A Single Dose of a Novel Anti-Human Short Half-Life Engineered CD45-Targeted Antibody-Drug Conjugate (ADC) Is Cytoreductive on Patient-Derived Tumors and Extends Survival Beyond Standards of Care in Multiple Pre-Clinical Models of Hematologic Malignancy

For patients with refractory or high-risk hematologic malignancies, like acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplant (Allo-HSCT) is a potentially curative approach. Morbidities and mortality associated with current conditioning regimens limit the use of this curative procedure. As a result, many eligible patients do not consider transplant and 2/3 of those transplanted are only able to tolerate a reduced intensity conditioning regimen, which is associated with increased relapse rates (Scott, J Clin Onc 2017). Thus, there is an urgent need for a safer and more effective conditioning agent with improved disease control. Our targeted antibody drug conjugate (ADC) approach is designed to improve the safety of current conditioning protocols by specifically depleting CD45+ cells. We developed a novel anti-human CD45-targeted short half-life ADC conjugated to amanitin (AM). CD45 is the ideal target for allo-HSCT conditioning because it is expressed on all hematopoietic cells (except erythrocytes, plasma cells and platelets), and most hematologic malignancies. Given their targeted specificity, anti-CD45-AM can potentially provide dual benefit to leukemia patients by combining effective conditioning for HSCT with depletion of target-bearing tumor cells. To demonstrate our engineered short half-life anti-human CD45-AM has anti-leukemic activity we tested it in human leukemic xenograft murine models. A panel of models were evaluated to mimic  untreated and refractory disease; AML PDX models (from treatment naive and relapsed post allogeneic HCT patients),  ALL cells from an immortalized cell line (REH-Luc), T-ALL patient-derived xenograft (PDX) model (from a patient progressing post DHAP chemotherapy). In the REH-Luc model, single doses of anti-CD45-AM were well tolerated, and cytoreductive resulting in delayed tumor growth compared to vehicle (PBS), isotype-AM, or standard of care (SoC) doxorubicin. Anti-CD45-AM treatment in the PDX AML, and T-ALL significantly decreased peripheral tumor burden resulting in delayed tumor growth compared to vehicle, isotype-AM, and comparable to 2 clinically validated standards of care (Ara-C, and dexamethasone respectively; figure 1). As designed for the transplant indication, the ADC had a reduced half-life compared to wild type antibody controls (16 vs 79h). These data in humanized murine xenograft models demonstrate that short half-life CD45-AM ADCs are potent targeted anti-leukemia agents. Together with prior reports demonstrating the potency of anti-CD45-AM as conditioning agents, these non-genotoxic ADCs may be useful in reducing disease burden and inducing durable remissions in patients after transplant particularly those who receive reduced intensity conditioning that are at high risk of relapse.