designed to carry the anticancer therapy to the site of a tumor where the linker allows the release of the therapy to kill the cancer cells, potentially reducing the risk for toxic side effects than with systemically administered chemotherapy.
In this podcast, Scott Lesley, head of discovery biologics for Merck Research Laboratories, chats with Vicki Goodman, vice president, therapeutic area head, oncology late-stage development, about how far the research community has come in developing ADCs — and where they can take us tomorrow in our mission to help save and improve lives.
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Merck ADCs Podcast
Scott Lesley: Hi, I’m Scott Lesley. I’m the head of discovery biologics for MRL, and I’m joined today by Vicki Goodman vice president clinical research, and we’re going to discuss a very exciting area of research, antibody drug conjugates, or ADCs for short.
Vicki Goodman: Thanks Scott. It’s great to be here. Do you want to give us a little bit of background on ADCs, what they are and what’s gotten us to this point in their research and development?
Scott Lesley: ADCs are a targeted form of chemotherapy. So on paper they’re actually very simple: It’s an antibody to a particular tumor antigen, typically, coupled to a small molecule payload through a linker.
Scott Lesley: ADC’s go back a very long time. They come from advances both in our understanding of how to target as well as advances in the platforms themselves. We have a growing understanding of both how we make those ADCs and what makes them, and that’s really what’s led to some of the recent successes in the field. We’re also finding that ADCs combine well with things like checkpoint inhibitors, and that’s also driving a lot of the success and the excitement around ADCs.
Vicki Goodman: The first ADC was approved back in 2000 and there were challenges with toxicity with that particular agent. And it was withdrawn from the market only to be re-introduced about a decade later. And what we’ve really seen is a significant increase in the number of ADCs that have been approved just over the last two years. So, I think that now roughly half of the ADCs that have ever been approved have been approved since 2019. Can you talk a little bit about what improvements in the technology have led to that? And in particular, what improvements have led to the ability to target solid tumors in addition to hematologic malignancies, which were the targets of some of the earlier ADCs that have led to the approval of more agents, more ADCs over just the last couple of years?
Scott Lesley: Yeah, well, I think the growth in the success for ADCs is in part a better understanding of what makes a good target. And that’s if you look at some of the earlier hematologic malignancies, there are some clear, very selective targets. Whereas with solid tumors, it’s a little bit more challenging, right? You have typically over-expression of a tumor antigen in the tumor, but there’s often a fair amount of normal tissue expression as well. And that’s an extra challenge when you talk about a targeted therapy where perhaps you’re delivering a very potent cytotoxic agent and you need to be able to selectively have that go to the tumor. And I think with some of the newer ADCs and the advancements there, there’s both an understanding of how to leverage the cytotoxic agents and the identification of a good solid tumor antigen has really been a large part of the success of the new ADCs.
Along with that is some advances in the linker technology. I mean, you don’t necessarily think of the linkers as being a really important part of the ADCs, but having that stability, and also then the release in the tumor microenvironment is really essential for creating what is essentially a targeted pro-drug.
Vicki Goodman: And for ADCs, you are using the antibody component essentially as a targeting mechanism to deliver a cytotoxic. And so that’s essentially putting something like zip code on it, right, that tells it the general direction of where to go. And then it binds in that area. And the molecule is internalized and that’s where the cytotoxic is released and then is able to do the damage. So, it’s really important not to have expression of that molecule, at least to a great extent, on normal tissues, right, or you have the potential there to damage those normal tissues. So, you need some level of difference of expression between the normal tissues and the tumor tissues in order to make sure that most of your ADC is going toward the tumor tissue and not toward your normal tissues where it can cause toxicities.
So, are there advances in terms of understanding the biology that have contributed to our understanding of what might be a good target for an ADC?
Scott Lesley: So, yes, I think in terms of identifying targets, I mean, there are a host of known tumor antigens that people have explored over the years. Things that make a good ADC target are things like the relative abundance versus normal tissue, like you mentioned. It’s also important that those tumor antigens are internalized relatively rapidly, right, because you typically want to bring payloads into the tumor cell. Often these targets are recycled back, and you can have essentially what is a pump to bring in antibody conjugate into the cell. There are thoughts that leveraging things like antigens that are in the tumor microenvironment themselves, not necessarily even on the tumor cells, could be affective ADCs. One of the principles that’s kind of played out here, especially for solid tumors, is the bystander effect. And the fact that once an ADC has bound to the target, the payload’s been released, that payload is available within the tumor microenvironment. So, you don’t necessarily have to target every tumor cell within the tumor.
Vicki Goodman: And that bystander effect that you mentioned where the payload is then once released from the ADC has an opportunity to go and damage other tumor cells in the area, that may be an important feature for an ADC, for example, where there’s differential expression of the target antigen on tumor cells. So, if it’s not uniformly expressed on all the tumor cells, you have an opportunity to damage those other tumor cells where there may be lower expression through the bystander effect.
Scott Lesley: Exactly. And these kinds of drugs are actually very complicated and finding sort of that sweet spot where you have the right level of expression, you have the right potency on your payload, you’re addressing the right biology through that payload, are all factors that combine. And then the antibodies themselves can be more than targeting agents, right? They can themselves, block receptor signaling. They may bring in complement. These are all factors that come into play when you’re designing a ADC.
