OBJECTIVES: Miltuximab® is a chimeric antibody targeting Glypican-1 (GPC-1), a cell surface antigen which is overexpressed in solid cancers. Miltuximab® has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. This first in human study used Miltuximab® radiolabelled with Gallium-67 ([67Ga]Ga-DOTA-Miltuximab®). The primary study endpoint was to establish safety and tolerability of Miltuximab®. Secondary endpoints were biodistribution, tumour targeting and pharmacokinetic analysis. METHODS: Four cohorts of three patients (9 with advanced prostate cancer, 2 with pancreatic and 1 with bladder cancer) were dosed with 1 mg, ~250 MBq of [67Ga]Ga-DOTA-Miltuximab®. Cohort 1 received [67Ga]Ga-DOTA-Miltuximab® alone, while cohorts 2-4 were pre-infused with increasing doses (3.5, 11.5 and 24 mg, respectively) of unlabelled Miltuximab®-DOTA 1 hour prior to [67Ga]Ga-DOTA-Miltuximab®. Safety and tolerability were assessed by clinical and standard laboratory assessments. Patients underwent whole body gamma-camera scans and SPECT/CT scans up to 144 h post-infusion. Total organ radiation exposure was determined by dosimetry of whole-body gamma scans. RESULTS: The dosing regimen was well tolerated, with no drug-related adverse events observed. Liver and spleen uptake of [67Ga]Ga-DOTA-Miltuximab® was observed. Liver uptake was reduced by pre-infusion of unlabelled Miltuximab®-DOTA. Dosimetry analysis showed a favorable exposure profile. [67Ga]Ga-DOTA-Miltuximab® targeting to tumour sites was observed in two prostate cancer patients who had failed enzalutamide treatment. Higher doses of unlabelled antibody achieved lower liver uptake and increased antibody serum half life. CONCLUSIONS: This study is the first in human for Miltuximab® a first in class antibody targeting GPC-1. The trial met its primary endpoint of safety, demonstrating its potential as a safe and tolerable monoclonal antibody. This safety data, together with targeting to tumour lesions and biodistribution information supports the further clinical development of Miltuximab® as a theranostic agent in a planned Phase I human trial.
OBJECTIVES: Miltuximab® is a chimeric antibody targeting Glypican-1 (GPC-1), a cell surface antigen which is overexpressed in solid cancers. Miltuximab® has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. This first in human study used Miltuximab® radiolabelled with Gallium-67 ([67Ga]Ga-DOTA-Miltuximab®). The primary study endpoint was to establish safety and tolerability of Miltuximab®. Secondary endpoints were biodistribution, tumour targeting and pharmacokinetic analysis. METHODS: Four cohorts of three patients (9 with advanced prostate cancer, 2 with pancreatic and 1 with bladder cancer) were dosed with 1 mg, ~250 MBq of [67Ga]Ga-DOTA-Miltuximab®. Cohort 1 received [67Ga]Ga-DOTA-Miltuximab® alone, while cohorts 2-4 were pre-infused with increasing doses (3.5, 11.5 and 24 mg, respectively) of unlabelled Miltuximab®-DOTA 1 hour prior to [67Ga]Ga-DOTA-Miltuximab®. Safety and tolerability were assessed by clinical and standard laboratory assessments. Patients underwent whole body gamma-camera scans and SPECT/CT scans up to 144 h post-infusion. Total organ radiation exposure was determined by dosimetry of whole-body gamma scans. RESULTS: The dosing regimen was well tolerated, with no drug-related adverse events observed. Liver and spleen uptake of [67Ga]Ga-DOTA-Miltuximab® was observed. Liver uptake was reduced by pre-infusion of unlabelled Miltuximab®-DOTA. Dosimetry analysis showed a favorable exposure profile. [67Ga]Ga-DOTA-Miltuximab® targeting to tumour sites was observed in two prostate cancer patients who had failed enzalutamide treatment. Higher doses of unlabelled antibody achieved lower liver uptake and increased antibody serum half life. CONCLUSIONS: This study is the first in human for Miltuximab® a first in class antibody targeting GPC-1. The trial met its primary endpoint of safety, demonstrating its potential as a safe and tolerable monoclonal antibody. This safety data, together with targeting to tumour lesions and biodistribution information supports the further clinical development of Miltuximab® as a theranostic agent in a planned Phase I human trial.
Authors: Neeta Pandit-Taskar; Joseph A O'Donoghue; Volkan Beylergil; Serge Lyashchenko; Shutian Ruan; Stephen B Solomon; Jeremy C Durack; Jorge A Carrasquillo; Robert A Lefkowitz; Mithat Gonen; Jason S Lewis; Jason P Holland; Sarah M Cheal; Victor E Reuter; Joseph R Osborne; Massimo F Loda; Peter M Smith-Jones; Wolfgang A Weber; Neil H Bander; Howard I Scher; Michael J Morris; Steven M Larson Journal: Eur J Nucl Med Mol Imaging Date: 2014-08-21 Impact factor: 9.236
Authors: Joaquim Bellmunt; Ronald de Wit; David J Vaughn; Yves Fradet; Jae-Lyun Lee; Lawrence Fong; Nicholas J Vogelzang; Miguel A Climent; Daniel P Petrylak; Toni K Choueiri; Andrea Necchi; Winald Gerritsen; Howard Gurney; David I Quinn; Stéphane Culine; Cora N Sternberg; Yabing Mai; Christian H Poehlein; Rodolfo F Perini; Dean F Bajorin Journal: N Engl J Med Date: 2017-02-17 Impact factor: 91.245
Authors: Shankar Vallabhajosula; Stanley J Goldsmith; Klaus A Hamacher; Lale Kostakoglu; Shota Konishi; Mathew I Milowski; David M Nanus; Neil H Bander Journal: J Nucl Med Date: 2005-05 Impact factor: 10.057
Authors: P J Russell; K T Ow; P N Tam; J Juarez; E A Kingsley; C F Qu; Y Li; P J Cozzi; R Martiniello-Wilks Journal: Cancer Immunol Immunother Date: 2004-07-28 Impact factor: 6.968
Authors: Flavio Forrer; Jianhua Chen; Melpomeni Fani; Pia Powell; Andreas Lohri; Jan Müller-Brand; Gerhard Moldenhauer; Helmut R Maecke Journal: Eur J Nucl Med Mol Imaging Date: 2009-04-07 Impact factor: 9.236
Authors: Teresa Carter; Katy Sterling-Levis; Kim Ow; Larissa Doughty; Meghan Hattarki; Deborah Shapira; Dean Hewish; Alexander A Kortt; Pamela J Russell Journal: Cancer Immunol Immunother Date: 2004-01-13 Impact factor: 6.968