Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy

Abstract

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies.

Nanoparticle T cell engagers for the treatment of acute myeloid leukemia

“…We have shown previously that the nanoTCE is not able to activate T cells alone; this is shown by the use of the Isotype/CD3. T cells do not activate following the binding of the nanoTCE alone; it only works following the engagement of the T cell and the target cell via nanoTCE which aligns with the kinetic segregation model for T cell receptor triggering [ 16 , 30 ]. Consequently, no T cell-mediated killing of AML cells was observed following treatment with Isotype/CD3 TCEs, while 50–75% killing was observed following treatment with CD33/CD3 nanoTCEs for 4 days ( Figure 3C ).…”

“…The procedure of making nanoTCEs has been previously described [ 16 ]. Briefly, nanoTCEs were prepared with three components: cholesterol, DPPC, and DSPE-PEG2000 with a molar ratio equivalent to 30: 65: 5.…”

“…We have previously developed a nanoparticle-based T cell engagers (nanoTCEs) technology that is based on conjugation of two monoclonal antibodies (mAbs) to the surface of a liposomal nanoparticle; one antibody is against a cancer antigen and the other is against the CD3 receptor on T cells [ 16 ]. NanoTCEs utilize existing mAbs which we conjugate to the surface of a nanoparticle, therefore taking advantage of the high specificity of existing mAb-based therapies, to engage and direct robust responses from the immune system (T cells).…”

“…NanoTCEs utilize existing mAbs which we conjugate to the surface of a nanoparticle, therefore taking advantage of the high specificity of existing mAb-based therapies, to engage and direct robust responses from the immune system (T cells). NanoTCEs have been shown to have clear advantages compared to both CAR-T cells and TCEs; nanoTCEs are: 1) simple to produce – the production of nanoparticles and chemical conjugation of readily available mAbs takes only a few hours; 2) prolonged pharmacokinetic profile (t 1/2 ~ 60 hours), 3) modular platform allowing customizable targeting of multiple tumor and immune cell antigens [ 16 ]. Moreover, nanoTCEs has demonstrated therapeutic efficacy in endogenous T cell activation as well as T cell-directed cancer cell lysis, both in vitro and in vivo .…”

Ultrasound‐Responsive Microfluidic Microbubbles for Combination Tumor Treatment

“…[10,12,13] Although there are many advantages, traditional administration of these drugs causes off-target accumulation and serious systemic adverse effects; [14][15][16] however, the delivery of nanomaterials remains limited by uncertain clearance mechanisms, poor maneuverability, and complex synthetic processes. [17][18][19] Thus, new drug carriers with improved administration techniques and biosecurity, as well as effective tumor-targeting, are required.…”