title: Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats.
abstract: Antibody-drug conjugates (ADCs) are designed to combine the exquisite specificity of antibodies to target tumor antigens with the cytotoxic potency of chemotherapeutic drugs. In addition to the general chemical stability of the linker, a thorough understanding of the relationship between ADC composition and biological disposition is necessary to ensure that the therapeutic window is not compromised by altered pharmacokinetics (PK), tissue distribution, and/or potential organ toxicity. The six-transmembrane epithelial antigen of prostate 1 (STEAP1) is being pursued as a tumor antigen target. To assess the role of ADC composition in PK, we evaluated plasma and tissue PK profiles in rats, following a single dose, of a humanized anti-STEAP1 IgG1 antibody, a thio-anti-STEAP1 (ThioMab) variant, and two corresponding thioether-linked monomethylauristatin E (MMAE) drug conjugates modified through interchain disulfide cysteine residues (ADC) and engineered cysteines (TDC), respectively. Plasma PK of total antibody measured by enzyme-linked immunosorbent assay (ELISA) revealed ∼45% faster clearance for the ADC relative to the parent antibody, but no apparent difference in clearance between the TDC and unconjugated parent ThioMab. Total antibody clearances of the two unconjugated antibodies were similar, suggesting minimal effects on PK from cysteine mutation. An ELISA specific for MMAE-conjugated antibody indicated that the ADC cleared more rapidly than the TDC, but total antibody ELISA showed comparable clearance for the two drug conjugates. Furthermore, consistent with relative drug load, the ADC had a greater magnitude of drug deconjugation than the TDC in terms of free plasma MMAE levels. Antibody conjugation had a noticeable, albeit minor, impact on tissue distribution with a general trend toward increased hepatic uptake and reduced levels in other highly vascularized organs. Liver uptakes of ADC and TDC at 5 days postinjection were 2-fold and 1.3-fold higher, respectively, relative to the unmodified antibodies. Taken together, these results indicate that the degree of overall structural modification in anti-STEAP1-MMAE conjugates has a corresponding level of impact on both PK and tissue distribution.
authors.affiliation: Department of Pharmacokinetic & Pharmacodynamic Sciences, Genentech Research & Early Development, South San Francisco, California 94080, United States.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Mundo
authors.forename: Crystal
authors.initials: C
authors.lastname: Zhang
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Valle
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Aimee
authors.initials: A
authors.lastname: Fourie
authors.forename: Josefa
authors.initials: J
authors.lastname: Chuh
authors.forename: Neelima
authors.initials: N
authors.lastname: Koppada
authors.forename: Ola
authors.initials: O
authors.lastname: Saad
authors.forename: Herman
authors.initials: H
authors.lastname: Gill
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
authors.forename: Bonnee
authors.initials: B
authors.lastname: Rubinfeld
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.forename: Kedan
authors.initials: K
authors.lastname: Lin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000276:immunology*; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008958:Models, Molecular; D009842:Oligopeptides / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D010088:Oxidoreductases / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D004220:Disulfides; D018796:Immunoconjugates; D009842:Oligopeptides; C513576:monomethylauristatin F; D010088:Oxidoreductases; C432763:STEAP1 protein, human