Abstract 521: CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells

Abstract

Abstract CD45 is highly expressed on the cell surface of all nucleated hematopoietic cells, including malignant cells of B, T and myeloid lineage. CD45, a receptor tyrosine phosphatase that has important roles in antigen receptor signaling, has multiple isoforms that are differentially expressed on immune cell subsets. Targeting of CD45 with antibody-based therapies, tested in conjunction with reduced dose chemotherapy and radiation regimens, has shown promise in preclinical models and clinical trials as a conditioning therapy for bone marrow transplant (BMT), although these approaches are associated with safety limitations. A single agent, targeted conditioning method could increase patient safety and eliminate genotoxic effects associated with the conditioning regimens. Conditioning therapy by depletion of CD45 positive cells specifically has potential applications in oncology as well as non-oncologic, hematopoietic disease settings where engraftment of donor or modified stem cells could provide benefit. Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Targeted ETBs are being developed to specifically target and destroy CD45 expressing cells. ETBs targeting CD45 specifically bind to, internalize into and then trigger cell death of the target cells in vitro. ETBs have been designed using antibody fragments that recognize all isoforms of CD45. The CD45 targeted ETB has shown high potency in immortalized blood cancer cell lines of T cell, B-cell and eosinophil origin, including leukemia and lymphoma cell lines. Additionally, the ability of the CD45 targeted ETBs to deplete primary cells from healthy donors has been demonstrated. The direct cell kill activity of the CD45 targeted ETBs have the potential to deplete immune cells in the periphery and the bone marrow, as well as to deplete malignant hematological cells expressing CD45. In vivo depletion of human immune cells in murine models by CD45 targeted ETBs will be evaluated. Citation Format: Aimee Iberg, Garrett L. Robinson, Sara LeMar, Joseph D. Dekker, Jay Zhao, Hilario J. Ramos, Melissa M. Singh, Erin K. Willert. CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 521.