Vicki Goodman: So, the ADC’s that have been approved to date are all approved as a single agent for treatment of various different both hematologic and solid tumors.
Scott Lesley: So, I think with ADCs what you really have is a targeted chemotherapy. And it’s clear that some payloads seem to work better than others, but it’s not just a single winner when it comes to payloads. There are multiple mechanisms out there. A lot of ADCs historically have used very potent cytotoxic agents, microtubular inhibitors, those sorts of things. And those agents, even when they’re released, again, either through bystander effect or just general chemotherapy can combine, well, I think with immunotherapy. Solid tumors have been challenging, and we’ve talked a little bit about the potential for novel tumor antigens and how those may play for solid tumors. From your perspective, is the recent ADC data encouraging for solid tumors?
Vicki Goodman: So, thanks Scott. I would say that, yes, it is. The early ADC approvals as we spoke about were all in hematologic malignancies. And just in the past few years, some of these have shown really remarkable activity in settings where other therapies have failed. And again, in patients who have disease that has been relapsed or refractory to other therapies. And so really seeing that these ADCs can offer quite a bit of benefit in those particular patients.
I think we’re in the early days in terms of thinking about combination therapies. I agree with you, I think the checkpoint inhibitor combinations are potentially very exciting and may move ADCs into earlier lines of therapy where patients are beginning to receive treatment in particular for disease that has spread outside of the primary tumor site. But I think that the advances that we’ve seen just in the last few years in terms of ADC is now really showing, demonstrating efficacy in a solid tumor setting is very encouraging. And certainly, we should expect to see more of that in the coming years.
Scott Lesley: Yeah, I agree. I think one of the opportunities with ADCs broadly is the full spectrum of payloads and payload types that you could apply. Do you see a particular payload class that you think really could be exploited beyond what we’re currently looking at in the field?
Vicki Goodman: Well, I would say that the current ADCs actually have a relatively small number of cytotoxic payloads that have been used. Most of them either targeting microtubules or causing DNA damage and through a limited number of mechanisms. And so not necessarily particularly one drug class of interest, but I would say that finding other mechanisms that don’t have cross-resistance with the existing mechanisms and thinking about relatively potent cytotoxics that, again, when you’re targeting them to the tumor cells you can spare normal tissue, I think are areas that certainly should be further explored. So, certainly there’s room for novel types of toxins that may, again, help improve the overall efficacy profile of these ADCs.
Maybe a question back to you. When you think about certain tumor types, and I’m just going to, for example, let’s say brain cancers, right, where antibodies may not be able to cross the blood-brain barrier and have an effect. Are there other mechanisms of targeting the chemotherapy in a way that might be more relevant for some of these other harder to reach tumor types?
Scott Lesley: So, there are. You can imagine almost any kind of delivery vehicle, right? So, there are examples I think of using things like peptides, peptide conjugates as a way to bind and deliver payloads. There are a number of different formats of antibodies that people are looking at for either more selective binding, or, like you say, being able to drive antibody exposure in tissues where they don’t normally get a lot of exposure. So, things like smaller antibody formats that have shorter half-lives are particularly interesting because as much as we want to sort of view antibodies as only binding to the tumor antigen, the reality is the majority of the antibody actually doesn’t end up binding to the tumor. It gets cleared by normal mechanism. And therefore you get exposure, whether it’s the liver or elsewhere to the payload.
And some of these smaller format antibodies or delivery vehicles have different half-lives, they have different clearance mechanisms, and therefore they have a different normal tissue exposure. And I think that’s actually a great opportunity for ADCs is looking at whether they’re, again, the small molecule formats or multi-specific dual targeting sort of approaches to drive a more selective binding of those antibodies.
There’s also the challenge of, particularly for solid tumors now, where if you have a tight-binding antibody, they may not actually make it deep into the cell, into the tumor. And there’s a lot of interest in exploring not only formats, but also affinities and multi-targeting as a way to drive exposure more deeply into the tumor.
Vicki Goodman: So, Scott, we’ve talked about a number of the opportunities with respect to ADCs, what do you see as the key challenges in terms of discovering and developing ADCs today?
Scott Lesley: Key challenges really kind of go back to what makes a good ADC, right? So, you need to have a good target. So, the challenge in many cases is finding that target that’s highly expressed, it’s internalized, it’s selective for the tumor. Having a good targeting agent, so if it’s an antibody, an antibody that is then specific for that tumor antigen has the right affinity, stability, epitope can actually be important, making sure that that antibody gets effectively internalized and then really matching up the linker payload properties to the therapy, right? So, having a stable linkage typically is what you’re going to want to have, understanding the importance of a bystander effect for whatever tumor type and how that factors into your payload design. I think these are all key factors for designing an effective ADC. Well, thanks, Vicki. It’s been great chatting with you today on ADCs. It’s been very informative.
Vicki Goodman: Thanks Scott. It’s been great speaking with you as well, and I’ve learned a lot from this conversation.