12 results on '"Spring, David R."'
Search Results
2. Disulfide re-bridging reagents for single-payload antibody-drug conjugates.
- Author
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King, Thomas A., Walsh, Stephen J., Kapun, Mia, Wharton, Thomas, Krajcovicova, Sona, Glossop, Melanie S., and Spring, David R.
- Subjects
ANTIBODY-drug conjugates ,MONOCLONAL antibodies ,DISULFIDES ,IMMUNOGLOBULINS ,WARHEADS ,INTEGERS - Abstract
Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs are significantly harder to synthesise. Here, we report the synthesis of ADCs loaded with a single warhead, using TetraDVP linkers which simultaneously re-bridge all four interchain disulfides of an IgG1 antibody. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Peroxide-cleavable linkers for antibody–drug conjugates.
- Author
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Ashman, Nicola, Bargh, Jonathan D., Walsh, Stephen J., Greenwood, Ryan D., Tiberghien, Arnaud, Carroll, Jason S., and Spring, David R.
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ANTIBODY-drug conjugates ,REACTIVE oxygen species ,PLASMA stability ,HYDROGEN peroxide ,MONOCLONAL antibodies - Abstract
Antibody–drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. Non-internalising antibody–drug conjugates.
- Author
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Ashman, Nicola, Bargh, Jonathan D., and Spring, David R.
- Subjects
ANTIBODY-drug conjugates ,EXTRACELLULAR matrix ,ANTIGENS - Abstract
Antibody–drug conjugates (ADCs) typically require internalisation into cancer cells to release their cytotoxic payload. However, this places stringent constraints on therapeutic development, requiring cancer targets that have high expression of internalising antigens and efficient intracellular processing. An alternative approach is emerging whereby the payloads can be released extracellularly from cleavable linkers upon binding to poorly-internalising antigens or other tumoral components. This removes the reliance on high antigen expression, avoids potentially inefficient internalisation, and can greatly expand the range of cancer targets to components of the extracellular tumour matrix. This review gives an overview of recent developments towards non-internalising ADCs, including emerging cancer-associated cell surface and extracellular proteins, cancer stromal targeting and the linking chemistry that enables extracellular payload release. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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5. Divinylpyrimidine reagents generate antibody–drug conjugates with excellent in vivo efficacy and tolerability.
- Author
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Walsh, Stephen J., Omarjee, Soleilmane, Dannheim, Friederike M., Couturier, Dominique-Laurent, Bexheti, Dorentina, Mendil, Lee, Cronshaw, Gemma, Fewster, Toby, Gregg, Charlotte, Brodie, Cara, Miller, Jodi L., Houghton, Richard, Carroll, Jason S., and Spring, David R.
- Subjects
ANTIBODY-drug conjugates - Abstract
The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody–drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
6. A dual-enzyme cleavable linker for antibody–drug conjugates.
- Author
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Bargh, Jonathan D., Walsh, Stephen J., Ashman, Nicola, Isidro-Llobet, Albert, Carroll, Jason S., and Spring, David R.
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ANTIBODY-drug conjugates ,ARYLSULFATASES ,GALACTOSIDASES - Abstract
A novel enzyme cleavable linker for antibody–drug conjugates is reported. The 3-O-sulfo-β-galactose linker is cleaved sequentially by two lysosomal enzymes – arylsulfatase A and β-galactosidase – to release the payload in targeted cells. An α-HER2 antibody–drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
7. Site-selective modification strategies in antibody–drug conjugates.
- Author
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Walsh, Stephen J., Bargh, Jonathan D., Dannheim, Friederike M., Hanby, Abigail R., Seki, Hikaru, Counsell, Andrew J., Ou, Xiaoxu, Fowler, Elaine, Ashman, Nicola, Takada, Yuri, Isidro-Llobet, Albert, Parker, Jeremy S., Carroll, Jason S., and Spring, David R.
- Subjects
ANTIBODY-drug conjugates ,AMINO acid residues ,CYTOTOXIC T cells - Abstract
Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs. [ABSTRACT FROM AUTHOR]
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- 2021
- Full Text
- View/download PDF
8. Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics.
