IgM labeled with Y-90 for intra-tumoral treatment of human patients with solid tumors
(1) Department of Radiation Oncology, Hotel-Dieu de France St. Joseph University Hospital, Beirut, Lebanon
(2) Phase2Therapy, The Hague, The Netherlands
(3) Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
(4) Lonza Ltd. Münchensteinerstrasse 38, CH-4002 Basel, Switzerland
Purpose: Prior translational research in nude mice with solid human tumor nodules showed that Y-90 labeled tumor reactive murine IgM diffused rapidly to viable tumor cells and decayed in the tumor and tumor-draining lymph nodes. Here, we test the reactivity of monoclonal murine IgM for Tenascin-C in formalinized solid human tumors tissue samples and estimate the radiation dose that Yttrium-90 labeled murine IgM reactive with Tenascin-C can deliver to a solid tumor and tumor draining lymph nodes.
Materials and Methods: Using Immunohistochemistry (IHC), mouse anti-human Tenascin-C IgG and IgM clones were tested for the detection of Tenascin-C in formalin fixed biopsies of patients with Glioblastoma multiforme (GBM), adeno carcinoma of the exocrine pancreas (PaCa)-, breast-, colon-, renal-, ovary- prostate carcinoma, cutaneous-, ocular- melanomas, and Ewing Sarcoma. An n=1 for all tumors except for PaCa and ocular melanomas, n= 11.
Monte-Carlo simulation and convolution calculations were used to determine the activity of Y-90 required for delivering 100Gy to a 50x50x50mm3 water-equivalent tumor model, assuming a homogeneous distribution of the radioimmunoconjugate throughout the model volume. Y-90 is an exclusive beta emitter with 0.935MeV average energy, maximum range of 10mm in water, therapeutic range of near 5mm and rapid fall-off thereafter.
Results: IHC has confirmed reactivity of IgM with Tenascin-C in all of the tested human solid tumors samples except for ocular melanoma. Positive and negative controls of IgM specificity were used. The dosimetry simulation predicted an Yttrium-90 activity of 217MBq to deliver a dose of 100Gy to the tumor model with a 6mm sharp dose fall off in surrounding normal tissues.
Conclusion: Loco-regional control of human solid tumors may be obtained with intra-tumoral administration of radiolabeled IgM targeting Tenascin-C. In Tenascin-C negative solid tumors such as ocular melanoma, other tumor-specific target(s) need to be identified.