Good afternoon, ladies and gentlemen, and welcome to Alector conference call and webcast, Crossing the Blood-Brain Barrier: Developing Alector's Next Generation of Investigational Therapies for Neurodegeneration. As a reminder, this conference call is being recorded. Currently, all participants are in a listen-only mode. There will be a question and answer session at the end of this call. I would now like to turn the call over to Katie Hogan, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
Thank you, operator. Hello, everyoone, and welcome to our event today. Before we begin, we'd like to go over just a couple of reminders. There will be a moderated question and answer session following prepared remarks. To submit a written question, please type it into the question and answer panel on the webcast. A webcast replay of this event will be available tomorrow after 3:00 P.M. Eastern. You can find it in the investor section under Events and Presentations on our website, www.alector.com. I'd like to note that during this presentation, we'll be making a number of forward-looking statements, and you can find our forward-looking statement here on this webcast. I also encourage you to see our SEC filings for more information. Turning now to our agenda. Joining me on the call are Dr. Arnon Rosenthal, our Chief Executive Officer, an Peter Heutink , our Chief Scientific Officer.
Today, they'll be talking about Alector's leadership in neurodegeneration. Next, Dr. An, professor and Robert A. Welch Distinguished University Chair in Chemistry and Director of the Texas Therapeutics Institute at UTHealth Houston, will discuss the state of drug delivery across the blood-brain barrier. Following Dr. An's remarks, Alector Lead Scientist, Dr. Eric Brown, and Dr. Maxime Aillagon will talk about Alector Brain Carrier in more detail, delving into the details about our proprietary blood-brain barrier approach, as well as potential applications. Then we'll invite Dr. Peter back for closing remarks, and finally, our Chief Financial Officer, Dr. Marc Grasso, will join us to moderate the Q&A portion of the discussion. At this time, I'd like to turn it over to Arnon and Peter.
Welcome, everyone. It's really heartwarming to see that hundreds of people registered to our webinar. As you know, for our drugs, we are striving to be both first and best in class. So, to the best of our knowledge, we are going to be the first to have data for a TREM2 activating drug in Alzheimer's disease by the end of the year. We are also going to be the first one to have Ph ase III data with a progranulin elevating drug in frontotemporal dementia by, around the end of next year. Likewise, we are, to the best of our knowledge, going to be the first one to have a progranulin elevating drug in Alzheimer's disease around the end of 2026.
So whereas with, with drugs, we are striving to be both best and first in class, with our technology, we strive to be best in class, and our Alector Brain Carrier platform has been over five years in the making. We took the time to understand the subtlety of the technology and how to adapt it to different targets, and now we think that we are finally ready. At this time, our blood-brain barrier technology is becoming an integral part of our drug discovery platform. We are using it in conjunction with novel targets, with validated targets. You have seen what blood-brain barrier technology have done to the Roche anti-beta antibody, for example. We have clinical drugs that work quite, quite well on their own, but they may be even better in conjunction with the blood-brain barrier technology, and we are exploring that.
And finally, we are exploring our blood-brain barrier technology in conjunction with non-protein therapeutics, like ASO. What we expect from our technology is to be able to deliver drugs at lower dosing with better brain distribution, possibly with the convenience of subcutaneous delivery. We will be able to develop protein and enzyme replacement drugs, something that was not possible without the technology. And as I mentioned, we will explore non-protein modalities. So at this webinar, we are going to focus on the technology, and we will show you just one example of incorporating the technology into drugs. But in future webinars, we will show examples of the different drug modalities that we are integrating the blood-brain barrier technology into. And we are not doing everything alone.
We are exploring the possibility of partnerships around the technology with different experts, and again, you will hopefully hear about it in the near future. I will now turn the podium to Peter to go into more details into our research and discovery efforts. Peter?
Thank you, Arnon. So Alector was founded approximately a decade ago with a vision that brought together the fields of human genetics, immunology, and neuroscience.
... and Alector has been pioneering immunoneurology as a novel therapeutic approach to treat neurodegenerative diseases. Immunoneurology is deeply rooted in the underlying genetics of neurodegenerative diseases, and our therapies harness the power of microglia, the brain's immune cells, to counteract neurodegeneration. Our clinical pipeline of immunoneurology programs includes latozinemab and AL101 that aim to elevate progranulin levels and are being developed in collaboration with GSK. Additionally, we're advancing AL002, our TREM2 activating candidate, in partnership with AbbVie. Latozinemab is currently being studied in a pivotal phase III trial for the treatment of frontotemporal dementia with progranulin mutations, while AL101 and AL002 are being studied in phase II trials for the treatment of early Alzheimer's disease. Our past research and development events have centered around our immunoneurology approach.
Today, however, we would like to focus on enhancing the delivery of our therapeutics to the brain using Alector Brain Carrier, or ABC for short, a proprietary, versatile blood-brain barrier technology platform. Dr. An and the team will actually go in much more detail, but at a high level, we know that the purpose of the blood-brain barrier is to maintain homeostasis and protect the brain by restricting access to it. From a therapeutic perspective, this actually presents a challenge to effective delivery of therapeutics that must cross the BBB for optimal results. Therefore, as a potential solution, we are developing Alector Brain Carrier to enhance brain penetration of therapeutic molecules, potentially optimizing efficacy and safety of critical therapeutics.
Employing a versatile approach, Alector Brain Carrier utilizes various fragments binding to specific BBB targets, achieving significant increases in brain concentrations across important cell types like neurons and microglia, and enabling customization to align with cargo specificity. Our Alector Brain Carrier technology platform complements our current late-stage portfolio. Grounded in immunoneurology, our late-stage clinical candidates already demonstrate effective brain penetration and target engagement. But in parallel, Alector Brain Carrier enables the delivery of additional drugs, additional novel drugs into the CNS, including antibodies, as well as protein and enzyme replacement therapies for the treatment of neurodegenerative diseases. This includes novel programs targeting, for example, GPNMB and GCase for Parkinson's disease, and you will hear more about GCase later on in this program, but also additional targets combined with our ABC technology for Alzheimer's disease, ALS, and Lewy body dementia.
We are also exploring the potential to selectively deploy our technology in a fit-for-purpose manner on our next generation programs. With a portfolio of first-in-class immunoneurology product candidates, we retain major rights to our latozinemab, AL101, and AL002 programs, while holding full ownership of our novel programs combined with our Alector Brain Carrier, targeting Parkinson's disease, Alzheimer's disease, ALS, and Lewy body dementia. Importantly, our IP portfolio across all programs contains more than 60 patent families, which include 100 issued patents and more than 500 pending patent applications, directed to more than 20 targets and/or technologies. Alector Brain Carrier marks an exciting step forward in our mission to pioneer effective treatments for neurodegenerative diseases, guided by innovation and driven by a commitment to improving patients' lives. Thank you again for your time today, and I look forward with you to speaking with you later in the program.
I will now turn it back over to Katie, who will introduce our key opinion leader on the BBB, Dr. An.
Thank you, Peter. With that background, I'm pleased to introduce you to Dr. An. Dr. An is a professor of molecular medicine and the Robert A. Welch Distinguished University Chair in Chemistry, and the director of Texas Therapeutics Institute at UTHealth Houston. He is a trailblazer in the development of antibody-based biologicals to treat cancers, spinal cord injuries, as well as Alzheimer's disease. One of his major areas of focus is developing technologies to deliver antibody-based therapies across the blood-brain barrier for the potential treatment of neurodegenerative diseases. He serves as Vice President, Drug Discovery for the university, and in this role, he closely collaborates with the Office of Technology Management to promote drug discovery and therapeutic innovation. With over 200 papers published in peer-reviewed journals and 45 filed patents, Dr. An is committed to improving health through novel interventions. Dr.
An, thank you for joining us here today. It's a pleasure to have you, and we look forward to your remarks.
