Hematopoietic stem cell engraftment

Inventors

AGARWAL, Rajni • Boyle, Janel Long • Cowan, Morton J. • Dvorak, Christopher • KWON, HYE-SOOK • Le, Anne • Logan, Aaron • Pang, Wendy • Parkman, Robertson • Roncarolo, Maria-Grazia • Weinberg, Kenneth • Shizuru, Judith A. • Prohaska, Susan Sweeney • Czechowicz, Agnieszka • Weissman, Irving L.

Assignees

University of California San Diego UCSD • Leland Stanford Junior University

Abstract

The present invention provides clinical evidence for a method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring myeloablative conditioning.

Core Innovation

The patent describes hematopoietic stem cell engraftment in an immunocompetent human patient by administering a human or humanized monoclonal antibody specific for CD117 (c-Kit). The approach includes infusing the CD117-specific antibody and allowing serum levels of the antibody specific for CD117 to drop to a level of less than 500 ng/ml before administering a cell composition enriched for CD34+ hematopoietic stem cells. Sustained levels of blood myeloid chimerism of at least about 1% donor type CD15+ cells are obtained after the enriched cell infusion.

The patent further characterizes engraftment and reconstitution as donor-derived multilineage reconstitution with sustained myeloid chimerism, including blood myeloid chimerism measured by donor type CD15+ cells. It describes use in immunocompetent recipients and also references immunodeficient recipients, including SCID, as part of the overall invention context. The CD117-specific antibody includes humanized antibody formats, including an AMG 191 example, with options such as an aglycosylated IgG1.

The described engraftment framework is also applied in combination with non-myeloablative conditioning regimens. Non-myeloablative conditioning includes total lymphoid irradiation and anti-thymocyte globulin, including referenced combinations such as low-dose TBI. The patent also addresses indications including myelodysplastic syndrome, acute myelogenous leukemia, and AML secondary to MDS, including use cases where the disclosed engraftment approach supports treatment in these blood-disorder contexts.

Claims Coverage

The claims coverage centers on a method that infuses a CD117-specific human or humanized monoclonal antibody, times administration relative to antibody serum decline, administers a CD34+-enriched cell composition, and requires sustained blood myeloid chimerism with donor CD15+ cells. Dependent claims further add inventive features including non-myeloablative conditioning, specific blood-disorder contexts, and HLA matching.

Overall, the claimed inventive coverage combines CD117-specific monoclonal antibody administration with timed serum clearance before CD34+ enriched cell infusion, and requires sustained blood myeloid chimerism measured using donor type CD15+ cells. Dependent claim coverage further specifies non-myeloablative conditioning using TLI and ATG, narrows indications to MDS and AML secondary to MDS, and adds HLA matching between the enriched CD34+ composition and the recipient.

Stated Advantages

Documented Applications