Antibody mediated conditioning with immunosuppression to enable allogeneic transplantation

Background

Hematopoietic (blood-forming) stem cell transplantation (HSCT) is the transplantation of autologous or allogeneic hematopoietic stem cells used to treat patients with cancer and disorders of the blood and immune system. Hematopoietic stem cells are immature cells that develop into various blood cell types and more stem cells and are found in the bone marrow and blood of patients. Stem cell transplantation is an infusion of stem cells which have been collected from the same patient (autologous) or from a donor (allogeneic). The optimal donor source is matched to the patient to improve HSCT success. While the best matches are often related siblings, there is a possibility of an unrelated match to the patient. When a matched sibling or matched unrelated donor cannot be found, then an alternative source must be tapped to obtain hematopoietic stem cells.

Before stem cells are given to patients, a conditioning regimen is administered in order to destroy unwanted or diseased cells and typically consists of chemotherapy or radiation therapy. The conditioning regimen is a critical step in HSCT as it helps prevent rejection of the transplanted cells and helps kill any unwanted (e.g., cancerous) cells that are in the body. Conventional conditioning regimens are often highly toxic (i.e., genotoxic), have multiple off-target effects, and carry a high risk of infection and cancer. One method to limit off-target effects is to use a targeted delivery agent (e.g., antibody) directed towards a protein expressed solely on a specific cell.

Technology Overview

CD117 (c-Kit) is a protein that is highly expressed primarily on hematopoietic stem cells and presents an opportunity to selectively eliminate hematopoietic stem cells. BCH scientists have developed a non-genotoxic conditioning regimen for allogeneic HSCT from an unmatched donor in collaboration with scientists at the National Institute of Allergy and Infectious Diseases. The method comprises the use of a CD117 antibody drug conjugate (ADC), which selectively kills hematopoietic stem cells, in combination with transient immunosuppression. This novel method safely and effectively enables robust allotransplantation from an alternative source of hematopoietic stems cells and is non-genotoxic.

Applications

• Conditioning regimen for allogeneic HSCT, gene therapy or gene editing therapy

Advantages

• High degree of donor stem cell engraftment
• Possible increase in unmatched donor population size for hematopoietic stem cell transplantation
• Larger number of stem cells likely available when compared with umbilical cord blood sources for HSCT
• Potentially superior adverse event profile when compared to conventional conditioning regimens
• Probable improvement of allo-tolerance involving allogeneic transplants

Publications

• Li Z, Czechowicz A, Scheck A, Rossi DJ, Murphy PM. Hematopoietic chimerism and donor- specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation. Nat Commun. 2019 Feb 6;10(1):616.