Thank you, Katie. I'm pleased to be here today with all of you to discuss the state of drug delivery across the BBB. That's blood-brain barrier. Before I start, I do want to disclose that I'm on the scientific boards or have equity interest in Immune-Onc Therapeutics, Ecdys Therapeutics, and CrossBridge Bio. I also participate in sponsored research with Merck Research Labs. The brain is a privileged site with highly regulated interfaces that controls the movement of substances and cells in and out of the brain. These barriers seek to keep the central nervous system isolated from peripheral toxins, and to extend the peripheral immune system, while at the same time ensuring adequate nutrient transport.
Examples of these barriers are the meningeal barrier, the blood-CSF barrier, that's a cerebral spinal cord spinal fluid barrier, ventricular barrier, and of course, the blood-brain barrier. While all these barriers are critical to maintaining homeostasis and protecting the brain's environment, when we consider central nervous system drug discovery and delivery, they collectively present unique challenges due to the lack of permeability they create for most small molecule drugs, and almost all large molecule therapeutics, such as antibodies and proteins. So what exactly is a blood-brain barrier or BBB? This barrier is between blood vessels and the brain tissue. The BBB is formed by a monolayer of brain endothelial cells, supported by pericytes and astrocytes.
Compared to other blood endothelial barriers, the blood-brain barrier or blood-brain barrier has an exceptionally low rate of nonspecific transport and high levels of export pumps, which actively remove potential toxins. This is not to say that the BBB is impermeable. In fact, it actively transport imported nutrients, such as sugars, amino acids, and minerals such as iron, through its highly specific transporters. Despite the difficulty of drug delivery across the BBB for treatment of central nervous diseases, the highly vascularized nature of the brain and the BBB present a potential avenue for drug delivery, which is the focus of this webinar today. It is well established that the blood-brain barrier creates low uptake of many therapeutic drugs, including antibodies.
For antibodies, in particular, the therapies has a very low, but yet significant rate of penetration across the BBB at about 0.1%-2% of the plasma levels. Due to the low level of brain penetration, and there's many associated clinical failures in the central nervous system disease space, significant effort, both in academia and also in industry, have been made to design therapies that can be delivered across BBB by targeting brain receptors to facilitate their passage through the brain through the blood-brain barrier. Now that we have briefly reviewed the challenges of delivering drugs, particularly, large molecule drugs such as antibodies, across the blood-brain barrier, let's take a moment to look at some of the potential BBB delivery technologies. There are two dimensions being explored simultaneously and also in parallel.
The first are the various routes of administration of the therapies. For example, direct brain injection that bypasses BBB, intra-cerebral or spinal cord injection, and intra-ventricular cerebral ventricular delivery into the CSF, or intranasal brain delivery to allow therapeutics to bypass the BBB altogether. There are also the technologies to increase the permeabilities of the BBB are crossing, either physically or chemically or in combination, to allow higher rates of nonspecific transport across the blood-brain barrier. For example, electric or magnetic stimulation, such as ultrasound, applied to the skull, can temporarily open the blood-brain barrier for drugs to enter the brain without permanent damage to the BBB. Similarly, chemicals such as the hyperosmotic agent mannitol can temporarily open the blood-brain barrier for drugs to enter the brain without permanent damage to the BBB.
These routes of administration offers a promise in some applications, but have a significant, significant risks and challenges for long-term, repeated administration of drugs, such as antibodies against chronic neurodegenerative diseases, such as Alzheimer's disease. The second category is the delivery vehicles. One class of these vehicles utilizes the viral vectors, such as AAV9 or AAV-rh10, nanoparticles, and extracellular vesicles, primarily for delivery of nucleic acid-based therapeutics, such as gene therapies and antisense oligonucleotides, which is also one of the focus of Alector's multiple drug modalities. Finally, there is this so-called receptor-mediated transcytosis approach to utilizing receptors on the BBB, such as the transferrin receptor, TFR, and the amino acid transporter CD98hc, which will be the focus of this webinar by the Alector scientists today.
Before I dive into the transferrin receptor as example for receptor-mediated transcytosis delivery of drugs across the BBB, I want to take a moment to explain what is exactly a receptor-mediated transcytosis. On the left side of the slide, you can see that it's an illustration of the high-level process, whereby molecules are transported across a cell by binding to specific receptors, which are themselves proteins. On the cell membrane, on one side of the cell, materials or cells being internalized, transcytosed across the cell, and then released on the other side. Upon reaching the opposite side of the cell, the vesicles containing the receptor-ligand complex fused with the cell membrane and release their content into the extracellular space of the other side of the cell. This process is known as a receptor-mediated transcytosis.
This process plays critical roles in multiple physiological processes, such as the nutrient absorption, immune response, and neurotransmitter recycling. The receptor-mediated transcytosis relies upon active transport, which unlike simple diffusion or bulk endocytosis, is highly selective. Only molecules that bind to a specific receptor are transported across the cell. On the right side of slide, you can see a schematic of the transferrin receptor, short for TFR, which is one of the most studied receptors for delivery of large molecule drugs such as antibodies, or proteins, or enzymes across the BBB. TFR is a type II transmembrane receptor, bound by other transport proteins such as transferrin, and it is highly expressed on the BBB. Transferrin receptor is a homodimer linked by disulfide bonds. The extracellular domain of the transferrin receptor consists of three domains: an apical domain, the helical domain, and the protease-like domain.
The transferrin receptor bind to iron-bound or hollow transferrin protein through the helical and the protease- like domain. You can imagine, for the discovery of a cargo for delivery of drugs through the BBB for targeted TFR, we do want to the antibody target is the helical or the protease-like domains. Otherwise, it could compete with natural ligand binding as potential side effects. So let's now with the apical domain, which is Alector's. Alector's scientists will discuss this in great detail. So now let's come back to the right side of the slide. Sorry, the left side of slide, which illustrated a bispecific carrier cargo antibody design. The gray arm of the bispecific antibody is the cargo, which is the therapy that you want to be delivered to the brain....
The right arm with bispecific antibody is a carrier. For example, an anti-transferrin receptor antibody, which bind to the transferrin receptor expressed on the BBB. After binding to the transferrin receptor, this bispecific antibody construct is now delivered across the BBB inside the brain. Once inside the brain, the cargo arm of the bispecific antibody engages the disease target. This is the nutshell how this technology works. So what must we consider in general when designing carriers for effective antibody or protein delivery across the BBB to target CNS targets? First, we start with the choice of receptor. With ideal candidates being highly expressed on the BBB.
So for example, the transferrin receptor, which is highly expressed on BBB, and if it with equivalent level and trafficking in model species such as mice, we need to have model systems to evaluate these constructs. Then we come to the antibody engineering. We need to consider modulating epitopes. That's where we design antibodies, where the antibody will bind to the receptor. As I mentioned, for the transferrin receptor, we do want to interfere with the normal ligand binding to the receptor. That's the helix and protease ligand domains. And we can also adjust the affinities of the antibodies bound to receptor. For example, for the transferrin receptor, if its affinity too high, you could trap, internalize the receptor themselves.
So we can adjust the affinities of the antibody-targeted receptors, as well as the formats of the antibody. For example, we can do a single chain variable, or Fab fragment, or full IgG, in these constructs. All these activities to ensure the lack of competition with the native ligands and retention of native function of the receptors. And then, of course, it is imperative that we characterize all these constructs, and their functions in vitro and in vivo. Specifically, we must verify brain penetration. We need to quantify brain uptake and confirm the biological effects, as well as potential therapeutic efficacy in the different animal models, including non-human primates.
So despite the many challenges which we discussed associated with central nervous system therapeutic development and the delivery of these drugs, we as researchers, both in academia and the industry, are very excited for the slow but steady progress and advancement in this field. We are looking into the future of BBB technologies and see the potential for many developments, including in vivo BBB models, such as tissues from human-induced pluripotent stem cells, development of BBB mathematical models that can predict what's happening in the clinic, exploring where in the brain we want to deliver the drugs, leveraging in vitro versus in vivo models, ensuring our study of the animal models can be translated to clinical human setting.
