The two studies demonstrate proof-of-concept that genetically engineered variants of cell surface receptors harboring single amino acid substitutions are fully functional but evade a paired immunotherapy directed against the wild-type molecule. This technology will enable the development of more efficient and safer targeted conditioning regimens for hematopoietic stem cell transplantation, gene therapies, and opens the path to more efficient cell and immunotherapy-based treatment approaches for hematological malignancies.
The first abstract was titled “Function-preserving single amino acid substitutions shield hematopoietic stem and progenitor cells from CD117 targeted immunotherapy in vivo.” The receptor tyrosine kinase c-KIT is expressed on normal hematopoietic stem cells but also on leukemia cells. Consequently, it is an attractive target for an antibody-based conditioning therapy.
The study showed that cells expressing a genetically engineered variant of CD117 are fully functional in vitro and contributed to the blood development in vivo, similar to unmodified HSCs expressing the wt receptor. Mice transplanted with a mix of human HSCs expressing either wt CD117 or the Cimeio shielded CD117 variant showed a selective depletion of wt CD117 cells, while those cells expressing the variant receptor were spared following the treatment with a monoclonal antibody directed against wt CD117.
The second abstract, titled “Engineered Single Amino Acid Substitutions Protect Hematopoietic Stem and Progenitor Cells From CD123 Targeted Immunotherapy,” focused on targeting the interleukin-3 receptor alpha-chain a cytokine receptor highly expressed on various hematological malignancies as well as normal hematopoietic cells. This abstract demonstrated that shielded CD123 cells were not depleted by a highly efficient CD123 targeted immunotherapy.
Collectively, these preclinical studies demonstrate the feasibility and efficacy of Cimeio’s SCIP platform, a novel and promising therapeutic approach to improve the outcomes for patients with benign and malignant hematological diseases in need of an HSC transplant.
“Many severe and late side effects following an HSC transplant are caused by untargeted and broadly toxic chemotherapeutics and radiation in conditioning regimens. The presented work is an encouraging and important step towards safer and efficient approaches to overcome these hurdles. Cimeio’s SCIP platform could allow more patients facing debilitating and fatal diseases to receive a life-saving HSC transplant.”
Suneet Agarwal, M.D., Ph.D., Co-Program Leader for the Stem Cell Transplant Center at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Associate Professor of Pediatrics at the Harvard Medical School, and member of the Cimeio Scientific Advisory Board
Last month, Cimeio announced the issuance of a foundational patent that covers a method for in vivo selective depletion of edited primary hematopoietic cells or non-edited primary hematopoietic cells, the basis of its SCIP platform.
About Cimeio
Cimeio is an applied gene editing and immunotherapy company developing a portfolio of Shielded-Cell & Immunotherapy Pairs™ which has the potential to transform hematopoietic stem cell transplant. Cimeio’s technology platform is based on the design and expression of modified variants of naturally occurring cell surface proteins in HSCs. These novel variants maintain their function but are resistant to depletion when targeted by a paired immunotherapy which has high affinity for the wild-type version of these proteins. This technology has significant therapeutic potential, which Cimeio is using to develop curative treatments for patients with genetic diseases, hematologic malignancies, and severe autoimmune disorders.