The Cellular Handshake
How Cell Avidity Reveals the Hidden Language of Immunotherapy
For decades, cancer researchers focused on the strength of single molecular bonds. Now, they're discovering that the collective strength of cellular interactions holds the key to designing smarter, safer immunotherapies.
Why the "Single Bond" Approach Falls Short
Imagine trying to predict the success of a handshake by only measuring the strength of one finger. This is analogous to traditional methods in immunotherapy development. Molecular affinity (the strength of a single receptor-ligand bond) has long been the gold standard, measured by techniques like surface plasmon resonance (SPR) or tetramer binding. Yet, these methods often fail to predict real-world therapeutic outcomes because they ignore the complex, dynamic environment where immune cells interact with targets – a crowded cell membrane where multiple bonds form simultaneously 1 4 .
Cell avidity emerges as the crucial missing piece: the integrated, total strength of multiple interactions between a cell (like a therapeutic T cell or NK cell) and its target (like a cancer cell or protein-coated surface). It's the difference between a single finger touch and a firm, full-palmed handshake.
Molecular Affinity
Traditional measurement of single receptor-ligand bond strength, often poorly correlating with therapeutic outcomes.
Cell Avidity
Integrated measurement of multiple interactions in physiological context, better predicting real-world efficacy.
Decoding the Cellular Handshake: How Avidity Works
Cell avidity isn't merely "affinity multiplied." It's a sophisticated biological phenomenon operating on multiple levels:
- Zero-Order Avidity 1
- The intrinsic affinity of a single binding event (e.g., one TCR recognizing its peptide-MHC).
- First-Order Avidity 2
- The combined strength from bivalent or multivalent binding (e.g., both arms of an antibody binding two antigens).
- Second-Order Avidity 3
- Synergistic interactions combining binding (e.g., Fab-antigen) with stabilization (e.g., Fc-Fc interactions).
- Third-Order Avidity 4
- Large-scale immune complex formation triggering effector functions (e.g., complement activation).
Why Cell Avidity Outperforms Traditional Affinity Measurements
| Parameter | Molecular Affinity (e.g., SPR) | Cell Avidity | Significance |
|---|---|---|---|
| Measurement Focus | Isolated molecule interaction | Cell-to-cell or cell-to-protein interaction in physiological context | Reflects real biological setting |
| Key Output | Dissociation constant (Kd) | Percentage of cells bound after force application; Binding kinetics under load | Measures functional binding strength relevant to tissues |
| Predicts | Binding potential in solution | Functional outcomes: Cytotoxicity, T cell activation, tumor penetration, safety profile | Directly correlates with therapeutic efficacy & safety |
| Limitations | Misses cellular context, often poorly correlates with function | More complex assay setup; Requires specialized instrumentation | Explains failure of high-affinity binders in clinical trials |
Spotlight Discovery: Biparatopic Antibodies Outsmart Cancer Resistance
A groundbreaking 2025 study led by Dr. Chaturantabut (Sellers Lab) exemplifies how cell avidity drives rational drug design. The team tackled a major challenge in cholangiocarcinoma (bile duct cancer): resistance to drugs targeting FGFR2 fusion proteins 1 3 .
Traditional bivalent antibodies binding the same FGFR2 epitope (monotopic) were limited. Could antibodies binding two distinct, non-overlapping epitopes (biparatopic) simultaneously generate superior avidity, block signaling more effectively, and force receptor internalization?
The Avidity-Driven Method:
Systematic creation of biparatopic antibody pairs targeting diverse FGFR2 extracellular domain epitopes.
Cell avidity assays using the z-Movi® platform measured the real binding strength under physiological force conditions.
Functional assays assessed signaling blockade, proliferation inhibition, and crucially, internalization.
Results & Eureka Moment:
FGFR2 Biparatopic Antibody Impact (Chaturantabut et al., 2025 JCI)
| Antibody Type | Cell Avidity (z-Movi % Bound) | Proliferation Inhibition | Activity Against Resistant Mutants | Receptor Internalization |
|---|---|---|---|---|
| Monotopic (Control) | Medium (40-60%) | Partial (~50-70%) | Limited (<20%) | Slow/Partial |
| Lead Biparatopic A | High (>85%) | >90% | >80% | Rapid & Robust |
| Lead Biparatopic B | Very High (>90%) | >95% | >85% | Rapid & Robust |
Illustration of biparatopic antibody binding to two distinct epitopes on FGFR2, creating superior avidity and forcing receptor internalization.
Beyond Antibodies: CAR-T Cells and the Avidity Threshold
The power of avidity extends dramatically to cellular therapies. A pivotal 2024 study published in Nature Immunology (Guruprasad et al.) investigated why CAR-T cells often fail in solid tumors like Hodgkin Lymphoma (HL). They identified the BTLA-HVEM axis as a major culprit within the immunosuppressive tumor microenvironment (TME) 5 .
- Exhibited low avidity binding to CD30+ HL tumor cells
- Weakened cellular handshake
- Reduced effector function
- Showed significantly higher avidity binding
- Stronger adhesion to tumor cells
- Enhanced downstream signaling
The Scientist's Toolkit: Measuring the Invisible Handshake
Understanding and leveraging cell avidity requires specialized tools moving beyond static snapshots:
Avidion® Platform
High-throughput automated cell avidity screening platform (up to 192 measurements/day).
Rapid ranking of large therapeutic candidate pools early in R&D 1 .
Fluorescently Labeled Beads
Beads coated with antibodies, proteins, or engineered cells.
Probes for standardized avidity measurements 1 .
Live-Cell Imaging
Tracks real-time interactions between immune cells and targets.
Correlates binding duration/strength with killing outcomes 9 .
The Future: Engineering Cellular Handshakes
Cell avidity is revolutionizing immunotherapy development:
Predictive Power
Cell avidity measurements correlate strongly with in vivo efficacy, outperforming traditional cytotoxicity or affinity assays 9 .
Overcoming the TME
Understanding how the TME regulates avidity offers new intervention points 7 .
Engineered immune cells interacting with cancer cells - the future of avidity-optimized immunotherapy.
Conclusion: From Snapshots to the Dynamic Picture
Cell avidity represents a paradigm shift. By capturing the integrated, dynamic, and mechanically relevant nature of cellular interactions, it provides a missing link between molecular binding and functional therapeutic outcomes. As tools like high-throughput avidity screening become mainstream, we move closer to rationally designing the next generation of immunotherapies – therapies engineered not just to bind, but to interact with the right strength, in the right context, to achieve lasting cures. The cellular handshake, once a mystery, is becoming a language we can understand and engineer.