Last but not least, we need to develop additional novel receptor-mediated transcytosis targets with CNS-restricted expression to reduce potential systemic toxicity. Thank you for your time, and I look forward to addressing questions that you might have at the end of this program. Katie, I'll give it back to you.
Thank you very much, Dr. An. I'm now pleased to introduce my colleague, Dr. Eric Brown, who will discuss Alector Brain Carrier in more detail. Eric, I'll turn it over to you.
Thank you, Katie, and thank you, Dr. An, for your excellent introduction of the blood-brain barrier. So here at Alector, we've worked hard for the last several years, first to build our ABC platform and then to optimize it for a wide variety of therapeutics. ABC is a BBB technology that is designed to enable precise and non-invasive peripheral delivery of therapeutics to the brain. We believe that efficacy and safety are optimized with its modular and tunable design, and we validated it for brain uptake with multiple therapeutic cargos. One of the main goals is to reduce the dose of peripheral antibody needed to achieve maximum efficacy, both to widen the therapeutic window and to potentially lower the cost of goods and facilitate subcutaneous delivery. ABC technology is based on the receptor-mediated transcytosis mechanism described by Dr.
An earlier, a simplified schematic of which is shown on the right-hand side of this slide. As Dr. An mentioned, we believe that using receptor-mediated transcytosis can allow us to convert the BBB from a barrier into a potential route of entry for drugs into the CNS... Our initial work in the ABC field has focused on two BBB receptors: transferrin receptor and CD98 heavy chain. Both of these receptors are highly expressed at the blood-brain barrier and have been shown to drive significant uptake of cargo into the brain, and yet they are differentiated both in their cell type localization and their mechanism of entry. Transferrin receptor, as Dr. An mentioned, is an iron transport receptor, and in our hands, it has been shown to rapidly drive cargo into the endolysosomal system of brain endothelial cells, as shown on the top right of this slide.
Meanwhile, CD98 heavy chain is a key member of several important amino acid transport complexes, such as LAT1 and LAT2, and it tends to drive cargo onto the cell surface of endothelial cells and allow for a much slower route of internalization and delivery across the blood-brain barrier. We think it's key to have ABC shuttles against multiple BBB targets in order to facilitate pairing with a wide variety of cargos. Our ABC technology has been designed to focus on three key strategies. The first is versatility, by which we mean the adaptability for a wide range of cargos, including antibodies, proteins, and potentially even nucleic acids. Second is tunability. Many parts of the ABC molecule are tunable, but one important consideration is affinity for the BBB receptor. And then a third one that is very important to us is translatability.
By this we mean in rapid translation of ABC molecules into validated clinical candidates that can transfer from mouse to non-human primate to the human clinical system. Looking in more detail at versatility, we've designed and validated ABC carriers in Fab, scFv, and VHH formats, and have then paired them with therapeutic cargos in multiple multi-specific formats, several of which are demonstrated on this slide. This system has been tailored for both antibody and protein cargos, and you can see examples of each. With at the center of this slide showing a monovalent brain carrier enabling the delivery of a bivalent antibody cargo, and on the right-hand side of the slide, a format for delivery of a monovalent protein cargo.
In terms of tunability, as I mentioned, several aspects of the ABC technology are tunable, such as the valency and Fc effector function chosen, but one of the most important factors is the affinity to the blood-brain barrier receptor itself. We have validated brain uptake of ABC molecules with over a 500-fold range of affinities to both transferrin receptor and CD98 heavy chain. Through this work, we've learned that lower affinity ABCs are particularly important in optimizing the efficacy and safety window, and are able to deliver sustained delivery of therapeutics into the CNS, and are most suitable for cargos that themselves have relatively slower rates of peripheral clearance, such as antibodies. Meanwhile, our work has shown that higher affinity ABCs drive a much more rapid brain uptake at the cost of a hit to the systemic clearance.
These high-affinity ABCs tend to be suitable for cargos that themselves have relatively rapid peripheral clearance, such as enzymes and proteins, and where it's most important to drive rapid brain uptake. In terms of translatability, we're looking at four key factors to enable translation of research molecules into clinical candidates. First, we developed a high-throughput screening format to enable rapid in vivo screening in human transferrin receptor and human CD98 heavy chain-expressing mice. We look to translate our biology by making affinity-matched panels of murine TFR, ABC surrogates for rapid testing and disease model systems. At the same time, we look for translatable safety by making sure we only move forward ABC shuttles that have equivalent affinities to human and cyno BBB receptors.
And finally, throughout the entire process, we conduct rigorous developability assessments to make sure that our ABC shuttles, and most importantly, our ABC shuttle cargo pairings, are developable and manufacturable therapeutics. We'll begin by looking at our TFR ABC platform. TFR ABC is a mature platform that has been used to deliver multiple types of therapeutic cargos to the brain. While we have ABC shuttle, TFR ABC shuttles available across a wide range of affinities, most of the data I'll be showing today is with a low-affinity anti-TFR panel, anti-TFR binder designed to facilitate the entry of antibody therapeutics. As you can see on the left-hand side of the slide, even the low-affinity anti-TFR scFv drives rapid brain uptake with a nearly 20-fold increase in antibody seen 24 hours post-IV dosing.
Because of the low affinity nature of the TFR scFv used in this ABC format, we see sustained delivery into the brain out to one week post-IV dosing, and this is also shown in the serum clearance data on the right-hand side of the slide, where you see a relatively minimal effect on serum clearance of this antibody cargo by the TFR ABC. Beyond looking at antibody cargos, obviously, it was most important for us to demonstrate the brain uptake of Alector antibody therapeutic cargos, two of which are shown on this slide. As you can see, both target two and target three IgG show an increase of seven to 15-fold increase in the brain parenchyma.
We think this is very important that in this and all subsequent brain uptake data shown, we're looking at antibody levels in what we call the vessel-depleted brain fraction, which means anybody that's completed the transcytosis process across the BBB and then been released into the parenchyma. As Dr. An mentioned, some blood-brain barrier-targeting antibodies can, in fact, get stuck in the brain vessels, and even though they might appear to be in the brain, they're not actually reaching the cell types of interest, such as neurons or microglia. Beyond looking at the raw brain uptake numbers, we think it's most striking to look at imaging data that shows the final biodistribution of antibody with the addition of ABC technology.
On the left-hand side of the slide, you can see an example of brain uptake of the Target3 IgG without ABC technology, and you can see that the minimal amount of antibody that penetrates the brain is really not deeply penetrating into the neuronal layers of interest, but is instead around the outskirts, outskirts of the brain and around the ventricles. Meanwhile, on the right-hand side of the slide, you can see that Target3 enabled with TFR technology shows a striking change in the brain biodistribution. One good example of this is looking at the hippocampus, where with Target3 IgG, the neuronal layer is essentially dark, whereas with Target3 TFR, you see a bright and precise staining of the neuronal cell layers.
This is driven by both the TFR arm of the molecule getting the drug across the BBB, and then the final biodistribution in the brain is really driven by a combination of binding to the BBB molecule and the cargo of interest. So TFR-ABC, we are happy to say, also shows translatable brain uptake from mice, which the previous data was shown in, into the non-human primate system. In this study, we did a two-dose IV injection into NHPs with two different antibody cargos. On the top in gray, you can see an increase in brain uptake of 15- to 40-fold across multiple brain regions tested. On the bottom in blue, you can see an increase in brain uptake of three to 8-fold in the same brain regions.
As with the murine system showed earlier, we also validate in the NHP brain that we're seeing significant, wide biodistribution and not, you know, focal distribution within the blood vessels on the right-hand side. Beyond looking at brain uptake, which can only be taken at a single time point per animal, we use serial CSF sampling, shown on the left-hand side of this slide, to demonstrate that we show enhanced brain uptake up to two weeks post-IV dosing in the NHP system. Even more strikingly, on the right-hand side of the slide, we can look at biomarker data for the Target 1 system. Target1 IgG is an Alector proprietary immunomodulatory antibody designed to activate microglia in the brain. On the right-hand side of this slide, we show biomarker data for one marker of microglial activation, soluble TREM2.
