Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance
Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent d...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.764540/full |
| _version_ | 1811245292588105728 |
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| author | Nick Evans Ruslan Grygorash Paul Williams Andrew Kyle Terrence Kantner Ravindra Pathak XiaoBo Sheng Fabio Simoes Hiteshri Makwana Ricardo Resende Elena de Juan Alan Jenkins David Morris Aurelie Michelet Frances Jewitt Felicity Rudge Nicolas Camper Anaïs Manin William McDowell Martin Pabst Antony Godwin Mark Frigerio Matthew Bird |
| author_facet | Nick Evans Ruslan Grygorash Paul Williams Andrew Kyle Terrence Kantner Ravindra Pathak XiaoBo Sheng Fabio Simoes Hiteshri Makwana Ricardo Resende Elena de Juan Alan Jenkins David Morris Aurelie Michelet Frances Jewitt Felicity Rudge Nicolas Camper Anaïs Manin William McDowell Martin Pabst Antony Godwin Mark Frigerio Matthew Bird |
| author_sort | Nick Evans |
| collection | DOAJ |
| description | Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16–34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3′-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures. |
| first_indexed | 2024-04-12T14:38:27Z |
| format | Article |
| id | doaj.art-e322c470d7fb4d25b6de4ac481fa6602 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T14:38:27Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e322c470d7fb4d25b6de4ac481fa66022022-12-22T03:29:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.764540764540Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo PerformanceNick EvansRuslan GrygorashPaul WilliamsAndrew KyleTerrence KantnerRavindra PathakXiaoBo ShengFabio SimoesHiteshri MakwanaRicardo ResendeElena de JuanAlan JenkinsDavid MorrisAurelie MicheletFrances JewittFelicity RudgeNicolas CamperAnaïs ManinWilliam McDowellMartin PabstAntony GodwinMark FrigerioMatthew BirdAntibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16–34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3′-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.https://www.frontiersin.org/articles/10.3389/fphar.2022.764540/fullantibody drug conjugate (ADC)crown ethercyclodextrinin vivoxenograft |
| spellingShingle | Nick Evans Ruslan Grygorash Paul Williams Andrew Kyle Terrence Kantner Ravindra Pathak XiaoBo Sheng Fabio Simoes Hiteshri Makwana Ricardo Resende Elena de Juan Alan Jenkins David Morris Aurelie Michelet Frances Jewitt Felicity Rudge Nicolas Camper Anaïs Manin William McDowell Martin Pabst Antony Godwin Mark Frigerio Matthew Bird Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance Frontiers in Pharmacology antibody drug conjugate (ADC) crown ether cyclodextrin in vivo xenograft |
| title | Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance |
| title_full | Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance |
| title_fullStr | Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance |
| title_full_unstemmed | Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance |
| title_short | Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance |
| title_sort | incorporation of hydrophilic macrocycles into drug linker reagents produces antibody drug conjugates with enhanced in vivo performance |
| topic | antibody drug conjugate (ADC) crown ether cyclodextrin in vivo xenograft |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.764540/full |
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