(P 302) HER2 PRETARGETED ALPHA PARTICLE RADIOIMMUNOTHERAPY FOR DESMOPLASTIC SMALL ROUND CELL TUMORS

Objective: Our goal is to determine if the alpha emitter 225-Ac can be used to eradicate DSRCT without toxicity using a HER2-directed self-assembling, disassembling (SADA) antibody platform for pretargeted radioimmunotherapy (PRIT).

Methods: Immunohistochemistry (IHC) was performed to evaluate binding of our HER2 Ab to a panel of DSRCT surgical specimens, DSRCT cell lines, and normal tissues. Xenograft tumors were established on the flanks of male BRG mice by injecting 4 million BER-DSRCT cells and Matrigel subcutaneously and allowing 3 weeks for engraftment before the start of treatment. SADA antibodies were injected iv (retroorbitally) 48-168 hours before iv (tail vein) administration of 225-Ac Proteus. Tumors were measured twice weekly using calipers. Mice were weighed twice weekly and evaluated for signs of gross toxicity (weight loss, petechiae, lethargy, etc). Blood was collected weekly for CBC and biweekly for serum chemistry to monitor kidney function. Blood was also collected 30 minutes after administration of SADA and immediately preceding administration of 225-Ac Proteus. ELISAs were performed on the serum from this blood to determine the peak (30 min post injection of SADA Abs) and trough (immediately preceding administration of 225-Ac Proteus) levels of circulating SADA antibodies.

Results: IHC shows strong binding of our HER2 Ab to a majority of DSRCT surgical specimens and cell lines and extremely limited binding to normal tissues. Xenograft mouse experiments show that 2 doses of HER2 SADA + 225-Ac Proteus (2 uCi per dose) can eliminate DSRCT xenografts ranging from 200 to more than 1000 mm3 without apparent toxicity. By monitoring CBC and measuring the trough level of SADA in the blood immediately preceding administration of 225-Ac, we determined that the ideal pretargeting interval is 96 hours, which results in eradication of tumors without treatment-related myelotoxicity.

Conclusion: Preclinical experiments show that the HER2 SADA antibody platform is a safe and effective method for delivery of alpha radiation to DSRCT. This treatment modality is capable of eliminating large (>1000 mm3) xenograft tumors without treatment-associated myelotoxicity. We propose that HER2-directed SADA PRIT is a promising strategy for DSRCT and should be further investigated.