Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain

Park, Hyunkyu; Kim, Donggeon; Kim, Eun‐Mi; Jason, K.; Lee, Hee Won; Yu, Suji; Oh, Joosung; Kim, Seok Hyung; Yoon, Yong‐Ho; Nam, Do Hyun

doi:10.3390/ijms18091968

Cited by 11 publications

(9 citation statements)

References 48 publications

(90 reference statements)

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“…To improve antibody-mediated intracellular drug delivery, we focused on mAbs targeting the PSI domain due to its unique location and function in the RON extracellular sequence [7, 8]. The use of antibody specific to the PSI domain for induction of MET internalization has been reported [33]. However, the use of mAbs targeting the PSI domain for drug delivery has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…In this sense, the PSI domain is responsible for the correct positioning of the ligand-binding site of RON. Studies also observe that mAbs binding to the PSI domain cause a rapid MET internalization by cancer cells [33]. This suggests that the use of mAbs to target the PSI domain to induce receptor internalization could be a critical pharmaceutical approach for drug delivery.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy

Tong

Feng

Suthe

et al. 2019

j. immunotherapy cancer

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BackgroundAntibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application.MethodMonoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice.ResultsH5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg.ConclusionH5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy

Tong

Feng

Suthe

et al. 2019

j. immunotherapy cancer

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“…As shown in Figure 3 , c-Met levels were reduced in the presence of CHX in a time-dependent manner, while pretreatment with all the proteasome inhibitors did not attenuate the c-Met degradation, suggesting that endogenous c-Met degradation and recycling in a rest condition is not through the proteasome system in H441 cells. Indeed, the lysosomal degradation of receptor tyrosine kinases, including c-Met, has been reported by several studies 26,27 . Further, we investigated the effects of proteasome inhibitors on exogenous c-Met.…”

Section: Resultsmentioning

confidence: 91%

Proteasome Inhibitors Diminish c-Met Expression and Induce Cell Death in Non-Small Cell Lung Cancer Cells

Dong

Tamaskar

et al. 2020

oncol res

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Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer andaccounts for 85% of all lung carcinomas. The hepatocyte growth factor receptor (c-Met) hasbeen considered a potential therapeutic target for NSCLC. Proteasome inhibition induces cellapoptosis and has been used as a novel therapeutic approach for treating diseases includingNSCLC; however, the effects of different proteasome inhibitors on NSCLC have not beenfully investigated. The aim of this study is to determine a precise strategy for treating NSCLCby targeting c-Met using different proteasome inhibitors. Three proteasome inhibitors,Bortezomib, MG132, and ONX 0914, were used in this study. Bortezomib (50 nM)significantly reduced c-Met levels and cell viability in H1299 and H441 cells, while similareffects were observed in H460 and A549 cells when a higher concentration (~100 nM) wasused. Bortezomib decreased c-Met gene expression in in H1299 and H441 cells, but it hadno effect in A549 and H460 cells. MG-132 at a low concentration (0.5 uM) diminished c-Met levels in H441 cells, while neither a low nor high concentration (~20 uM) altered c-Metlevels in A549 and H460 cells. A higher concentration of MG-132 (5 uM) was required fordecreasing c-Met levels in H1299 cells. Furthermore, MG-132 induced cell death in all fourcell types. Among all four cell lines, H441 cells expressed higher levels of c-Met andappeared to be the most susceptible to MG-132. MG-132 decreased c-Met mRNA levels inboth H1299 and H441 cells. ONX 0914 reduced c-Met levels in H460, H1299, and H441cells but not in A549 cells. c-Met levels were decreased the most in H441 cells treated withONX 0914. ONX 0914 did not alter cell viability in either H441, however, it did induce celldeath among H460, A549, and H1299 cells. This study reveals that different proteasomeinhibitors produce varied inhibitory effects in NSCLS cell lines.

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“…The role of PSI domain in the regulation of MET is still unknown. Recently, an antagonistic antibody specific to the PSI domain of MET, IRCR201, has been reported ( 75 ). IRCR201 is a human IgG1 bivalent antibody, which induces rapid depletion of MET protein via the lysosomal degradation pathway and inhibits tumor growth in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor

et al. 2021

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The Hepatocyte growth factor (HGF) and its receptor (MET) promote several physiological activities such as tissue regeneration and protection from cell injury of epithelial, endothelial, neuronal and muscle cells. The therapeutic potential of MET activation has been scrutinized in the treatment of acute tissue injury, chronic inflammation, such as renal fibrosis and multiple sclerosis (MS), cardiovascular and neurodegenerative diseases. On the other hand, the HGF-MET signaling pathway may be caught by cancer cells and turned to work for invasion, metastasis, and drug resistance in the tumor microenvironment. Here, we engineered a recombinant antibody (RDO24) and two derived fragments, binding the extracellular domain (ECD) of the MET protein. The antibody binds with high affinity (8 nM) to MET ECD and does not cross-react with the closely related receptors RON nor with Semaphorin 4D. Deletion mapping studies and computational modeling show that RDO24 binds to the structure bent on the Plexin-Semaphorin-Integrin (PSI) domain, implicating the PSI domain in its binding to MET. The intact RDO24 antibody and the bivalent Fab2, but not the monovalent Fab induce MET auto-phosphorylation, mimicking the mechanism of action of HGF that activates the receptor by dimerization. Accordingly, the bivalent recombinant molecules induce HGF biological responses, such as cell migration and wound healing, behaving as MET agonists of therapeutic interest in regenerative medicine. In vivo administration of RDO24 in the murine model of MS, represented by experimental autoimmune encephalomyelitis (EAE), delays the EAE onset, mitigates the early clinical symptoms, and reduces inflammatory infiltrates. Altogether, these results suggest that engineered RDO24 antibody may be beneficial in multiple sclerosis and possibly other types of inflammatory disorders.

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Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain

Cited by 11 publications

References 48 publications

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy

Proteasome Inhibitors Diminish c-Met Expression and Induce Cell Death in Non-Small Cell Lung Cancer Cells

Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor

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