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Developing & Optimizing Acute Myeloid Leukemia Specific Therapeutic Antibodies [CRISPR Screen]

ABSTRACT: Following nearly five decades with few approved therapies for acute myeloid leukemia (AML), the last three years have brought stellar progress with the U.S. Food and Drug Administration approving a number of new therapies for AML patients. Despite these advances, there are several high-risk patient AML populations with dismal survival on the order of months including those with primary refractory disease, those whose AML developed from an antecedent hematologic disorder, and those with high risk cytogenetic or mutational profiles (such as TP53 mutations or a complex karyotype). Furthermore, therapeutic options are limited for those unfit to receive cytotoxic chemotherapy due to age or co-morbidities. These treatment challenges clearly illustrate the need for improved therapeutic approaches in AML. Here we identify that antibody therapies for AML can be enhanced via optimization of (1) Fab target selection, and (2) engineering the Fc portion of the antibody to maximally engage receptors on immune effector cells. We demonstrate that antibodies targeting a novel AML-specific cell surface marker known as U5 snRNP200 have therapeutic efficacy in AML. Finally, we performed a whole-genome CRISPR screen to identify mechanisms by which U5 snRNP200 traffic to the cell surface. This revealed a requirement for cell-surface CD32a to enable U5 snRNP200 cell membrane localization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205028 | GEO | 2022/12/02

REPOSITORIES: GEO

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