scholarly journals A successful search for new, efficient, and silver-free manufacturing processes for key platinum(ii) intermediates applied in antibody–drug conjugate (ADC) production

2020 ◽  
Vol 22 (7) ◽  
pp. 2203-2212
Author(s):  
Eugen Merkul ◽  
Niels J. Sijbrandi ◽  
Ibrahim Aydin ◽  
Joey A. Muns ◽  
Ruud J. R. W. Peters ◽  
...  
Keyword(s):  
Manufacturing Processes ◽  
Important Class ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Successful Search ◽  
Antibody Drug

A silver-free amination procedure was developed to obtain an important class of Pt(II) complexes as direct precursors for antibody-drug conjugates.

Axially-substituted silicon phthalocyanine payloads for antibody-drug conjugates

Synlett ◽  
2021 ◽  
Author(s):  
Kazuki Takahashi ◽  
Akira Sugiyama ◽  
Kei Ohkubo ◽  
Toshifumi Tatsumi ◽  
Tatsuhiko Kodama ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Antibody Drug ◽  
Silicon Phthalocyanine

IR700, a silicon phthalocyanine (SiPc) photosensitizer, is an antibody-drug conjugate payload used clinically. It is, however, the sole SiPc payload to date, possibly due to the difficulty of its synthesis, resulting from its asymmetric phathalocyanine skeleton. Here we report a new axially-substituted SiPc payload with easier synthesis. Trastuzumab conjugated with the SiPc showed light- and antigen-dependent cytotoxicity in HER2-overexpressed cancer cell lines.

scholarly journals A RAGE-Targeted Antibody-Drug Conjugate: Surface Plasmon Resonance as a Platform for Accelerating Effective ADC Design and Development

Antibodies ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 7 ◽  
Author(s):  
Gareth D. Healey ◽  
Asa Frostell ◽  
Tim Fagge ◽  
Deyarina Gonzalez ◽  
R. Steven Conlan
Keyword(s):  
Surface Plasmon Resonance ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Wide Range ◽  
Endosomal Ph ◽  
Antibody Drug

Antibodies, antibody-like molecules, and therapeutics incorporating antibodies as a targeting moiety, such as antibody-drug conjugates, offer significant potential for the development of highly efficacious drugs against a wide range of disorders. Despite some success, truly harnessing the superior targeting properties of these molecules requires a platform from which to effectively identify the best candidates for drug development. To streamline the development of antibody-drug conjugates targeting gynecological cancers within our laboratory, we incorporated surface plasmon resonance analysis (Biacore™ T200) into our development toolkit. Antibodies, selected based on positive ELISA screens as suitable for development as antibody-drug conjugates, were evaluated using surface plasmon resonance to determine a wide range of characteristics including specificity, kinetics/affinity, the effect of linker binding, the impact of the drug to antibody ratio, and the effect of endosomal pH on antibody-antigen binding. Analysis revealed important kinetics data and information regarding the effect of conjugation and endosomal pH on our antibody candidates that correlated with cell toxicity and antibody internalization data. As well as explaining observations from cell-based assays regarding antibody-drug conjugate efficacies, these data also provide important information regarding intelligent antibody selection and antibody-drug conjugate design. This study demonstrates the application of surface plasmon resonance technology as a platform, where detailed information can be obtained, supporting the requirements for rapid and high-throughput screening that will enable enhanced antibody-drug conjugate development.

A versatile acid-labile linker for antibody–drug conjugates

MedChemComm ◽  
2014 ◽  
Vol 5 (9) ◽  
pp. 1355-1358 ◽  
Author(s):  
Mathew C. Finniss ◽  
Kevin S. Chu ◽  
Charles J. Bowerman ◽  
J. Christopher Luft ◽  
Zishan A. Haroon ◽  
...  
Keyword(s):  
Low Ph ◽  
Silyl Ether ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Acid Labile ◽  
Antibody Drug

Silyl ether chemistry was used as the linker for an antibody drug conjugate to release a chemotherapeutic at low pH.

scholarly journals Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates

2019 ◽  
Vol 10 (14) ◽  
pp. 4048-4053 ◽  
Author(s):  
Warren Viricel ◽  
Guy Fournet ◽  
Sabine Beaumel ◽  
Emeline Perrial ◽  
Sébastien Papot ◽  
...  
Keyword(s):  
Drug Loading ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Highly Loaded ◽  
Antibody Drug

A new antibody-drug conjugate (ADC) chemical drug-linker platform based on polysarcosine enables increased drug-loading, improved pharmacokinetics and exquisite in vivo potency.

scholarly journals An antibody drug conjugate targeting a GSTA glycosite-signature epitope of mucin1 expressed by non-small cell lung cancer

2019 ◽  
Author(s):  
Deng Pan ◽  
Yubo Tang ◽  
Jiao Tong ◽  
Chengmei Xie ◽  
Jiaxi Chen ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Tumor Xenograft ◽  
Live Cells ◽  
Nsclc Cell Line ◽  
Mouse Tumor ◽  
Antibody Drug Conjugate ◽  
Multiple Cancer ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

