e14061 Background: Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Current standard of care provides only a modest improvement in overall survival and is associated with poor quality of life. Therapure has developed a novel drug delivery platform based upon the attachment of therapeutic drugs to hemoglobin (Hb) as a means of targeting the liver. TBI 302 is a hemoglobin-drug conjugate (HDC) designed to deliver the anticancer drug floxuridine (FUdR) to the liver to improve the effectiveness of treatment for HCC. Systemic toxicity associated with free FUdR restricts its use to locoregional administration (0.2-0.5 mg/kg/d) via continuous hepatic arterial infusion (HAI). Although HAI of FUdR can reduce tumor burden, toxicity from HAI FUdR and complications associated with direct hepatic infusion pumps can be significant. HDC technology uses Hb as an innovative drug carrier that exploits the natural pathway for hemoglobin clearance predominantly through the liver to provide selective drug targeting while preserving FUdR activity following intravenous (IV) infusion. Methods: To establish a safe starting dose for a first-in-human Phase 1 trial, a GLP-compliant repeat dose preclinical safety study of TBI 302 in cynomolgus monkeys was conducted. TBI 302 administered by 1-hour IV infusion once per week for 8 weeks at doses of 2, 5, and 10.5 mg/kg. Results: Increasing doses of TBI 302 resulted in proportional area under the concentration-time curve (AUC) and maximum concentration (Cmax) of total plasma FUdR. No clinical signs or biochemical toxicity was associated with IV infusion of TBI 302. The no-observed-adverse effect level (NOAEL) of TBI 302 was determined to be the highest dose level of 10.5 mg/kg. TBI 302 is estimated to have a half-life of 5 hours in humans. Conclusions: A Phase I safety study of TBI 302 as second line therapy in HCC has been approved by the US FDA. The primary objective is to determine safety and tolerability of TBI 302. The secondary objectives are to determine TBI 302 pharmacokinetics and effects on tumor burden. Therapure's HDC platform represents a new class of therapy that offers liver-specific targeting for a wide range of hepatic diseases, while potentially reducing drug toxicity.

Abstract Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide; few treatment options are available, especially for advanced stage disease. Therapure has developed a novel drug delivery platform based upon the attachment of drugs to hemoglobin (Hb) as a means of targeting the liver. TBI 302 is a hemoglobin-drug conjugate (HDC) designed to deliver the anticancer drug floxuridine to the liver to improve treatment for HCC. Systemic toxicity associated with free floxuridine restricts its use to locoregional administration (0.2-0.5 mg/kg/d) via continuous hepatic arterial infusion. Although hepatic arterial infusion of floxuridine can reduce hepatic tumor burden, toxicity from floxuridine and complications associated with direct hepatic infusion pumps can be significant. HDC technology exploits the natural pathway for hemoglobin clearance through the liver to provide selective drug targeting while preserving floxuridine activity following standard intravenous (IV) infusion. In a preclinical efficacy study of TBI 302, mice bearing human liver cancer cell line-derived orthotopic liver tumors received twice-weekly tail vein dosing of saline, 3.7 mg/kg floxuridine, or TBI 302. Following 6 weeks of treatment, 70% of the orthotopically implanted mice treated with 170.5 mg/kg TBI 302 (3.7 mg/kg floxuridine) had no measurable liver tumors, indicating suppression of tumor growth. In contrast, only 30% of mice treated with an equivalent dose of unconjugated floxuridine and 20% of mice treated with saline experienced liver tumor growth suppression. These results demonstrate the capability of the HDC platform to enhance the efficacy of cytotoxics through liver targeting. To establish a safe starting dose for a first-in-human Phase 1 trial, a GLP-compliant repeat dose preclinical safety study of TBI 302 in cynomolgus monkeys was conducted. TBI 302 administered by 1-hour IV infusion once per week for 8 weeks at doses of 2, 5, and 10.5 mg/kg (0.08, 0.19, and 0.4 mg/kg floxuridine, respectively) was well tolerated at all dose levels. Increasing doses of TBI 302 resulted in proportional increases in area under the concentration-time curve (AUC) and maximum concentration (Cmax) of total plasma floxuridine. No clinical signs or biochemical toxicity was associated with IV infusion of TBI 302. The no-observed-adverse effect level (NOAEL) of TBI 302 was determined to be the highest dose level of 10.5 mg/kg (0.4 mg/kg floxuridine). A Phase I safety study of TBI 302 as second-line therapy in HCC has been approved by the FDA. The primary objective is to determine safety and tolerability of TBI 302. Secondary objectives are to determine TBI 302 pharmacokinetics and effects on tumor burden. Therapure's HDC platform represents a new class of therapy that offers liver-specific targeting, while potentially reducing extra-hepatic toxicity of drugs. Citation Format: Steve Brookes, Murray J. Cutler, Jin Seog Seo, Gord Adamson, David Bell. A first-in-class hemoglobin-floxuridine conjugate for the treatment of advanced stage liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2055.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTStructure and Reactivity of Dinuclear Cobalt(III) Complexes with Peroxide and Phosphate Diester Analogues Bridging the Metal IonsJin Seog Seo, Rosemary C. Hynes, Daniel Williams, Jik Chin, and Nack-Do SungView Author Information Department of Chemistry, McGill University Montreal, Canada H3A 2K6 Department of Agricultural Chemistry Chung-Nam National University, Taejeon 305-764 Korea Cite this: J. Am. Chem. Soc. 1998, 120, 38, 9943–9944Publication Date (Web):September 10, 1998Publication History Received8 April 1998Published online10 September 1998Published inissue 1 September 1998https://pubs.acs.org/doi/10.1021/ja9811905https://doi.org/10.1021/ja9811905rapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views588Altmetric-Citations35LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Hydrolysis,Metals,Organophosphorus compounds,Oxides,Phosphates Get e-Alerts

The phosphate monoester in 2-H is hydrolyzed an unprecedented 10(11) times more rapidly than the corresponding unbound phosphate. Clean conversion of the bidentate monoester (2-H) to the tridentate inorganic phosphate (3), together with the crystal structure of an analog of 2-H, provides detailed mechanistic insight into the hydrolysis reaction.[GRAPHICS]gradients for coherence-transfer selection in combination with H-1 detection is a powerful method for obtaining two- and three-bond H-1-C-13 connectivities between hyperfine-shifted resonances.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHydrogen abstractions from thiophenols by benzoyloxy radicalsSung Soo Kim, Jin Seog Seo, and Moon Hwan YoonCite this: J. Org. Chem. 1987, 52, 16, 3691–3693Publication Date (Print):August 1, 1987Publication History Published online1 May 2002Published inissue 1 August 1987https://pubs.acs.org/doi/10.1021/jo00392a038https://doi.org/10.1021/jo00392a038research-articleACS PublicationsRequest reuse permissionsArticle Views260Altmetric-Citations11LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts