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1.
Mol Cancer Ther ; 23(1): 84-91, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37774393

RESUMO

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.


Assuntos
Imunoconjugados , Humanos , Imunoconjugados/química , Ensaios Antitumorais Modelo de Xenoenxerto , Trastuzumab/farmacologia , Trastuzumab/química , Receptor ErbB-2/metabolismo , Cisteína
2.
Chem Commun (Camb) ; 56(17): 2622-2625, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32016211

RESUMO

The synthesis and single crystal structures of Am(iii) and Cm(iii) thiocyanate complexes are reported along with an isostructural series of lanthanide thiocyanate complexes. Because the complexes are isostructural, a comparative study of the metal-thiocyanate bonds was conducted using Raman spectroscopy indicating very similar and electrostatic metal-ligand interactions.

3.
Dalton Trans ; 45(24): 9871-83, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-26924711

RESUMO

Five heteroleptic Cu(i)bis(phenanthroline) chromophores with distinct variation in the steric bulk at the 2,9-phenanthroline position were synthesized using the HETPHEN method, and their ground and excited state properties are described. Analysis of the crystal structures reveals a significant distortion from tetrahedral geometry around the Cu(i) centre which is attributed to favourable aromatic interactions between the two phenanthroline ligands. Ultrafast and nanosecond transient optical spectroscopies reveal that the excited state lifetime can be tuned across two orders of magnitude up to 74 nanoseconds in acetonitrile by changing the 2,9-substituent from hydrogen to sec-butyl. X-ray transient absorption spectroscopy at the Cu K-edge confirmed Cu(i) oxidation to Cu(ii) and revealed a decrease of the Cu-N bond lengths in the excited state. The ground and excited state characterization presented here will guide the integration of CuHETPHEN chromophores into complex electron donor-acceptor architectures.

4.
Chemistry ; 21(44): 15575-82, 2015 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-26493880

RESUMO

The synthesis, X-ray crystal structure, vibrational and optical spectroscopy for the eight-coordinate thiocyanate compounds, [Et4 N]4 [Pu(IV) (NCS)8 ], [Et4 N]4 [Th(IV) (NCS)8 ], and [Et4 N]4 [Ce(III) (NCS)7 (H2 O)] are reported. Thiocyanate was found to rapidly reduce plutonium to Pu(III) in acidic solutions (pH<1) in the presence of NCS(-) . The optical spectrum of [Et4 N][SCN] containing Pu(III) solution was indistinguishable from that of aquated Pu(III) suggesting that inner-sphere complexation with [Et4 N][SCN] does not occur in water. However, upon concentration, the homoleptic thiocyanate complex [Et4 N]4 [Pu(IV) (NCS)8 ] was crystallized when a large excess of [Et4 N][NCS] was present. This compound, along with its U(IV) analogue, maintains inner-sphere thiocyanate coordination in acetonitrile based on the observation of intense ligand-to-metal charge-transfer bands. Spectroscopic and crystallographic data do not support the interaction of the metal orbitals with the ligand π system, but support an enhanced An(IV) -NCS interaction, as the Lewis acidity of the metal ion increases from Th to Pu.

5.
Chem Sci ; 6(12): 7258-7266, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28757986

RESUMO

This manuscript describes a combination of DFT calculations and experiments to assess the reduction of borazines (B-N heterocycles) by η6-coordination to Cr(CO)3 or [Mn(CO)3]+ fragments. The energy requirements for borazine reduction are established as well as the extent to which coordination of borazine to a transition metal influences hydride affinity, basicity, and subsequent reduction steps at the coordinated borazine molecule. Borazine binding to M(CO)3 fragments decreases the thermodynamic hydricity by >30 kcal mol-1, allowing it to easily accept a hydride. These hydricity criteria were used to guide the selection of appropriate reagents for borazine dearomatization. Reduction was achieved with an H2-derived hydride source, and importantly, a pathway which proceeds through a single electron reduction and H-atom transfer reaction, mediated by anthraquinone was uncovered. The latter transformation was also carried out electrochemically, at relatively positive potentials by comparison to all prior reports, thus establishing an important proof of concept for any future electrochemical B[double bond, length as m-dash]N bond reduction.

6.
Angew Chem Int Ed Engl ; 53(12): 3173-7, 2014 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-24519845

RESUMO

Boron clusters are proposed as a new concept for the design of magnesium-battery electrolytes that are magnesium-battery-compatible, highly stable, and noncorrosive. A novel carborane-based electrolyte incorporating an unprecedented magnesium-centered complex anion is reported and shown to perform well as a magnesium-battery electrolyte. This finding opens a new approach towards the design of electrolytes whose likelihood of meeting the challenging design targets for magnesium-battery electrolytes is very high.

7.
Biotechnol Prog ; 29(5): 1131-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23798487

RESUMO

Monoclonal antibodies (mAbs) are currently the dominant class of biopharmaceuticals. Due to the high dosage requirements of most mAb therapeutics, high productivity and low aggregation are prevailing criteria during cell line generation and process development. Given that light chains (LCs) play an important role in antibody folding and assembly, and that most mAb producing cell lines also manufacture free LCs, we sought to investigate whether there was a relationship between free LC levels in cell culture media and mAb productivity/quality. To this end, a series of analytical methods were developed in order to quantify free LC content in cell culture media and assess mAb productivity and aggregation levels. Afterwards, conditioned media samples from different cell lines at identical culturing conditions and a single clone under varying culturing conditions were analyzed. Higher LC expression was found to correlate with higher cell viability, higher mAb productivity, and lower aggregation. While LC expression cannot yet be definitively considered the root cause of these phenomena, these results are consistent with the role of LCs in mAb production, suggesting that free LC expression levels may potentially serve as a parameter for cell line generation and cell culture process optimization.


Assuntos
Anticorpos Monoclonais/biossíntese , Meios de Cultura/química , Cadeias Leves de Imunoglobulina/biossíntese , Proteínas Recombinantes/biossíntese , Animais , Células CHO , Sobrevivência Celular , Cromatografia Líquida , Clonagem Molecular , Cricetulus , Eletroforese em Gel de Poliacrilamida , Regulação da Expressão Gênica , Imunoglobulina G/biossíntese , Espectrometria de Massas , Dobramento de Proteína
8.
Angew Chem Int Ed Engl ; 51(52): 13168-72, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23161604

RESUMO

Recharging spent BN fuel: {Cr(CO)(3)} mediates the reduction of borazines by hydride and methyl nucleophiles to generate anionic complexes of dearomatized hexamethylborazine. Subsequent quenching leads to the release of a substituted cyclotriborazane, successfully demonstrating the stepwise reduction of a B=N bond.

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