Target-Specific T Cell Activation
For our lead clinical SQZ™ APC product candidate, we engineer cells to drive efficient MHC-I mediated antigen presentation. MHC-I antigen presentation is vital to activate a target specific CD8 T cell response.
1 Creating SQZ™ APCs
We squeeze a patient’s own immune cells with disease-specific antigens to create SQZ APCs. Squeezing delivers antigen into the cytosol of cells, where antigen is loaded onto MHC-I molecules. Antigen sequences presented by the MHC-I surface molecules activate CD8 T cells as part of their APC-T cell “handshake.”
4 SQZ APC-T Cell Handshake
Once delivered back into the patient, the SQZ APCs present antigen via MHC-I to CD8 T cells. This “handshake” between the SQZ APC and the CD8 T cell occurs when the MHC-I presented sequence matches with the T cell’s receptor (or TCR). Once complete, the CD8 T cell will be activated and proceed to seek out and kill its target.
7 T Cells Attack Target Cells
CD8 T cells can travel and infiltrate tissues all over the body to access the intended target. Once the target cell has been identified by the TCR, it is killed by the CD8 T cell.
Enhancing our APCs to Create eAPCs
SQZ™ APCs are designed to meaningfully improve CD8 T cell activation by enabling robust MHC-I presentation of target antigens. This provides the critical ‘signal 1’ to CD8 T cells with which other vaccine mechanisms have struggled.
SQZ™ enhanced APCs (eAPCs) further build on these capabilities by using mRNA to provide additional stimulatory signals to the CD8 T cells (‘signal 2’ and ‘signal 3’) in the context of their target antigen. This modification to our APCs aims to enable more potent CD8 T cell responses, with a broader addressable patient population, while maintaining the desired specificity.
More Functions for More Patients
We can continuously enhance the functions of our cell therapy platforms. SQZ™ eAPCs are engineered with multiple mRNA cargos that can potentially drive even more powerful immune activation for a broader patient population.
Enhancing APC Functions
There are multiple signals that contribute to effective CD8 T cell activation during the APC-T cell handshake. Beyond the MHC-I antigen (signal 1), our eAPCs use multiple mRNA cargos to express co-stimulatory molecules (signal 2) and membrane-bound cytokines (signal 3) that ultimately could improve the quantity and quality of T cell response.
Expanding APC Targets
The use of mRNA technology allows us to encode full target proteins thereby broadening the targeted antigen repertoire. This is designed to generate a more polyclonal T cell response and expand the number of patients who can be treated by our APC therapies.
Increasing APC Applicability
By encoding broader antigen repertoires and establishing a multiplexed mRNA-based cell engineering process, the eAPCs could expand our addressable patient population and could make it easier to translate the platform for future products in other indications.
SQZ™ APCs for Oncology
SQZ APCs are currently being investigated in a Phase I clinical trial for HPV+ tumors, including cervical, head & neck, and anal cancers. SQZ APCs in oncology are being developed in partnership with Roche.
The SQZ APCs are engineered with tumor-specific antigens and are designed to direct CD8 killer T cells to precisely attack a patient’s cancer. The SQZ APC platform has preclinically demonstrated the potential to induce robust immune responses against a broad range of tumor targets. The SQZ APC platform could serve as the basis for a broad portfolio of treatments for cancer patients.
Our lead SQZ APC product candidate, SQZ-APC-HPV, is focused on HPV+ solid tumors. SQZ-APC-HPV is being evaluated in a Phase 1 clinical trial for the treatment of HPV16+ advanced or metastatic solid tumors.
SQZ™ APCs for Infectious Disease
We plan to begin clinical development in chronic diseases, such as Hepatitis B Virus (HBV), and explore future applications in acute and emerging infectious diseases.
Similar to oncology, CD8 T cells play a critical role in controlling and potentially curing many infectious diseases. Insufficient activation of CD8 T cells by APCs is likely a key problem that has inhibited success of therapeutic vaccines in infectious disease.
SQZ APCs and eAPCs in infectious diseases have the potential to drive powerful and specific CD8 T cell responses against infected cells. These mechanisms could be applicable to many chronic and acute infectious diseases in both prophylactic and therapeutic patient settings.