Molecular Cancer Therapeutics最新文献

{"title":"SDP-LIV1, a Novel and Optimized LIV-1 Antibody-drug Conjugate Demonstrating Superior Anti-Tumor Efficacy and Favorable Safety Profile for Treatment of Solid Tumors.","authors":"Yani Peng, Changyong Yang, Liwei Dong, Xing Sun, Wei Zheng, Yanling Gong, Qing Shi, Ping Ji, Simeng Chen, Wei Zhang, Cheng Liao","doi":"10.1158/1535-7163.MCT-24-0752","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0752","url":null,"abstract":"<p><p>LIV-1 is a transmembrane protein belonging to the zinc transporter family and a promising target for antibody-drug conjugate therapy due to its broad expression in tumors and limited normal tissue expression. Ladiratuzumab vedotin (SGN-LIV1A), a LIV-1 targeting ADC with payload of monomethyl auristatin E, has been discontinued from clinical development. The preliminary clinical results demonstrated promising efficacy in triple-negative breast cancer but no response in hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer, and typical monomethyl auristatin E-related adverse events were observed. Here, we demonstrated a novel LIV-1 directed ADC, SDP-LIV1, consisting of an in-house developed anti-LIV-1 antibody conjugated to a proprietary topoisomerase I inhibitor via a cleavable GGFG (glycine-glycine-phenylalanine-glycine) linker, with an optimized average drug-to-antibody ratio of 6. Preclinical studies revealed that SDP-LIV1 showed promising in vitro and in vivo efficacy in breast and gastric cancers with favorable preclinical pharmacokinetics and safety profiles, suggesting that SDP-LIV1 has great potential for the clinical treatment of patients with solid tumor expressing LIV-1.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Anti-CD47 Antibody TJH2201: Efficacious Tumor Suppression with Reduced RBC Toxicity via a SIRPα-Independent Mechanism.","authors":"Huan Zhang, Fufan He, Lei Cao, Haiqing Ni, Ninghuan Li, Yang Liu, Min Wu, Ya Liu, Bing Wu, Li Li, ZhiHai Wu, Xiaomin Ling, Shuaixiang Zhou, Yiming Li, Shuxuan Deng, Weiwei Wu, Qian Chu","doi":"10.1158/1535-7163.MCT-25-0425","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0425","url":null,"abstract":"<p><p>The CD47/SIRPα axis serves as a \"don't eat me\" signal, protecting normal cells from phagocytosis, but in the meantime, enabling immune evasion by tumor cells. While substantial progress has been made in developing CD47 antagonists, achieving a balance between hematotoxicity and anti-tumor efficacy remains a critical challenge. Here, we demonstrated that the bivalent anti-CD47 antibody, Hu5F9, caused severe anemia in both human CD47 knock-in mice lacking the CD47/SIRPα signal and human CD47/SIRPα double knock-in mice with complete signal, suggesting the CD47/SIRPα signal is not essential. Moreover, the single-arm CD47 antibody Hu5F9/gp120 exhibited only mild red blood cell (RBC) destruction in vitro and in vivo. These findings reveal that RBC toxicity induced by anti-CD47 antibodies is determined by the bivalency of the antibody rather than the CD47/SIRPα signal engagement. Based on this, we engineered TJH2201, a novel anti-CD47 antibody that avoids RBC agglutination while retaining high-affinity CD47 binding, robust signaling blockade, and enhanced pro-phagocytosis activity in vitro. In xenograft models with Raji and MV-4-11 cells, TJH2201 demonstrated potent anti-tumor activity without inducing body weight loss. These results suggest that TJH2201 is a promising CD47 antagonist that balances anti-tumor efficacy and hematological safety, providing a new therapeutic approach for CD47-expressing malignancies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing of the Macrolide Antibiotic Clarithromycin for the Prevention of Lung Cancer.","authors":"Shanshan Deng, Tabish Hussain, Thais F Bartelli, Manu M Sebastian, Melody Zarghooni, Walter V Velasco, Brandon Somerville, Linda Phan, Michelle I Savage, Yurong Song, John L Clifford, Humam Kadara, Florencia McAllister, Powel H Brown, Seyed Javad Moghaddam, C Marcelo Aldaz","doi":"10.1158/1535-7163.MCT-25-0392","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0392","url":null,"abstract":"<p><p>Drug repurposing is the process of reusing existing pharmaceuticals for novel clinical purposes, which offers advantages such as streamlined clinical trial access and reduced drug development costs. Clarithromycin (CAM), a member of the macrolide antibiotics family, is a promising candidate for repurposing in cancer therapy due to its known preclinical and clinical immunomodulatory and anti-cancer properties. In the current study, we investigated whether CAM could be repurposed as a preventive treatment for KRAS-mutant lung cancer, a subtype of lung adenocarcinoma that is strongly associated with heavy smoking. CCSPCre; LSL-KrasG12D mice at an early stage of tumor development were treated with different doses of CAM