title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Department of Molecular Oncology, Genentech Research, South San Francisco, California. ronf@gene.com jasundi@gene.com.
authors: Jyoti
authors: J
authors: Asundi
authors: Department of Translational Oncology, Genentech Research, South San Francisco, California.
authors: Lisa
authors: L
authors: Crocker
authors: Department of Translational Oncology, Genentech Research, South San Francisco, California.
authors: Jarrod
authors: J
authors: Tremayne
authors: Touro University, California College of Pharmacy, California.
authors: Peter
authors: P
authors: Chang
authors: Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
authors: Chie
authors: C
authors: Sakanaka
authors: Department of Translational Oncology, Genentech Research, South San Francisco, California.
authors: Josh
authors: J
authors: Tanguay
authors: Department of Translational Oncology, Genentech Research, South San Francisco, California.
authors: Susan
authors: S
authors: Spencer
authors: Department of Pathology, Genentech Research, South San Francisco, California.
authors: Sreedevi
authors: S
authors: Chalasani
authors: Department of Protein Chemistry, Genentech Research, South San Francisco, California.
authors: Elizabeth
authors: E
authors: Luis
authors: Department of Discovery Oncology, Genentech Research, South San Francisco, California.
authors: Karen
authors: K
authors: Gascoigne
authors: Department of Oncology Biomarker Development, Genentech Research, South San Francisco, California.
authors: Rupal
authors: R
authors: Desai
authors: Department of Oncology Biomarker Development, Genentech Research, South San Francisco, California.
authors: Rajiv
authors: R
authors: Raja
authors: Department of Bioinformatics, Genentech Research, South San Francisco, California.
authors: Brad A
authors: BA
authors: Friedman
authors: Department of Bioinformatics, Genentech Research, South San Francisco, California.
authors: Peter M
authors: PM
authors: Haverty
authors: Department of Molecular Oncology, Genentech Research, South San Francisco, California.
authors: Paul
authors: P
authors: Polakis
authors: Department of Pathology, Genentech Research, South San Francisco, California. ronf@gene.com jasundi@gene.com.
authors: Ron
authors: R
authors: Firestein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D000954:Antigens, Surface / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; C439870:LY6E protein, human; D034741:RNA, Small Interfering