35 results on '"Antoine Maruani"'
Search Results
2. Modular chemical construction of IgG-like mono- and bispecific synthetic antibodies (SynAbs)
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Fabien Thoreau, Peter A. Szijj, Michelle K. Greene, Léa N. C. Rochet, Ioanna A. Thanasi, Jaine K. Blayney, Antoine Maruani, James R. Baker, Christopher J. Scott, and Vijay Chudasama
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General Chemical Engineering ,General Chemistry - Abstract
In recent years there has been rising interest in the field of protein–protein conjugation, especially related to bispecific antibodies (bsAbs) and their therapeutic applications. These constructs contain two paratopes capable of binding two distinct epitopes on target molecules and are thus able to perform complex biological functions (mechanisms of action) not available to monospecific mAbs. Traditionally these bsAbs have been constructed through protein engineering, but recently chemical methods for their construction have started to (re-)emerge. While these have been shown to offer increased modularity, speed and for some methods, even the inherent capacity for further functionalization (e.g., with small molecule cargo), most of these approaches lacked the ability to include a fragment crystallizable (Fc) modality. The Fc component of IgG antibodies offers effector function and increased half-life. Here we report a first-in-class disulfide re-bridging and click-chemistry-based method for the generation of Fc-containing, IgG-like mono- and bispecific antibodies. These are in the FcZ (FabX)-FabY format, i.e., two distinct Fabs and an Fc, potentially all from different antibodies, attached in a homogeneous and covalent manner. We have dubbed these molecules synthetic antibodies (SynAbs). We have constructed a bispecific T cell-engager (BiTE) SynAb, FcCD20-(FabHER2)-FabCD3, and have confirmed that it exhibits the expected biological functions, including the ability to kill HER2+ target cells in a co-culture assay with T cells. more...
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- 2023
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Catalog
3. Copper‐Catalyzed Preparation of Alkenylboronates and Arylboronates
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Safiul Alam, Rejaul Karim, Amarta Kumar Pal, Antoine Maruani, and Aminur Khan
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Hydroboration ,Chemistry ,Organic Chemistry ,Copper catalyzed ,Organic chemistry ,Regioselectivity ,Physical and Theoretical Chemistry - Published
- 2021
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4. A Plug-and-Play Approach for the De Novo Generation of Dually Functionalized Bispecifics
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Peter A. Szijj, Vijay Chudasama, James R. Baker, Stephen Caddick, Antoine Maruani, João C. F. Nogueira, and Calise Bahou
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Pharmacology ,Bispecific antibody ,010405 organic chemistry ,Plug and play ,Chemistry ,Organic Chemistry ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,Computational biology ,Limiting ,021001 nanoscience & nanotechnology ,01 natural sciences ,Antibody fragments ,Epitope ,0104 chemical sciences ,3. Good health ,Click chemistry ,0210 nano-technology ,Biotechnology - Abstract
Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target, thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics has emerged: bispecific antibodies. Bispecific formation using chemical methods is rare and low-yielding and/or requires a large excess of one of the two proteins to avoid homodimerization and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular, and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalization of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalized bispecifics with controlled loading in a modular and convergent manner. more...
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- 2020
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5. Aerobically-initiated C(sp3)–H bond amination through the use of activated azodicarboxylates
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André Shamsabadi, Nehaal Ahmed, Antoine Maruani, and Vijay Chudasama
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Solvent ,Atmospheric oxygen ,Chemistry ,Hydrogen bond ,Radical ,Organic Chemistry ,Organic chemistry ,Physical and Theoretical Chemistry ,Bond formation ,Nitrogen source ,Biochemistry ,Amination - Abstract
Significant advancements in C-N bond formation via C-H bond functionalisation have made it a staple in the production of nitrogen-containing compounds in both industry and academia. However, transition metal-free synthesis, particularly in the case of C(sp3)-N formation, has remained a significant challenge to the synthetic community. Herein we report a procedure for α-C(sp3)-H amination of ethereal compounds through use of azodicarboxylates as the nitrogen source and freely-available atmospheric oxygen to access ethereal radical intermediates via aerobic C-H activation. The use of fluorinated alcohols as solvent is observed to greatly increase the efficiency of the reaction and we show experimentally and theoretically the key role of H-bonding between fluorinated alcohols and azodicarboxylates. Calculations of the condensed Fukui functions of a H-bonded fluorinated alcohol-azodicarboxylate complex correlates with a significantly increased susceptibility of azodicarboxylates to undergo reaction with radicals, which informs a number of recent reports in the literature. more...
