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Characterization of Tissue Distribution, Catabolism, and Elimination of an Anti-Staphylococcus aureus THIOMAB Antibody-Antibiotic Conjugate in Rats.
Cai, Hao; Yip, Victor; Lee, M Violet; Wong, Sylvia; Saad, Ola; Ma, Shuguang; Ljumanovic, Nina; Khojasteh, S Cyrus; Kamath, Amrita V; Shen, Ben-Quan.
Afiliação
  • Cai H; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Yip V; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Lee MV; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Wong S; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Saad O; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Ma S; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Ljumanovic N; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Khojasteh SC; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Kamath AV; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California.
  • Shen BQ; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (H.C., V.Y., A.V.K., B.-Q.S.), BioAnalytical Sciences (M.V.L., S.W., O.S.), Drug Metabolism and Pharmacokinetics (S.M., S.C.K.), and Safety Assessment (N.L.), Genentech Inc., South San Francisco, California shen.ben@gene.com.
Drug Metab Dispos ; 48(11): 1161-1168, 2020 11.
Article em En | MEDLINE | ID: mdl-32839277
Invasive Staphylococcus aureus infection is a leading cause of infectious disease-related deaths because S. aureus survives within host phagocytic cells, from which the bacteria are not adequately eliminated using current antibiotic treatments. Anti-S. aureus THIOMAB antibody-antibiotic conjugate (TAC), an anti-S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC and the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches. Intravenous injection of unconjugated [14C]dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [14C]dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route, with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites. In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection. SIGNIFICANCE STATEMENT: The present studies provide a comprehensive investigation of the absorption, distribution, metabolism/catabolism, and elimination of the first antibody-antibiotic conjugate developed for the treatment of an infectious disease. Although many antibody-drug conjugates are in development for various disease indications, only a limited amount of absorption, distribution, metabolism/catabolism, and elimination information is available in the literature. This study demonstrates the use of radiolabeling technology to delineate the absorption, distribution, metabolism/catabolism, and elimination properties of a complex modality and help address the key questions related to clinical pharmacological studies.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoconjugados / Antibacterianos / Anticorpos Antibacterianos Limite: Animals / Female / Humans / Male Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoconjugados / Antibacterianos / Anticorpos Antibacterianos Limite: Animals / Female / Humans / Male Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2020 Tipo de documento: Article
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