HSC Engraftment is Enhanced by Combining Mobilization with Anti-C-Kit and Anti-CD47 Based Conditioning in Hematopoietic Stem Cell Transplantation.

Abstract

A significant limitation of hematopoietic stem cell transplantation (HSCT) that reduces its application across more disease areas and more geographically diverse populations is the toxicity from chemotherapy-based conditioning. A potential solution is to replace chemotherapy with monoclonal antibodies, but the replacement must result in therapeutically relevant levels of engraftment. In some cases, this level of engraftment can be quite low (<10%) but in others situations must be significantly higher. Naked monoclonal antibody therapy (without using a potentially toxic drug conjugate) alone has been inconsistent in generating high levels of engraftment. Agents that mobilize hematopoietic stem and progenitor cells (HSPCs) out of the bone marrow niche are safely used as a method to harvest HSPCs as a source of cells for HSCT. We hypothesized that mobilization might sensitize HSPCs to monoclonal antibody depletion to facilitate high levels of donor cell engraftment. We provide evidence to support this hypothesis by showing in different mouse models of HSCT that mobilization consistently, safely and reproducibly generates higher levels of engraftment when combined with a specific monoclonal antibody conditioning cocktail compared to monoclonal antibody therapy alone. This combination therapy is a promising approach to allowing HSCT to be applied to more diseases and broader populations than current chemotherapy-based conditioning permits.