for 10 weeks. While exhibiting an excellent safety profile, CAM was able to prevent the development of premalignant and malignant lung lesions in a dose-dependent manner. In addition, CAM significantly reduced the infiltration of neutrophils/PMN-MDSCs and inhibited the mRNA expression of pro-tumor inflammatory cytokines IL-6, TNFα, and IL-1β, as well as M2 macrophage markers Fizz1 and Arginase1 in the lung tumor microenvironment (TME). Moreover, we investigated the effect of CAM in reshaping the intestinal and lung microbiome. Long-term CAM usage decreased intestinal microbiome diversity, but more notably, significantly increased the abundance of the probiotic genus Muribaculaceae while decreasing the abundance of Desulfovibrioi, a genus associated with the promotion of various malignancies. Taken together, we conclude that CAM could provide promising cancer prevention efficacy in KRAS-mutant lung cancer due to its immunomodulatory properties on the TME, and its regulatory effects on the microbiome.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunocompetent mouse models of cancer reveal the superiority of cellular targets over stromal targets for the development of anticancer bispecific antibodies.","authors":"Stefanie K Pfister, Frauke Seehusen, Francesco Prisco, Giulia Rotta, Abdullah Elsayed, Ettore Gilardoni, Gudrun Thorhallsdottir, Christian Pellegrino, Markus G Manz, Emanuele Puca, Dario Neri, Roberto De Luca","doi":"10.1158/1535-7163.MCT-25-0340","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0340","url":null,"abstract":"<p><p>Bispecific antibodies are a rapidly advancing class of biopharmaceuticals with substantial potential for cancer immunotherapy. While bispecific antibodies have shown notable success in treating certain hematological malignancies, their application for solid tumors remains limited. The extra domain B of fibronectin (EDB) represents a promising pan-tumoral stromal target, offering an attractive alternative to conventional cellular tumor antigens, which often face limitations with respect to specificity in solid tumors. In this study, we describe the generation and characterization of a T cell engaging bispecific antibody which targets murine CD3 using the 2C11 clone and EDB with the L19 clone. Specifically, the bispecific antibody consists of a Fab fragment (targeting CD3) fused with two single-chain Fv fragments (targeting EDB) at the C-terminus. The bispecific antibody was produced in Chinese Hamster Ovary cells and purified to homogeneity. To compare stromal and cellular targeting, two murine tumor cell lines naturally secreting EDB in the stroma were transduced to express the target on the cell surface. In both cell lines, biodistribution analysis revealed increased tumor uptake in the cellular model compared to the stromal one. Similarly, treating immunocompetent cellular EDB tumor-bearing mice with the bispecific antibody improved anti-cancer activity. By contrast, no significant therapeutic benefit was observed in the stromal model. These findings underscore the importance of direct tumor cell targeting compared to stromal targeting for effective bispecific antibody therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting AEBP1 to mitigate pro-tumor activity of cancer-associated fibroblasts and increase therapeutic efficacy to anti-PD-1.","authors":"Suchitra Natarajan, Khoa Nguyen, Heyuan Li, Elysia Saputra, Cindy Li, Gukhan Kim, Yu Liu, Hong Sun, Muhammad N Ramli, Ling Li, William J Monis, Wendy M Blumenschein, Dewan Hossain, Aleksandra K Olow, Xin Yu","doi":"10.1158/1535-7163.MCT-24-1121","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1121","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that promote tumor progression either directly through tumor-CAF interactions or indirectly by influencing tumor infiltrating immune cells, thereby creating an immunosuppressive TME. High stromal signatures have been associated with reduced therapeutic efficacy and resistance to immune checkpoint blockades. AEBP1 is predominantly expressed in myofibroblasts, and its expression is further increased in CAFs that produce the extracellular matrix (ECM). It has two isoforms: the extracellular isoform binds to collagen and promotes collagen remodeling, while the intracellular isoform modulates transcription and signaling. We observed the expression of both isoforms in primary human CAFs. Our data showed that combined knockout of both AEBP1 isoforms via gene editing decreased CAF proliferation, collagen gel contractility, and CAF-mediated tumor cell proliferation in vitro. AEBP1 knockout mouse fibroblasts demonstrated reduced activity in both in vitro assays and in vivo within a co-implantation mouse model. RNA Sequencing revealed that AEBP1 knockout downregulated the collagen biosynthesis and ECM organization-related pathways in mouse fibroblasts and