Molecular Cancer Therapeutics最新文献

{"title":"Characteristics of a CCL21 Gene-Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non-Small Cell Lung Cancer.","authors":"Michael S Oh, Camelia Dumitras, Ramin Salehi-Rad, Linh M Tran, Kostyantyn Krysan, Raymond J Lim, Zhe Jing, Shahed Tappuni, Aaron Lisberg, Edward B Garon, Steven M Dubinett, Bin Liu","doi":"10.1158/1535-7163.MCT-24-0435","DOIUrl":"10.1158/1535-7163.MCT-24-0435","url":null,"abstract":"<p><p>The treatment of non-small cell lung cancer has made major strides with the use of immune checkpoint inhibitors; however, there remains a significant need for therapies that can overcome immunotherapy resistance. Dendritic cell (DC) vaccines have been proposed as a therapy that can potentially enhance the antitumor immune response. We have embarked on a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDC) modified to express the chemokine C-C motif chemokine ligand 21 (CCL21-DC) given in combination with pembrolizumab. In this study, we report a comprehensive characterization of this CCL21-DC vaccine and interrogate the effects of multiple factors in the manufacturing process. We show that the cellular makeup of the CCL21-DC vaccine is heterogeneous because of the presence of passenger lymphocytes at a proportion that is highly variable among patients. Single-cell RNA sequencing of vaccines revealed further heterogeneity within the moDC compartment, with cells spanning a spectrum of DC phenotypes. Transduction with a CCL21-containing adenoviral vector augmented CCL21 secretion by moDCs, but otherwise had a minimal effect on vaccine characteristics. A single freeze-thaw cycle for stored vaccines was associated with minor alterations to the DC phenotype, as was the use of healthy donors rather than patient autologous blood. Our results highlight important considerations for the production of DC vaccines and identify underexplored factors that may affect their efficacy and immunologic impact.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"286-298"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Mechanisms of Interstitial Lung Disease Induced by Antibody-Drug Conjugates Based on Quantitative Analysis of Drug Distribution.","authors":"Shigehiro Koganemaru, Hirobumi Fuchigami, Chihiro Morizono, Hiroko Shinohara, Yasutoshi Kuboki, Keiji Furuuchi, Toshimitsu Uenaka, Toshihiko Doi, Masahiro Yasunaga","doi":"10.1158/1535-7163.MCT-24-0267","DOIUrl":"10.1158/1535-7163.MCT-24-0267","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADC) are a rapidly advancing category of therapeutic agents with notable anticancer efficacy. However, the emergence of interstitial lung disease as a severe ADC-associated adverse event highlights the need to better understand the underlying mechanisms. In this study, xenograft model mice with tumors expressing different levels of the trophoblast antigen 2 (TROP2) were generated by subcutaneously transplanting the various TROP2-expressing cancer lines. The mice received different doses of TROP2-eribulin, a novel TROP2-targeting ADC, composed of an anti-TROP2 antibody and the eribulin payload, joined by a cleavable linker. The concentration and distribution of TROP2-eribulin, as well as the pharmacokinetics of eribulin release, were assessed in tumor and lung tissues. Analysis of tumor tissue showed that the concentration of released eribulin was approximately 10-fold higher in NCI-H2110 (high TROP2 expression) than in A549 (low TROP2 expression), whereas analysis of lung tissue showed that TROP2-eribulin was distributed in lung tissue in a dose-dependent manner, regardless of TROP2 expression, with significantly more eribulin released in the high-dose group than in the other dose groups (P < 0.05). Immunofluorescence assay analysis showed that TROP2-eribulin localized to alveolar macrophages. In the analysis using human leukemia monocytic cell, the concentration of eribulin released from TROP2-eribulin was significantly reduced by the use of an Fc receptor inhibitor (P < 0.05). These results revealed that Fcγ receptor-mediated uptake by alveolar macrophages releases the cytotoxic payload into lung tissue, helping to clarify the pathogenesis of ADC-induced interstitial lung disease.