scholarly journals Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Hang-Ping Yao ◽  
Liang Feng ◽  
Sreedhar Reddy Suthe ◽  
Ling-Hui Chen ◽  
Tian-Hao Weng ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Therapeutic Efficacy ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Humanized Antibody ◽  
Pharmacokinetic Profiles ◽  
Ron Receptor ◽  
Antibody Drug

Antibody-Drug Conjugate PCMC1D3-Duocarmycin SA as a Novel Therapeutic Entity for Targeted Treatment of Cancers Aberrantly Expressing MET Receptor Tyrosine Kinase

2021 ◽  
Vol 21 ◽  
Author(s):  
Rachel Hudson ◽  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Dhavalkumar Patel ◽  
Ming-Hai Wang
Keyword(s):  
Cancer Therapy ◽  
Tumor Growth ◽  
Receptor Tyrosine Kinase ◽  
Targeted Cancer Therapy ◽  
Xenograft Tumor ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Met Receptor Tyrosine Kinase ◽  
Duocarmycin Sa ◽  
Antibody Drug

Background: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials. Objective: Here we report the preclinical and therapeutic evaluation of a novel anti-MET antibody-drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy. Methods: The monoclonal antibody PCMC1D3 (IgG1a/κ), generated by a hybridoma technique and specific to one of the MET extracellular domains, was selected based on its high specificity to human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization efficacy ranging from 6.5 to 17.2h dependent on individual cell lines. Results: Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation. The calculated IC50 values for cell viability reduction were 1.5 to 15.3 nM. Results from mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10 mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor growth and inhibition, was around 2 mg/kg bodyweight. Taken together, PCMC1D3-DCM was effective in targeting inhibition of tumor growth in xenograft models. Conclusion: This work provides the basis for the development of humanized PCMC1D3-DCM for MET-targeted cancer therapy in the future.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals A Novel HER3-Targeting Antibody–Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization

2019 ◽  
Vol 25 (23) ◽  
pp. 7151-7161 ◽  
Author(s):  
Yuuri Hashimoto ◽  
Kumiko Koyama ◽  
Yasuki Kamai ◽  
Kenji Hirotani ◽  
Yusuke Ogitani ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug
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