Discovery And Development Of Medi7247, A Novel Pyrrolobenzodiazepine (Pbd)-Based Antibody Drug Conjugate Targeting Asct2, For Treating Hematological Cancers

The neutral amino acid transporter, ASCT2, is frequently overexpressed in several cancers to sustain “glutamine addiction” of cancer cells. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue samples revealed high prevalence of membranous ASCT2 expression in several hematological cancers, including MM, AML, and DLBCL summarized in Table1. ASCT2 expression was predominantly on the plasma membrane of the carcinoma cells. ASCT2 staining was observed in almost all the samples with high positivity (>2+ and in >50% of tumor cells) in 98, 74 and 55% of MM, AML and DLBCL samples respectively. Additionally, flow cytometry analyses suggest significantly high expression of ASCT2 in bone marrow (BM) samples from AML and MM patients in comparison to BM from healthy donors. Also, our data suggest relatively less expression of ASCT2 in LT-HSC (long term hematopoietic stem cells) in comparison to prominent myeloid-associated marker CD33. In contrast, we found similar expression profile of ASCT2 and CD33 in downstream lineage-committed progenitor cells, such as MPP (multi potent progenitors) and CP (common progenitors). Furthermore, IHC evaluated across normal tissues suggest restricted ASCT2 expression in the normal tissues of vital organs.