Therapeutic efficacy of ¹⁷⁷Lu‐CHX‐A″‐DTPA‐hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

Abstract

BACKGROUND. This study investigated the biodistribution and therapeutic efficacy of 177 Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo. METHODS. The in vitro cytotoxicity of 177 Lu labeled hu3S193 on Le y positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177 Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177 Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo. RESULTS.177 Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177 Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 AE 3.9%ID/g observed at 120 hr post-injection. In RIT studies, 177 Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350 mCi was determined for 177 Lu-hu3S193. Combination of 177 Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy. CONCLUSIONS.177 Lu-hu3S193 RIT is effective as a single agent in the treatment of Le y positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies.

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

“…As an example, the maximum follow-up time was respectively 77 and 102 days in two studies performed with antibodies labeled with lutetium-177 [6,7]. However, in one study performed with a 177 Lu-labeled anti-Lewis Y antibody the maximum follow-up time was 150 days after injection of an activity of 12.95 MBq, comparable to that of the present study, and no oncogenic effect was observed [8]. Furthermore, a lot of preclinical studies have been carried out with antibodies labeled with iodine-131, which has a half-life longer than that of lutetium-177, and oncogenic effects have never been reported.…”

Targeted Radiotherapy of Prostate Cancer with a Gastrin-Releasing Peptide Receptor Antagonist Is Effective as Monotherapy and in Combination with Rapamycin

“…Furthermore, a plethora of preclinical data have emerged indicating that treatment with various protein kinase inhibitors confers radiosensitivity on prostate cancer models, including those that target Akt, sphingosine kinase, aurora kinase A and B, and Wee1 (37)(38)(39)(40)(41). Most of these studies used external-beam radiation; however, 1 group reported additive effects when a 177 Lu-labeled anti-Lewis Y monoclonal antibody was combined with an epidermal growth factor receptor kinase inhibitor in an in vivo prostate cancer model (42).…”

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

“…The combination of radioimmunotherapy with chemotherapy to induce enhanced antitumor effects has been extensively explored in preclinical models (23)(24)(25)(26)(27)(28) and in a small number of phase I/II studies in patients with advanced solid tumors, with a suggestion of antitumor activity in some (29)(30)(31)(32)(33)(34). The aim of this approach is to use chemotherapy as a radiosensitizer, so that cancer cell cycle is arrested in the radiosensitive G(2)/M phase and efficacy is improved.…”