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- 2020
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6. Aerobically-initiated C(sp
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André, Shamsabadi, Antoine, Maruani, Nehaal, Ahmed, and Vijay, Chudasama
- Abstract
Significant advancements in C-N bond formation via C-H bond functionalisation have made it a staple in the production of nitrogen-containing compounds in both industry and academia. However, transition metal-free synthesis, particularly in the case of C(sp3)-N formation, has remained a significant challenge to the synthetic community. Herein we report a procedure for α-C(sp3)-H amination of ethereal compounds through use of azodicarboxylates as the nitrogen source and freely-available atmospheric oxygen to access ethereal radical intermediates via aerobic C-H activation. The use of fluorinated alcohols as solvent is observed to greatly increase the efficiency of the reaction and we show experimentally and theoretically the key role of H-bonding between fluorinated alcohols and azodicarboxylates. Calculations of the condensed Fukui functions of a H-bonded fluorinated alcohol-azodicarboxylate complex correlates with a significantly increased susceptibility of azodicarboxylates to undergo reaction with radicals, which informs a number of recent reports in the literature. more...
- Published
- 2020
7. A Plug-and-Play Approach for the
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Antoine, Maruani, Peter A, Szijj, Calise, Bahou, João C F, Nogueira, Stephen, Caddick, James R, Baker, and Vijay, Chudasama
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Epitopes ,Antibodies, Bispecific ,Antibodies, Monoclonal ,Click Chemistry - Abstract
Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target, thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics has emerged: bispecific antibodies. Bispecific formation using chemical methods is rare and low-yielding and/or requires a large excess of one of the two proteins to avoid homodimerization and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular, and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalization of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalized bispecifics with controlled loading in a modular and convergent manner. more...
- Published
- 2020
8. Bispecifics and antibody–drug conjugates: A positive synergy
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Antoine Maruani
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0301 basic medicine ,Drug ,Bispecific antibody ,Immunoconjugates ,biology ,business.industry ,media_common.quotation_subject ,Drug Synergism ,Computational biology ,Monospecific antibody ,Drug synergism ,03 medical and health sciences ,Safety profile ,030104 developmental biology ,Antibodies, Bispecific ,Drug Discovery ,biology.protein ,Humans ,Molecular Medicine ,Medicine ,Antibody ,business ,media_common ,Conjugate - Abstract
Bispecific antibodies (BsAbs) are antibodies with two different paratopes. In the past decade, advances in protein engineering have enabled the development of more than 100 formats of BsAbs. With two BsAbs approved for therapeutic use and more than 60 in clinical trials, this research area has shifted from being effervescent to being a mainstream therapeutic development topic. In parallel, recent progress in protein conjugation and cytotoxicity of small molecule drugs has resulted in a boom in monospecific antibody therapeutics development such as antibody-drug conjugates (ADCs). Recent examples have demonstrated how BsAbs approaches can be used to generate ADCs with better efficacy and safety profile. Rather than examining these two different yet similar areas independently, this minireview will explore the potential synergies that can exist between them. more...
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- 2018
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9. Correction: Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation
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Calise Bahou, Richard J. Spears, Abil E. Aliev, Antoine Maruani, Marcos Fernandez, Faiza Javaid, Peter A. Szijj, James R. Baker, and Vijay Chudasama
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Materials Chemistry ,Metals and Alloys ,Ceramics and Composites ,General Chemistry ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials - Abstract
Correction for ‘Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation’ by Calise Bahou et al., Chem. Commun., 2019, 55, 14829–14832, https://doi.org/10.1039/C9CC08362F. more...
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- 2022
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10. Assembly of High-Potency Photosensitizer–Antibody Conjugates through Application of Dendron Multiplier Technology
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Miffy. H. Y. Cheng, Vijay Chudasama, Francesca Bryden, João M. M. Rodrigues, Huguette Savoie, Ross W. Boyle, Andrew Beeby, and Antoine Maruani
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Dendrimers ,Immunoconjugates ,Porphyrins ,Cell Survival ,Receptor, ErbB-2 ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,010402 general chemistry ,01 natural sciences ,Absorbance ,chemistry.chemical_compound ,Drug Delivery Systems ,Cell Line, Tumor ,Neoplasms ,Dendrimer ,Humans ,Photosensitizer ,Cytotoxicity ,Pharmacology ,Photosensitizing Agents ,Bioconjugation ,010405 organic chemistry ,Chemistry ,Singlet oxygen ,Organic Chemistry ,Trastuzumab ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,Immunoglobulin G ,Biotechnology ,Conjugate - Abstract
Exploitation of photosensitizers as payloads for antibody-based anticancer therapeutics offers a novel alternative to the small pool of commonly utilized cytotoxins. However, existing bioconjugation methodologies are incompatible with the requirement of increased antibody loading without compromising antibody function, stability, or homogeneity. Herein, we describe the first application of dendritic multiplier groups to allow the loading of more than 4 porphyrins to a full IgG antibody in a site-specific and highly homogeneous manner. Photophysical evaluation of UV-visible absorbance and singlet oxygen quantum yields highlighted porphyrin-dendron 14 as the best candidate for bioconjugation; with subsequent bioconjugation producing a HER2-targeted therapeutic with average loading ratios of 15.4:1. In vitro evaluation of conjugate 18 demonstrated a nanomolar photocytotoxic effect in a target cell line, which overexpresses HER2, with no observed photocytotoxicity at the same concentration in a control cell line which expresses native HER2 levels, or in the absence of irradiation with visible light. more...