human CAFs. Importantly, AEBP1 loss in fibroblasts led to significant alterations in tumor cell phenotypes, including a marked reduction of tumor cells exhibiting an epithelial-mesenchymal transition signature in vivo. Furthermore, AEBP1 knockout in CAFs enhanced the anti-PD-1-induced effector T cell function and the anti-PD-1 efficacy. Our findings indicate that AEBP1 plays a crucial role in regulating the function of CAFs within the TME. Targeting AEBP1 could be a promising strategy to inhibit the tumor-promoting activities of CAFs and to overcome resistance to anti-PD-1 immunotherapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Preclinical Biology for Ewing Sarcoma: An International Effort.","authors":"Filemon S Dela Cruz, Elizabeth A Stewart, Didier Surdez, Jessica D Daley, Alice Soragni, Eleni M Tomazou, Jaime Alvarez-Perez, Tamar Y Feinberg, James F Amatruda, Shireen S Ganapathi, Joyce E Ohm, Christine M Heske, Sarah Cohen-Gogo, Dusan Pesic, Joshua O Nash, Adam Shlien, Elizabeth A Roundhill, Susan A Burchill, Brian D Crompton, Elizabeth R Lawlor, David M Loeb, Olivier Delattre, Jaume Mora, Katia Scotlandi, Damon R Reed, Patrick J Grohar, Thomas G P Grünewald, Heinrich Kovar, Kelly M Bailey","doi":"10.1158/1535-7163.MCT-25-0428","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0428","url":null,"abstract":"<p><p>Ewing sarcoma is an aggressive bone and soft-tissue cancer affecting adolescents and young adults. In vitro and in vivo models of Ewing sarcoma have been instrumental in advancing our understanding of Ewing sarcoma biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease for which effective treatment options remain limited. Through an international collaborative effort between the Children's Oncology Group Bone Tumor Committee and the Euro Ewing Consortium, we review the current landscape of preclinical modeling used in Ewing sarcoma research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and nonmammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in Ewing sarcoma modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically relevant Ewing sarcoma models to enable translation of preclinical findings into effective therapeutic strategies for patients with Ewing sarcoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF23"},"PeriodicalIF":5.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting arginine metabolism via ALDH2/ARG2 axis blockade potentiates immune checkpoint inhibitors in colorectal cancer.","authors":"Lu Cai, Yonglong Cao, Jiawei Zhang, Kaiwen Xi, Aimin Li, Hong Zhang","doi":"10.1158/1535-7163.MCT-25-0404","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0404","url":null,"abstract":"<p><p>Metabolic reprogramming constitutes a key mechanism driving immunotherapy resistance in colorectal cancer (CRC), though the immunomodulatory role of L-arginine metabolism remains poorly defined. Through metabolomic profiling, we identified aldehyde dehydrogenase 2 (ALDH2) as a critical regulator depleting intracellular L-arginine pools in CRC cells. High Performance Liquid Chromatography (HPLC) analysis of cell supernatants further demonstrated that ALDH2 overexpression significantly diminishes extracellular L-arginine availability. Functionally, this arginine deficiency suppressed CD8+ T cell proliferation while inducing the attenuation of anti-tumor efficacy. Mechanistic studies revealed that ALDH2 upregulates Pre-B-Cell Leukemia Homeobox 3 (PBX3), which enhances arginase 2 (ARG2) transcription to promote L-arginine catabolism. This process suppresses glycolysis in CD8+ T cells, ultimately compromising their effector functions. Notably, ALDH2-high tumors exhibited resistance to immune checkpoint blockade (ICB), whereas combinatorial ARG2 inhibition and ICB therapy synergistically restored antitumor immunity. These findings nominate ARG2 as a novel therapeutic target and propose dual metabolic-immunologic intervention as a promising strategy for ICB-resistant CRC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of the Efficacy of a Cyclin-dependent Kinase Inhibitor Ribociclib in Combination with Letrozole Against Patient-Derived Glioblastoma Cells.","authors":"Sidharth N Gadgil, Aniruddha S Karve, Gary A Gudelsky, Bhavesh B Gabani, Mario Medvedovic, Shravani P Kulkarni, Timothy N Phoenix, David R Plas, Trisha M Wise-Draper, Soma Sengupta, Biplab Dasgupta, Lalanthica Yogendran, Pankaj B Desai","doi":"10.1158/1535-7163.MCT-25-0277","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0277","url":null,"abstract":"<p><p>Ongoing studies suggest that letrozole (LTZ), a drug used in the treatment of breast cancer, can potentially be repurposed as a novel therapeutic for glioblastoma (GBM). In a phase 0/1 trial in recurrent GBM patients we observed that LTZ permeates into the GBM tissue and triggers dose-dependent changes in the expression of genes