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"242-250"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82.","authors":"Susana S Najera, Christopher J Ricketts, Laura S Schmidt, Julia I Medina, Keita Saito, Lilia Ileva, Jeffrey R Brender, Amy M James, Cody J Peer, Brad Gouker, Baktiar O Karim, Olga Chernova, Catherine Wells, Ming-Hui Wei, Youfeng Yang, Xiaohu Zhang, Carleen Klumpp-Thomas, Jameson Travers, Lu Chen, Kelli M Wilson, Sameer H Issaq, William D Figg, Simone Difilippantonio, Joseph D Kalen, Murali C Krishna, Craig J Thomas, Michele Ceribelli, Christine M Heske, Daniel R Crooks, Jordan L Meier","doi":"10.1158/1535-7163.MCT-24-0225","DOIUrl":"10.1158/1535-7163.MCT-24-0225","url":null,"abstract":"<p><p>Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted tricarboxylic acid cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted a high-throughput drug screen in HLRCC cell lines, which identified a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Human HLRCC tumors and HLRCC-derived cell lines exhibited elevated NAMPT expression compared with controls. FH-deficient HLRCC cells, but not FH-restored HLRCC or normal kidney cells, were sensitive to NAMPT inhibition. HLRCC cell line viability was significantly decreased in both 2D and 3D in vitro cultures in response to the clinically relevant NAMPT inhibitor OT-82. NAMPT inhibition in vitro significantly decreased the total amount of NAD+, NADH, NADP, NADPH, and poly-ADP-ribose levels, and the effects of NAMPT inhibition could be rescued by the downstream NAD precursor nicotinamide mononucleotide (NMN), confirming the on-target activity of OT-82. Moreover, NAMPT inhibition by OT-82 in two HLRCC xenograft models resulted in severely reduced tumor growth. OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated RCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"200-213"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470225","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":"Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling.","authors":"Fanny Volat, Ragini Medhi, Lauren Z Maggs, Marcel A Deken, Alice Price, Lauren Andrews, Jonathan Clark, Diane Taylor, Alan Carruthers, Ewan Taylor-Smith, Natalia Pacheco, Simon A Rudge, Amy Fraser, Andrea F Lopez-Clavijo, Bebiana C Sousa, Zoë Johnson, Giusy Di Conza, Lars van der Veen, Pritom Shah, Hilary Sandig, Hayley J Sharpe, Stuart Farrow","doi":"10.1158/1535-7163.MCT-23-0522","DOIUrl":"10.1158/1535-7163.MCT-23-0522","url":null,"abstract":"<p><p>Autotaxin (ATX), encoded by ENPP2, is a clinical target in pancreatic ductal adenocarcinoma (PDAC). ATX catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME), yet the protumorigenic action of the ATX/LPA axis in PDAC remains unclear. In this study, by interrogating patient samples and cell line datasets, we show that the PDAC TME, rather than cancer cells, is responsible for the majority of ENPP2 expression and highlight a key role for cancer-associated fibroblast (CAF)-derived ATX in autocrine and paracrine protumorigenic signaling. Using the clinical-stage ATX inhibitor, IOA-289, we identified connective tissue growth factor (CTGF), also known as CCN2, as a downstream mediator of ATX signaling in the PDAC CAF-derived cell line, 0082T. Genetic ablation or pharmacologic inhibition of ATX in 0082T CAFs reduced CTGF secretion via modulation of LPA/LPA receptor signaling. Despite the loss of ATX function, extracellular levels of LPA were paradoxically increased, indicating a role for ATX beyond its enzymatic activity and suggesting a role for its LPA chaperone function in the LPA/LPA receptor signaling in CAFs. As CAFs are the main source for CTGF in the PDAC TME, these findings suggest a role for ATX in promoting a protumorigenic microenvironment via modulation of CAF secretion not only via its LPA-producing activity but also via its LPA chaperone function, providing a potential mechanism for the antitumor effects of ATX inhibition.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"230-241"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682268","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":"HPV and p53 Status as Precision Determinants of Head and Neck Cancer Response to DNA-PKcs Inhibition in Combination with Irradiation.","authors":"Liana Hayrapetyan, Selina M Roth, Aurélie Quintin, Lusine Hovhannisyan, Matúš Medo, Rahel Riedo, Julien G Ott, Joachim Albers, Daniel M Aebersold, Yitzhak Zimmer, Michaela Medová","doi":"10.1158/1535-7163.MCT-23-0794","DOIUrl":"10.1158/1535-7163.MCT-23-0794","url":null,"abstract":"<p><p>Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to p53 degradation, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of nonhomologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. In this study, we investigated the responses of a panel of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination in vitro and in vivo. IR-induced DNA damage combined with peposertib administration shortly before IR results in decreased cell viability and proliferation and causes DNA repair delay in all studied HNSCC cell lines. However, our data confirm that the actual cell fate upon this treatment is determined by cellular p53 and/or HPV status. Cells lacking functional p53 due to its degradation by HPV or due to a loss-of-function mutation are arrested in the G2/M phase of the cell cycle and eliminated by apoptosis, whereas p53-proficient HNSCC cell lines preferentially undergo senescence. This is also recapitulated in vivo, where HPV+ UD-SCC-2 xenografts display stronger and more durable responses to the combined treatment as compared with p53 wild-type UM-SCC-74A tumors. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"214-229"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling the Acute Mucosal Toxicity of Fractionated Radiotherapy Combined with the ATM Inhibitor WSD0628.","authors":"Darwin A Garcia, Sneha Rathi, Margaret A Connors, Michael Grams, Rachael A Vaubel, Katrina K Bakken, Lauren L Ott, Brett L Carlson, Zeng Hu, Paul A Decker, Jeanette E Eckel-Passow, Danielle M Burgenske, Wei Zhong, Joshua D Trzasko, Michael G Herman, William F Elmquist, Nicholas B Remmes, Jann N Sarkaria","doi":"10.1158/1535-7163.MCT-24-0664","DOIUrl":"10.1158/1535-7163.MCT-24-0664","url":null,"abstract":"<p><p>Ataxia Telangiectasia-mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"299-309"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy.","authors":"Ahmad Joshkon, Wael Traboulsi, Magali Terme, Richard Bachelier, Hussein Fayyad-Kazan, Françoise Dignat-George, Alexandrine Foucault-Bertaud, Aurelie S Leroyer, Nathalie Bardin, Marcel Blot-Chabaud","doi":"10.1158/1535-7163.MCT-24-0008","DOIUrl":"10.1158/1535-7163.MCT-24-0008","url":null,"abstract":"<p><p>Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting immune checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICPs, necessitating to further study the underlying mechanisms of exhaustion. VEGFa, a proangiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICPs, justifying in part the use of an anti-VEGFa mAb, bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICPs. In addition, sCD146 favors protumoral M2-type macrophages and induces the secretion of proinflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with the anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"275-285"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470224","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 Characterization of XB002, an Anti-Tissue Factor Antibody-Drug Conjugate for the Treatment of Solid Tumors.","authors":"Seema Kantak, Raffaella Faggioni, Allen G Cai, Maryam M Bhatti, Jing Li, Inna Vainshtein, Jackie Cheng, Brian A Mendelsohn, Jacques Gaudreault, Thi-Sau Migone, Jan-Willem Theunissen","doi":"10.1158/1535-7163.MCT-24-0002","DOIUrl":"10.1158/1535-7163.MCT-24-0002","url":null,"abstract":"<p><p>Tissue factor (TF) is overexpressed in various cancers and is typically associated with poor clinical outcomes. XB002 is an anti-TF antibody-drug conjugate designed to selectively deliver a cytotoxic payload to TF-expressing tumors while minimizing TF-related adverse events, particularly bleeding. The conjugate consists of a zovodotin linker-payload attached to a mAb (clone 25A3) that binds TF with high affinity (KD = 0.86 nmol/L). In vitro coagulation assays confirmed that 25A3 does not interfere with the clotting cascade; even at a concentration of 100 nmol/L, it did not affect the activation of coagulation factor X or thrombin generation. XB002 demonstrated efficient internalization in TF-expressing cancer cell lines, exhibiting potent cytotoxicity at subnanomolar concentrations. In the HPAF-II xenograft model, a regimen of XB002 (1.5 mg/kg, i.v.) administered once weekly for two weeks achieved complete tumor regression, with no detectable tumor growth up to five weeks after the second dose. In murine patient-derived xenograft models, a single dose of XB002 (10 mg/kg, i.v.) inhibited tumor growth across multiple cancer models, including bladder, cervical, gastric, head and neck squamous cell carcinoma, and non-small cell lung cancers. Remarkably, complete tumor regression was observed in the cervical cancer and head and neck squamous cell carcinoma models within 30 days of treatment. In nonhuman primate studies, XB002 demonstrated favorable pharmacokinetics with exposure in the desired therapeutic range and no signs of bleeding or neutropenia. Collectively, these data highlight XB002's broad-spectrum antitumor activity and strongly support its further clinical development.