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- 2017
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11. Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation
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James R. Baker, Marcos Fernández, Vijay Chudasama, Richard J Spears, Peter A. Szijj, Calise Bahou, Antoine Maruani, Abil E. Aliev, and Faiza Javaid
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Linked protein ,010405 organic chemistry ,Metals and Alloys ,General Chemistry ,Glutathione ,010402 general chemistry ,Human serum albumin ,01 natural sciences ,Catalysis ,3. Good health ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Materials Chemistry ,Ceramics and Composites ,medicine ,Extracellular ,Cleavable linker ,Maleimide ,Linker ,medicine.drug ,Cysteine - Abstract
Herein we report a retro-Michael deconjugation pathway of thiol-pyridazinedione linked protein bioconjugates to provide a novel cleavable linker technology. We demonstrate that the novel pyridazinedione linker does not suffer from off-target modification with blood thiols (e.g., glutathione, human serum albumin (HSA)), which is in sharp contrast to an analogous maleimide linker. more...
- Published
- 2019
12. Synthesis and activation of an iron oxide immobilized drug-mimicking reporter under conventional and pulsed X-ray irradiation conditions
- Author
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Anna, Barosi, Petra, Dunkel, Erwann, Guénin, Yoann, Lalatonne, Philippe, Zeitoun, Isabelle, Fitton, Clément, Journé, Alberto, Bravin, Antoine, Maruani, Hamid, Dhimane, Laurence, Motte, and Peter I, Dalko more...
- Abstract
An efficient nano-sized delivery system is presented here allowing the immobilized, picolinium-tethered organic ligand to be released by X-ray irradiation. A marked difference was observed in the fragmentation efficiency by using conventional Cs-137 more...
- Published
- 2019
13. A Plug-and-Play Approach for the De Novo Generation of Dually Functionalised Bispecifics
- Author
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Antoine Maruani, Peter A. Szijj, Calise Bahou, João C. F. Nogueira, Stephen Caddick, James R. Baker, and Vijay Chudasama
- Abstract
Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics in clinical trials and on the market interact with only one target thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics emerged: bispecific antibodies.Bispecific formation using chemical methods is rare and low yielding and/or requires a large excess of one of the two proteins to avoid homodimerisation. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalisation of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalised bispecifics with controlled loading in a modular and convergent manner. more...
- Published
- 2019
- Full Text
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14. Disulfide Modified IgG1: An Investigation of Biophysical Profile and Clinically Relevant Fc Interactions
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Vijay Chudasama, Richard J Spears, Elizabeth A. Love, James R. Baker, Siobhán Leonard, Calise Bahou, Kathryn Armour, and Antoine Maruani
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Immunoconjugates ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,01 natural sciences ,Immunoglobulin G ,Biophysical Phenomena ,Humans ,Disulfides ,Pharmacology ,Antibody-dependent cell-mediated cytotoxicity ,Bioconjugation ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Receptors, IgG ,Rational design ,Antibody-Dependent Cell Cytotoxicity ,Trastuzumab ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Immunoglobulin Fc Fragments ,Covalent bond ,biology.protein ,Biophysics ,Antibody ,0210 nano-technology ,Function (biology) ,Biotechnology ,Conjugate - Abstract
Modification of immunoglobulin G (IgG) 1 proteins in cancer treatment is a rapidly growing field of research. Antibody-drug conjugates (ADCs) exploit the targeted nature of this immunotherapy by conjugating highly potent drugs to antibodies, allowing for effective transport of cargo(s) to cancerous cells. Of the many bioconjugation strategies now available for the formation of highly homogeneous ADCs, disulfide modification is considered an effective, low-cost, and widely accepted method for modifying IgG1s for improved clinical benefit. However, little is known about how disulfide modification impacts clinically relevant fragment crystallizable (Fc) region interactions. Although often overlooked as a secondary ADC function, Fc interactions could prove key in the rational design of cancer cell-targeting ADCs through consideration of potent mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). This work explores different IgG1 disulfide modification techniques and the effect they have on quantifiable secondary IgG1 Fc interactions (e.g., CD16a and FcRn). The solvent accessible disulfide residues of trastuzumab, a clinically relevant IgG1, were modified to provide a range of bioconjugates with differing amounts of interchain covalent linkages. It was found that by natively rebridging the IgG1 model, all tested Fc functionalities were not significantly affected. Additionally, in non Fc-specific biophysical experiments (e.g., thermal stability/aggregation), the natively rebridged species provided an exceptional profile, showing no significant change from the tested native antibody. Conjugates with significant disruption of the covalent connectivity of IgG1 chains resulted in a suboptimal Fc profile (CD16a kinetics or ADCC activity), in addition to substandard non Fc-specific attributes (thermal stability). These results advocate native disulfide rebridging as an excellent synthetic strategy for forming homogeneous IgG1 bioconjugates, with no reported negative impact on biophysical profile relative to the native antibody. more...