regulating cell cycle (e.g. CDKN2A/N2B, CDK4). Based on these observations, we hypothesized that a combination of cyclin dependent kinase (CDK) 4/6 inhibitors with LTZ may result in synergistic anti-GBM activity. Therefore, we assessed the anti-tumor effects of LTZ in combination with ribociclib, a third-generation CDK4/6 inhibitor and the brain pharmacokinetics of ribociclib. Using cell viability and neurosphere growth assay against a panel of patient-derived GBM lines both compounds were found to be cytotoxic when used as single agents and were strongly synergistic when used in combination. We then assessed the DNA damaging effects (ɣH2AX induction), cell cycle arrest and the induction of apoptosis (Annexin V-FITC/PI) of both compounds as single agents and when used in combination. LTZ potentiated ribociclib-induced DNA damage and cell cycle arrest leading to apoptosis. Systemic and brain pharmacokinetics analysis of ribociclib in Sprague-Dawley (SD) rats by serial blood and brain extracellular fluid (ECF) sampling showed that ribociclib penetrates the blood-brain barrier with a partitioning coefficient (Kpu, u, brain) of about 10%. Overall, our studies suggest that a combination of ribociclib with LTZ is likely to be strongly synergistic against GBM at concentrations of the drugs that can be achieved in the brain.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.","authors":"Ujas A Patel, Mary Y Shi, Jalal M Kazan, Kevin C J Nixon, Xiaozhuo Ran, Sree N Nair, Olivia Huang, Lifang Song, Mansi K Aparnathi, Michael Y He, Mehran Bakhtiari, Rehna Krishnan, Razan K Hessenow, Vivek Philip, Troy Ketela, Verena Jendrossek, Razqallah Hakem, Housheng H He, Robert Kridel, Benjamin H Lok","doi":"10.1158/1535-7163.MCT-24-0861","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0861","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected patients with SCLC but could be enhanced with radiosensitizers. In this study, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug single-guide RNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose modification factor10 = 1.14-1.69) and clonogenic assays (dose modification factor10 = 1.16-1.41). We assessed changes in chromatin accessibility by assay for transposase-accessible chromatin using sequencing and IR-induced DNA damage and repair using γH2AX foci detection, double-strand break (DSB) repair assays, and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 knockdown or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Antitumor Efficacy of a Novel Anti-c-Kit Antibody-Drug Conjugate, NN3201, in c-Kit-Positive Tumors.","authors":"Chansik Kim, Jinwoo Park, Jin-Ock Kim, Han-Jik Ko, Jin Gu Cho, Yeonjy Lee, Jina Lee, TaeMin Wi, Jiwoo Moon, Sohyeon Park, Jaeyoung Song, Sun-Hwa Lee, Gong Sung, Sang Gyu Park","doi":"10.1158/1535-7163.MCT-25-0396","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0396","url":null,"abstract":"<p><p>Overexpression and gain-of-function mutations of c-Kit have been implicated in cancers including gastrointestinal stromal tumors, small cell lung cancer, acute myeloid leukemia, and systemic mastocytosis. In clinics, small-molecule c-Kit inhibitors often result in secondary c-Kit mutations or are ineffective despite c-Kit overexpression. We developed NN3201, a novel c-Kit-targeting antibody-drug conjugate, via rational design to evaluate its anticancer activity in c-Kit-positive tumors and preclinical pharmacologic profiles. A fully human c-Kit antibody NN2101 was conjugated to monomethyl auristatin E with a Drug-to-Antibody Ratio (DAR) of 4 utilizing a ThioBridge linker to generate NN3201. Antitumor efficacies of NN3201 were evaluated in c-Kit-positive cancer cell lines, cell line-derived xenografts, and patient-derived xenografts. NN3201 selectively binds to c-Kit and is rapidly internalized. By its design, NN3201 exhibits no antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity and possessed decreased binding to FcγRs. Inhibition of stem cell factor/c-Kit downstream signaling pathways, cell-cycle arrest, and bystander effect were demonstrated as mechanisms of action for NN3201. In xenograft models, NN3201 showed superior efficacy regardless of c-Kit mutations. Repeated intravenous administration of NN3201 was well tolerated in cynomolgus monkeys, confirming the no observed adverse effect level of NN3201 to be 2 mg/kg and the highest nonseverely toxic dose to be >2 mg/kg. NN3201 exhibited significant c-Kit-dependent antitumor efficacies in various tumor models, followed by favorable pharmacokinetic and toxicity profiles in cynomolgus monkeys. These data suggest that NN3201 is a promising therapeutic in small cell lung cancer and gastrointestinal stromal tumors and warrant evaluation in a phase I clinical study.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":5.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}