Finding The Therapeutic Window: Using Single-Cell Biology To Build More Selective T-Cell Engagers

A conversation between Cyril Konto, MD, CEO, Shennon Biotechnologies, and Morgan Kohler

The development of precision immunotherapies against solid tumors requires researchers to overcome the fundamental challenges, from identifying differentiated targets, to finding highly functional therapeutic binders, to predicting potential safety risks before candidates reach the clinic. However, addressing these challenges demands functional insights at the single-cell level and an integrated approach.

Cyril Konto, MD, CEO of Shennon Biotechnologies, discusses the company’s oncology pipeline, which includes programs in small cell lung cancer, ovarian cancer, and hepatocellular carcinoma, and spans antibody and TCR-based T-cell engagers.

Target selection remains a major challenge in solid tumor drug discovery. What distinguishes a target that is merely biologically interesting from one that you believe has genuine therapeutic potential?

For us, the distinction comes down to whether there is evidence that a target can support a meaningful therapeutic window. We look at several factors, including how strongly and consistently the target is expressed on tumor cells relative to healthy tissue, its prevalence across patients, its accessibility to a therapeutic, and whether engaging that target can generate the desired immune response without unacceptable activity in normal cells. A target can be scientifically compelling, but if it lacks sufficient tumor selectivity or functional relevance, it may not translate into an effective therapy.

This is where we believe ShennonBio’s platform can make a difference. Rather than evaluating targets based primarily on expression, we study the functional interactions between tumor cells, immune cells, and the surrounding microenvironment at single-cell resolution. This allows us to assess not only whether a target is present, but whether targeting it is likely to produce a therapeutically meaningful response in the biological context of a patient’s tumor.

How is the field’s understanding of the tumor microenvironment changing the way companies think about developing immunotherapies for solid tumors?

The field has increasingly recognized that a solid tumor isn't simply a collection of cancer cells. It is an ecosystem. Immune suppression, stromal cells, heterogeneous antigen expression, and other components of the tumor microenvironment can all influence whether a therapy succeeds or fails.

That has important implications for drug discovery. It's not enough to design a molecule that performs well against a tumor cell in isolation. We need to understand how that molecule behaves in a much more complex biological environment and whether it can generate a durable immune response within that environment. We believe studying these interactions at single-cell resolution can help us identify biology that may be missed by more conventional approaches.

T-cell engagers have generated substantial clinical interest, but their development has also highlighted challenges around efficacy and safety. What have researchers learned from the first generation of these therapies that is influencing current discovery programs?

The first generation of these therapies demonstrated that redirecting T cells can be an extraordinarily powerful therapeutic mechanism, particularly in hematologic malignancies. At the same time, we learned that potency alone isn't sufficient. Some early approaches underestimated the complexity of translating that potency into solid tumors, where target expression can be heterogeneous, the tumor microenvironment can suppress immune activity, and antigens may also be expressed at lower levels on healthy tissues.

Those lessons have changed how we think about preclinical development. It is increasingly important to characterize target expression and antigen density across both tumor and healthy tissues, understand how activity changes at different levels of target expression, and evaluate therapies in models that more closely reflect the cellular complexity of human tumors. Preclinical studies also need to interrogate potential on-target, off-tumor activity early rather than treating safety as something that can be addressed later in development.

The goal for the next generation is to engineer therapies that can distinguish tumor from healthy tissue more precisely and generate sufficient activity within the tumor microenvironment while maintaining an appropriate therapeutic window.

How do you think about balancing potency with selectivity when developing immune-based therapeutics for solid tumors?

We don't view maximum potency as the objective. The objective is the right biological activity within an appropriate therapeutic window.

With immune-based therapies, particularly T-cell engagers, extremely potent activity can become a liability if the target is also present on healthy cells. Selectivity therefore has to be considered from the beginning of target discovery rather than addressed only during molecule optimization.