- Published
- 2019
15. Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody
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Antoine Maruani, Stephen Caddick, Eifion Robinson, Mark E. B. Smith, João P. Nunes, Vessela Vassileva, James R. Baker, R. Barbara Pedley, João C. F. Nogueira, and Vijay Chudasama
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Drug ,Chemistry, Multidisciplinary ,TRASTUZUMAB ,BIOCONJUGATION ,General Chemical Engineering ,media_common.quotation_subject ,THERAPEUTIC INDEX ,Pharmacology ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Therapeutic index ,Trastuzumab ,In vivo ,LINKER STABILITY ,medicine ,BREAST-CANCER ,TECHNOLOGY ,REAGENTS ,STRATEGY ,media_common ,Science & Technology ,Bioconjugation ,010405 organic chemistry ,SITE-SPECIFIC CONJUGATION ,General Chemistry ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,ATTACHMENT ,body regions ,Chemistry ,Monomethyl auristatin E ,chemistry ,Physical Sciences ,medicine.drug ,Conjugate - Abstract
Herein we report the use of pyridazinediones to functionalise the native solvent accessible interstrand disulfide bonds in trastuzumab with monomethyl auristatin E (MMAE). This method of conjugation delivers serum stable antibody–drug conjugates (ADCs) with a controlled drug loading of 4. Moreover, we demonstrate that the MMAE-bearing ADCs are potent, selective and efficacious against cancer cell lines in both in vitro and in vivo models. more...
- Published
- 2017
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16. Antibody fragments as nanoparticle targeting ligands: a step in the right direction
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Daniel A. Richards, Vijay Chudasama, and Antoine Maruani
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Disease specific ,Computer science ,fungi ,food and beverages ,Nanoparticle ,Nanotechnology ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Antibody fragments ,3. Good health ,0104 chemical sciences ,Chemistry ,Targeted nanoparticles ,Nanomedicine ,0210 nano-technology ,Targeting ligands - Abstract
Recent advances in nanomedicine have shown that dramatic improvements in nanoparticle therapeutics and diagnostics can be achieved through the use of disease specific targeting ligands., Recent advances in nanomedicine have shown that dramatic improvements in nanoparticle therapeutics and diagnostics can be achieved through the use of disease specific targeting ligands. Although immunoglobulins have successfully been employed for the generation of actively targeted nanoparticles, their use is often hampered by the suboptimal characteristics of the resulting complexes. Emerging data suggest that a switch in focus from full antibodies to antibody derived fragments could help to alleviate these problems and expand the potential of antibody–nanoparticle conjugates as biomedical tools. This review aims to highlight how antibody derived fragments have been utilised to overcome both fundamental and practical issues encountered during the design and application of antibody–targeted nanoparticles. more...
- Published
- 2017
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17. Recent advances in the construction of antibody–drug conjugates
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Stephen Caddick, Vijay Chudasama, and Antoine Maruani
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Drug ,Immunoconjugates ,General Chemical Engineering ,medicine.medical_treatment ,media_common.quotation_subject ,Nanotechnology ,Computational biology ,010402 general chemistry ,01 natural sciences ,Targeted therapy ,Food and drug administration ,Antibody Specificity ,Antibodies monoclonal ,medicine ,Humans ,media_common ,Therapeutic window ,010405 organic chemistry ,Chemistry ,Antibodies, Monoclonal ,General Chemistry ,0104 chemical sciences ,body regions ,Pharmaceutical Preparations ,Drug Design ,Drug delivery ,Clinical evaluation - Abstract
Antibody-drug conjugates (ADCs) comprise antibodies covalently attached to highly potent drugs using a variety of conjugation technologies. As therapeutics, they combine the exquisite specificity of antibodies, enabling discrimination between healthy and diseased tissue, with the cell-killing ability of cytotoxic drugs. This powerful and exciting class of targeted therapy has shown considerable promise in the treatment of various cancers with two US Food and Drug Administration approved ADCs currently on the market (Adcetris and Kadcyla) and approximately 40 currently undergoing clinical evaluation. However, most of these ADCs exist as heterogeneous mixtures, which can result in a narrow therapeutic window and have major pharmacokinetic implications. In order for ADCs to deliver their full potential, sophisticated site-specific conjugation technologies to connect the drug to the antibody are vital. This Perspective discusses the strategies currently used for the site-specific construction of ADCs and appraises their merits and disadvantages. more...
