TY - JOUR
T1 - An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies
AU - Asundi, Jyoti
AU - Crocker, Lisa
AU - Tremayne, Jarrod
AU - Chang, Peter
AU - Sakanaka, Chie
AU - Tanguay, Josh
AU - Spencer, Susan
AU - Chalasani, Sreedevi
AU - Luis, Elizabeth
AU - Gascoigne, Karen
AU - Desai, Rupal
AU - Raja, Rajiv
AU - Friedman, Brad A.
AU - Haverty, Peter M.
AU - Polakis, Paul
AU - Firestein, Ron
PY - 2015/7/15
Y1 - 2015/7/15
N2 - 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 (ADC) 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 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC 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. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.
AB - 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 (ADC) 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 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC 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. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.
UR - http://www.scopus.com/inward/record.url?scp=84942932701&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-0156
DO - 10.1158/1078-0432.CCR-15-0156
M3 - Article
C2 - 25862760
AN - SCOPUS:84942932701
VL - 21
SP - 3252
EP - 3262
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 14
ER -