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
  • 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.

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