- Published
- 2016
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18. A facile, one-pot procedure for the conversion of aromatic aldehydes to esters, as well as thioesters and amides, via acyl hydrazide intermediates
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George Watkins, Ahmed R. Akhbar, Maximillian T. W. Lee, Henry Baggs, Daniel A. Richards, Vijay Chudasama, André Shamsabadi, and Antoine Maruani
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chemistry.chemical_compound ,chemistry ,010405 organic chemistry ,General Chemical Engineering ,Organic chemistry ,lipids (amino acids, peptides, and proteins) ,General Chemistry ,010402 general chemistry ,Hydrazide ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences - Abstract
Herein we present an efficient method for the synthesis of esters from aromatic aldehydes via readily accessible acyl hydrazides. The developed reaction protocol is shown to be tolerant of a range of aromatic aldehydes, bearing various functionalities, as well as being amenable to the synthesis of thioesters and amides. more...
- Published
- 2016
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19. The Use of 3,6-Pyridazinediones in Organic Synthesis and Chemical Biology
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Antoine Maruani, Maximillian T. W. Lee, and Vijay Chudasama
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Pyridazine ,chemistry.chemical_compound ,010405 organic chemistry ,Chemistry ,Diels alder ,Chemical biology ,Posttranslational modification ,Organic chemistry ,Organic synthesis ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Abstract
This article gives an overview of the use of 3,6-pyridazinediones in organic synthesis and chemical biology with an emphasis on recent developments. The properties of pyridazinediones, how they are constructed and how they have been applied in various fields of organic synthesis, medicinal chemistry and chemical biology will be highlighted. more...
- Published
- 2016
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20. Dual modification of biomolecules
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Daniel A. Richards, Antoine Maruani, and Vijay Chudasama
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Models, Molecular ,chemistry.chemical_classification ,010405 organic chemistry ,Oligonucleotide ,Chemistry ,Biomolecule ,Organic Chemistry ,Oligonucleotides ,Proteins ,Nanotechnology ,DUAL (cognitive architecture) ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Chemical Moiety ,Proteins metabolism ,Click chemistry ,Click Chemistry ,Physical and Theoretical Chemistry ,Bioorthogonal chemistry - Abstract
With the advent of novel bioorthogonal reactions and "click" chemistry, an increasing number of strategies for the single labelling of proteins and oligonucleotides have emerged. Whilst several methods exist for the site-selective introduction of a single chemical moiety, site-selective and bioorthogonal dual modification of biomolecules remains a challenge. The introduction of multiple modules enables a plethora of permutations and combinations and can generate a variety of bioconjuguates with many potential applications. From de novo approaches on oligomers to the post-translational functionalisation of proteins, this review will highlight the main strategies to dually modify biomolecules. more...
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- 2016
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21. Synthesis of a novel HER2 targeted aza-BODIPY-antibody conjugate: synthesis, photophysical characterisation and in vitro evaluation
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Vijay Chudasama, Miffy. H. Y. Cheng, Huguette Savoie, Antoine Maruani, and Ross W. Boyle
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Boron Compounds ,Fluorophore ,Immunoconjugates ,Infrared Rays ,Receptor, ErbB-2 ,Breast Neoplasms ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Antibodies ,Fluorescence ,chemistry.chemical_compound ,Aza-bodipy ,Humans ,Physical and Theoretical Chemistry ,Bioconjugation ,biology ,010405 organic chemistry ,Organic Chemistry ,Antibody conjugate ,Photochemical Processes ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,Neoplasm Proteins ,chemistry ,biology.protein ,Female ,Antibody ,Conjugate ,Protein Binding - Abstract
We herein report the synthesis and analysis of a novel aza-BODIPY-antibody conjugate, formed by controlled and regioselective bioconjugation methodology. Employing the clinically relevant antibody, which targets HER2 positive cancers, represents an excellent example of an antibody targeting strategy for this class of near-IR emitting fluorophore. The NIR fluorescence and binding properties were validated through in vitro studies using live cell confocal imaging. more...