As you can see, the naked IgG without TFR technology shows a very modest PD effect, which is enhanced 300- to 400-fold, 300%-400%, upon addition of the TFR-ABC technology. This data actually matches with prior studies done with Target1 IgG at four or 12 times higher doses than was done in this study, enabling the potential to lower the peripheral dose needed in order to achieve maximum efficacy. Importantly, in the same study, we also looked for safety phenotypes, such as the well-understood anemia phenotypes often seen with TFR-binding antibodies. Throughout the two-dose duration of the study, we saw no impact on markers of anemia, such as red blood cell counts or hemoglobin. We also looked more deeply at reticulocyte levels.
So reticulocytes are immature red blood cells that express very high levels of transferrin receptor and which are often killed upon addition of anti-TFR therapeutics. Interestingly, we saw no reduction in reticulocytes after the first administration of any of the test articles, but we did see decreases in reticulocytes in some of the animals after the second dose with some of our TFR-binding antibodies. So this is a very important property that we're evaluating in all further TFR-ABC studies, as it's modulatable with many of the tunable properties of ABC, such as valency, effector function, and obviously affinity to the TFR receptor. Beyond looking at brain uptake and safety, we're also obviously interested in making sure that all of our molecules have favorable manufacturability profiles.
We took the same Target3 TFR IgG shown in a previous slide and assessed it with a rigorous developability assessment. We looked both at high concentration stability, multiple stress conditions, and also multiple measures of self-interaction to show that this molecule has a strong potential for therapeutic administration. Importantly, we were able to increase the concentration up to 150 mg per ml without any impact on product quality, indicating a potential for subcutaneous dosing. While most of the data I've shown so far has been with a low-affinity anti-TFR-ABC to facilitate antibody transport, we've also validated brain uptake for a wide variety of human and cyno affinity-matched shuttles in order to facilitate transport of cargos with a wide variety of mechanism of action. Importantly, we've also validated affinity-matched surrogate panels to enable us to test cargo ABC pairings in different model disease systems.
We validated binders in both ScFv and Fab format at relatively similar affinities in order to match all the different formats we discussed earlier. Moving beyond TFR, we'll next take a look at our CD98 ABC platform. CD98 ABC is not as mature as TFR ABC, but we're seeing exciting differences in the kinetics of brain uptake and safety profiles that make us think it's a highly orthogonal platform that will allow us to better pair with diverse cargos that may not be amenable to TFR ABC transport, such as those that require bivalent formats or that require active effector function Fc.... To look back at some of our initial screening data, we screened across multiple antibody formats and showed several sequence families with strong increases in brain uptake.
This data is shown from 1 sequence family in our high-throughput screening format, where we can see an increase in up to eight-fold increase in antibody level in the vessel-depleted brain fraction, 48 hours post-IV dosing. Next, we took some of these shuttles and applied them to a more final therapeutic format, where we see even more striking increases in brain uptake. As you can see on the left-hand side of the slide, even 24 hours post-dosing, we see a 10-fold increase in brain uptake in the hCD98 heavy chain, ECD knock-in mice model system. This brain uptake actually increases substantially four a nd seven days, peaking at over 20-fold over the format-matched isotype antibody. And as you can see, the increase in brain uptake is sustained well past two weeks past IV administration.
As with the TFR system, we also use imaging data to confirm the final biodistribution of our antibodies. As you can see on the right-hand side of the slide, the CD98 heavy chain ABC, in this case, with an isotype control Fab cargo, shows widespread brain biodistribution. Without an active cargo, we don't see as striking a subcellular localization as with the TFR-ABC. But again, you can see that the crossing across the blood-brain barrier is complete in all brain regions assessed. If we look at some of the differences between CD98 ABC and TFR ABC, we can easily see the potential to pair with different types of cargos.
As you can see on the left-hand side of the slide, TFR-ABC shows a high Cmax at a relatively short time frame, one to two days post-IV injection, and this can be even further enhanced with higher affinity TFR-ABC. Meanwhile, on the right-hand side of the slide, you see the potential for sustained brain uptake with CD98 heavy chain ABC, which, as I said, has both high initial brain uptake, but even further increases one to two weeks post-dosing. And again, just to note, all of this data is with an isotype control cargo, and the final brain biodistribution and brain uptake patterns are going to be cargo dependent. We also wanted to look at initial safety data for our CD98 ABC panel. So on the left-hand side of this slide, as Dr.
An mentioned earlier, one key consideration for ABC or any BBB shuttle is that they not interfere with native functions of the receptor. So obviously, one of the main functions of CD98 heavy chain is its role in amino acid uptake. So we took care to screen our CD98 ABC molecules to ensure that any that we move forward do not decrease amino acid uptake after induction on human cells. So on the left-hand side of the slide, you can see brain uptake or amino acid uptake data, which is in particular uptake of leucine through the LAT1 complex. On the right-hand side of the slide, you can see some of our initial in vivo safety data. So we thought it was important to measure changes in hematological parameters, as CD98 heavy chain is expressed on many cell types within the hematopoietic system.
We saw no notable changes in anemia, markers such as red blood cell counts, which are shown here, or hemoglobin for two weeks post-IV injection. Importantly, we also saw no major immunological changes in immune cell type populations, which is also a key consideration. Beyond isotype control cargo, we've now paired CD98 ABC with multiple electrotherapeutic cargos. On this slide, you can see in the middle, Target 2 IgG, for which addition of CD98 ABC technology facilitates a ninefold increase in brain uptake, 72 hours post-IV dosing. You can see Target 4 IgG, for which addition of the CD98 ABC technology increases brain uptake by tenfold. Again, in the murine model system. As with our TFR ABC system, we've worked hard to validate that these target CD98 heavy chain pairings are developable therapeutics.
This is some initial manufacturability data indicating that both Target 2, Target 3, and Target 4, all of which are proprietary Alector antibodies, pair well with the CD98 ABC system and are viable as therapeutic candidates. Like with the TFR example, we've been working to validate CD98 heavy chain binders across a wide range of affinities. We've seen validated brain uptake for binders with single digit up to around 500 nanomolar binding to CD98 heavy chain. And here we're showing data for one particular, very well-characterized antibody family. As you can see, as with TFR-ABC, we only move forward molecules that have highly matched affinities between human CD98 and cyno CD98 receptors.
Interestingly, there's a mechanistic difference where we don't see brain uptake with the load of very low affinity, anti-CD98 ABCs, as we did with anti-TFR, and we think this is really due to the differentiated mechanism of brain uptake seen with these two receptors. So I know I've gone through a lot of data pretty fast, so I just wanted to highlight some of the key strengths in the current status of our ABC platform. We've validated brain uptake in multiple different formats with multiple types of ABC binders for both TFR and CD98 ABC across, relatively wide affinity ranges. Our ABC platform, because it does not, you know, require any engineering in the antibody Fc itself, is thus compatible with any sort of Fc engineering, looking at either effector function or half-life extension.
We've generated matched human cyno affinity panels for both TFR and CD98 ABC, and generated matched murine surrogate panels for TFR-ABC, which is currently a work in progress for CD98 ABC. In terms of brain uptake, we've shown high absolute and fold increased levels in NHP and mice brain for TFR-ABC, and in the mouse brain for CD98-ABC. In terms of application to Alector programs, we've demonstrated increase in brain uptake with five cargos for TFR-ABC and three for CD98-ABC, with multiple other programs ongoing, and both have been shown to pair well with protein cargos in certain applications. One example of which will be shown in the next section of this deck. Thank you, Katie. I will turn the deck back over to you.
Thank you very much, Eric. At this time, I'm pleased to introduce Dr. Maxime Aillagon, one of our lead scientists, who will talk more about the potential applications of our ABC platform. Maxime?
