Raghav Garg

Allogenic hematopoietic cell transplantation (alloHCT) is the process of taking donor blood stem cells also called hematopoietic stem cells (HSCs), and transplanting them into a patient to treat cancer or other blood diseases. The donor blood will attack the old blood and kill malignant cells and leukemia. Graft versus host disease occurs when the donor T cells derived from donor HSCs attack nonmalignant tissues like the gut, skin, etc. This technique therefore relies in part on donor T cell responses against host alloantigens that are shared between leukemia and nonmalignant cells. Donor T cell damage to host alloantigen bearing tissues can culminate in graft-vs-host disease (GVHD) that has significant morbidity and mortality. I employed the novel technique OF Co-localization dependent Latch Orthogonal Cage-Key Protein” (“Co-LOCKR”). With Co-LOCKR, rather than relying exclusively on CARs for on-target AML sensitivity/specificity, a 3-module solution is implemented targeting the key players CD33, CLEC12A and CD83. AML cells have a unique surface expression of CD83 that distinguishes them from other progenitor cells. Therefore, generating nanobodies that targets cells that are CLEC12A/CD33 and CD83 would allow efficient targeting of AML cells. This nanobody is then engineered with a “cage” and “latch.” The cage sequesters the latch protein except for when a specific “key” is presented. This key is engineered onto the nanobody that targets CD83. The interaction with the cage-latch complex, causes a conformational change in the cage, releasing the latch exposing an altered Bim protein.