- Published
- 2018
22. Regioselective and Stoichiometrically Controlled Conjugation of Photodynamic Sensitizers to a HER2 Targeting Antibody Fragment
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Vijay Chudasama, Stephen Caddick, Antoine Maruani, Huguette Savoie, Ross W. Boyle, Francesca Bryden, and Mark E. B. Smith
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Porphyrins ,Receptor, ErbB-2 ,medicine.medical_treatment ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Healthy tissue ,Photodynamic therapy ,Antibodies, Monoclonal, Humanized ,Antibody fragments ,Immunoglobulin Fab Fragments ,Structure-Activity Relationship ,Tumor Cells, Cultured ,medicine ,Humans ,Disulfides ,Pharmacology ,Photosensitizing Agents ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Regioselectivity ,Stereoisomerism ,Trastuzumab ,Highly selective ,Combinatorial chemistry ,Biochemistry ,Homogeneous ,biology.protein ,Antibody ,Biotechnology ,Conjugate - Abstract
The rapidly increasing interest in the synthesis of antibody-drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin-antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case. more...
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- 2014
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23. Next generation maleimides enable the controlled assembly of antibody–drug conjugates via native disulfide bond bridging
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João P. Nunes, Mark E. B. Smith, Vijay Chudasama, Stephen Caddick, James R. Baker, Antoine Maruani, Kerry A. Chester, and Felix F. Schumacher
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Drug ,media_common.quotation_subject ,macromolecular substances ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Antibodies ,Maleimides ,medicine ,Molecule ,Doxorubicin ,Disulfides ,Physical and Theoretical Chemistry ,skin and connective tissue diseases ,neoplasms ,media_common ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Disulfide bond ,Trastuzumab ,Combinatorial chemistry ,Small molecule ,3. Good health ,body regions ,Homogeneous ,biology.protein ,Antibody ,Conjugate ,medicine.drug - Abstract
Highly homogeneous ADCs are generated by the efficient bridging of interchain disulfide bonds in trastuzumab, using next generation maleimides., The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody–drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody. more...
- Published
- 2014
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24. Enabling the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering
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Maximillian T. W. Lee, Antoine Maruani, Daniel A. Richards, Vijay Chudasama, Stephen Caddick, and James R. Baker
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0301 basic medicine ,Scaffold ,biology ,Chemistry ,General Chemistry ,Combinatorial chemistry ,03 medical and health sciences ,030104 developmental biology ,Biochemistry ,biology.protein ,Antibody ,Overall efficiency ,Conjugate - Abstract
A novel reagent/strategy enables the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering., The generation of antibody conjugates with a loading of two modules is desirable for a host of reasons. Whilst certain antibody engineering approaches have been useful in the preparation of such constructs, a reliable method based on a native antibody scaffold without the use of enzymes or harsh oxidative conditions has hitherto not been achieved. The use of native antibodies has several advantages in terms of cost, practicality, accessibility, time and overall efficiency. Herein we present a novel, reliable method of furnishing antibody conjugates with a loading of two modules starting from a native antibody scaffold. more...
- Published
- 2016
25. ChemInform Abstract: Dual Modification of Biomolecules
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Antoine Maruani, Daniel A. Richards, and Vijay Chudasama
- Subjects
chemistry.chemical_classification ,Chemical Moiety ,chemistry ,Oligonucleotide ,Biomolecule ,Nanotechnology ,General Medicine ,DUAL (cognitive architecture) ,Bioorthogonal chemistry - Abstract
With the advent of novel bioorthogonal reactions and “click” chemistry, an increasing number of strategies for the single labelling of proteins and oligonucleotides have emerged. Whilst several methods exist for the site-selective introduction of a single chemical moiety, site-selective and bioorthogonal dual modification of biomolecules remains a challenge. The introduction of multiple modules enables a plethora of permutations and combinations and can generate a variety of bioconjuguates with many potential applications. From de novo approaches on oligomers to the post-translational functionalisation of proteins, this review will highlight the main strategies to dually modify biomolecules. more...
- Published
- 2016
- Full Text
- View/download PDF
26. ChemInform Abstract: A Facile, One-Pot Procedure for the Conversion of Aromatic Aldehydes to Esters, as well as Thioesters and Amides, via Acyl Hydrazide Intermediates
- Author
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George Watkins, André Shamsabadi, Ahmed R. Akhbar, Daniel A. Richards, Vijay Chudasama, Maximillian T. W. Lee, Antoine Maruani, and Henry Baggs
- Subjects
chemistry.chemical_compound ,chemistry ,lipids (amino acids, peptides, and proteins) ,General Medicine ,Hydrazide ,Combinatorial chemistry - Abstract
Herein we present an efficient method for the synthesis of esters from aromatic aldehydes via readily accessible acyl hydrazides. The developed reaction protocol is shown to be tolerant of a range of aromatic aldehydes, bearing various functionalities, as well as being amenable to the synthesis of thioesters and amides. more...