Thank you, Katie. It's my pleasure to present how Alector is applying our ABC platform for protein replacement therapies in neurodegeneration. Today, we're specifically focusing on our brain-penetrant GCase enzyme replacement therapy for the treatment of Parkinson's disease. I'll start by describing the genetic rationale for targeting GCase. Mutations in GBA1 are some of the most common genetic risk factors for Parkinson's disease and Lewy body dementia. Up to 15% of Parkinson's disease patients and up to 30% of Lewy body dementia patients carry mutations in GBA1. Based on these statistics, we estimate about 1 million GBA1 mutation carriers for each of these patient populations worldwide. We also note that individuals that carry two mutations in GBA1, so two mutated copies of the GBA1 gene, are affected with the lysosomal storage disorder, Gaucher disease.
Though the most common subtype, Gaucher Type 1, does not present with neurologic symptoms, these patients also have increased risk of developing Parkinson's. In the next slide, I'll describe the function of this disease-modulating gene. The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase, or GCase. This enzyme catalyzes the hydrolysis of its substrates, glucosylceramide and glucosylsphingosine, into their lipid and sugar components. When mutations reduce GCase activity, you have an increase in toxic accumulation of these substrates. We believe this substrate accumulation contributes to the increased risk and accelerated progression of Parkinson's disease observed in GBA1 mutation carriers. Our goal is to restore GCase activity by providing brain-penetrant enzyme replacement therapy to reduce substrate levels back to normal. Importantly, we believe that rescuing GCase activity directly will be more efficient at reducing glucosylsphingosine than glucosylceramide substrate inhibition.
Observational studies published in the last few years support the hypothesis that GCase activity and substrate accumulation are linked to Parkinson's disease progression. The figure on the left demonstrates that patients with lower GCase activity in the CSF at time of diagnosis tended to decline faster in their cognitive scores than patients with the highest GCase activity in yellow. The figure on the right shows the stratification of patients based on their ratio of glucosylceramide levels to sphingomyelin in the CSF. The red line shows patients with the highest baseline glucosylceramide to sphingomyelin ratio. That is to say, these are the patients with the higher relative glucosylceramide levels, and these patients progress faster than patients with lower glucosylceramide levels in blue.
Together, these data support the hypothesis that reduced GCase activity and increased lipid substrate levels contribute to the faster clinical progression of Parkinson's disease in GBA1 mutation carriers. Parkinson's disease is a chronic, progressive, neurodegenerative disease. Its symptoms can be categorized into motor and non-motor impairments, and approximately 90,000 Americans are diagnosed with PD each year, and no disease-modifying treatment is approved to slow progression of PD. There is a strong genetic component to Parkinson's disease, with 10% of PD being familial, and as mentioned before, 5%-15% of patients carry mutations in GBA1. Our solution for patients that carry GBA1 mutations is a brain-penetrant enzyme replacement therapy. Our therapeutic is composed of three moieties: an engineered enzyme optimized for expression, stability, and activity, an Fc fragment to enhance serum half-life of GCase, and an ABC moiety to facilitate brain penetration.
The versatility of the ABC platform allowed us to test several protein formats for optimal expression and stability. The tunability of the platform allowed us to optimize the ABC target and antibody affinity for maximum tissue and cell delivery. And finally, availability of affinity-matched anti-mouse surrogate molecules allows us to test our candidates in commercially available, genetically engineered neuron models. Now, I'd like to share some data that we're generating in this program. GCase exerts its function in the lysosome of cells. As such, it's important that our therapeutic be able to traffic to that compartment for optimal activity. In the experiment on the left, we treated human neuroblastoma cells with GCase ABC overnight. We then stained those cells for the early endosomal marker, EEA1, and the lysosomal marker, LAMP1.
As you can see on the top left panel in the overlay, there's a significant portion of the GCase ABC signal in green that overlaps with the lysosomal signal in purple, and that overlap is shown in white, in white, demonstrating the ability of GCase ABC to traffic to this organelle. On the right, we use the GCase-activated fluorescent substrate to measure enzymatic activity in cells. The non-fluorescent substrate is conjugated to glucose. GCase catalyzes the removal of this glucose moiety, which allows the substrate to fluoresce, and we measure this signal by flow cytometry. Our goal is to restore GCase activity in brain cells to reduce substrate levels back to normal.
What the data on the right is showing you is that our GCase ABC protein was able to restore GCase activity in GBA1 knockout human neuroblastoma lines at concentrations below five nanomolar, which is compatible with intravenous delivery. In contrast, recombinant GCase without ABC in black was not able to fully rescue a GCase activity to wild type levels, as shown with the dotted line. As Eric presented earlier, our ABC platform encompasses a range of ABC affinities. We therefore tested the effect of varying the target affinity of our ABC moiety on the rescue of GCase activity. What we found was that as the affinity to ABC increase, the concentration requires to achieve full rescue of mouse neuroblastoma cells was reduced. This relationship between ABC affinity and concentration required for rescue of GBA knockout cells is shown on the right panel.
This data showcases a range of affinities that are compatible for our therapeutic hypothesis and allowed us to explore different affinities in vivo. Our mouse in vivo results show that higher ABC affinity was associated with faster clearance, as shown on the left panel, through serum concentration at different time points after injection. Concurrently, the level of brain uptake, measured as GCase activity in the vessel-depleted fraction, was the highest with medium affinities, with up to 44% increase in GCase activity over controls. In summary, we believe that GBA1 mutation-carrying patients may benefit from enzyme replacement therapy to halt or slow down progression of Parkinson's disease. The data I've shared with you shows that our ABC platform allows recombinant GCase to rescue glucocerebrosidase activity in GBA knockout cell lines.
The tunability of our ABC platform allowed us to experimentally determine the optimal balance between cell rescue and brain parenchyma delivery to achieve over 40% increase in GCase activity in the brain of wild type mice. I hope this data was a good showcase of the vast potential and application for our ABC technology platform. I'd like to thank you all for your attention, and I will now turn it back to Peter.
Thank you, Maxime. So in summary, Alector holds a leadership position in the fast-evolving field we term immunoneurology, which lies really at the intersection of genetics, immunology, and neurology. Our ambitious goal is to deliver multiple transformative therapies to patients years ahead of others. We seek to do this not only through the development of novel therapies, which harness the innate immune system to address major unmet needs in neurodegenerative disease, but in parallel through the delivery of these therapies via Alector Brain Carrier. We believe our proprietary versatile blood-brain barrier technology platform has the potential to move us into the next era of CNS solutions for millions of patients and their loved ones desperately in need of progress.
We are dedicated to advancing the development of our ABC technology, which currently encompasses antibodies as well as protein enzyme replacement therapies aimed at potentially treating neurodegenerative diseases such as Alzheimer's disease, ALS, Parkinson's disease, and Lewy body dementia. You've seen that the modular nature of ABC allows the affinity, valency, and format of the final therapeutic to be harmonized with the mechanism of action and cell type specificity of the associated cargo. Our technology's adaptability is demonstrated through the versatile bispecific formats, complemented by customizable Fc adaptations for optimized effector function, half-life, and single chain configurations. Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile. Overall, our potential first-in-class clinical-stage assets, our proprietary ABC technology platform, our experienced team, and world-class partners position us well today and serve as catalysts for our future growth and success.
Marc, we are now ready to begin the Q&A portion of our program.
Thank you, Peter. We have a good number of folks in the queue for questions. So operator, if you'd like to advance to our first question.
Thank you. At this time, we'll conduct a question and answer session. As a reminder, to ask a question, you need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by. We'll go by the Q&A roster. Our first question will come from the line of Pete Stavropoulos from Cantor Fitzgerald. Your line is open.
Hi, thank you for hosting this event. Very informative. Exciting to see more details about the platform. You know, for Dr. An or Dr. Brown, you know, can you just give us a little bit more color around, you know, how you're thinking about affinity of the brain carriers, either CD98 or transferrin receptor, for optimal delivery? And will the affinity need to be tuned for delivery of various modalities? And in terms of delivery, is there enrichment in different parts of the brain when you use different affinities for either of the two, CD98 or transferrin receptor? And if so, you know, how can you leverage these properties for across various diseases?