- Author
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Charoenpattarapreeda, Jiraborrirak, Walsh, Stephen J., Carroll, Jason S., and Spring, David R.
- Subjects
MARINE natural products ,ANTIBODY-drug conjugates ,THERAPEUTICS ,CANCER cells ,NATURAL products - Abstract
Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
9. Cleavable linkers in antibody–drug conjugates.
- Author
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Bargh, Jonathan D., Isidro-Llobet, Albert, Parker, Jeremy S., and Spring, David R.
- Subjects
ANTIBODY-drug conjugates ,DRUG development ,BIOCHEMICAL mechanism of action - Abstract
Antibody–Drug Conjugates (ADCs) are now established as a major class of therapeutics for the clinical treatment of cancer. The properties of the linker between the antibody and the payload are proven to be critical to the success of an ADC. Although ADC linkers can be 'non-cleavable', the vast majority of ADCs in clinical development have specific release mechanisms to allow controlled linker cleavage at the target site and are thus termed 'cleavable'. In recent years, the development of new methods of drug release from ADCs has continued in parallel to the deepening understanding of the biological processes underlying the mechanisms of action of pre-existing technologies. This review summarises the advances in the field of cleavable linker technologies for ADCs. [ABSTRACT FROM AUTHOR]
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- 2019
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10. The development of vinylheteroarene linkers for proteinogenic cysteine modification and studies towards applying (+)-discodermolide as a novel payload in antibody-drug conjugates
- Author
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Seki, Hikaru and Spring, David R.
- Subjects
protein modification ,antibody-drug conjugates ,biotherapeutics - Abstract
Antibody-drug conjugates (ADCs) are an emerging class of anticancer agents which combine the cell-targeting properties of a monoclonal antibody and the cytotoxicity of a small molecule drug. The antibody, cytotoxin and the covalent linker which connects the two units must be optimised for the ADC to have favourable pharmacokinetic, toxicology, and overall pharmacological profiles. The first project describes the design, synthesis, and evaluation of vinylheteroarene linkers for the post-translational modification of proteinogenic cysteine residues. It was hypothesised that the variable heteroarene ring electronics would greatly affect the conjugate addition reaction rate and resulting bioconjugate stability. Thus, a panel of vinylheteroarenes with differing heterocyclic groups were synthesised and evaluated for their suitability. Using small molecule model systems, vinylheteroarene linkers were assessed for cysteine reactivity and chemoselectivity, and conjugate stability to identify the optimum linker. The lead linker was utilised to modify a number of protein substrates with various functionality, including the synthesis of a homogeneous, stable and biologically active ADC. The reagent was also efficient in labelling proteome-wide cysteines in cell lysates. The efficiency and selectivity of these reagents as well as the stability of the products makes them suitable for the generation of biotherapeutics or studies in chemical biology. The second project describes studies towards using (+)-discodermolide as a cytotoxic payload in ADCs. Discodermolide is a polyketide natural product which displays potent activity as an antimitotic agent and is known to be effective against a range of malignancy types. It was desired was to attach discodermolide to an antibody using a cleavable linker which would enable traceless release of the cytotoxin. The alcohol groups in discodermolide presented an opportunity to achieve this in a chemically tractable way. Thus, a valine-alanine-para-aminobenzylcarbonyl-hemiaminal linker was designed for the selective cleavage and payload release by lysosomal cathepsin enzymes. Importantly, this linker strategy allows the synthesis of linker-payloads in one synthetic step, making this a promising approach for the rapid assembly of ADCs using unexplored alcohol cytotoxins. Using this linker, a discodermolide ADC was successfully synthesised which can be used for biological evaluation.
- Published
- 2021
- Full Text
- View/download PDF
11. Development of stapled peptide targeted covalent inhibitors and synthesis of novel ADC payloads for applications in cancer therapy
- Author
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Charoenpattarapreeda, Jiraborrirak and Spring, David R.