- Published
- 2016
- Full Text
- View/download PDF
27. ChemInform Abstract: The Use of 3,6-Pyridazinediones in Organic Synthesis and Chemical Biology
- Author
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Maximillian T. W. Lee, Antoine Maruani, and Vijay Chudasama
- Subjects
chemistry.chemical_compound ,Chemistry ,Chemical biology ,Organic chemistry ,Organic synthesis ,Nanotechnology ,General Medicine - Abstract
This article gives an overview of the use of 3,6-pyridazinediones in organic synthesis and chemical biology with an emphasis on recent developments. The properties of pyridazinediones, how they are... more...
- Published
- 2016
- Full Text
- View/download PDF
28. Site-selective multi-porphyrin attachment enables the formation of a next-generation antibody-based photodynamic therapeutic
- Author
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Vijay Chudasama, Antoine Maruani, Stephen Caddick, Huguette Savoie, Ross W. Boyle, and Francesca Bryden
- Subjects
Porphyrins ,Stereochemistry ,medicine.drug_class ,Cell Survival ,Alkyne ,Monoclonal antibody ,Catalysis ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Materials Chemistry ,medicine ,Structure–activity relationship ,Humans ,chemistry.chemical_classification ,Photosensitizing Agents ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Metals and Alloys ,Antibodies, Monoclonal ,General Chemistry ,Photosensitizing Agent ,Combinatorial chemistry ,Porphyrin ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Photochemotherapy ,Alkynes ,Ceramics and Composites ,biology.protein ,Azide ,Antibody ,Linker - Abstract
Herein we present a significant step towards next-generation antibody-based photodynamic therapeutics. Site-selective modification of a clinically relevant monoclonal antibody, with a serum-stable linker bearing a strained alkyne, allows for the controlled Cu-free "click" assembly of an in vitro active antibody-based PDT agent using a water soluble azide porpyhrin. more...
- Published
- 2015
29. A platform for efficient, thiol-stable conjugation to albumin's native single accessible cysteine
- Author
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Mikael B. Caspersen, Antoine Maruani, Eifion Robinson, Karl Nicholls, Malcolm J. Saxton, João P. Nunes, Stephen Caddick, James R. Baker, Vijay Chudasama, Maurício Morais, and Mark E. B. Smith
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endocrine system ,education ,Biochemistry ,behavioral disciplines and activities ,Mass Spectrometry ,Protein Structure, Secondary ,Hydrolysis ,chemistry.chemical_compound ,Protein structure ,Albumins ,Organic chemistry ,Humans ,Cysteine ,Sulfhydryl Compounds ,Physical and Theoretical Chemistry ,Maleimide ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Albumin ,Maleates ,Hydrogen-Ion Concentration ,Combinatorial chemistry ,humanities ,3. Good health ,Thiol ,Click chemistry ,Click Chemistry ,Conjugate - Abstract
Thiol-stable albumin biologics are enabled by controlled, quantitative hydrolysis of maleimide–albumin conjugates, i.e. with no retro-Michael., Herein we report the use of bromomaleimides for the construction of stable albumin conjugates via conjugation to its native, single accessible, cysteine followed by hydrolysis. Advantages over the classical maleimide approach are highlighted in terms of quantitative hydrolysis and absence of undesirable retro-Michael deconjugation. more...
- Published
- 2015
30. A mild TCEP-based para-azidobenzyl cleavage strategy to transform reversible cysteine thiol labelling reagents into irreversible conjugates
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Stephen Caddick, Pierre Canavelli, Shamim Alom, Maximillian T. W. Lee, Rachel E. Morgan, Vijay Chudasama, and Antoine Maruani
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Models, Molecular ,Phosphines ,Cleavage (embryo) ,Benzoates ,Catalysis ,chemistry.chemical_compound ,Succinimide ,Labelling ,Materials Chemistry ,Organic chemistry ,Cysteine ,Sulfhydryl Compounds ,Maleimide ,chemistry.chemical_classification ,Molecular Structure ,Staining and Labeling ,Metals and Alloys ,General Chemistry ,Combinatorial chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry ,Reagent ,Ceramics and Composites ,Thiol ,TCEP ,Indicators and Reagents - Abstract
It has recently emerged that the succinimide linkage of a maleimide thiol addition product is fragile, which is a major issue in fields where thiol functionalisation needs to be robust. Herein we deliver a strategy that generates selective cysteine thiol labelling reagents, which are stable to hydrolysis and thiol exchange. more...
