At SITC 2023, we presented two posters that illustrate how we’re leveraging our CD3 T-cell engager platform to discover and develop immuno-oncology therapeutics for multiple tumor targets.
A rational approach for selecting CD3-binding antibodies for T-cell engager development
Fine-tuning CD3-binding affinity is not enough.
A commonly used approach for T-cell engager development is to modify the affinity of non-proprietary CD3-binding antibodies to mitigate the risk of cytokine release syndrome. However, our data presented at SITC demonstrates that CD3 affinity alone is not sufficient to optimize T-cell engager function.
A streamlined, function-first approach.
T-cell engager function is determined by the complex interplay between parameters that make up the immune synapse, including binding affinities, epitopes, geometries, and specificities for the CD3- and tumor-binding arms. To address this challenge, we developed a data-backed approach for selecting CD3-binding antibodies for different tumor targets based on function rather than individual binding parameters.
Previously, we presented data describing development of our T-cell engager platform, which includes novel CD3-binding antibodies, discovery capabilities for challenging tumor targets, and high-throughput bispecific engineering and characterization. By integrating the insights presented at SITC, we’re now able to strategically select functionally diverse CD3-binding arms to then test empirically for each tumor target.
Leveraging the platform for multiple tumor targets.
We’re now using this platform to discover and develop T-cell engagers for multiple programs. Our presentation included data from two of these programs targeting prostate-specific membrane antigen (PSMA) and melanoma-associated antigen 4 (MAGE-A4).
Discovery and development of functional and specific T-cell engagers against a MAGE-A4 pMHC
Unlocking inaccessible antigens inside tumor cells.
T-cell engagers that recognize intracellular tumor peptides displayed on major histocompatibility complexes (pMHCs) can help immune cells fight cancer. However, developing effective T-cell engagers against pMHCs is challenging because the tumor-binding arm needs to bind the target with high affinity and specificity.
An integrated T-cell engager platform for challenging pMHC targets.
We have developed an integrated technology platform to streamline the discovery, engineering, and high-throughput assessment of T-cell engagers against pMHC targets. Previously, we presented data on the discovery of 45 diverse, specific, and developable antibodies against MAGE-A4, a pMHC expressed by many solid tumors, but not by most healthy tissues.
We presented new data at SITC 2023 on the strategic selection and pairing of these MAGE-A4-pMHC binders with antibodies from our CD3 platform to generate hundreds of MAGE-A4xCD3 T-cell engagers for high-throughput, multi-parameter functional and specificity assessments.
A panel of functional T-cell engagers against MAGE-A4.
We identified 12 functional and specific MAGE-A4 x CD3 antibodies with potent T-cell-mediated tumor-cell killing, low cytokines and high binding specificity to MAGE-A4-pMHC. In addition, we used high-resolution structural assessments to demonstrate diverse antibody binding orientations to MAGE-A4-pMHC.
We will continue to profile these T-cell engagers through additional functional, specificity, and developability assessments.