Development and Translational Application of an Integrated, Mechanistic Model of Antibody-Drug Conjugate Pharmacokinetics.
Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition. The model includes explicit representation of all DAR species; DAR-dependent sequential deconjugation of the drug, resulting in the conversion of higher DAR to lower DAR species; and DAR-dependent antibody/ADC clearance. PK profiles of multiple analytes (total antibody, drug-conjugated antibody, and/or antibody-conjugated drug) for different ADC molecules and targets in rodents and cynomolgus monkeys were used for model development. The integrated cross-species model was successful in capturing the multi-analyte PK profiles after administration of purified ADCs with defined DAR species and ADCs with mixtures of DAR. Human PK predictions for DSTP3086S (anti-STEAP1-vc-MMAE) with the platform model agreed well with PK (total antibody and antibody-conjugated drug concentrations) measurements in the dose-ranging phase I clinical study. The integrated model is applicable to various other ADCs with different formats, conjugated drugs, and linkers, and provides a valuable tool for the exploration of mechanisms governing disposition of ADCs and enables translational predictions.
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Siddharth
S
Sukumaran
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Crystal
C
Zhang
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Douglas D
DD
Leipold
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Ola M
OM
Saad
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Keyang
K
Xu
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Kapil
K
Gadkar
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Divya
D
Samineni
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Bei
B
Wang
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Marija
M
Milojic-Blair
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Montserrat
M
Carrasco-Triguero
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Bonnee
B
Rubinfeld
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Paul
P
Fielder
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA.
Kedan
K
Lin
Genentech Research and Early Development, 1 DNA Way, South San Francisco, California, 94080, USA. ramanujan.saroja@gene.com.
Saroja
S
Ramanujan
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003198:Computer Simulation; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D008954:Models, Biological; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D057170:Translational Research, Biomedical
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; C513576:monomethylauristatin F; C495575:monomethyl auristatin E
DSTP3086S; antibody-drug conjugate; clinical translation; drug deconjugation; drug-to-antibody ratio (DAR); mathematical modeling
J Pharmacokinet Pharmacodyn. 2010 Jun;37(3):221-42
20424896
Nat Biotechnol. 2003 Jul;21(7):778-84
12778055
Pharm Res. 2015 Jun;32(6):1884-93
25446772
Clin Cancer Res. 2015 Nov 15;21(22):5139-50
26156394
Bioanalysis. 2013 Jan;5(2):201-26
23330562
Pharm Res. 2015 Jun;32(6):1907-19
25467958
J Pharmacokinet Pharmacodyn. 2014 Feb;41(1):35-47
24322877
AAPS J. 2014 Sep;16(5):994-1008
24917179
Cancer Chemother Pharmacol. 2014 Aug;74(2):399-410
24939213
Methods Mol Biol. 2013;1045:117-31
23913144
MAbs. 2011 Jan-Feb;3(1):61-6
20962582
Clin Cancer Res. 2004 Oct 15;10(20):7063-70
15501986
Bioconjug Chem. 2014 Apr 16;25(4):656-64
24559399
Bioconjug Chem. 2011 Oct 19;22(10):1994-2004
21913715
Methods Mol Biol. 2009;525:445-67, xiv
19252846
Clin Pharmacokinet. 2013 Aug;52(8):657-72
23553425
Methods Mol Biol. 2013;1045:71-100
23913142
J Pharmacokinet Pharmacodyn. 2012 Dec;39(6):643-59
23151991
Br J Cancer. 2016 Feb 16;114(4):362-7
26742008
Nat Biotechnol. 2012 Jan 22;30(2):184-9
22267010