Our approach is to understand the biology at high resolution: where the target is expressed, on which cells, at what levels, and in what biological context. Preclinically, that means characterizing target expression across tumor and healthy tissues, evaluating the functional activity and selectivity of our therapeutic candidates, and studying how they perform in models designed to reflect the complexity of the tumor microenvironment.

We are particularly focused on understanding the relationship between target density, potency, and selectivity. We want to know not simply whether a candidate can kill tumor cells, but whether it can maintain that activity across heterogeneous tumor populations while minimizing activity against healthy cells. Those studies help inform both target selection and therapeutic design before a program advances toward the clinic.

Ultimately, the goal is to build as much understanding of the therapeutic window as possible preclinically so that we are advancing candidates that are potent enough to eliminate tumor cells while being sufficiently selective to minimize activity against healthy tissue.

What role do you expect biomarker development and patient selection to play in determining which patients ultimately benefit from T-cell engager therapies?

We expect biomarkers and patient selection to be extremely important. Solid tumors are heterogeneous, and even patients with the same tumor type can have meaningful differences in target expression, immune cell composition, and tumor microenvironment.

The more precisely we can understand those differences, the better positioned we are to identify patients whose tumors have the biological characteristics required for a particular therapy to work. Over time, we believe T-cell engager development will increasingly involve matching the right target and therapeutic design with the right patient population rather than treating solid tumors as biologically uniform diseases.

What are the biggest remaining scientific challenges in developing effective T-cell engagers for solid tumors, and where does the field need to make the most progress?

There are several interconnected challenges: finding truly tumor-selective targets, addressing heterogeneous target expression, achieving effective T-cell activity within an immunosuppressive tumor microenvironment, and maintaining a therapeutic window that allows meaningful efficacy without unacceptable toxicity.

Target identification is particularly important because many of the downstream challenges are ultimately constrained by the underlying biology of the target. Better molecules can optimize a target, but they can't necessarily overcome fundamentally unfavorable biology. We believe the field needs better ways to interrogate human tumor biology at cellular resolution and identify targets based on functional interactions between cells, rather than relying primarily on expression or association.

One limitation of many current discovery approaches is that they can provide a relatively static view of tumor biology. Expression data can tell us which genes or proteins are present, but not necessarily how individual tumor and immune cells interact, which interactions are functionally important, or how those relationships influence therapeutic response. Solid tumors are dynamic, heterogeneous ecosystems, and important biology can be obscured when we look at averaged signals across large populations of cells. By studying functional interactions at the single-cell level, we believe we can uncover therapeutic vulnerabilities that may be difficult to identify through conventional approaches alone.

As ShennonBio moves from discovery toward clinical development, what are the key scientific milestones you want to see from the pipeline over the next several years, and what would those milestones tell you about the potential of the programs?

The most important milestone will be demonstrating that the biology we discover through our platform translates into therapeutics with compelling preclinical profiles and, ultimately, meaningful activity in patients.

In the nearer term, we want to continue validating novel targets, advance our lead programs through candidate selection and IND-enabling development, and generate increasingly translational data demonstrating selectivity, efficacy, and an appropriate therapeutic window.

As those programs enter the clinic, the key question becomes whether the biological insights that drove target identification and binder selection translate into patients. If we can demonstrate that, it would validate not only individual programs but the broader approach behind ShennonBio: using high-resolution functional biology to uncover therapeutic opportunities in solid tumors that conventional discovery approaches may have missed.

About The Expert

Cyril Konto, MD, is CEO of Shennon Biotechnologies and a biopharma executive with 20 years of experience across oncology, immunology, and advanced biologics. He previously served as CEO of Ichnos Glenmark Innovation, where he led the company’s strategic transformation and secured major partnerships, including a $1.9 billion-plus deal with AbbVie. Earlier, he held leadership and clinical development roles at Allogene Therapeutics, Pfizer, and Bristol Myers Squibb, contributing to the development of medicines including Elrexfio, Yervoy, and Opdivo. He is an oncologist by training and earned his medical degree from Université René Descartes in Paris.