AI Article Synopsis
- Antibody-drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) dimers are showing promise in clinical trials for treating cancer.
- Next-gen designs focus on adding tumor-selective triggers and using less potent PBDs to enhance treatment effects.
- The study found that β-glucuronidase-cleavable SG3600 ADCs outperformed traditional SG3400 ADCs in terms of efficacy and stability, relying on β-glucuronidase for their activity.
Article Abstract
Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. β-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a β-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on β-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous β-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2019.06.044 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Triple-Negative Breast Cancer Aptamer-Targeting Porous Silicon Nanocarrier.
ACS Appl Mater Interfaces
January 2025
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Common treatment approaches for triple-negative breast cancer (TNBC) are associated with severe side effects due to the unfavorable biodistribution profile of potent chemotherapeutics. Here, we explored the potential of TNBC-targeting aptamer-decorated porous silicon nanoparticles (pSiNPs) as targeted nanocarriers for TNBC. A "salt-aging" strategy was employed to fabricate a TNBC-targeting aptamer functionalized pSiNP that was highly colloidally stable.
View Article and Find Full Text PDFDrug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.
Tetrahedron
February 2025
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, Texas 76798-7348, United States.
Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels.
View Article and Find Full Text PDFAdvances in Novel Systemic Therapies for the Management of Cutaneous T Cell Lymphoma (CTCL).
Curr Hematol Malig Rep
January 2025
Department of Hematology, Winship Cancer Institute, Atlanta, GA, USA.
Purpose Of Review: Cutaneous T cell lymphomas (CTCLs) are comprised of a heterogenous group of non-Hodgkin lymphomas that can be difficult to treat and are often refractory to standard therapies. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes, accounting for the majority of CTCLs. There is no standard of care, and no treatments are curative.
View Article and Find Full Text PDFAntibody-drug conjugates targeting SSEA-4 inhibits growth and migration of SSEA-4 positive breast cancer cells.
Cancer Lett
January 2025
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan.
Although breast cancer treatment has evolved significantly in recent years, drug resistance remains a major challenge. To identify new targets for breast cancer, we found that stage-specific embryonic antigen 4 (SSEA-4) is expressed in all subtypes of breast cancer cell lines, and the increased expression of the associated enzymes β3GalT5 and ST3Gal2 correlates with poor recurrence-free survival (RFS) in breast cancer. We also found that SSEA-4 antibodies can be rapidly internalized into breast cancer cells, a property that makes SSEA-4 an attractive target for antibody-drug conjugates (ADCs).
View Article and Find Full Text PDFThe potential of antibody-drug conjugates for effective therapy in diffuse large B-cell lymphoma.
Expert Opin Biol Ther
January 2025
OU Stephenson Cancer Center, Oklahoma City.
Introduction: Antibody-drug conjugates (ADCs) are a rapidly evolving class of anti-cancer drugs with a significant impact on management of hematological malignancies including diffuse large B-cell lymphoma (DLBCL). ADCs combine a cytotoxic drug (a.k.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!