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Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

Zuckerman, Jonathan E. and Gritli, Ismael and Tolcher, Anthony and Heidel, Jeremy D. and Lim, Dean and Morgan, Robert and Chmielowski, Bartosz and Ribas, Antoni and Davis, Mark E. and Yen, Yun (2014) Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA. Proceedings of the National Academy of Sciences of the United States of America, 111 (31). pp. 11449-11454. ISSN 0027-8424. PMCID PMC4128111. doi:10.1073/pnas.1411393111.

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Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)–based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.

Item Type:Article
Related URLs:
URLURL TypeDescription material CentralArticle
Davis, Mark E.0000-0001-8294-1477
Yen, Yun0000-0003-0815-412X
Additional Information:Copyright © 2014 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, June 20, 2014 (sent for review May 29, 2014) We thank the patients who participated in the clinical trials. The clinical trial was sponsored by Calando Pharmaceuticals. J.E.Z. is supported by National Institutes of Health National Institute of General Medical Sciences Training Grant GM08042 and the University of California at Los Angeles–Caltech Medical Scientist Training Program. Author contributions: A.T., A.R., and Y.Y. designed research; A.T., D.L., R.M., B.C., A.R., and Y.Y. performed research; J.E.Z., I.G., J.D.H., M.E.D., and Y.Y. analyzed data; A.T., A.R., and Y.Y. directed clinical site; A.T., D.L., R.M., B.C., A.R., and Y.Y. recruited patients; and J.E.Z., I.G., M.E.D., and Y.Y. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Calando PharmaceuticalsUNSPECIFIED
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
Non-Subject Keywords:translational medicine, DNA proliferation, DNA replication, maximum tolerance dose, dose limiting toxicity
Issue or Number:31
PubMed Central ID:PMC4128111
Record Number:CaltechAUTHORS:20140717-114522722
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Official Citation:Jonathan E. Zuckerman, Ismael Gritli, Anthony Tolcher, Jeremy D. Heidel, Dean Lim, Robert Morgan, Bartosz Chmielowski, Antoni Ribas, Mark E. Davis, and Yun Yen Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA PNAS 2014 111 (31) 11449-11454; published ahead of print July 21, 2014, doi:10.1073/pnas.1411393111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:47295
Deposited By: George Porter
Deposited On:21 Jul 2014 19:53
Last Modified:10 Nov 2021 17:37

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