title: Novel detection of DNA-alkylated adducts of antibody-drug conjugates with potentially unique preclinical and biomarker applications.
abstract: BACKGROUND
  MDX-1203 is an antibody-drug conjugate (ADC) currently in clinical trials for the treatment of renal carcinoma. The active ingredient of MDX-1203 is a DNA minor groove-binding cytotoxic drug that forms a covalently linked adduct with an adenine base. Formation of this adenine adduct prevents DNA replication, thus triggering cell death.
  
  
  RESULTS
  A method has been developed to successfully isolate, identify and quantitate the adenine adduct using LC-MS/MS. The method is highly useful to validate the mode of action of this class of ADCs. Additionally, we have demonstrated that this method could potentially be utilized to assess the efficacy of the ADC in in vitro studies by measuring the amount of adenine adduct in various cells expressing the antigen.
  
  
  CONCLUSIONS
  Upon validation, this method could serve as an invaluable tool to evaluate compounds in preclinical in vivo models and in utilizing the DNA adduct as a potential biomarker.
authors: Protein Chemistry, Biologics Discovery California, Bristol-Myers Squibb Company, 700 Bay Road, Redwood City, CA 94063, USA.
authors: Lourdes
authors: L
authors: Thevanayagam
authors: Alasdair
authors: A
authors: Bell
authors: Indrani
authors: I
authors: Chakraborty
authors: Bilal
authors: B
authors: Sufi
authors: Sanjeev
authors: S
authors: Gangwar
authors: Allen
authors: A
authors: Zang
authors: Vangipuram
authors: V
authors: Rangan
authors: Chetana
authors: C
authors: Rao
authors: Zemin
authors: Z
authors: Wang
authors: Chin
authors: C
authors: Pan
authors: Coling
authors: C
authors: Chong
authors: Pina
authors: P
authors: Cardarelli
authors: Shrikant
authors: S
authors: Deshpande
authors: Mohan
authors: M
authors: Srinivasan
mesh_terms: D000478:Alkylation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018736:DNA Adducts; D018796:Immunoconjugates; D007211:Indoles; C585822:MDX-1203