Author: Shin, Seunggun ; Chun, Younghwa ; Jung, Jin Kyo ; Jung, Doo Young ; Lee, Byeong Sung ; Lee, Jin Soo ; Cho, Hyun Yong ; Kweon, Sohui ; Go, Areum ; Mathi, Gangadhar Rao

FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC₅₀ values as low as 0.025 nM in Trop2-positive FaDu cells. In vivo, Sac-CL2A-FL118 showed 130 % tumor growth inhibition (TGI) at 7 mg/kg in Trop2-expressing xenografts surpassing Trodelvy®. Pharmacokinetic evaluations revealed that FL118-ADCs exhibited a 2.6-fold increase in AUC and approximately 1.7-fold higher C_max compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.

01 Mar 2025·Journal of Pharmaceutical and Biomedical Analysis

Post-column denaturation-assisted hydrophobic interaction chromatography−mass spectrometry for rapid and in-depth characterization of positional isomers in cysteine-based antibody-drug conjugates

Article

Author: Wang, Hongxia ; Zhang, Zhengqi ; Schuessler, Hillary A ; Liu, Anita P

Antibody-drug conjugates (ADCs) represent a significant advancement in targeted cancer therapy, offering the potential to selectively deliver cytotoxic drugs to tumor cells while minimizing systemic toxicity. However, the structural complexity of ADCs, particularly those conjugated through cysteine residues, poses significant analytical challenges. Due to the hydrophobicity of ADCs, Hydrophobic interaction chromatography (HIC) is often the method of choice to analyze the drug-to-antibody ratio (DAR). However, it requires high-concentration salts, which are often incompatible with mass spectrometry (MS) analysis. By employing ammonium acetate as an MS-compatible salt and integrating a 4-way liquid junction cross configuration for simultaneous introduction of the makeup flow and splitting the flow right before coupling to a mass spectrometer, we achieve high-quality separation and sensitive mass spectrometric analysis. This innovative setup allows for simultaneous DAR measurement and positional isomer characterization by switching the makeup flow solvent from water to a denaturation solution. Our method offers a streamlined and effective approach to ADC characterization, facilitating the identification of positional isomers without the need for fractionation or multiple chromatographic steps. The versatility and robustness of this HIC-MS method are demonstrated through the analysis of two ADCs, highlighting its potential for broad application in ADC development and quality control.

01 Feb 2025·Current Opinion in Obstetrics & Gynecology

Antibody–drug conjugates as targeted therapy for treating gynecologic cancers: update 2025

Review

Author: Herrington, Nasim ; Silverstein, Jordyn ; Konecny, Gottfried ; Karlan, Beth

Purpose of reviewProvide the most up-to-date information on the dynamic landscape of antibody–drug conjugates (ADCs) in gynecologic cancers. We discuss the latest research that supports the approved ADCs and outline the ongoing trials and preliminary results that may lead to ADC approvals in the future. Current gaps in knowledge and areas for future research are discussed.Recent findingsADCs are rapidly changing the landscape of gynecologic cancer care. Three ADCs are currently FDA approved and used routinely in clinical practice, with many more currently in clinical development. The most common ADC target is folate receptor alpha of which there are 8 different folate receptor targeting ADCs in development. Other targets under investigation include trophoblast cell surface antigen-2 (Trop-2), claudin-6 (CLDN6), cadherin-6 (CDH6), nectin-4, HER-2 and B7-H4. ADCs can cause new and unique adverse effects, including ocular toxicities and interstitial lung disease.SummaryADCs offer the opportunity for a more effective and personalized treatment approach for gynecologic cancer patients. Side effects must be closely monitored, and preventive measures must be followed to maximize benefit and minimize toxicity. A better understanding of the role of target proteins as biomarkers to predict response to ADCs will be critical for successful clinical implementation of ADCs and further research in this area is necessary.

100 Deals associated with Precision ADCs(Prelude Therapeutics/AbCellera Biologics)

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Preclinical	US	AbCellera Biologics, Inc.	26 Jan 2024
Hematologic Neoplasms	Preclinical	-	Prelude Therapeutics, Inc.	26 Jan 2024
Solid tumor	Preclinical	-	Prelude Therapeutics, Inc.	26 Jan 2024
Solid tumor	Preclinical	US	AbCellera Biologics, Inc.	26 Jan 2024

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