ABSTRACT
We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 20 μCi 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (10 μCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.
Significance This study reports a novel CD46 targeted 212Pb alpha particle radioimmunotherapy, 212Pb-TCMC-YS5, that is well tolerated and shows potent anti-tumor activity (tumor growth inhibition and increase of animal survival) in vivo in three prostate cancer small animal models, i.e., a subcutaneous and an intraprostate orthotopic mCRPC cell line-derived xenograft models, and a prostate cancer patient-derived xenograft model. Given that YS5 is a clinical stage human antibody, this YS5-based 212Pb alpha particle therapy has potential of translation to the clinic for treatment of mCRPC patients.
Competing Interest Statement
YSu is an inventor of intellectual properties around the CD46 epitope, the CD46 targeting human antibody, and therapeutic targeting of CD46, which were licensed to Fortis Therapeutics, Inc. SB is an inventor of intellectual properties around the CD46 epitope, the CD46 targeting human antibody, and therapeutic targeting of CD46, which were licensed to Fortis Therapeutics, Inc. YSeo holds equity of Molecular Imaging and Therapeutics, Inc., which were converted to equity of Fortis Therapeutics that licensed intellectual properties from the University of California. RRF reports prior grant funding from Fukushima SiC, outside the existing work. RD received honoraria for consulting from Astellas, Astra Zeneca, Aveo, Bayer, BMS, Exelixis, EMD Serono, Gilead, Hengrui, Hinova, Janssen, Merck, Myovant, Pfizer, Propella, Sanofi Genzyme, Seattle Genetics, Tavanta, outside of the submitted work. BL is a founder, board member and equity holder of Fortis Therapeutics, Inc., which licensed intellectual properties from the University of California and is conducting clinical trials on CD46 targeting agents. BL also holds equity of Molecular Imaging and Therapeutics, Inc., which were converted to equity of Fortis Therapeutics. BL is an inventor of intellectual properties around the CD46 epitope, the CD46 targeting human antibody, and therapeutic targeting of CD46. JH holds equity of Molecular Imaging and Therapeutics, Inc., which were converted to equity of Fortis Therapeutics that licensed intellectual properties from the University of California. The other authors declare no potential conflict of interest.
Footnotes
New data has been added (Fig 3) to describe the acute and long-term toxicity as assessed by blood analysis.
