PURPOSE: Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived alpha-emitting radioisotope (211)At. EXPERIMENTAL DESIGN: Immunodeficient nude mice bearing established HER2/neu-positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[(211)At]astatophenethyl)succinamate ((211)At-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with (211)At-SAPS T84.66 diabody targeting the carcinoembryonic antigen or (211)At-SAPS on a diabody specific for the Müllerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line. RESULTS: A single i.v. injection of (211)At-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 muCi dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 muCi dose was used. Treatment of mice bearing the same tumors with (211)At-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 muCi of (211)At-SAPS on the anti-Müllerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect. CONCLUSIONS: These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived alpha-emitting radioisotopes.
PURPOSE: Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficientmouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived alpha-emitting radioisotope (211)At. EXPERIMENTAL DESIGN:Immunodeficientnude mice bearing established HER2/neu-positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[(211)At]astatophenethyl)succinamate ((211)At-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with (211)At-SAPS T84.66 diabody targeting the carcinoembryonic antigen or (211)At-SAPS on a diabody specific for the Müllerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line. RESULTS: A single i.v. injection of (211)At-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 muCi dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 muCi dose was used. Treatment of mice bearing the same tumors with (211)At-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 muCi of (211)At-SAPS on the anti-Müllerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect. CONCLUSIONS: These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived alpha-emitting radioisotopes.
Authors: R Schier; J D Marks; E J Wolf; G Apell; C Wong; J E McCartney; M A Bookman; J S Huston; L L Houston; L M Weiner Journal: Immunotechnology Date: 1995-05
Authors: Jaspreet Singh Jaggi; Barry J Kappel; Michael R McDevitt; George Sgouros; Carlos D Flombaum; Catalina Cabassa; David A Scheinberg Journal: Cancer Res Date: 2005-06-01 Impact factor: 12.701
Authors: Vladimir S Talanov; Alexander T Yordanov; Kayhan Garmestani; Diane E Milenic; Hans C Arora; Paul S Plascjak; William C Eckelman; Thomas A Waldmann; Martin W Brechbiel Journal: Nucl Med Biol Date: 2004-11 Impact factor: 2.408
Authors: Jaspreet Singh Jaggi; Surya V Seshan; Michael R McDevitt; Krista LaPerle; George Sgouros; David A Scheinberg Journal: J Am Soc Nephrol Date: 2005-06-29 Impact factor: 10.121
Authors: G P Adams; J E McCartney; M S Tai; H Oppermann; J S Huston; W F Stafford; M A Bookman; I Fand; L L Houston; L M Weiner Journal: Cancer Res Date: 1993-09-01 Impact factor: 12.701
Authors: D Scott Wilbur; Ming-Kuan Chyan; Donald K Hamlin; Holly Nguyen; Robert L Vessella Journal: Bioconjug Chem Date: 2011-05-05 Impact factor: 4.774
Authors: Damian J Green; Mazyar Shadman; Jon C Jones; Shani L Frayo; Aimee L Kenoyer; Mark D Hylarides; Donald K Hamlin; D Scott Wilbur; Ethan R Balkan; Yukang Lin; Brian W Miller; Sofia H L Frost; Ajay K Gopal; Johnnie J Orozco; Theodore A Gooley; Kelly L Laird; Brian G Till; Tom Bäck; Brenda M Sandmaier; John M Pagel; Oliver W Press Journal: Blood Date: 2015-01-27 Impact factor: 22.113
Authors: Brian W Miller; Sofia H L Frost; Shani L Frayo; Aimee L Kenoyer; Erlinda Santos; Jon C Jones; Damian J Green; Donald K Hamlin; D Scott Wilbur; Darrell R Fisher; Johnnie J Orozco; Oliver W Press; John M Pagel; Brenda M Sandmaier Journal: Med Phys Date: 2015-07 Impact factor: 4.071