PURPOSE:

Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through Antibody Drug Conjugates (ADCs) that facilitate greater potency via target specific delivery of highly potent cytotoxic agents.

 

EXPERIMENTAL DESIGN:

In this study, we used a bioinformatics approach to identify the Lymphocyte antigen 6 locus E (LY6E), an interferon-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target dependent LY6E-ADC killing was investigated both in vitro and in vivo using patient derived xenograft models.

 

RESULTS:

Using in silico approaches, we found LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. Immunohistochemical analysis revealed high LY6E protein expression in a number of tumor types, such as, breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E expressing xenograft models.

 

CONCLUSION:

Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumor types with current unmet medical need.