Thanks, Pete. Dr. An, any high-level comments, and maybe, Eric, you could comment more specifically for our efforts.
Yes. Yeah, that's actually a very good question. So the, so the... As Peter said in his remarks that, for target use, transferrin receptor or the CD98 heavy chain, the future receptors. So we want to design fit for purpose delivery vehicles. That is actually you precisely that, where we want to deliver drug to the brain. And, so the affinities can be tuned, of course, based on both in vitro and in vivo validation. And so the idea that is, for every drug molecule we design, we want to select the best affinity. And, also, we can also modulate the format, you know, valency in fact, as well as efficacy engineering.
So in summary, yes, I think the Alector platform is a collection of multiple antibodies targeting these receptors. You can pick, choose, then select the best molecule for the specific drug you want to design. Eric?
Yes. As Dr. An mentioned, this is a large part of the reason why we designed such a modular format with such a wide range of binders, because we've already seen with different classes of cargos that we really do require some changing of the affinity, and this is due to a lot of different properties, brain uptake, making sure the drug doesn't get stuck in the blood vessels, and then also ensuring peripheral safety, right? So lower affinity you can get away with often helps with some of the measures of safety, such as the anemia phenotype mentioned or potential degradation of either TFR CD98 heavy chain receptor.
So this is why we have a suite of binders that anytime a new target comes up, you know, we really try to apply multiple affinity binders against both targets and then screen both in vitro and in vivo to make sure that we have the optimal pairing. But it's definitely not a one-size-fits-all approach.
Okay. And, in terms of different affinities, enrichment in different parts of the brain, or is it uniform?
Yeah, so that's an interesting question. I mean, what we've seen across multiple cargos is that, at least for TFR and CD98 heavy chain, we see relatively broad biodistribution in different brain regions. And what might actually have more of an impact on the final distribution is the cargo itself, right? So as you saw in that target three example, target three is itself expressed on neurons and microglia, and you could see a very striking staining of, for example, that neuronal layer in the hippocampus. But that wasn't just due to the TFR technology, that was due to a combination of both TFR and target three binding.
Got it. Thank you. And for the GBA1, the GCase program, you know, on the pipeline slide, I see Parkinson's, I see LBD. However, you know, I do not see Gaucher. Can you just help me understand the rationale for going after Parkinson's and LBD and excluding Gaucher, if that's the case? You know, which to me, you know, at least at the surface, seems like the easiest population to show efficacy in and perhaps the fastest path forward.
Yeah. Maxime or Peter, do you want to comment there?
You want to start, Maxime, or shall I?
Yeah. So I think, you know, we reviewed, of course, the Parkinson's, LBD, and Gaucher and decided to focus on Parkinson's disease. We feel that while you can see a signal of activity in Gaucher patients, because the disease is mostly peripheral, it's unclear whether this would necessarily be informative as to potential efficacy in Parkinson's disease. So at this point, we've decided to focus directly on the largest population.
Okay. Thank you for taking my questions.
Thanks, Pete.
Thanks.
Operator, I think we're ready for the next question from the line, and I'm also monitoring the questions on the chat.
One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley. Your line is open.
Thanks for taking my questions. You showed data with significant uptake of cargos in mice by seven to 15-fold for TFR and seven to 10-fold for CD98 HC. What is the optimal increase in uptake of cargo that you look for, and is there a minimal increase or point where it can be too great? Then I have a follow-up.
Yeah. Thanks, Jeff. Eric, do you want to start there?
Yeah, I'll take that one. I mean, just to note, we have seen increases of up to 20-fold in the murine system for both TFR and CD98 at the C-max. I wouldn't say there's necessarily a highest level of brain uptake, but what we see is that the, the greater fold change we see, then the more we could decrease the peripheral dose and still get that maximum efficacious dose into the brain. So we really, I mean, as high as we can go, as low as we can drive the peripheral dose level, we think will give us significant safety advantages, like was seen in the, in the Roche example with trastuzumab.
Great. And then, currently, your preclinical programs are 100% owned by Alector. How are you thinking about the partnership strategy for these programs? And do you plan to partner these programs like your lead programs, or are there specific programs that you want to keep wholly owned? Thanks.
Yeah. Thanks, Jeff. Maybe I'll start there, and Arnon, please add. So yeah, you're right, Jeff. These are proprietary programs, and we're advancing them on our own, and we have, you know, disclosed programs like GCase and undisclosed programs. I will say that, you know, we do have interest from pharma, and we have to balance that, you know, as we look at advancing these programs. I can say, you know, thankfully, we're in a financial position where we can advance these on our own, for some time and through value creating events. But at the same time, for the right situations, it may make sense to consider partnerships as well, and we are in discussions there.
Arnon, anything else you would add there?
Yes, basically, our ultimate goal is to have fully owned drugs, but if there are great opportunities to partner the same way we partnered our TREM2 asset and progranulin assets, we will absolutely explore that. Means we have a very sort of a broad pipeline, and we rather have a drug developing partnership rather than not be able to develop it because of limited resources. But as Marc said, at this point, we have enough resources to develop these programs on our own, and we'll keep doing that.
Thanks, Jeff.
Thank you.
Operator, we can go to our next question.
Our next question comes from the line of Alec Stranahan from Bank of America. Your line is open.
Great. Thanks, guys, for taking my questions. Just two quick ones from me. Pretty encouraging preclinical data, especially on the PK side. I guess, as you move your ABCs closer to the clinic, how do you plan to optimize, or how are you thinking about testing dose and dosing frequency, in Phase I studies? And maybe as a follow-up, how translatable would you say the non-human primate data is in terms of understanding PK and safety, either in terms of the blood-brain barrier composition, permeability, or normal tissue expression? Thanks.
Yeah. Thanks, Alec. Good questions. Maybe Eric, do you want to start there, and Peter and Arnon can add if appropriate?
I mean, obviously, we plan to do dose range finding studies in non-human primates to rigorously evaluate these parameters. I would say, I mean, there's always some translatability gap as you go into the clinic, and we're doing the best we can to minimize this by, as I said, mapping out expression profiles in these model systems, as well as making sure we're always working with affinity match surrogates, so both in terms of KD, but also K on, K off characteristics between the human and the cyno receptors. On the engineering side, that's kind of the best we can do. And the PK folks obviously will have a lot more to say on that.
Yes, in human, for each of our drugs, we have a pharmacodynamic biomarker. For our progranulin-elevating drugs, we wanted to retain high level of progranulin throughout the treatment, and this was what determined the dosing level and dosing regimen. For our TREM2 activating drug, we had three different biomarkers downstream of the TREM2 activation that we wanted to retain active or active intermittently. So, the pharmacodynamic biomarker will determine the dosing and dosing frequency with our blood-brain barrier technology, initially in non-human primate, and then in human.
Great. Thank you.
Thanks, Alec. Maybe just moving to the chat. I see Yaron had a question: Is there anything specific to the ABC technology that would prevent conjugation with other modalities in the future, like ASOs, RNAi, et cetera? Maybe, Arnon or Peter, if you want to comment there.
Yeah, I mean, we think that the platform is fully suitable to couple a wide range of different molecules, and so this is something that we are actively investigating. We started with antibodies. This was how the platform was originally developed. We realized the potential to use protein and enzymes as possible cargos, and similarly, we think that ASOs or even small molecules would be feasible, and we are exploring these possibilities, and we hope to report on some of them in other events.
Great. Operator, maybe we can go to our next question from the line.
Yes. Our next question will come from the line of Carter Gould from Barclays. Your line is open.
Hi, this is Leon Wang on for Carter Gould. I have a question on the receptors. I know in your conference, you mentioned that the TFR receptors are expressed in reticulocytes, but I was just wondering where, you know, might these receptors be expressed elsewhere in the body? Is there, like, a specific concentration anywhere else notable that you can mention? And also, does these receptors kind of vary, either as a person age and also in different disease states? Thanks.
