Aulos’ Selective Antibody Surmounts Limits of Existing IL-2 Therapeutics, Mimetics

15 Nov 2021
www.biospace.com
CollaborateAntibodyImmunotherapy
Aulos Bioscience is developing a computationally-designed antibody that binds to Interleukin-2 (IL-2) in a selective and potent way, giving it the potential to replace other IL-2 therapies in solid tumor treatments. This preclinical data was presented at the Society for Immunotherapy of Cancer (SITC’s) 36th Annual Meeting, November 10-14, prior to an upcoming Phase I/II trial. The investigational drug, a monoclonal antibody dubbed AU-007, directs a patient’s own IL-2 toward immune activation while simultaneously preventing IL-2’s immune suppression activities. AU-007, therefore, appears to overcome the limitations of direct IL-2 therapy and IL-2 mimetics. BioSpace caught up with Aulos CEO Aron Knickerbocker before the presentation. Here’s what he told us. BioSpace (BSp): What’s unique about AU-007? Aron Knickerbocker (AK): IL-2’s diverse activities on the immune system are regulated by a family of IL-2 receptors that contain various subunits: CD25, CD122 and CD132. CD25 plays a dominant role in the immunosuppressive and vascular activation activities of IL-2. Aulos’ mAb redirects a patient’s own IL-2 away from the high-affinity CD25-containing receptors on T regulatory cells to lower affinity receptors that lack CD25 on T effector cells, shifting the IL-2 activity away from immune suppression and towards immune activation. More specifically, it blocks the binding of IL-2 to CD25, but not to CD122 and CD132. This allows for immune activation, but we believe it also will subdue the immune suppression, vascular leak syndrome, pulmonary edema and hypotension that are also mediated by IL-2. BSp: What are the challenges with this approach? AK: One of the challenging aspects of drugging the IL-2 pathway is that T effector cells make and secrete more IL-2 when they are stimulated through their dimeric IL-2 receptors and presented with antigens. So, exogenous forms of IL-2, even so-called non-alpha IL-2 derivatives, actually drive the production of endogenous IL-2 by activated T effector cells. The newly-produced endogenous IL-2 then, typically, will bind to the high-affinity IL-2 receptors on immunosuppressive T regulatory cells. (This is) because those receptors bind at 100 times tighter binding affinity than the lower affinity IL-2 receptors on effector cells. This results in a negative feedback loop that we believe blunts the anti-cancer efficacy of other IL-2 based therapies. By preventing IL-2’s binding to CD25 and the trimeric receptors that contain CD25, we believe AU-007 will have a significant competitive advantage in terms of efficacy and safety. The efficacy advantage is generated by transforming a negative feedback loop to T regulatory cells into a positive feedback loop on the T effector cells. The safety advantage is generated by preventing IL-2 from binding to the trimeric receptors on vasculature and thus preventing the otherwise-ensuing lung edema, hypotension and vascular leak syndrome. Because AU-007 is a human IgG1 antibody, we also believe we can dose it every few weeks, and that the product has a low risk of immunogenicity. BSp: What real difference can this new type of IL-2 therapeutic make to solid tumor treatment? AK: We have known for years that IL-2 has anti-cancer activity and that it can even lead to durable, complete responses in some patients. The issue is that it is often quite toxic, and so it does not currently get much use. Over the last few years, there has been a major push to widen the “therapeutic index” and create IL-2 based therapeutics that offer more efficacy with less toxicity. This has been challenging because IL-2 binds both to immunosuppressive and immune-activating cells, which can confound realizing efficacy gains, as well as to vasculature, which drives adverse events such as vascular leak syndrome, swelling in the lungs and hypotension. BSp: Why is it just now being developed, and why are you the first to do so? AK: We were not the first to have this concept of an antibody to the CD25-binding domain of IL-2, but it was a technical tour de force to make it a reality as a clinical candidate. IL-2 is a very small cytokine protein with only 153 amino acids, and the part of it that binds to CD25 is an even smaller patch. Imagine trying to parachute out of an airplane and land right on the top step of an Olympic podium in the middle of a stadium – it’s not an easy assignment. We only wanted our antibody to cover one of the steps on the podium so the other two would be unoccupied and free to interact with CD122 and CD132. Conventional antibody technologies failed to achieve the specificity and affinity needed to land solely on this very small epitope and stay on it. BSp: What did you do differently to develop AU-007, and why couldn't the drug have been generated using standard antibody discovery methods? AK: Our product, AU-007, is a human antibody that was computationally evolved by world-class machine learning with our partners and co-founders at Biolojic Design in Israel. The artificial intelligence approach used to design our antibody mimics the way our own immune system makes antibodies and employs proprietary machine learning algorithms that rationally design specific, highly selective and functional antibodies capable of executing novel therapeutic biological activities. The machine learning algorithms have been trained on a massive dataset from billions of amino acid sequences from antibodies and their target epitopes, so the machine learns from Mother Nature which amino acids in which positions and spatial orientations improve complementarity to a given target epitope. BSp: You are planning to initiate a Phase I/II trial next. What are its goals? AK: We will be evaluating different dose levels of AU-007 to assess the safety pro to identify a dose to take forward to later phases of development. We will also include measurements of the antibody’s pharmacokinetics, as well as measurements of pharmacodynamic effects in the tumor and peripheral blood, such as changes in T cell populations and cytokine levels. Additionally, we will be looking at efficacy assessments such as objective response rates, depth of response, response durability and progression-free survival.
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