Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer
Amy A. Lo, Jennifer Johnston, Ji Li, Danielle Mandikian, Maria Hristopoulos, Robyn Clark, Dorothee Nickles, Wei‐Ching Liang, Kathy Hötzel, Debra Dunlap, Thinh Pham, Hao Cai, Meric Ovacik, Daniel Bravo-Perez, Elaine Mai, Dionysos Slaga, Diego Ellerman, James Ziai, Klára Tótpál, Genee Lee, C. Andrew Boswell, Jian Payandeh, Yan Wu, Teemu T. Junttila
Abstract
Abstract Ovarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with ∼70% prevalence in the serous cancer subset. Bispecific antibodies targeting CD3 on T cells and a tumor antigen on cancer cells have demonstrated significant clinical activity in hematologic cancers. We have developed an anti-LYPD1/CD3 T-cell-dependent bispecific antibody (TDB) to redirect T-cell responses to LYPD1 expressing ovarian cancer. Here we characterize the nonclinical pharmacology of anti-LYPD1/CD3 TDB and show induction of a robust polyclonal T-cell activation and target dependent killing of LYPD1 expressing ovarian cancer cells resulting in efficient in vivo antitumor responses in PBMC reconstituted immune-deficient mice and human CD3 transgenic mouse models. Anti-LYPD1/CD3 TDB is generally well tolerated at high-dose levels in mice, a pharmacologically relevant species, and showed no evidence of toxicity or damage to LYPD1 expressing tissues.