Eric, do you want to start there?
I will take this one. So I will say, I mean, none of these receptors are perfectly only at the blood-brain barrier. So transferrin receptor, highly expressed on reticulocytes, and it is expressed in endothelial cells at a lower level in several other peripheral organs, such as the liver. CD98 heavy chain is also expressed in some other peripheral organs. Off the top of my head, I can think of the spleen, the kidney. So these are things that we are kind of evaluating in both murine and NHP studies to make sure that we're not seeing any undue effects there, particularly with CD98 heavy chain on immune cells, because that's one of its functions beyond amino acid uptake, is also mediating integrin signaling, which is important for B and T cell maturation. So we're trying to keep an eye on all of these potential phenotypes.
I may have forgotten the second half of your question.
No problem. I was just wondering, essentially, what's the variability between one -
Ah, yes.
I guess.
So we had our bioinformatics team take a look at this, most especially in disease settings, right? So when we were evaluating BBB receptors several years back to see which would be the most suitable, we only picked those that did not have substantial decrease, particularly in, neurological diseases such as Alzheimer's. Because obviously, I mean, that, at the time, was our largest potential patient population, so we wanted to make sure that, you know, these receptors aren't downregulated in the disease state. In many cases, they're actually, they can be upregulated because the disease brain has, changes in the, in the homeostasis that actually make it more activated.
Great. Thank you.
Operator, I think we can go to our next question from the line.
Okay, one moment for our next question. Our next question will come from the line of Tom Shrader from BTIG. Your line is open.
Good afternoon, and thank you for the session. You've mentioned several times about getting protein stuck in vessels. Can you drive something that looks like ARIA? Is that... Are we gonna have to think about that for some payloads?
Those are almost two separate questions. So definitely it's been demonstrated both in the past and in our internal data, that both higher affinity anti-TFR ABCs, but also sometimes specific cargo ABC pairings, can cause the antibody or the protein cargo to get mislocalized into the endolysosomal system and not released on the other side, which is where we really want it to get to in the parenchyma. In terms of driving ARIA, I think that is really a more cargo-specific phenomenon. I'm not sure if that has as much to do with getting anybody stuck inside, like in the vesicle portion of the cell. It might be a little bit more related to anybody accumulating on, you know, the outside of the cell, where there's presence of peripheral amyloid deposits. But I think that's a very cargo-dependent question.
Cargo and disease.
Go ahead, Tom.
I had a broad follow-up for Dr. An. So much of CNS disease is transmembrane proteins. Is gene therapy the only way to get at that, or on your sort of playbook, are some things that you might, vesicles or something, where you might be able to get transmembrane proteins in? Just kind of a view to the future.
Yes. Actually, transmembrane proteins, you mean, intracellular targets. If it's expressed on the cell surface, actually, those receptors are, these proteins are good antibody targets. Antibodies do not get into the cell very well. So, if for targets that is intracellular, inside the cell, a gene therapy will be a better option. So, as Eric has showed that, this is, the drug section that we talk about today has two parts. One is the cargo. That could be antibody targeting extracellular proteins or membrane protein, or could it be a small molecule that can target the intracellular targets, or gene therapy is also target intracellular proteins.
As a delivery vehicle, that could be antibody targeting transferrin receptor, CD98 heavy chain, or maybe some future target, antibody targeting different receptors. So, recently, as you all know, antibody can link to drugs, called antibody-drug conjugates. In fact, antibodies today can conjugate with a, with a linker, conjugate small molecules, antisense or oligonucleotides, you know, you know, this is for gene therapies, for example, and also, other proteins. And a couple of these, BBB crossing capability, so you can really open up multiple avenues targeting different targets. Including actually, recently, people started looking for antibodies can also, similar to PROTAC, where you have antibody degraders.
These modalities can also be delivered across the BBB to target neurodegenerative diseases. Of course, Alector is not working on this, but for brain tumor, which also suffers as drugs cannot get use of the brain, can also benefit from this BBB crossing technologies.
Thank you, Dr. An. Operator, I think we're ready for our next question.
One moment for our next question. Our next question will come from the line of Myles Minter from William Blair. Your line is open.
Hi. Thanks for the presentation. Very insightful. Maybe for Dr. An and maybe the Alector team can comment on it as well. Just the anemia signals that we're seeing clinically with transferrin receptor conjugates here, I think it appears in Denali, certainly had an issue there. And even if you look at the Trontinemab data for the anti-amyloid antibody from Roche, showed there was a potential anemia signal in that, that self-subsided. So is that something that's inherent to TFR sort of shuttling mechanisms that we're using to cross the blood-brain barrier here? Or is that more something to do with, like, the Fc region or the effector regions or the payloads of the drugs, and this can be engineered out? I know you're looking at this potential signal across your platforms.
Just wondering whether it's inherent to TFR, and if you do see that signal, you're gonna have to go elsewhere with another shuttling mechanism. Thanks.
Yeah. I see the anemia signal is actually mostly related to TFR because the target is the endothelial cells. So the TFR as a delivery vehicle has been tested in the clinic. You mentioned about Denali, also Genentech and Roche, recently. So the safety is a question. There was already a question about the safety issue. So to me, let's say you did desire a chronic drug for chronic neurodegeneration, like Alzheimer's disease. Ideally, you want to have a drug that can be administered subcutaneously, say, 1 ml of injection.
So then you want to find a safety window that's not going to cause anemia or the transferrin receptor internalization because of the high affinity of your vehicle or the avidity effect of your vehicle. So that's why I think the Alector's approach of to identify a pa-... You know, you make available multiple affinities antibodies targeted transferrin receptor. Then you based on the clinical dosing strategy to find the best affinity, either lower or higher, you have the you target delivery, say, maybe five times for brain penetration, but yet you do not have the the side effects such as as anemia signal. So I think it's fit for purpose.
I like the word of fit for purpose, where you, for a particular drug design, you need to have a specific vehicle with the appropriate affinity, avidity, and also the format, such as single chain or IgG or Fab fragment.
Thanks, Dr. An. Eric, or maybe on anything-
Just to add a little bit to that. I mean, I think the anemia phenotype is an inherent risk in TFR therapeutics, but it's not an inherent outcome. I mean, we showed data from a study using modulated effector function Fc, where we didn't see an anemia phenotype. We've conducted other studies with, you know, different, maybe more active Fcs, and we see that's one of the more key routes by which you can tune the anemia phenotype. We also think that there are some inherent pairings where even with effectorless Fc, you might be able to drive the anemia phenotype by physically associating, you know, immune cells with the reticulocytes through co-engagement.
So this is, I think, one of the most important reasons why we need to have ABC technology against multiple receptors at multiple different affinity ranges, because we've seen even in our hands, much less the clinical data, that we can modulate these properties. But, you know, it, it really comes down to the mechanism of action of the cargo, right? Like, if the cargo is gonna require active effector function, we're gonna have some risk of anemia, as was seen with Trontinemab, right? That's an active effector function to drive depletion of amyloid beta plaques, and it's kind of a little bit inherent in that specific case. So yeah, flexibility, I think, is the, the key.
Yeah. Eric, I just also want to add that, this vehicle, targeted TFR or CD98 heavy chain, maybe future vehicles.
It is very similar to a drug target. You're looking for the drug has efficacy, but it is with use safety window. This is exactly the same say, this vehicle also has a safety window. You want to identify the affinity or dosing, or avidity, or format, this combination of all these that the vehicle should be safe. Like Eric said, it should not say immediate signal. If that's the case, you need to redesign your drug molecule.
Great, thanks.
Just a quick follow-up on the GBA program. Sorry, just a quick one.
Yeah.
Are you using a degradable or ionizable linker for that, GCase molecule? Or when it's actually in the lysosome, are we expecting the full antibody scaffold to be there, with also the active, enzyme? Thanks.
Maxime, do you wanna-
Yeah, good question.