AbstractBackgroundAntibodies targeting abnormally glycosylated proteins have been ineffective in treating cancer. Antibody-drug conjugates are emerging as an efficient option, which allow specific delivery of drugs into tumors. We and others have dissected the abnormally glycosylated tandem repeat region of MUC1 glycoprotein as three site-specific glycosylated neoantigen peptide motifs (PDTR, GSTA, GVTS) for monoclonal antibody binding.MethodsInternalization of monoclonal antibodies was studied by immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples were studied by immunohistochemistry. The efficacy of anti-MUC1 ADCs were evaluated with various cancer cell lines and mouse tumor xenograft model.ResultsWe describe an anti-MUC1 ADC by conjugating GSTA neoantigen-specific 16A with monomethyl auristatin E (MMAE). 16A-MMAE showed potent antitumoral efficacy with IC50 ranging from 0.2 to 49.4 nM toward multiple types of cancer cells. In vivo, 16A-MMAE showed dose-dependent inhibition of tumor growth in mouse xenograft of NCI-H838 NSCLC cell line, with minimum effective dose at 1 mg/kg. At the dose of 3 mg/kg, 16A-MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1.ConclusionsThe high antitumoral efficacy of 16A-MMAE suggest that aberrant glycosylated MUC1 neoantigen is a target with high positivity in multiple cancer types for ADC development. Personalized therapy may be achieved by development of glycosite-specific antibody-drug conjugates.

scholarly journals Linker Design Impacts Antibody-Drug Conjugate Pharmacokinetics and Efficacy via Modulating the Stability and Payload Release Efficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Dian Su ◽  
Donglu Zhang
Keyword(s):  
Critical Role ◽  
Systemic Circulation ◽  
Dose Fractionation ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
The Stability ◽  
Antibody Drug

The development of antibody-drug conjugates (ADCs) has significantly been advanced in the past decade given the improvement of payloads, linkers and conjugation methods. In particular, linker design plays a critical role in modulating ADC stability in the systemic circulation and payload release efficiency in the tumors, which thus affects ADC pharmacokinetic (PK), efficacy and toxicity profiles. Previously, we have investigated key linker parameters such as conjugation chemistry (e.g., maleimide vs. disulfide), linker length and linker steric hindrance and their impacts on PK and efficacy profiles. Herein, we discuss our perspectives on development of integrated strategies for linker design to achieve a balance between ADC stability and payload release efficiency for desired efficacy in antigen-expressing xenograft models. The strategies have been successfully applied to the design of site-specific THIOMABTM antibody-drug conjugates (TDCs) with different payloads. We also propose to conduct dose fractionation studies to gain guidance for optimal dosing regimens of ADCs in pre-clinical models.

scholarly journals HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

2019 ◽  
Author(s):  
Gabriel Rinnerthaler ◽  
Simon Peter Gampenrieder ◽  
Richard Greil
Keyword(s):  
Kinase Inhibitors ◽  
Clinical Investigation ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Oncogenic Driver ◽  
Antibody Drug

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has increased meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

scholarly journals A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Tobias Weber ◽  
Athanasios Mavratzas ◽  
Stefan Kiesgen ◽  
Stephanie Haase ◽  
Benedikt Bötticher ◽  
...  
Keyword(s):  
Leukemia Cell ◽  
Cancer Therapeutics ◽  
Size Exclusion ◽  
Single Chain ◽  
Antibody Drug Conjugate ◽  
Disulfide Linkage ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) have evolved as a new class of potent cancer therapeutics. We here report on the development of ADCs with specificity for the B-cell lineage specific (surface) antigen CD22 being expressed in the majority of hematological malignancies. As targeting moiety a previously generated humanized anti-CD22 single-chain variable fragment (scFv) derivative from the monoclonal antibody RFB4 was reengineered into a humanized IgG1 antibody format (huRFB4). Onconase (ranpirnase), a clinically active pancreatic-type ribonuclease, was employed as cytotoxic payload moiety. Chemical conjugation via thiol-cleavable disulfide linkage retained full enzymatic activity and full binding affinity of the ADC. Development of sophisticated purification procedures using size exclusion and ion exchange chromatography allowed the separation of immunoconjugate species with stoichiometrically defined number of Onconase cargos. A minimum of two Onconase molecules per IgG was required for achieving significantin vitrocytotoxicity towards lymphoma and leukemia cell lines. Antibody-drug conjugates with an Onconase to antibody ratio of 3 : 1 exhibited an IC50of 0.08 nM, corresponding to more than 18,400-fold increased cytotoxicity of the ADC when compared with unconjugated Onconase. These results justify further development of this ADC as a promising first-in-class compound for the treatment of CD22-positive malignancies.

Sign in / Sign up

Export Citation Format

Share Document