Pan-Specific γ9δ2 T-Cell Antibodies For Activation And Targeted Cancer Immunotherapy

SUMMARY

A panel of pan-specific Vγ9Vδ2 TCR-recognizing antibodies that allosterically trigger T-cell activation to engage and kill cancer cells, making it highly applicable for targeted cancer therapy.

The Unmet Need: Strategy to safely and effectively harness Vγ9Vδ2 T cells for immunotherapeutic interventions

• The field of immunotherapy has increasingly focused on harnessing specialized T-cell subsets that bridge innate and adaptive immunity, offering a promising avenue for combating cancers and infectious diseases. Among these, the role of unconventional γδ T cells has garnered significant attention due to their MHC-unrestricted recognition capabilities. This potential is underscored by the need to activate immune responses in patients who do not respond to existing therapies, highlighting a critical gap in current treatment paradigms. Despite advancements in immunological research, limitations in targeting these cells have been evident, driving the search for more refined approaches.

• Current strategies to engage γδ T cells face considerable challenges. Many of these methods suffer from suboptimal activation, inadequate binding specificity, and low affinity between targeting agents and the T-cell receptors, which limits their effectiveness across diverse patient populations. Additionally, rapid dissociation rates and insufficient structural insights impede the rational design of therapies that can robustly and reliably trigger these cells. These challenges underscore the urgent need for innovative techniques that overcome the inherent complexities in selectively stimulating γδ T cells for therapeutic gain.

The proposed solution: Novel panel of high-affinity antibodies that selectively bind the Vγ9Vδ2 T-cell receptor conferring pan-specificity across diverse patient populations

• The faculty inventor utilized a panel of antibodies developed through competitive phage display that bind the Vγ9Vδ2 T-cell receptor with remarkable specificity and high affinity (KD of 0.12 nM). With proven binding to and activation of γ9δ2 T cells in both engineered systems and primary human cells, the technology includes a modular bispecific T-cell engager format that couples the antibody Fab fragment with a HER2-targeting antibody for redirecting cytotoxic activity against cancer cells.

• This approach stands out due to its pan-specificity across diverse patient populations and exceptional binding kinetics, ensuring a stable and effective complex formation. The integration of high-resolution structural insights with robust preclinical validation demonstrates a clear differentiation from conventional T-cell targeting methods. Its unique ability to bridge innate and adaptive immunity, without reliance on conventional peptide recognition, further distinguishes its potential in advancing targeted immunotherapeutic strategies for cancer treatment.

ADVANTAGES

ADVANTAGES

• High affinity binding to the Vγ9Vδ2 TCR, ensuring stable and specific interaction

• Pan-specific recognition across diverse patient populations due to conservation of key motifs

• Efficient activation of γδ T cells, leading to potent cytotoxic responses against cancer cells

• Modular bispecific T-cell engager design enables versatile targeting of various cancer markers

APPLICATIONS

• Cancer immunotherapy development

• Bispecific T-cell engager therapy

• γδ T cell therapy

• Research tool

March 19, 2025

Proof of concept

Patent Pending

Licensing,Co-development

Anthony Kossiakoff