Yeah, so this is a fusion protein. There's no degradable linker. The whole construct gets taken up by the cell and is active in the cell.
Great. Thanks for the questions.
Thanks, Myles. Operator, I think we're ready for our next one from the line.
Thank you. One moment for our next question. Our next question comes from the line of Paul Matteis from Stifel. Your line is open.
Hey, this is James on for Paul. Thanks for taking our question, and I actually had a kind of a follow-up one to Miles's question there, and you kind of sort of answered it, but just wondering, you know, you noted that preclinically in NHPG, you haven't seen any sort of anemia with your TFR1 program. So just kind of wondering, you know, how de-risking is that as it relates to kind of going into the clinic and, you know, what have we learned from these other programs in terms of how much safety can be de-risked here? And then just kind of separately, I'm sorry if I missed this, but just kind of curious where timeline, timelines stand today for some of these lead programs and, you know, when we can expect more updates. Thanks.
Yeah. Yeah, thanks, James. Maybe Eric, do you wanna start on the first part, then I can pick up on timelines?
Yeah. I mean, in terms of translatable safety, that was a favorable initial safety outcome. That particular molecule hasn't progressed to, you know, like a GLP tox study, which is where we would really expect to, you know, fully map out the safety risks. So I will say that we are still currently evaluating the safety on a program-by-program basis when we apply the ABC technology, and then we map it out in, you know, a DRF study, a GLP tox study to make sure we have the most data we can before going into the clinic.
Yeah.
But for the timing, I will look to Peter.
Thanks, Eric. Yeah. So I think for the GCase program that we just discussed, we are starting to basically plan out our non-human primate studies and to move towards our lead molecule. So that's where we stand at this moment, and we'll be happy to update you when we get further down the line.
Yeah. We're also advancing a number of undisclosed programs as well.
Yeah.
We'll keep you updated, James. I know that's not too satisfying right now, but things are progressing in a fairly broad manner.
Oh, great. That's, that's helpful. Thank you.
You bet. Our next question from the line, operator.
One moment for our next question. Our next question comes from the line of Anand Ghosh from H.C. Wainwright. Your line is open.
Hey. Hi, thanks. I have a couple of questions. The first one is, you know, with respect to the anemia data, what's the rationale, when you see, some aspect of anemia coming back, with the second dosing and not with the first dosing?
Eric, do you wanna start there?
Yeah, that was kind of a surprising phenotype that we saw there. I mean, one potential consideration, considering we had two dosing events 28 days apart with a human Fc, is that we might have started to develop some ARIA between the first and second dose. Not ARIA. We might have developed some anti-drug antibody between the first and second dose that might have enhanced some of the, you know, effector function of, you know, the antibody after the second dose. But we have not fully mapped that out. We were surprised to see differences between the first and second dose.
Got it. You know, so you mentioned ARIA. You know, when you look at the Trontinemab data from Roche, they hardly seen any ARIA with their blood-brain barrier platform. And so, you know. And if you think looking at your TREM2 program, so first of all, why does it mechanistically make sense using a transport like ABC kind of transport platform, where you don't see such a drastic ARIA, which you will see in normal kind of infusion system?
Yeah, maybe Eric, if you wanna start, and Arnon, if you wanna comment as well.
I mean, I think there's two effects in the specific Trontinemab example. One, they were enabling themselves to use significantly lower dose by adding the anti-TFR technology on. And the second is by shuttling, you know, the drug out of the serum, where the ARIA effect might well be, you know, due to perivascular macrophages on amyloid deposits that aren't even in the CNS at all, right? So the drug level in the serum might be what's most important in driving that. And by lowering the dose and actually decreasing the systemic clearance through TFR, both of those mechanisms might decrease the drug level that's actually being exposed to the cell types that are driving the ARIA phenotype.
Very nice. And you know, so one of the criticism with the trontinemab data was also with respect to ADA, which you kind of mentioned also with your antibody or with your system, but and the immunoinflammatory aspect of trontinemab. So what, you know, what are the ways you are thinking to kind of de-risk your platform concerning these two kind of side effects?
Eric?
Yeah, that, that is a really excellent question. So obviously, we try to map out in silico that our shuttles themselves are, you know, highly human and highly non-immunogenic. In terms of mapping that into the clinic, I think that's something you really have to keep an eye on. Like, when I mention ADA of a human antibody dosed into a non-human primate, that's not necessarily something you would expect to mimic when you're dosing a human antibody into a human in the clinic. So I think that's just something we're really gonna have to keep an eye on in our Phase I safety studies.
Mm. Okay, and, you know, I have my last question, which is, you know, for targets related to TREM2 or, let's say, in future, some other immunomodulatory targets, what are the safety implications concerning, you know, how much of expression you want to see, especially with respect to these kind of cell surface receptors? And so what are the, you know, like, what kind of safeguards you will have as you are designing these platforms, specifically for immunomodulatory molecules like TREM2?
Yeah. I think Dr. An gave a pretty good answer in terms of everything comes down to therapeutic window, right? So how much drug do we need to activate that receptor to the degree that we need to? And then at that dose level, are we seeing unacceptable safety risks? So again, I think it's a really case-by-case phenomenon where we have to evaluate both TFR and potentially CD98 ABC technology, particularly because, you know, immunomodulatory antibodies might require things like active effector function, Fc, which are less compatible potentially with the TFR technology. So this is why we think it's great that we have functional shuttles against both.
Got it.
Thank you, Anand-
Thank you
... for the detailed questions. Appreciate that. I, operator, I think we have time for a couple more from the line.
Thank you. One moment for our next question. Our next question will come from the line of Graig Suvannavejh from Mizuho. Your line is open.
Hi, thanks for taking our question. This is Charles Ong with Graig. Just taking a look at the competitive landscape, how does ABC differ from some of the other programs out there, like Denali's or, and Voyager's? And where do you see Alector's competitive advantage to be at? Thanks.
Eric, you want to take that one?
I'll take that one, too. So I think we've worked hard for the last several years to ensure that we're seeing, at the very least, equivalent, but in most cases, better brain uptake than has been at least published for our competitor shuttles. But to be honest, we feel like really our main advantage in the competitive landscape is pairing best-in-class ABC technology with our portfolio of novel immunomodulatory and neuroimmunology targets. So at least to me, I think... I don't want to say, like, our technology necessarily blows everyone else's out of the water, but it's really the pairing of best-in-class ABC technology with our portfolio that enables our value proposition.
Thanks, Charles, for the question. Operator, do we have, do we have an additional question on the line?
Yes, we have one more question. One minute. One moment. Our next question will come from the line of Corinne Jenkins from Goldman Sachs. Your line is open.
Hi, this is Omari Hayles for Corinne. Question for us is, how should we think about the level of GCase enzyme needed to restore normal levels of glycosphingolipids?
Yeah, Maxime, do you want to maybe comment there?
Yeah, thanks for this question. So in GBA mutation carriers, Parkinson's disease patients, their reduction in GCase activity is about 30%-50% compared to non-GBA mutation carriers. So this is what we're targeting to fully restore as far as GCase activity. And the data that we shared with you today is sort of on that, that scale of activity that we're achieving in vivo in mouse.
Maybe a follow-up question.
Go ahead. Go ahead, Omari.
Follow-up question. Sure. Maybe a follow-up question is, do you think you need to restore above normal or levels above normal for... to see clinical benefit?
So I think, you know, that will come mostly from pharmacodynamic readouts, as mentioned earlier. So we'll be measuring... What we want to achieve is reduction or normalization of the substrate levels, and that is what we're going to determine in vivo by testing different amounts of GCase ABC and see what is the minimum amount required to restore normal glucosylceramide levels in the brain of genetically engineered murine models. So that's, you know, data to be determined, yet to be shown in a later time point.
Great. Thank you.
Well, we appreciate all the detailed questions, including some that came in on the chat that we didn't have time for, and we'll look to follow up on those. And we want to thank everyone for their time today. With that, I think we'll turn it back over to the operator to conclude the call.
Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.