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"251-260"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody-Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors.","authors":"Zeng Wang, Meijun Zheng, Mengyao Li, Huaqing Lu, Nanxi Liu, Yongdong Chen, Nian Yang, Wanqin Zeng, Yijun Dong, Jia Li, Zhixiong Zhu, Chen Yang, Zongliang Zhang, Qizhong Lu, Hexian Li, Liangxue Zhou, Hui Yang, Aiping Tong","doi":"10.1158/1535-7163.MCT-24-0319","DOIUrl":"10.1158/1535-7163.MCT-24-0319","url":null,"abstract":"<p><p>Bispecific antibodies (BsAb) and antibody-drug conjugates (ADC) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADC), which combine the targeting capabilities of BsAbs with the cytotoxic potential of ADCs, offer a novel approach to overcoming several challenges associated with ADCs, including limited internalization, off-target toxicity, and drug resistance. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as a highly expressed protein in a variety of solid tumors, making it a promising therapeutic target. We developed a BsAb targeting SLC3A2 and PD-L1 and conjugated it to monomethyl auristatin E (MMAE) to create the SLC3A2/PD-L1 BsADC. The SLC3A2/PD-L1 BsAb effectively blocked PD-1 binding to PD-L1 and activated T cells while also facilitating lysosomal targeting and degradation of poorly internalized PD-L1 antibodies. The SLC3A2/PD-L1 BsADC demonstrated superior antitumor efficacy in PD-L1 low-expressing tumor cells compared with single-target ADCs in both in vitro studies and in multiple xenograft and immunocompetent mouse models. Overall, our engineered SLC3A2/PD-L1 BsADC exhibited enhanced internalization and improved tumor cell targeting, highlighting the potential of lysosome-targeting BsAbs in advancing ADC therapeutic strategies for solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"261-274"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730737","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":"First-line Apatinib Combined With Tislelizumab and Chemotherapy for Advanced Gastric and Gastroesophageal Junction Adenocarcinoma Patients with Poor Prognosis.","authors":"Wenjie Zhang, Jing Wang, Wei Shi, Hu Qiu, Shaobo Ke, Yuanyuan Tian, Yi Gong, Caiyutian Zhang, Jiamei Chen, Yong Wu, Wensi Zhao, Yongshun Chen","doi":"10.1158/1535-7163.MCT-24-0143","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0143","url":null,"abstract":"<p><p>In this prospective, open-label, exploratory study (RENMIN-213), patients with previously untreated, HER2-negative, advanced G/GEJ adenocarcinoma patients with signet ring cell carcinoma or peritoneal metastasis, were enrolled to receive 8 cycles of apatinib, tislelizumab, and chemotherapy every 3 weeks, with a maintenance therapy with apatinib plus tislelizumab for a maximum of 1 year. Homogeneous patients receiving ICIs combined with chemotherapy at the same time were deemed as the control group for efficacy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), biomarkers, health-related quality of life (HRQoL), and safety. A total of 33 patients (median [range] age, 60 [32-72] years; 21 [63.6%] male; 11 [33.3%] signet ring cell carcinoma; 30 [90.9%] peritoneal metastasis) were enrolled and deemed evaluable for efficacy analysis. Of these patients, 32 (97%) were without progression disease, of whom one (3.0%) patient had complete response and 18 (54.6%) had partial response. 6 patients (18.2%) were able to undergo surgery after treatment. After propensity score matching, the median PFS was 10.17 months (95% CI: 7.13-13.21) of apatinib combined with tislelizumab and chemotherapy group, as compared with 6.0 months in ICIs combined with chemotherapy group. The median DOR increased from 4.5 months to 8.7months. ORR increased from 33.3% to 54.6% and DCR increased from 87.9% to 97.0%. Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 11 patients (33.3%), patients' HRQoL improved after treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080516","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}