Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia.
Priscilla DoLacey A PerdueAndrew ChyongRae HunterJodi DouganCurtis J HenryChristopher C PorterErik C DreadenPublished in: ACS combinatorial science (2020)
Therapies that bind with immune cells and redirect their cytotoxic activity toward diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells toward leukemic B cells and simultaneously cotargets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bispecific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of composition-function relationships. Using this approach, we identified CD19 × CD3 × IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.
Keyphrases
- cell therapy
- single cell
- high throughput
- acute myeloid leukemia
- induced apoptosis
- bone marrow
- endothelial cells
- cell cycle arrest
- systemic lupus erythematosus
- stem cells
- small molecule
- emergency department
- binding protein
- current status
- quantum dots
- highly efficient
- mesenchymal stem cells
- lymph node metastasis
- sensitive detection
- pi k akt
- bioinformatics analysis