Abstract IA17: T cell receptor-like antibody 8F4 targets leukemia and non-hematopoietic cancer

Adaptive anti-tumor immune surveillance of leukemia, called the graft-versus-leukemia (GVL) effect in the setting of allogeneic stem cell transplantation (alloSCT), is responsible for inducing and maintaining long term remission. However, although donor T cells mediate GVL, they also mediate graft-versus-host disease (GVHD), which results in significant morbidity and can be fatal, and is thus a substantial barrier to the more widespread application of alloSCT for many patients with hematological malignancies. CD8 T cells are activated by cognate peptide/MHC-I target cell antigens through binding of clonally unique αβ-heterodimer T cell receptors (TCRs) on the cell surface. Thus, because GVL and GVHD target antigens can be unique, immunotherapy strategies that target GVL antigens such as adoptively transferred T cells could be developed to mediate GVL without GVHD. Likewise, TCR-like monoclonal antibodies (mAbs) that similarly bind to peptide/MHC-I also could be useful as novel immunotherapeutic agents to mediate GVL in the absence of cellular therapies. Moreover, if potent anti-tumor activity was mediated by such TCR-like mAbs, they could have advantages over adoptively transferred donor T cells, including easier standardized manufacturing, ease of dose and scheduled administration, and they could be given to patients in the absence of an alloSCT. We identified PR1, an HLA-A2-restricted 9-mer peptide a peptide derived from aberrantly expressed proteinase 3 (P3) and neutrophil elastase (NE) in myeloid leukemia, as a leukemia-associated target antigen for CD8 T cells that mediate GVL. PR1-specific CD8 T cells target HLA-A2+ AML, CML and MDS but not normal hematopoietic cells and they contribute to cytogenetic and molecular remission of myeloid leukemia. We developed a murine TCR-like mAb that binds to PR1/HLA-A2 (8F4) and showed that 8F4 mediated complement-dependent cytotoxicity (CDC) of AML, CML and MDS progenitor cells and blasts, but not normal bone marrow cells. Because 8F4 did not eliminate normal human hematopoietic cells in a xenograft model, we humanized 8F4 to an IgG1 isotype (h8F4). In AML PDX models, 8F4 and h8F4 eliminated HLA-A2+ AML and leukemia stem cells (LSCs). In preclinical safety models, only mild reversible blood cytopenia was observed after multiple-dose IV administration of high-dose 8F4. Based on these findings, h8F4 is being developed for a first-in-human phase I safety study in HLA-A2+ patients with high-risk AML. In addition, 8F4