Development on Novel Therapeutic Antibodies for Cancer Derived from Single Human B Cells
Christina Lingham:
Hi everyone. I'm Christina Lingham from the PEGS Boston Summit. I'm really pleased to have the opportunity to speak with Dr. Edward Patz of Duke University Medical Center to talk with us about development of novel therapeutic antibodies for cancer derived from single human B cells. He will be giving a talk at the Antibodies for Cancer Therapy Track this May 1st and 2nd in Boston, Massachusetts. Ned, thank you for joining us.
Edward Patz:
Thank you very much for having me.
Christina Lingham:
Can you outline what you consider to be some of the greatest obstacles to developing novel antibodies from single human B cells?
Edward Patz:
I believe that the greatest obstacle for developing novel antibodies from this type of approach is really to identify the appropriate targets. That has really been the problem with doing this sort of approach, that it's not clear what the appropriate targets are. Once we identify those targets from a procedure and method strategy, we've worked out the techniques for analyzing, and identifying, and sorting out the single B cells. But it's really understanding which B cells that we should encounter and which B cells we really need to isolate, and these very specific targets, which these B cells will attack. Actually the B cells in the antibodies that the B cells make, which they will have functional consequences and potentially hold the tumors in check.
Christina Lingham:
Can you describe your method and how you recognized a novel and unexpected target in lung cancer?
Edward Patz:
The method is an unusual strategy beginning with the understanding that there are some patients who have cancer, often detected for other reasons, not because they're symptomatic, who have what we consider to be exceptional outcomes. Understanding that probably in many different types of tumors, there are such patients that exist.
We know this well in prostate cancer. We see many patients die with the disease rather than from the disease. We know in breast cancer, and particularly with DCIS, some of those tumors will never actually progress. Even in lung cancer, which is thought to be unusual, but we did find that in some of the screening trials that almost 20% of the lung cancers we estimate that were detected, probably were considered over-diagnosed. If they'd never been in the screening trial, we never looked, we never would've found them, and they would've died from some other cause and with their disease, rather than from their disease.
I think the approach we took was a unique approach, looking at these, what we consider exceptional outcomes individuals. We identify them, and then what we did was we tried to understand potentially what sort of immune mechanisms that they are using to hold their tumors in check to never really have what we consider clinically significant malignancy. That, first of all, was one of the important pieces of this, so we identified a certain cohort of patients who did exceptionally well. From that then, we probed these patients' serum looking for antibodies that were common to those who did exceptionally well versus those who had more aggressive disease, who eventually developed metastasis and died from the disease.
We didn't really know, since nobody's ever really done this before with antibodies, we didn't really know what to expect. We let the body basically tell us. We took leads and cues from the native immune response to tell us what the appropriate targets were, rather than often a more traditional approach, which is to understand mechanistic pathways by which tumor cells are disregulated. We let the body, the cues from the native immune response, tell us and direct us to the appropriate targets.
I'm not sure that we really know that they were unexpected. We just had no idea in any way what to expect when looking at the immune response in patients with cancer, which I think in many ways, we understand sort of the cellular response oftentimes when we see a patient with cancer. We really don't understand very well how the immune response keeps cancers in check and how the immune response develops when you have this slowly progressive tumor, which requires mutations over many years. We didn't know what to expect from this. We let the body again lead us and provide us with cues into what the appropriate targets were that potentially could be serviced, therapeutic targets for these patients with cancer.
Christina Lingham:
What is the current status of the first novel antibody you developed? And is this going into clinical trials?
Edward Patz:
That's right. The first antibody is a proof of principle, so we can really demonstrate that this sort of strategy, this sort of approach, and this whole paradigm and platform, which we have developed, will be useful. The first antibody, we made a recombinant completely human derived antibody from that, and we now know how to mass produce it.
We have finally begun manufacturing and have the resources necessary to manufacture it, and we are looking to go ahead. We are going to manufacture the antibody. They're looking to be in clinical trials, hopefully within about 18 months from now. We are further developing it. We're doing all our pre-clinical studies. We've designed a phase one trial in solid tumors, and we hope to be in clinical trials within about 18 months.
Christina Lingham:
What advice do you have for people introducing novel antibody therapeutics in the clinical setting?
Edward Patz:
I'm going to be somewhat provocative and say that if you're really trying to introduce a novel antibody, be prepared for very hard work and a lot of fight. Unfortunately, developing of novel drugs is enormously resource intensive, requires a lot of time and effort, and is very difficult to actually try a new paradigm and a novel target, novel mechanism, and novel antibody, that most investors, most drug companies, even most granting agencies, are risk adverse.
This is high risk, but potentially high gain, because we felt that we did not want to just develop the next type of targeted therapy. We didn't want another drug very similar in class to other drugs, which is, when you look at most portfolios of the vast majority of bio-techs and even pharmaceuticals are doing right now, and that we wanted to take a completely novel strategy. But to do that requires resources, and it's very difficult to actually generate enough interest in that until you've proved it.
It's a very difficult process trying to convince other individuals that this is worthwhile, particularly since many of the standard metrics, which are used to see the efficacy of a drug, don't necessarily always hold up. What I mean by that is that we often use animal models, but there's very poor correlation between the animal model data and what actually happens in human clinical trials. Even though many people understand that, they still want some metric to show that it's going to de-risk the whole program. There are very few metrics, which you can convince in trying to go outside and try to standardize new metrics to show that this may be effective, is very, very difficult.
We have found this to be an extraordinarily difficult process, hard to get a lot of traction, but fortunately we were able to generate enough resources to move this into a phase one trial. Hopefully we'll be able to show that these types of strategies and paradigm shift will actually pay off and have really significantly improvements in patient outcome.
Most importantly, one of the things we learned about these types of drugs is that since this was discovered in patients, we know what the titers were in patients. We do not see any off-target effects. Hopefully they'll have a very few or minimal toxicity and off-target effect, so it would be much better tolerated than current therapies.
Christina Lingham:
What are some of the most exciting new developments emerging for antibodies derived from single human B cells?
Edward Patz:
I think that, again, this field is in its infancy. Nobody has done this before. This will be the first completely human derived antibody from humans, at least in oncology, to go into a clinical trial. I think the development is just showing that this new paradigm, that this type of approach, can be used to not only target the tumor cells, but then also to modulate the rest of the immune system to get a much more long term durable response, will really be the most exciting thing, that this is a way in which we can circumvent some of the toxicities, that we can be much more targeted by directing what the immune system has already told us by using this, and that hopefully patients will not only do better, but have less toxicity when associated with some of these types of novel antibodies.
Christina Lingham:
Ned, thank you for your time and insights today.
Edward Patz:
Thank you so much for having me.
Christina Lingham:
That was Dr. Edward Patz of the Duke University Medical Center. He'll be speaking in the Antibodies for Cancer Therapy Track this May 1st and 2nd in Boston, Massachusetts at the PEG Summit. If you'd like to hear him in person, go to PEGSummit.com, and enter the key code "podcast."
I'm Christina Lingham. Thank you for listening.