By Jonathan Kagan

Today, ai3Bio launched with $48M to directly target and eliminate disease-causing Th17 cells at their source, in a single step. Read the full announcement here.

I’ve spent my career studying how the immune system surveys our body for threats (infection, injury, cancer) and how it decides when and how to act. That understanding is what led me to recently describe it as a master dial: precise, responsive, and usually right.

However, for more than 15 million Americans, the dial gets stuck in the wrong position, and the immune system attacks the body it’s meant to protect. Existing therapies largely suppress the immune system to calm symptoms or target B cells through indirect processes, leaving the T cells driving many severe autoimmune diseases untouched.

We’re introducing ai3Bio to close this gap. Building on the latest breakthroughs in our understanding of innate immunity, we’re focused on resetting the master dial through precise, targeted depletion of disease-causing T cells. The new company is built around that idea, with backing from UPMC Enterprises and Ziff Capital Partners, who saw the opportunity to address a market that has passed $130 billion without delivering lasting relief for patients.

At ai3Bio, we’re focused on resetting the immune system’s master dial through precise, targeted depletion of disease-causing T cells.

Our name reflects three disciplines that make this new paradigm possible: advanced immunology, autoimmunity, and artificial intelligence.

The Discovery Behind ai3Bio
Our approach starts by identifying exactly which cells are driving autoimmune disease in a given patient. Look at the most widely used therapeutics for autoimmune and inflammatory disease today, and nearly all of them are antibodies aimed at specific cytokines like TNF, IL-17, and IL-23. These drugs neutralize damage after the fact, but the cells producing it remain.

We used an AI platform to study diseased tissue directly and identify the cells responsible instead. Across a wide range of autoimmune conditions, Th17 cells — a type of “helper” T cell — produce too many of these cytokines, resulting in inflammation that attacks healthy tissues.

Our computational platform found that these malfunctioning T cells share the same marker: CD161. It doesn’t matter which cytokine is behind the damage in a given patient: the cells making it are almost always CD161-positive. By precisely targeting Th17 cells and other CD161+ T cells, we can address inflammation across diseases that have historically been treated as unrelated.

Identifying the connection between malfunctioning Th17 cells and so many autoimmune diseases was the first step. Turning that discovery into a therapy meant answering a second question: once you know which cells to remove, how do you clear them from the body? We’ve developed two platforms that answer that question, using distinct mechanisms suited to different biological contexts.

  • STARx (Selective T cell Apoptosis Therapy) works by forcing T cells to eliminate themselves from the body, in a safe and anti-inflammatory manner.
  • T Deplete works by flagging Th17 and other inflammatory T cells for elimination by the immune system’s existing cleanup crew.

STARx: Direct, In Vivo Apoptosis
STARx is built to trigger apoptosis directly in disease-causing Th17 cells, drawing on a natural immune signaling pathway called cGAS-STING. Apoptosis is the body’s natural process for clearing unwanted cells, and it happens constantly without setting off the dangerous inflammatory response that other forms of cell death can trigger.

The protein cGAS senses DNA where it doesn’t belong, and produces a signal called cGAMP. That signal activates a signal transduction pathway named after its central component: STING.

STING was discovered in 2008 as a master switch of the immune system, and early research showed it could activate dendritic cells to stimulate protective T cells, right as checkpoint inhibitors were proving that boosting T cells could drive cancers into remission. But STING sits hidden inside cells, out of reach for antibodies, so researchers turned to small molecules that could activate it from within. Those drugs did activate STING in dendritic cells as intended, but failed to produce durable anti-tumor responses in humans, and the field’s enthusiasm cooled.

The reason took years to uncover: STING behaves differently depending on which cell it acts in.

In dendritic cells, STING stimulates T cells. In T cells, STING kills them. That distinction, a liability in cancer, is exactly what autoimmune disease needs.

The missing piece was precision: small molecules can’t tell one cell type from another, so they activate STING everywhere they go. My team solved this by engineering a modified version of cGAS called cGASΔN, delivered as mRNA rather than a small molecule so it can be aimed at a specific cell type. It’s carried inside a lipid nanoparticle, or LNP, paired with a high-affinity antibody that guides it to CD161-marked Th17 cells. Once there, it triggers those cells to undergo apoptosis.

Preclinical testing of blood samples from patients with diverse autoimmune diseases demonstrated that the LNP technology removed disease-causing Th17 cells, prevented new Th17 cells from forming, and reset the inflammatory cytokines that cause autoimmune symptoms. Studies in non-human primates have established the utility of this preclinical therapy to target T cells, and additional work is underway to derisk this exciting new technology.

T Deplete: A Targeted Antibody Approach
Our second platform, T Deplete, is a standalone depleting antibody that binds to CD161-marked Th17 cells and kills them using a mechanism called antibody-dependent cellular cytotoxicity (ADCC). ADCC leverages the patient’s own immune system — specifically, natural killer (NK) cells — to target and eliminate disease-causing cells.

More than 20 depleting antibodies (such as those targeting CD20, CD19, CD38, CD52, or specific cell surface markers) have brought significant benefit to patients and have been approved by the FDA which provides strong validation of the ADCC approach. However, most approved depleting antibodies for autoimmune disease target B cells, leaving considerable unmet need for diseases that are driven largely by pathogenic T cells.

While a number of other T cell depleting antibodies have been tested in different autoimmune diseases, there have been few successes. This is likely due to the fact that they either target all T cells leading to side effects and severe immune suppression or they target the wrong T cells and do not deplete the most relevant T cell subsets that drive disease.

T Deplete selectively depletes the pathogenic “bad actor” T cell subsets while sparing those that do not drive autoimmunity.

T Deplete demonstrated potent efficacy in non-human primates suffering from experimental autoimmune disease, with IND-enabling safety studies underway that will advance to first-in-human trials in autoimmune disease.

The People Behind the Platform
I’m fortunate to be building ai3Bio alongside a powerhouse team. CEO and repeat entrepreneur Dr. Steven Altschuler brings more than 20 years of deep experience leading consequential biotech companies. Drug-discovery veteran Dr. Michael Lyman is Chief Technology Officer, with deep experience bringing therapeutic antibodies to the clinic. Nick Seaver, Chief Financial and Business Officer, brings sharp financial and operational leadership, including building out the company’s AI-driven infrastructure. Our board is chaired by Fabian Tenenbaum of UPMC Enterprises.

Our scientific advisory board brings even more firepower. It includes John Maraganore, strategic advisor to the company, scientific advisory board member, and founding CEO of Alnylam Pharmaceuticals, alongside Alexander Rudensky, Ruslan Medzhitov, Vijay Kuchroo, Arlene Sharpe, Dario Vignali and Greg Delgoffe. The expertise of these luminaries spans all areas of inflammation and disease, including world class experience in Th17 cells, regulatory T cells, cancer immunotherapy, and innate immunity. Several are members of the National Academy of Sciences.

What’s Next
Our near-term focus is advancing both STARx and T Deplete through IND-enabling work toward an initial patient trial in 2027.

Validation in one autoimmune indication builds a foundation we can extend to others, reusing the same target, biology, and delivery infrastructure across a broader portfolio.

Studying how the innate immune system recognizes and responds to threats has been the work of my career. Resetting that system is the life-changing work ahead of us: moving millions of patients from a lifetime of managing their disease to the possibility of lasting remission. This is just the beginning.

To learn more about ai3Bio, visit https://ai3.bio/contact.