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Enhanced Efficacy of Radioimmunotherapy with ⁹⁰Y-CHX-A''-DTPA-hu3S193 by Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling with EGFR Tyrosine Kinase Inhibitor AG1478

Authors' Affiliations: ¹ Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia; ² Epithelial Biochemistry Laboratory, Parkville, Victoria, Australia; and ³ Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Andrew M. Scott, Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Level 1, Harold Stokes Building, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5876; Fax: 61-3-9496-5892; E-mail: andrew.scott{at}ludwig.edu.au.

Purpose: Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model.

Experimental Design: The humanized anti–Lewis Y antibody hu3S193 and the EGFR tyrosine kinase inhibitor AG1478 were studied. BALB/c nude mice were engrafted with A431 squamous carcinoma cells. Initial biodistribution properties of the ⁹⁰Y-CHX-A''-DTPA-hu3S193 were evaluated in this model. In therapy experiments, cohorts of four to five xenografted mice were treated with saline as placebo, 0.4 mg AG1478 i.p. (six doses over 2 weeks), single i.v. injections of unlabeled hu3S193, or ⁹⁰Y-CHX-A''-DTPA-hu3S193 (12.5, 25, 50, or 100 µCi). The combination of 0.4 mg AG1478 i.p. and 25 µCi ⁹⁰Y-CHX-A''-DTPA-hu3S193 i.v. was subsequently evaluated in the A431 model.

Results: ⁹⁰Y-CHX-A''-DTPA-hu3S193 retained excellent immunoreactivity after radiolabeling. The biodistribution study showed excellent uptake in tumor (90.33 ± 38.84%ID/g) peaking at 24 to 72 hours after injection and with prolonged retention. ⁹⁰Y-CHX-A''-DTPA-hu3S193 significantly inhibited A431 xenograft growth at 25, 50, and 100 µCi doses. The combination of 0.4 mg AG1478 with a single dose of 25 µCi ⁹⁰Y-CHX-A''-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone (P = 0.013).

Conclusions: The efficacy of radioimmunotherapy with ⁹⁰Y-CHX-A''-DTPA-hu3S193 is significantly enhanced by EGFR tyrosine kinase inhibitor AG1478. Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted.

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