Radiolabeled Immunoglobulin Therapy for Patients with Solid Tumors

IgM labeled with Y-90 for intra-tumoral treatment of human patients with solid tumors

Nabil Khater 1, 2*, Marcel Kap 3, Rima Sayah 1, Dimor Elbers 4, Huib M Vriesendorp 2

(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. M√ľnchensteinerstrasse 38, CH-4002 Basel, Switzerland

Abstract

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.