Research Project
9680313
Project Summary / Abstract Despite recent advances in allogeneic stem cell transplantation, graft-versus-host disease (GVHD, an immunologic attack by donor cells directed against the recipient) and reactivation of latent viral infections remain major sources of post-transplant morbidity and mortality and limit the applicability of bone marrow transplant. The morbidity of GVHD is particularly unwelcome in non-malignant conditions where elimination of the underlying disease is not dependent on immunologic rejection. GVHD is primarily mediated by T cells contained in the graft (hematopoietic cells obtained from the donor) which recognize host (recipient) antigens as being foreign. Studies in mice and humans demonstrate that naïve and central memory T cells, which may be discriminated from hematopoietic stem cells and effector memory T cells on the basis of expression of the cytokine receptor CCR7, are responsible for GVHD. Experience over decades of allogeneic transplant demonstrates the GVHD may be avoided entirely by removing T cells or selectively transplanting only CD34+ hematopoietic stem cells at the expense of impaired antiviral immunity resulting in life-threatening reactivation of Herpes viruses and other infections which limit the overall success of the transplant. This project proposes to develop a novel, fully humanized, biotinylated antibody targeting CCR7 to be used with a commercial immuno-magnetic bead separation device (CliniMACS®, Miltenyi, Cambridge, MA) to remove naïve and central memory T cells from allogeneic hematopoietic stem cell grafts for the purpose of preventing GVHD while preserving antiviral immunity. This application will support selection of an optimal antibody from among several fully-human anti-CCR7 antibody clones developed by MSM Protein Technologies on the basis of efficiency of target T cell depletion. The selected antibody will be produced under manufacturing conditions suitable to the FDA for use in ex-vivo cell processing and in quantity sufficient to conduct future clinical-scale validation. This work will enable formal application to the FDA for an investigational device exemption (IDE) in support of a first in human pilot trial in patients undergoing stem transplantation for non-malignant hematologic disorders including sickle cell anemia and thalassemia. This study is submitted in response to PHS 2018-02 Omnibus Solicitation of the NIH, DCD and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44]) to NHLBI for Phase I funding.