- Subjects
616.99 ,cancer ,protein-protein interactions ,stapled peptides ,covalent inhibitors ,targeted covalent inhibitors ,p53-MDM2 ,hemiasterlin ,antibody-drug conjugates ,total synthesis ,Ugi reaction ,multicomponent reactions ,targeted therapeutics - Abstract
Cancer is one of the leading causes of deaths worldwide with 1 in 2 people estimated to develop the disease during their lifetimes. While great progress has been made in curing cancers, new therapeutics are still necessary to tackle this collection of diseases and minimise side-effects. This thesis presents two approaches towards the development of novel bioactive molecules with application in cancer therapeutics. 1) Development of stapled peptide-targeted covalent inhibitors (SPTCIs) of p53-MDM2 protein-protein interaction (PPI). Herein, the development and synthesis of three novel electrophilic staples and four stapled peptides are described. The stapled peptides bear moieties to covalently target a surface-exposed lysine residue on MDM2, an important anti-apoptotic protein overexpressed in many cancer cells. Led by computational modelling and kinetic studies on stability and reactivity of the electrophiles, an SPTCI with an apparent Kd of 7.1 nM was discovered. The stapled peptide was built using two-component Cu-catalysed azide-alkyne cycloaddition (CuAAC) and an activated ester electrophile for targeted covalent inhibition. The peptide showed selective and complete covalent binding to MDM2. Crucially, this proof-of-concept study sets the basis for the development of SPTCIs for a wider range of PPIs. 2) Novel total synthesis of hemiasterlin and its use as a payload in antibody-drug conjugates (ADCs). This thesis details the novel synthesis of hemiasterlin, an anti-mitotic marine natural product with low- to sub-nM potencies against several cancer cell lines. Rapid construction of hemiasterlin was achieved, through a four-component Ugi reaction, in total 14 steps (longest linear sequence of 10 steps) in 11% overall yield. The convergent synthetic route also enabled the synthesis of taltobulin (HTI-286), a similarly potent synthetic analogue. Through the synthesis of complex linker-drug molecules, two ADCs were made to investigate the potential of the two molecules as payloads. Remarkably, the conjugates were found to have mid-pM cytotoxicity against antigen-expressing breast cancer cell lines and no appreciable activity against antigen-negative cancer cells.
- Published
- 2020
12. Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics
- Author
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Jason S. Carroll, David R. Spring, Stephen J. Walsh, Jiraborrirak Charoenpattarapreeda, Charoenpattarapreeda, Jiraborrirak [0000-0002-0316-9608], Walsh, Stephen J [0000-0002-3164-1519], Carroll, Jason S [0000-0003-3643-0080], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
Cell Survival ,Receptor, ErbB-2 ,Taltobulin ,Molecular Conformation ,antibody-drug conjugates ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Hemiasterlin ,Catalysis ,chemistry.chemical_compound ,Rare Diseases ,Cell Line, Tumor ,Breast Cancer ,medicine ,Humans ,Cytotoxicity ,5 Development of treatments and therapeutic interventions ,total synthesis ,targeted therapeutics ,Cancer ,Cell Proliferation ,hemiasterlin ,Natural product ,34 Chemical Sciences ,010405 organic chemistry ,Chemistry ,Antibody–Drug Conjugates ,multicomponent reactions ,Communication ,Total synthesis ,3405 Organic Chemistry ,General Chemistry ,General Medicine ,medicine.disease ,Combinatorial chemistry ,Communications ,0104 chemical sciences ,Orphan Drug ,5.1 Pharmaceuticals ,Cancer cell ,Ugi reaction ,Generic health relevance ,Drug Screening Assays, Antitumor ,Oligopeptides ,Biotechnology - Abstract
Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics., Hemiasterlin, a highly cytotoxic marine natural product (see structure), was synthesised by a multicomponent approach with a longest linear sequence of 10 steps. Its use in a targeted therapeutic was demonstrated by incorporation as a payload in an antibody–drug conjugate (ADC), which showed mid‐picomolar cytotoxicity against HER2‐expressing cancer cell lines.
- Published
- 2020
- Full Text
- View/download PDF
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