2. Academic Validation
  3. 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

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

  • Clin Cancer Res. 2015 Jul 15;21(14):3252-62. doi: 10.1158/1078-0432.CCR-15-0156.
Jyoti Asundi 1,  Lisa Crocker 2,  Jarrod Tremayne 2,  Peter Chang 3,  Chie Sakanaka 4,  Josh Tanguay 2,  Susan Spencer 2,  Sreedevi Chalasani 5,  Elizabeth Luis 6,  Karen Gascoigne 7,  Rupal Desai 8,  Rajiv Raja 8,  Brad A Friedman 9,  Peter M Haverty 9,  Paul Polakis 10,  Ron Firestein 11
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, Genentech Research, South San Francisco, California. [email protected] [email protected].
  • 2 Department of Translational Oncology, Genentech Research, South San Francisco, California.
  • 3 Touro University, California College of Pharmacy, California.
  • 4 Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
  • 5 Department of Pathology, Genentech Research, South San Francisco, California.
  • 6 Department of Protein Chemistry, Genentech Research, South San Francisco, California.
  • 7 Department of Discovery Oncology, Genentech Research, South San Francisco, California.
  • 8 Department of Oncology Biomarker Development, Genentech Research, South San Francisco, California.
  • 9 Department of Bioinformatics, Genentech Research, South San Francisco, California.
  • 10 Department of Molecular Oncology, Genentech Research, South San Francisco, California.
  • 11 Department of Pathology, Genentech Research, South San Francisco, California. [email protected] [email protected].
PMID: 25862760 DOI: 10.1158/1078-0432.CCR-15-0156
Abstract

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 tumor types with current unmet medical need.

Figures
Products