- Published
- 2014
31. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy
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Antoine, Maruani, Mark E B, Smith, Enrique, Miranda, Kerry A, Chester, Vijay, Chudasama, and Stephen, Caddick
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Immunoconjugates ,Microscopy, Confocal ,Receptor, ErbB-2 ,Photoelectron Spectroscopy ,Antineoplastic Agents ,Breast Neoplasms ,Trastuzumab ,Antibodies ,Mass Spectrometry ,Article ,body regions ,Drug Delivery Systems ,Cell Line, Tumor ,Humans ,Click Chemistry ,Electrophoresis, Polyacrylamide Gel ,Chromatography, Liquid - Abstract
Although recent methods for the engineering of antibody–drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines., Antibody–drug conjugates are a class of therapeutic combining the directing ability of antibodies with the cell-killing ability of cytotoxic drugs. Here the authors describe an approach based on click chemistry that enables the rapid assembly of dual-modified antibodies with potential for new therapeutic modalities. more...
- Published
- 2014
32. A rapid, site-selective and efficient route to the dual modification of DARPins
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Ramiz I. Nathani, Stephen Caddick, Vijay Chudasama, Stephen R. Martin, Paul Moody, Mark E. B. Smith, and Antoine Maruani
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Ankyrins ,Receptor, ErbB-2 ,Nanotechnology ,Computational biology ,Protein Engineering ,01 natural sciences ,Catalysis ,03 medical and health sciences ,Materials Chemistry ,Site selective ,Ankyrin ,Humans ,Cysteine ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,010405 organic chemistry ,Chemistry ,Circular Dichroism ,Metals and Alloys ,General Chemistry ,Protein engineering ,Recombinant Proteins ,0104 chemical sciences ,3. Good health ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Ceramics and Composites ,Mutagenesis, Site-Directed ,Ankyrin repeat ,Protein Binding - Abstract
Herein we describe a rapid, simple method for dual modification of DARPins by introduction of cysteine mutations at specific positions that results in a vast difference in their thiol nucleophilicity, allowing for sequential modification., Designed ankyrin repeat proteins (DARPins) are valuable tools in both biochemistry and medicine. Herein we describe a rapid, simple method for the dual modification of DARPins by introduction of cysteine mutations at specific positions that results in a vast difference in their thiol nucleophilicity, allowing for clean sequential modification. more...
- Published
- 2014
33. A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones
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Lourdes Castañeda, James R. Baker, Vijay Chudasama, Elizabeth A. Hull, Richard J. Fitzmaurice, Antoine Maruani, João P. Nunes, Cristina Marculescu, Mark E. B. Smith, Trang M. Tran, Zoë V. F. Wright, Stephen Caddick, and Lyn H. Jones more...
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Thiomaleimides ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Transferability ,Chemical modification ,Pyridazinediones ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Article ,0104 chemical sciences ,3. Good health ,Reagent synthesis ,Reagent ,Bromomaleimides ,Drug Discovery ,Reagents for cysteine modification ,ComputingMethodologies_COMPUTERGRAPHICS - Abstract
Graphical abstract, Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomaleimides and bromopyridazinediones. more...
- Published
- 2012
34. Acid-cleavable thiomaleamic acid linker for homogeneous antibody–drug conjugation
- Author
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Kerry A. Chester, Felix F. Schumacher, James R. Baker, Mark E. B. Smith, Antoine Maruani, Lourdes Castañeda, Vijay Chudasama, Enrique Miranda, and Stephen Caddick
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biology ,010405 organic chemistry ,Thiomaleamic acid ,Stereochemistry ,Chemistry ,Metals and Alloys ,Disulfide bond ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,3. Good health ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Homogeneous ,Drug conjugation ,Materials Chemistry ,Ceramics and Composites ,biology.protein ,Molecule ,Antibody ,Linker ,Conjugate - Abstract
In this communication we describe a novel acid-cleavable linker strategy for antibody–drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody–drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload. more...
- Published
- 2013
- Full Text
- View/download PDF
35. A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy
- Author
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Rifat Hamoudi, James R. Baker, Laurence Lovat, Antoine Maruani, Halla W. Reinert, Stephen Caddick, I. Stamati, Mohammed A. Butt, João P. Nunes, M. Qurashi, Laura Funnell, Hayley Pye, A. May, Mahendra P Deonarain, Mark E. B. Smith, Vijay Chudasama, Jared S Marklew, and Gokhan Yahioglu more...
- Subjects
0301 basic medicine ,Theranostic Nanomedicine ,Cell Survival ,Receptor, ErbB-2 ,medicine.medical_treatment ,Nanotechnology ,Photodynamic therapy ,Flow cytometry ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Trastuzumab ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Humans ,Physical and Theoretical Chemistry ,Cell Proliferation ,Photosensitizing Agents ,biology ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,Chemistry ,Cancer ,medicine.disease ,In vitro ,030104 developmental biology ,Photochemotherapy ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Adenocarcinoma ,Antibody ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments’ lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities. more...
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