DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies
DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
Procopiou, George
4a8347c7-8dc2-41d3-a0d0-5e5036819813
Jackson, Paul J. M.
a8f66bdd-98e9-43c7-b6c2-753659dc60e1
Auer, Jennifer
d9478a93-7b4c-46cc-9d64-e657bf9f91e4
Di Mascio, Daniella
915ed5fb-e344-42eb-bca6-86b52e5200e8
Pepper, Chris
d98085c8-4674-4a8e-9698-cff8194440e1
Miraz Rahman, Khondaker
6f57e1a3-b2d4-42a3-89f1-2344f515e6cd
Fox, Keith
9da5debc-4e45-473e-ab8c-550d1104659f
Thurston, David E.
9e2a56ac-259f-4977-a087-9d97c9003fbb
29 July 2022
Procopiou, George
4a8347c7-8dc2-41d3-a0d0-5e5036819813
Jackson, Paul J. M.
a8f66bdd-98e9-43c7-b6c2-753659dc60e1
Auer, Jennifer
d9478a93-7b4c-46cc-9d64-e657bf9f91e4
Di Mascio, Daniella
915ed5fb-e344-42eb-bca6-86b52e5200e8
Pepper, Chris
d98085c8-4674-4a8e-9698-cff8194440e1
Miraz Rahman, Khondaker
6f57e1a3-b2d4-42a3-89f1-2344f515e6cd
Fox, Keith
9da5debc-4e45-473e-ab8c-550d1104659f
Thurston, David E.
9e2a56ac-259f-4977-a087-9d97c9003fbb
Procopiou, George, Jackson, Paul J. M., Auer, Jennifer, Di Mascio, Daniella, Pepper, Chris, Miraz Rahman, Khondaker, Fox, Keith and Thurston, David E.
(2022)
DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies.
Communications Biology, 5 (1), [741].
(doi:10.1038/s42003-022-03633-0).
Abstract
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
Text
s42003-022-03633-0
- Version of Record
More information
Accepted/In Press date: 24 June 2022
Published date: 29 July 2022
Additional Information:
Funding Information:
All authors except C.P. are either paid employees/consultants (G.P., P.J.M.J., D.E.T.) or recipients of grants funded by Femtogenix Ltd (D.d.M, K.R.F.). G.P., P.J.M.J., K.M.R and D.E.T. hold shares and/or share options in the company. C.P declares no competing interests.
Identifiers
Local EPrints ID: 468976
URI: http://eprints.soton.ac.uk/id/eprint/468976
ISSN: 2399-3642
PURE UUID: c9ffa73b-dab1-49b4-b022-194090aafaa3
Catalogue record
Date deposited: 02 Sep 2022 18:43
Last modified: 06 Jun 2024 01:32
Export record
Altmetrics
Contributors
Author:
George Procopiou
Author:
Paul J. M. Jackson
Author:
Jennifer Auer
Author:
Chris Pepper
Author:
Khondaker Miraz Rahman
Author:
David E. Thurston
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
