scholarly journals Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1705
Author(s):  
Cristina Martín-Sabroso ◽  
Irene Lozza ◽  
Ana Isabel Torres-Suárez ◽  
Ana Isabel Fraguas-Sánchez
Keyword(s):  
Clinical Stage ◽  
Chemotherapeutic Agents ◽  
Current Status ◽  
Antibody Drug Conjugate ◽  
Cancer Disease ◽  
Drug Conjugates ◽  
Selective Delivery ◽  
Tumor Level ◽  
Cervical Tumors ◽  
Antibody Drug

In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

scholarly journals Systematic identification of regulators of antibody-drug conjugate toxicity using CRISPR-Cas9 screens

2019 ◽  
Author(s):  
C. Kimberly Tsui ◽  
Robyn M. Barfield ◽  
Curt R. Fischer ◽  
David W. Morgens ◽  
Amy Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Chemotherapeutic Agents ◽  
Target Antigen ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Therapy Targets ◽  
Systematic Identification ◽  
Antibody Drug

AbstractAntibody-drug conjugates (ADCs) selectively deliver highly toxic chemotherapeutic agents to target antigen-expressing cells and have become an important cancer treatment in recent years. However, the molecular mechanisms by which ADCs are internalized and activated within cells remain unclear. Here we use CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Our results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. We identify and characterize C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Through comparative analysis of CRISPR screens with ADCs bearing a noncleavable linker versus a cleavable valine-citrulline (VC) linker, we show that a subset of late endosomal and lysosomal regulators are selectively essential for toxicity of noncleavable linker ADCs. We further show that cleavable VC linkers are rapidly processed upon internalization and therefore surprisingly appear to bypass the requirement of lysosomal delivery. Lastly, we show that inhibition of sialic acid biosynthesis sensitizes cells to ADC treatment by increasing the rate of ADC internalization. This sensitization was observed using several ADCs targeting different antigens in diverse cancer cell types, including the FDA-approved ADC trastuzumab emtansine (T-DM1) in Her2-positive breast cancer cells. Together, these results reveal novel regulators of endolysosomal trafficking, provide important insights to guide future ADC design, and identify candidate combination therapy targets as well as potential mechanisms of ADC resistance.

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 Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation

2019 ◽  
Author(s):  
Susanna K. Elledge ◽  
Hai L. Tran ◽  
Alec H. Christian ◽  
Veronica Steri ◽  
Byron Hann ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Xenograft Model ◽  
Antibody Engineering ◽  
Antibody Drug Conjugate ◽  
Site Specific ◽  
Drug Conjugates ◽  
Mouse Xenograft Model ◽  
Random Modification ◽  
The Stability ◽  
Antibody Drug

AbstractChemical modification of antibodies is one of the most important bioconjugations utilized by biologists and biotechnology. To date, the field has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently we have developed oxaziridine chemistry for highly selective and efficient sulfimide modification of methionine called redox-activated chemical tagging (ReACT). Here, we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and generally good reaction efficiencies with the panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than ten-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, likely because of their reduced access to water. There was also a ten-fold variation in stability depending on the nature of the oxaziridine, which we determined was inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs and antibody drug conjugate potencies were comparable to those reported for cysteine-maleimide modifications of trastuzumab. We also found our antibody drug conjugates to be potent in a breast cancer mouse xenograft model. These studies provide a roadmap for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation.

scholarly journals Targeted Fluorogenic Cyanine Carbamates Enable In Vivo Analysis of Antibody-Drug Conjugate Linker Chemistry

2021 ◽  
Author(s):  
Syed Usama ◽  
Sierra Marker ◽  
Donald Caldwell ◽  
Nimit Patel ◽  
Yang Feng ◽  
...  
Keyword(s):  
Near Infrared ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Lysosomal Accumulation ◽  
Cellular Signal ◽  
In Vivo Analysis ◽  
Cellular Permeability ◽  
Therapeutic Platform ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker between the antibody and the drug payload plays an essential role in the efficacy and tolerability of these agents. New methods that quantitively assess cleavage efficiency in complex tissue settings could provide valuable insights into the ADC design process. Here we report the development of a near-infrared (NIR) optical imaging approach that measures the site and extent of linker cleavage in mouse models. This approach is enabled by a superior variant of our recently devised cyanine carbamate (CyBam) platform. We identify a novel tertiary amine-containing norcyanine, the product of CyBam cleavage, that exhibits dramatically in-creased cellular signal due to improved cellular permeability and lysosomal accumulation. The resulting cyanine lysosome-targeting carbamates (CyLBams) are ~50X brighter in cells, and we find this strategy is essential for high-contrast in vivo targeted imaging. Finally, we compare a panel of several common ADC linkers across two antibodies and tumor models. These studies indicate that cathepsin-cleavable linkers provide dramatically higher tumor activation relative to hindered or non-hindered disulfides – an observation that is only apparent with in vivo imaging. This strategy enables quantitative comparisons of cleavable linker chemistries in complex tissue settings with implications across the drug delivery landscape.

