Multiantigen T-Cell Hybridizers: A Two-Component T-Cell-Activating Therapy.
M Tommy GamblesShannuo LiIsaac KendellJiahui LiDouglas SborovPaul ShamiJiyuan YangJindřich KopečekPublished in: ACS nano (2024)
Multispecific T-cell-engaging scaffolds have emerged as effective anticancer therapies for the treatment of hematological malignancies. Approaches that modulate cancer cell targeting and provide personalized, multispecific immunotherapeutics are needed. Here, we report on a modular, split antibody-like approach consisting of Fab' fragments modified with complementary morpholino oligonucleotides (MORFs). We synthesized a library of B-cell-targeting Fab'-MORF1 conjugates that self-assemble, via a Watson-Crick base pairing hybridization, with a complementary T-cell-engaging Fab'-MORF2 conjugate. We aptly titled our technology multiantigen T-cell hybridizers (MATCH). Using MATCH, cancer-specific T-cell recruitment was achieved utilizing four B-cell antigen targets: CD20, CD38, BCMA, and SLAMF7. The antigen expression profiles of various malignant B-cell lines were produced, and using these distinct profiles, cell-specific T-cell activation was attained on lymphoma, leukemia, and multiple myeloma cell lines in vitro . T-cell rechallenge experiments demonstrated the modular approach of MATCH by sequentially activating the same T-cell cohort against three different cancers using cancer antigen-specific Fab'-MORF1 conjugates. Furthermore, MATCH's efficacy was demonstrated in vivo by treating xenograft mouse models of human non-Hodgkin's lymphoma with CD20-directed MATCH therapy. In the pilot study, a single dose of MATCH allowed for long-term survival of all treated mice compared to saline control. In a second in vivo model, insights regarding optimal T-cell-to-target cell ratio were gleaned when a ratio of 5:1 T-cell-to-target cell MATCH-treated mice significantly delayed the onset of disease compared to higher and lower ratios.
Keyphrases
- cancer therapy
- single cell
- cell therapy
- papillary thyroid
- signaling pathway
- endothelial cells
- mouse model
- acute myeloid leukemia
- diffuse large b cell lymphoma
- squamous cell
- high fat diet induced
- squamous cell carcinoma
- young adults
- drug delivery
- adipose tissue
- skeletal muscle
- mesenchymal stem cells
- single molecule
- insulin resistance
- pluripotent stem cells
- induced pluripotent stem cells