PO.ET07.02 · 实验与分子治疗
Human blood micronucleated reticulocytes: Application as a pharmacodynamic biomarker for DNA double strand breaks in oncology drug development
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摘要 Abstract
Introduction: Micronucleated reticulocytes (MN-RET) are a well-established biomarker of chromosomal damage, and their assessment is traditionally included as part of regulatory-based, product safety testing during preclinical development. Adaptation of the methodology to high-throughput flow cytometric analysis broadened the utility of the assay and enabled practical translation to human subjects. Most recently, this methodology has been used to demonstrate target engagement via the induction of MN-RET as a biomarker of efficacy during the development of therapies targeting DNA double strand break-repair pathways.
Methods: To support this application, we have conducted studies in clinical models to define basic methodological parameters. In an effort to better understand baseline values over time/between subjects and reproducibility, we evaluated technical replicate variability in MN-RET frequencies based on blood specimens from 14 subjects. Intra-subject variability was based on serial blood draws from 6 subjects, and inter-subject variation was based on up to 344 subjects age 0 to 73 years.
Results: Human models demonstrate increased MN-RET frequencies following exposure to known DNA damaging agents. Inter-subject variation (≥77%) was much greater than intra-subject and technical replicate variability. The relatively large inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%). Neither age nor sex affected inter-subject variation of the MN-RET frequency. In a clinical setting, patients treated with PARP inhibitors at a labelled dose showed elevated MN-RETs, demonstrating the increased unrepaired DNA damage as an indicator of target engagement induced by treatment.
Summary: This translational biomarker of chromosomal damage represents a unique and powerful tool for use in the development of cancer therapies that elicit DNA double strand breaks.
利益披露 Disclosure
J. C. Bemis,
Litron Laboratories Employment, Patent.
C. Baxter,
Artios Pharma Limited Employment, Stock.
G. Langford,
Artios Pharma Limited Employment, Stock Option.
Bicycle Therapeutics Stock.
T. A. Yap,
Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, Bristol Myers Squibb, Boundless Bio, Clovis, Constellation, Cytier, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, ).
Genetech, Haihe, Ideaya, Immunesensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi ).
Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivance, Zenith ).
Abbvie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, BioCity Pharma, Blueprint, Boxer Other, Consultant.
Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cyubrexa, Daiichi Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio Other, Consultant.
EcoR1 Capital, Elipses Pharma, EMD Serono, Entos, F-star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Ideaya Biosciences, Indience, Ignyta, I-Mab, Immunesensor Other, Consultant.
Impact Therapeutics, Institute Gustave Roussy, Intellisphere, Jansen, Kyn, MEI Pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey Other, Consultant.
OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Repare, resTORbio, Roche, Ryvu, Therapeutics, SAAK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover Other, Consultant.
TD2, Terremoto Biosciences, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voroni Inc, Xinthera, Zai Labs, Zielbio Other, Consultant.
S. V. Ulahannan,
Eisai, AstraZeneca, IgMBiosciences Other, Advisory Board.
Abbive Inc, Adlai Nortye, ArQule Inc, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Ciclomed LLC, Erasca, Evelo Biosciences Inc, Exelexis, ExTheraMedical ).
G1 Therapeutics Inc, GlaxoSmithKline GSK, IGM Biosciences, Inmcyte, Isofol, Klus Pharma Inc, Macrogenics, Merck Co Inc, Mersana Therapeutics, OncoMed Pharmaceuticals Inc, Pfizer, Qurgen ).
Regneron Inc, Revolution Medicines Inc, Synermore Biologica Co, Takeda, Tesaro, Tempest, Vigeo Therapeutics Inc ).
N. Lakhani,
Janssen Oncology Other, Consulting.
Alexo, Ascentage, Beigene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapetics Other, Consulting.
InhibRx, Incytem Jounce Therapeutics, Livzon, Northern Biologica, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Systems, Genmab, Odonate, Mersana, Seagen, Alpine Pharma, Celgene Other, Consultant.
Helsinn Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, GlaxoSmithKline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics Other, Consulting.
SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural Oncology, Quanta Therapeutics, Circle Pharma, Day One Biopharmaceuticals, Revolution Medicines, ALX Oncology, Adcentrx, Astellas Other, Consultant.
Astellas Pharma, Bright Peak Therapeutics, BioNTech SE, Bristol Myers Squibb/Celgene, Roche, Treeline Biosciences Other, Consultant.
B. Bashir,
Merck/Esai, Fate/Ono Therapeutics, KAHR Medical, Tempus AI Other, Advisory Board.
Guardant Research Other, Speaker's Bureau.
Amgen, AstraZeneca, Avenzo, Artios, Bicycle Therapeutics, Boehringer Ingelheim, Elucida Oncology, Fate Therapeutics, Gritstone Bio, Ikena Oncology, Jazz Pharma, Johnson & Johnson Innovative Medicine ).
KAHR Medical, Kumquat Biosciences, Lyell Immunopharma, Merck, Pionyr Immunopharma, RasCal Therapeutics, Syros, Tarveda, Targeted Diagnostics & Therapeutics ).
K. N. Moore,
Aadi, AstraZeneca, Abbive, BioNTech, Corcept, Caris, Duality, Daiichi Sankyo, Eisai, GSK, Immunogen, Iovance, Janssen, Loxo/Lilly, Mersana, Merck, Novartis Other, Advisory Board/Honoraria.
Regeneron, Schrodinger, Takeda, Verastem, Whitehawk, Zymeworks, Zentalis Other, Advisory Board/Honoraria.
P. Shah,
Gilead Biosciences Other, Consulting.
AstraZeneca Other, Consulting.
S. Avlasevich,
Litron Laboratories Employment.
D. Torous,
Litron Laboratories Employment.
S. Dertinger,
Litron Laboratories Employment, Patent.