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer

2021 ◽  
Author(s):  
Kirollos S Hanna ◽  
Samantha Larson ◽  
Jenny Nguyen ◽  
Jenna Boudreau ◽  
Jennifer Bulin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Second Line ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Advanced Bladder Cancer ◽  
Checkpoint Inhibitor Therapy ◽  
Antibody Drug

Abstract Disclaimer In an effort to expedite the publication of articles pandemic, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The treatment landscape of advanced bladder cancer continues to evolve with novel therapeutics approved in recent years and many in the pipeline. Here we review the role of the novel agents enfortumab vedotin and sacituzumab govitecan in treatment of advanced disease. Summary Patients with advanced bladder cancer often first receive platinum-based therapy, while immune checkpoint inhibitors offer a maintenance option following cytotoxic chemotherapy or a second-line option. Despite various first- and second-line options, patients with significant comorbidities and treatment-related adverse events will experience disease progression requiring alternative treatment. Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates approved in patients with advanced bladder cancer following platinum-based and immune checkpoint inhibitor therapy. Following platinum-based therapy and immunotherapy in patients with advanced bladder cancer, enfortumab vedotin, targeting Nectin-4, improves overall survival while sacituzumab govitecan, targeting Trop-2, is associated with a 27% response rate. With these new approaches to disease management, however, it remains critical to understand safety, efficacy, and operational considerations to optimize outcomes. Conclusion When selecting an antibody-drug conjugate to treat patients with bladder cancer, it is important to note the adverse event profile of each agent to optimize outcomes and safety for patients.

Targeting CD30 in Hodgkin Lymphoma: Antibody-Drug Conjugates Make a Difference

2012 ◽  
pp. 162-166 ◽  
Author(s):  
Catherine S. M. Diefenbach ◽  
John P. Leonard
Keyword(s):  
Hodgkin Lymphoma ◽  
Large Cell ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugate ◽  
Lymphoid Malignancies ◽  
Drug Conjugates ◽  
First Line Therapy ◽  
Resistant Disease ◽  
Relapsed Disease ◽  
Antibody Drug

Overview: CD30 expression is characteristic of the malignant Reed-Sternberg cell in Hodgkin lymphoma (HL) and several other lymphoid malignancies, such as anaplastic large-cell lymphoma (ALCL). Although unconjugated anti-CD30 antibodies have had minimal therapeutic activity in patients with HL as single agents, the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin has demonstrated activity that has resulted in its recent regulatory approval for the treatment of patients with relapsed HL and ALCL. Approximately 75% of patients with recurrent HL achieve objective responses, with the principal toxicity being peripheral neuropathy. Ongoing studies are evaluating treatment with this agent as part of first-line therapy, for patients with relapsed disease, and for patients with resistant disease and limited other options. Brentuximab vedotin demonstrates the therapeutic value of antibody-drug conjugation and serves as a model of how a novel, targeted approach can be employed to potentially further improve outcomes in settings where curative chemotherapeutic regimens are already available.

scholarly journals Interconversion of unexpected thiol states affects stability, structure and dynamics in engineered antibody for site-specific conjugation

2020 ◽  
Author(s):  
C. T. Orozco ◽  
M. J. Edgeworth ◽  
P. W. A. Devine ◽  
A. R. Hines ◽  
O. Cornwell ◽  
...  
Keyword(s):  
Disulfide Bridge ◽  
Antibody Drug Conjugate ◽  
Site Specific ◽  
Drug Conjugates ◽  
Cytotoxic Compounds ◽  
Stability Structure ◽  
Biophysical Techniques ◽  
The Stability ◽  
Small Molecule Therapeutics ◽  
Antibody Drug

AbstractAntibody drug conjugates have become one of the most actively developed classes of drugs in recent years. Their great potential comes from combining the strengths of large and small molecule therapeutics: the exquisite specificity of antibodies and the highly potent nature of cytotoxic compounds. More recently, the approach of engineering antibody drug conjugate scaffolds to achieve highly controlled drug to antibody ratios has focused on substituting or inserting cysteines to facilitate site-specific conjugation. Herein, we characterise an antibody scaffold engineered with an inserted cysteine that formed an unexpected disulfide bridge. A combination of mass spectrometry and biophysical techniques have been used to understand how the additional disulfide bridge forms, interconverts and changes the stability and structural dynamics of the antibody. Insight is gained into the local and global destabilisation associated with the engineering and subsequent disulfide bonded variant that will inform future engineering strategies.

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.

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