title: Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates.
abstract: OBJECTIVE
  THIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.
  
  
  METHODS
  Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.
  
  
  RESULTS
  An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.
  
  
  CONCLUSIONS
  Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.
authors.affiliation: Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sukumaran
authors.forename: Kapil
authors.initials: K
authors.lastname: Gadkar
authors.forename: Crystal
authors.initials: C
authors.lastname: Zhang
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhakta
authors.forename: Luna
authors.initials: L
authors.lastname: Liu
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Aimee
authors.initials: A
authors.lastname: Fourie-O'Donohue
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Saroja
authors.initials: S
authors.lastname: Ramanujan
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
authors.forename: Kedan
authors.initials: K
authors.lastname: Lin
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D003545:Cysteine; D005260:Female; D008297:Male; D008657:Metabolic Clearance Rate; D008819:Mice, Nude; D016513:Mice, SCID; D008954:Models, Biological; D009368:Neoplasm Transplantation; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000068878:Trastuzumab / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C486624:Steap protein, mouse; D013438:Sulfhydryl Compounds; D003545:Cysteine; D000068878:Trastuzumab